Next Article in Journal
Analysis of Endophyte Diversity of Rheum palmatum from Different Production Areas in Gansu Province of China and the Association with Secondary Metabolite
Next Article in Special Issue
Administration of Bovine Milk Oligosaccharide to Weaning Gnotobiotic Mice Inoculated with a Simplified Infant Type Microbiota
Previous Article in Journal
Extracellular Polymeric Substance Protects Some Cells in an Escherichia coli Biofilm from the Biomechanical Consequences of Treatment with Magainin 2
Previous Article in Special Issue
Apple Pomace and Performance, Intestinal Morphology and Microbiota of Weaned Piglets—A Weaning Strategy for Gut Health?
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Microorganisms
Volume 9
Issue 5
10.3390/microorganisms9050977
microorganisms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Systematic Review: The Gut Microbiome and Its Potential Clinical Application in Inflammatory Bowel Disease

by
Laila Aldars-García
1,2,
María Chaparro
1,2,† and
Javier P. Gisbert
1,2,*,†
1
Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, 28006 Madrid, Spain
2
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28006 Madrid, Spain
*
Author to whom correspondence should be addressed.
†
Authors share co-senior authorship.
Microorganisms 2021, 9(5), 977; https://doi.org/10.3390/microorganisms9050977
Submission received: 5 April 2021 / Revised: 22 April 2021 / Accepted: 29 April 2021 / Published: 30 April 2021
(This article belongs to the Special Issue Gut Microbiota and Nutrients)
Browse Figure
Review Reports Versions Notes

Abstract

:
Inflammatory bowel disease (IBD) is a chronic relapsing–remitting systemic disease of the gastrointestinal tract. It is well established that the gut microbiome has a profound impact on IBD pathogenesis. Our aim was to systematically review the literature on the IBD gut microbiome and its usefulness to provide microbiome-based biomarkers. A systematic search of the online bibliographic database PubMed from inception to August 2020 with screening in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. One-hundred and forty-four papers were eligible for inclusion. There was a wide heterogeneity in microbiome analysis methods or experimental design. The IBD intestinal microbiome was generally characterized by reduced species richness and diversity, and lower temporal stability, while changes in the gut microbiome seemed to play a pivotal role in determining the onset of IBD. Multiple studies have identified certain microbial taxa that are enriched or depleted in IBD, including bacteria, fungi, viruses, and archaea. The two main features in this sense are the decrease in beneficial bacteria and the increase in pathogenic bacteria. Significant differences were also present between remission and relapse IBD status. Shifts in gut microbial community composition and abundance have proven to be valuable as diagnostic biomarkers. The gut microbiome plays a major role in IBD, yet studies need to go from casualty to causality. Longitudinal designs including newly diagnosed treatment-naïve patients are needed to provide insights into the role of microbes in the onset of intestinal inflammation. A better understanding of the human gut microbiome could provide innovative targets for diagnosis, prognosis, treatment and even cure of this relevant disease.

1. Introduction

The gastrointestinal microbiota comprises a collection of microbial communities, including viruses, bacteria, archaea and fungi, inhabiting the gastrointestinal tract [1]. The constitution and diversity of the microbiota in different sections of the gastrointestinal tract are highly variable and its concentration increases steadily along it, with small numbers in the stomach and very high concentrations in the colon [2,3]. This community has been linked to many diseases, including inflammatory bowel disease (IBD) [4].
IBD encompasses a group of chronic inflammatory bowel pathologies of idiopathic origin that affect millions of people throughout the world; the two most important pathologies covered by this term are Crohn’s disease (CD) and ulcerative colitis (UC) [5]. IBD is not curable and shows a chronic evolution, with alternating periods of exacerbation and remission. This situation entails a high burden on health care systems, which try to provide treatment and to ensure quality of life for these complex patients who often require lifelong medical attention.
The microbiota of the gastrointestinal tract is frequently proposed as one of the key players in the etiopathogenesis of IBD. Studies in animal models and humans have shown that there is a persistent imbalance of the intestinal microbiome (which refers to the gut microbiota and their collective genetic material) related to IBD, with a substantial body of literature providing evidence for the relation of the human gut microbiome and IBD [4,6,7,8,9,10]. Despite all this evidence, it has been difficult to determine whether these changes in the microbiome are the cause of IBD or rather the result of inflammation after IBD onset. The consequence of this relationship between the human gut and microbes is that pharmacological therapies, diet and other interventions targeted to the host will also significantly impact the gut microbiota. Most of the existing studies attempting to determine whether dysbiosis is causative or a consequence of inflammation had certain limitations, such as disparities in methodologic approaches, including different techniques used to analyze the gut microbiome, different sampling sites (stool/mucosa) or site of inflammation, lack of prospective data, small cohort sizes, restricted focus on bacteria, different disease activities and influence of treatment interventions.
We conducted a systematic review to comprehensively collate the body of evidence surrounding the relationship between the gut microbiome and IBD. Our objective was to describe the associations between IBD and dysbiosis and the potential clinical translation of microbiome-based biomarkers.

2. Methodology

2.1. Search Strategy

An electronic search was conducted using the MEDLINE database via PubMed to identify published articles on the gut microbiome and IBD, from inception to August 2020. The search strings used were:
[(“ulcerative colitis” [MeSH Terms]) OR (“colitis” [All Fields] AND “ulcerative” [All Fields]) OR (“ulcerative colitis” [All Fields]) OR (“crohn disease” [MeSH Terms]) OR (“crohn” [All Fields] AND “disease” [All Fields]) OR (“crohn disease” [All Fields]) OR (“crohn’s disease” [All Fields]) OR (“inflammatory bowel diseases” [MeSH Terms]) OR (“inflammatory bowel diseases” [All Fields])] AND (“microbiome” [All Fields] OR “microbiota” [All Fields]).
Moreover, the reference lists of the included studies were revised to identify further relevant studies.
The work was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement in Appendix A [11].

2.2. Eligibility Criteria

The inclusion criteria were intestinal microbiome studies comparing IBD patients with controls; performed on fecal, intestinal lavage or intestinal tissue samples; focused on human adults; written in English.
Studies were excluded if they reported data on IBD complications or postsurgery (pouchitis, fistulae, among others); studied other conditions in addition to IBD (irritable bowel syndrome, Clostridium difficile infection, primary sclerosing cholangitis, among others); were abstracts from conference proceedings, letters to editor, reviews or reported only one patient.

3. Results

A total of 5267 records were identified from the PUBMED database. Of 190 papers remaining after screening, 23 did not include controls, 22 included other pathologies and 2 were in silico studies. A total of 143 papers were ultimately included.

3.1. Gut Microbiome Studies in IBD: Methodologic Aspects

The main methodologic characteristics of the studies included in this review are summarized in Table 1 (IBD gut microbiome studies using non-next-generation sequencing [NGS] approaches) and Table 2 (IBD gut microbiome studies using NGS approaches).

3.1.1. Study Design

Across the included studies, populations ranged from 2 to 531 patients, many of them with a small sample size that reduced the precision of the estimations. Thus, since many results are limited by sample size, further studies with larger cohorts are desirable to confirm these results and to clarify the significance of the microbiome in the pathogenesis of IBD.
In addition, to date, most published studies in IBD are cross-sectional (121 out of the 143 reviewed studies). However, longitudinal designs are required to capture changes that precede or coincide with disease and symptom onset, and to mechanistically relate microbiome shifts with disease pathogenesis. Overall, longitudinal studies in IBD (only 15% of the included studies) indicate that there is decreased stability in the microbiota composition in UC and CD patients [18,23,25,118,131,132,138,149]. These dynamic changes emphasize the importance of longitudinal sampling for a better understanding of taxa stability in individuals.
The IBD microbiome varies not only over time but also with treatment [80,155,156]. Newly diagnosed patients with no treatment provide an ideal scenario to study the potential etiopathogenesis related to intestinal dysbiosis that occurs in IBD. Mouse and human studies have proven that the gut microbiome is required for disease onset, as germ-free mice rarely develop the disease [157,158], antibiotics can prevent disease onset in mice [159] and ameliorate (but not cure) the disease in humans [160].
However, prior IBD microbiome studies have mostly included subjects with an established treatment; of the 143 microbiome studies included herein, only 11 included treatment-naïve patients [15,66,69,75,81,84,87,93,117,118,123], sometimes only on a small subset of the cohort, and only one was conducted prospectively.
Results on newly diagnosed treatment-naïve patients showed that gut dysbiosis is already established at the beginning of the disease. The dysbiotic profile in the gut of newly diagnosed treatment-naïve IBD patients presents reduced microbial abundance, less biodiversity in the structure of microbial communities, and differential bacterial abundances compared to the profile of established and treated IBD patients or control groups. Conversely, one study showed none or minor microbial differences between these patients and a control group [84].
Current knowledge, despite some controversy, provides valuable insights supporting the idea that microbial alterations may precede IBD onset. Given the limited number of studies in this type of patients, no consistent conclusion can be inferred, and further work is needed to investigate in depth the gut dysbiosis of newly diagnosed treatment-naïve IBD patients.

3.1.2. Microbiome Analysis Methods

Culture-independent and -dependent methods for microbial community analysis have both been used to describe microorganisms from different environments, including the human gut. However, due to the inability to culture the majority of the resident bacteria from the gastrointestinal tract, culture-independent methods have proven much more reliable and faster in profiling complex microbial communities.
Culture-independent techniques are based on sequence divergences of the small subunit ribosomal RNA (16S rRNA) or other target gene regions. Some of these techniques are quantitative real-time PCR (qPCR), denaturing gradient gel electrophoresis (DGGE), terminal restriction fragment length polymorphism (T-RFLP), fluorescence in situ hybridization (FISH), DNA microarrays, and NGS. All these techniques, except for NGS, are referred herein as non-NGS techniques.
Currently, there are many differences in study design and methodology among studies, making translation of basic science results into clinical practice a challenging task. Among the studies included in this review, very few used culture-dependent techniques (7 out of 143); and over the years, NGS became the most employed technique—79 studies used NGS, while 64 studies used non-NGS approaches.
Lately, the most widely used approaches are amplicon gene sequencing, predominantly the 16S rRNA gene (16S rDNA), and whole-genome shotgun sequencing, both NGS techniques.
Another recent technique much less used in this field is flow cytometry. A recent study demonstrated that cytometry fingerprints can be used as a diagnostic tool to classify samples according to CD state [154]. These results highlight the potential of flow cytometry as a tool to conduct rapid and cheaper diagnostics of microbiome-associated diseases.

3.1.3. Sample Type and Site

Currently, bacterial diversity in the human gut is determined through analysis of the luminal content (stool) and mucosal biopsies; however, the stool microbiome differs from the mucosa-associated microbiome [161]. Most of the bacteria are tightly adhered to the mucus and this mucosa-adhered microbiota may be associated with the pathogenesis of the disease [9,76]. Changes observed in stool samples likely represent an indirect measure of what is happening at the mucosal surface, where microorganisms interact more intimately with the host and induce disease.
The studies reviewed herein used fecal data, biopsy data or both, and most of them showed differences between fecal and biopsy samples [13,32,47,80,89,93,96,130], although a few studies found similarities [52,76]. The reported differences in microbial composition related to whether the sample origin was fecal or mucosal indicate that each biological sample represents a different environment thus emphasizing the importance of experimental design. Biopsies are primarily recommended for the dissection of the complex pathogenesis of IBD, whereas feces could effectively detect key biomarkers, enabling non-invasive continuous disease monitoring.
In biopsy samples, sampling site can also be a confounding factor. Many studies have compared the microbiome of inflamed and non-inflamed tissue from the same IBD patient. Regarding the effect of gut inflammation on the microbiota, there are some discrepancies among studies. Some researchers did not find significant differences in the mucosa-associated bacteria between apparently normal and inflamed mucosa in IBD patients [15,66,100,127,128,147]. Conversely, other studies found gut microbiome differences between inflamed and non-inflamed regions in mucosal biopsies [19,44,72,78,120,125,134,144]. This difference was also observed in fungal communities of inflamed mucosa, which are distinguishable from those of the non-inflamed area [63].
In spite of the controversial results, there is evidence supporting that inflamed and non-inflamed tissue samples in both CD and UC may present some differential microbiota composition suggesting that a comparison of mucosal samples obtained from identical sites in IBD patients and non-IBD controls is needed to avoid the confounding effect of inflammation in the assessment of the microbial profile.

3.1.4. Structural and Functional Analysis

IBD microbiome studies have typically focused on characterizing the composition of a community and less attention has been paid to functional profiles of the microbes within a community. Functional information can be inferred from the taxa through bioinformatic approaches or directly assessed via whole-genome shotgun sequencing.
Function is more informative than taxonomy [162] as it provides information on possible mechanisms acting on microbes and on microbe–host interactions, which are important for understanding microbial communities, specially microbiome-related diseases. The loss of a particular function could be more biologically meaningful than the loss of a single or a group of species.
The vast majority of the studies published on the IBD microbiome to date have focused on taxonomy and the reported associations in the IBD gut microbiome are largely limited to identifying high-level taxonomic classification (ranging from phyla to genera) given, for example, the limitations of amplicon gene sequencing for reliable species identification.
Some IBD gut microbiome studies have assessed the change in microbial function compared to healthy subjects. Outcomes of such studies showed a quite distinct change in microbial functions, such as fecal tryptic activity, oxidative response or lipid and glycan metabolism pathways [52,80,83,88,132]. Based on these results, it is necessary to redirect the study of dysbiosis from a purely compositional definition to a definition that includes functional changes of the microbiota.

3.2. Dysbiosis in IBD

The microbiome is different among healthy individuals around the globe [163], and the great differences found between the microbiomes of apparently healthy people complicate the definition of a healthy microbiome. Despite this divergence, the vast and diverse microbial gut community lives in relative balance in healthy individuals. Dysbiosis refers to an imbalance in microbial species, which is commonly associated with impaired gut barrier function and inflammatory activity [164]. It encompasses major traits such as loss of beneficial microbes, expansion of pathobionts, and loss of diversity [3] (Figure 1). The following sections will describe the key alterations found in the gut of IBD patients.

3.2.1. Defining the Gut Microbiome in IBD

Although the gastrointestinal tract contains trillions of resident microorganisms that include bacteria, archaea, fungi and viruses, the studies revised herein highlighted that current research on microbiome is mainly focused on bacteria.

Bacterial Dysbiosis

It has consistently been shown that there is a disease-dependent restriction of biodiversity and an imbalanced bacterial composition associated with IBD. The abundance of beneficial microorganisms such as Clostridium groups IV and XIVa, Bacteroides, Suterella, Roseburia, Bifidobacterium species and Faecalibacterium prausnitzii is reduced, whereas some pathogens such as Proteobacteria members (including invasive and adherent Escherichia coli), Veillonellaceae, Pasteurellaceae, Fusobacterium species, and Ruminococcus gnavus are increased [4]. Most of the studies have revealed that in IBD patients, commensal bacteria are depleted and the microbial community is less diverse [14,22,37,48,80,94,106,108,126,143,150,152,153].
The increase in the phylum Proteobacteria, which includes multiple genera considered potentially pathogenic such as Escherichia, Salmonella, Yersinia, Desulfovibrio, Helicobacter or Vibrio, has been extensively reported in IBD patients [17,22,34,35,58,76,113,116,126,135,165].
In the Firmicutes phylum, F. prausnitzii, an anti-inflammatory commensal bacterium, is frequently decreased in CD, while less evidence has been reported in UC, where it is sometimes increased and in other studies decreased [14,22,51,59,73,89,109,140,142,166,167]. Specific decrease in Roseburia spp. in patients with IBD has also been consistently noted [56,59,76,99,115,116,130]. Both bacteria are known to be involved in the production of butyrate, an important energy source for intestinal epithelial cells, which strengthens gut barrier function and exerts important immunomodulatory functions [168]. In this same phylum, the mucin degrader R. gnavus is frequently increased in IBD patients’ gut, which may impair barrier stability and contribute to inflammation [38,76,103,111,116,132,140,144].

Fungal Dysbiosis

Despite the large body of literature on the IBD gut bacterial microbiome, little has been published on the gut mycobiome; specifically, only nine studies reviewed herein included fungal analysis.
Fungi are ubiquitous and their presence in the gastrointestinal tract has been demonstrated [169]. It was already evidenced many years ago that antibodies directed against mannoproteins of Saccharomyces cerevisiae (ASCA) were associated with CD, suggesting an inappropriate immune response to fungi in these patients [170].
Although fungi only constitute approximately 0.1% of the total microbial community in the gut [171], changes in gut mycobiota have been reported in IBD patients. However, results on fungal diversity are controversial; compared to controls, some studies have shown that fungal diversity is decreased in UC patients [107,112], and in CD, diversity and richness have been reported to be either increased [24,63], reduced [103,133], or unchanged [101]. Findings across fungal studies have consistently shown an increase in fungal load, especially in Candida albicans [24,63,101,102,107,133].
Nowadays, the exact mechanisms of intestinal fungi in IBD remain unclear and microbiome studies need to include fungi to properly address the complex challenges of this promising field.

Viral Dysbiosis

The human gut virome includes a diverse collection of viruses, mostly bacteriophages, directly impacting on human health [172]. In this systematic review, only seven studies included viral analysis [87,90,93,95,129,132,136]. Alterations in IBD gut virome showed an expansion of Caudovirales and an inverse correlation between the virome and bacterial microbiome, suggesting an hypothesis where changes in the gut virome may affect bacterial dysbiosis [90,95,129,136]. The use of data on both bacteriome and virome composition would contribute to improve classification between health and disease.
These findings suggest that the loss of virus-bacterium relationships can cause microbiota dysbiosis and intestinal inflammation. However, whether viruses have a direct role in IBD pathogenesis, or merely reflect underlying dysbiosis remains to be determined.

Archaeal Dysbiosis

The human gut microbiota also contains prokaryotes of the domain Archaea. Methane-producing archaea (methanogens) have been associated with disorders of the gastrointestinal tract and dysbiosis. Methanogens play an important role in digestion, improving polysaccharide fermentation by preventing accumulation of acids, reaction end-products and hydrogen gas [173].
The two reviewed studies including archaeal analysis have shown that the variable prevalence of methanogens in different individuals may play an important role on IBD pathogenesis [61,71]. Lecours et al. showed that the abundance of Methanosphaera stastmanae in fecal samples was significantly higher in IBD patients than in healthy subjects. Interestingly, only IBD patients developed a significant anti-Msp. stadtmanae immunoglobulin G response, indicating that the composition of archaeal microbiome appears to be an important determinant of the presence or absence of autoimmunity [61].
The other study demonstrated an inverse association between Methanobrevibacter smithii load and susceptibility to IBD, which could be extended to IBD patients in remission as they found that Mbb. smithii load was markedly higher in healthy subjects compared to IBD patients [71].
Although archaeal diversity in the gastrointestinal tract is far lower than that of bacteria, these microorganisms can also exert inflammatory effects and their consideration in microbiome studies may be crucial for developing optimal diagnostics and prognostics tools.

Disease Activity and Severity

Different disease activity and severity have been described among IBD patients with a given clinically defined condition, suggesting that, in the context of microbiome dysfunction, each condition may present different microbial profiles. The reviewed studies showed a clear difference in the gut microbiota associated with different disease activity and severity in IBD patients.
Dysbiosis was evidenced by Tong et al. [83] at remission, where highly preserved microbial groups accurately classified IBD status during disease quiescence, suggesting that microbial dysbiosis in IBD may be an underlying disorder not only associated with active disease. In general, compared to inactive disease, bacterial diversity and richness are reduced in active disease. Studies of intestinal microbiota in active/inactive IBD patients have consistently shown an increase in F. prausnitzii and Clostridiales in inactive IBD compared to active IBD, and the increase in Proteobacteria in active IBD compared to inactive IBD. Besides, F. prausnitzii and R. hominis display an inverse correlation with disease activity [51,54,56,59,60,68,114,135,137,139,149].
Some studies showed that the genus Bifidobacterium is significantly decreased in stool samples during the active phase of CD and UC compared to the remission phase [43,49,68]. On the contrary, biopsies showed a higher abundance of Bifidobacterium during active UC, and the proportion of Bifidobacterium was significantly higher in biopsies than in the fecal samples in active CD patients [60]. Some controversial results were also found as other researchers did not find a correlation between microbiota and disease actitivity [35,45,50,101,105,138].
Regarding IBD severity, different microbial abundance was detected in both biopsies and fecal samples from patients with more aggressive disease, and gut dysbiosis was not only related to current activity but also to the course of the disease. In biopsies, Firmicutes showed a significant decrease and Proteobacteria a significant increase in more aggressive CD [135], and Bifidobacterium was inversely correlated with IBD severity [54,135,149]. The risk of flare was associated with reduced microbial richness, increased dysbiosis index and higher individualized microbial instability [74,122,132,137,146,153].
This area is still in its infancy and some results are inconsistent between studies. Several studies have evidenced microbiota signatures of disease activity and severity and the likelihood of a flare-up. However, more research is necessary to identify specific microbial taxa.

3.3. Gut Microbiome-Based Biomarkers in IBD

Ideal biomarkers should be easy to obtain, easy to determine, non-invasive, cheap, and capable of providing rapid and reproducible results. Non-invasive tests for IBD are already available, including serum antibodies [174,175], imaging-based screenings [176], and fecal biomarkers [177]. However, endoscopy remains the gold standard for IBD diagnosis, as the aforementioned non-invasive tests are limited to active disease and their outcome can be interfered by diseases other than IBD limiting their clinical utility.
As a non-invasive, cost-effective technique, microbiome-based biomarkers might have great potential for early-stage disease detection and disease course prognosis as well as for treatment based on patient stratification. To this end, several attempts have been made to develop indices of dysbiosis based on relative abundances of selected microbial taxa in IBD patients compared to those of a healthy population. In stool samples, a machine learning algorithm using a combination of 50 operational taxonomic units was able to differentiate remission from active CD [178], and the genera Collinsella and Methanobrevibacter could be used to differentiate between UC and CD [109]. In biopsies, Faecalibacteria and Papillibacter were indicators of IBD status [98], F. prausnitzii and E. coli were used for differential diagnosis of CD (ileal/colonic) [30], supervised learning classification models were able to classify IBD at specific intestinal locations [65], and microbiome shifts predicted patient outcome [62,64,132,137,145,154]. In biopsies, stool and blood a dysbiosis score accurately stratified IBD patients [132].
In the previous sections, differential results on the gut microbiome between CD and UC, IBD and healthy subjects or between different disease activities have been described. Such research on the IBD microbiome has evidenced that (1) alterations in the abundance of certain microbial taxa or (2) in the structure of the microbial community, (3) the decreased bacterial richness and/or diversity and (4) the decreased microbial community stability could be used as potential biomarkers in the field.
Nevertheless, due to the high microbiome diversity between individuals, and within the same individual over time, the predictive value of these potential indicators is currently far below the level required for utility in diagnosis, prognosis, or response to treatment. Nonetheless, the increasing number of microbiome studies along with the use of longitudinal approaches pave the way to the refinement of microbiome-based biomarkers as useful disease indicators.

4. Concluding Remarks and Future Perspectives

The study of the human microbiome and its involvement in human health is nowadays one of the most active research topics in biomedicine. A simple search for “Microbiota” and “disease” within PubMed Database reveals almost 28,000 hits to date (august 2020). Given the potential clinical application of the microbiome, the number of studies in this field is rapidly increasing. However, some limitations can be found across these studies, including different methodologic approaches, small cohort sizes, different microbiome analysis methods and sample types and sites, main focus on bacteria, and influence of disease activity and treatment interventions. Therefore, these limitations result in variable findings, difficulty to establish comparison between studies and lack of reproducibility of microbiome signatures across studies.
Recent studies based on novel DNA sequencing methods have revealed major differences in microbial taxonomic and functional composition between IBD patients and healthy individuals. The current knowledge guides us to move our focus from community composition to the understanding of the interactions between microbial functions and the IBD gut microbiome.
The microbiota is very specific to an individual and variable in time, and therefore studies need to go from searching for correlation to searching for causation through longitudinal approaches. One important factor that we must keep in mind when studying the microbiome is that it is a “living entity” subject to variability. This variability is even more evident in the IBD microbiome. To better understand the IBD–microbiome connection, we require prospective longitudinal studies, along with following populations with early-onset IBD. The question of whether dysbiosis precedes the development of IBD and sets the inflammatory process, or merely reflects the altered immune and metabolic environment of the inflamed mucosa, remains to be answered. For this reason, it is of paramount importance to study newly diagnosed treatment-naïve patients, where the microbiome can be studied at the beginning of the disease and without the influence of any IBD treatment. Developing unified approaches to the accurate quantitative assessment of the gut microbiome would contribute to comparisons among studies and to its further clinical application.
The main feature in IBD gut dysbiosis is the decrease in beneficial bacteria and the increase in pathogens. Gut microbiome studies are mainly focused on bacteria, yet beyond bacteria, the gut microbiome is composed of other microorganisms such as viruses, fungi or archaea, which play a role in IBD etiology and/or in bacterial population control. In addition, it is currently known that disease activity and severity influence the gut microbiome, thereby affecting the results. IBD can be considered as a “multimicrobial” disease with no single causative microorganism, in which more severe disease is linked to reduced gut microbial diversity, and proliferation or reduction in specific taxa. Therefore, future studies should include the whole community for a deeper understanding of this disease.
The usefulness of the gut microbiome as a tool towards targeted non-invasive biomarkers for IBD has been evaluated by compelling studies. An acceptable biomarker may help in early diagnosis and classification of IBD as well as in the prediction of disease outcome. Overall, IBD clinical management would benefit from the identification of microbiome-based biomarkers, which could provide less invasive assessment tools, enable personalized treatments, and reduce the health care economic burden associated with IBD. Collectively, these microbiome data represent a valuable data source that can be continually mined to identify associations between the microbiome and IBD for a deeper pathophysiological understanding which may promote the development of clinical strategies, including disease prevention, treatment, stratification and assessment of high-risk population.

Author Contributions

Guarantor of the article: L.A.-G., M.C. and J.P.G. contributed to the study conception and design, literature search, data collection and interpretation, and to the writing of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work is supported by Sara Borrell contract CD19/00247 from the Instituto de Salud Carlos III (ISCIII) to L.A.-G.

Data Availability Statement

All data used, generated or analyzed during this study are included in this published article.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Appendix A

Table
Table A1. PRISMA Checklist.
Table A1. PRISMA Checklist.
Section/Topic # Checklist Item Reported on Page #
TITLE
Title1Identify the report as a systematic review, meta-analysis, or both.1
ABSTRACT
Structured summary2Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.1
INTRODUCTION
Rationale3Describe the rationale for the review in the context of what is already known.1–2
Objectives4Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).2
METHODS
Protocol and registration5Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.2
Eligibility criteria6Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.2
Information sources7Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.2
Search8Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.2
Study selection9State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).2
Data collection process10Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.2
Section/topic#Checklist itemReported on page #
Data items11List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.N/A
Risk of bias in individual studies12Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.N/A
Summary measures13State the principal summary measures (e.g., risk ratio, difference in means).N/A
Synthesis of results14Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.N/A
Risk of bias across studies15Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).N/A
Additional analyses16Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.N/A
RESULTS
Study selection17Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.2
Study characteristics18For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.3–8
Risk of bias within studies19Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).N/A
Results of individual studies20For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.N/A
Synthesis of results21Present results of each meta-analysis done, including confidence intervals and measures of consistency.N/A
Risk of bias across studies22Present results of any assessment of risk of bias across studies (see Item 15).N/A
Additional analysis23Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).N/A
Section/topic#Checklist itemReported on page #
DISCUSSION
Summary of evidence24Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).N/A
Limitations25Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).N/A
Conclusions26Provide a general interpretation of the results in the context of other evidence, and implications for future research.8–9
FUNDING
Funding27Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.9

References

  1. Hoyles, L.; Swann, J. Influence of the human gut microbiome on the metabolic phenotype. In The Handbook of Metabolic Phenotyping; Elsevier Inc.: Amsterdam, The Netherlands, 2018; pp. 535–560. ISBN 9780128122938. [Google Scholar]
  2. Rajilic-Stojanovic, M.; Figueiredo, C.; Smet, A.; Hansen, R.; Kupcinskas, J.; Rokkas, T.; Andersen, L.; Machado, J.C.; Ianiro, G.; Gasbarrini, A.; et al. Systematic review: Gastric microbiota in health and disease. Aliment. Pharmacol. Ther. 2020, 51, 582–602. [Google Scholar] [CrossRef] [PubMed]
  3. Thursby, E.; Juge, N. Introduction to the human gut microbiota. Biochem. J. 2017, 474, 1823–1836. [Google Scholar] [CrossRef]
  4. Pittayanon, R.; Lau, J.T.; Leontiadis, G.I.; Tse, F.; Yuan, Y.; Surette, M.; Moayyedi, P. Differences in gut microbiota in patients with vs without inflammatory bowel diseases: A systematic review. Gastroenterology 2020, 158, 930–946e1. [Google Scholar] [CrossRef]
  5. Medina Benítez, E.; Fuentes Lugo, D.; Suárez Cortina, L.; Prieto Bozano, G. Enfermedad inflamatoria intestinal. In Protocolos Diagnóstico-Terapéuticos de Gastroenterología, Hepatología y Nutrición Pediátrica SEGHNP-AEP; Ediciones Ergon: Madrid, Spain, 2010; pp. 151–160. [Google Scholar]
  6. Khan, I.; Ullah, N.; Zha, L.; Bai, Y.; Khan, A.; Zhao, T.; Che, T.; Zhang, C. Alteration of gut microbiota in inflammatory bowel disease (IBD): Cause or consequence? IBD treatment targeting the gut microbiome. Pathogens 2019, 8, 126. [Google Scholar] [CrossRef] [Green Version]
  7. Ni, J.; Wu, G.D.; Albenberg, L.; Tomov, V.T. Gut microbiota and IBD: Causation or correlation? Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 573–584. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Zhou, M.; He, J.; Shen, Y.; Zhang, C.; Wang, J.; Chen, Y. New frontiers in genetics, gut microbiota, and immunity: A rosetta stone for the pathogenesis of inflammatory bowel disease. BioMed Res. Int. 2017, 2017, 8201672. [Google Scholar] [CrossRef]
  9. Zuo, T.; Ng, S.C. The gut microbiota in the pathogenesis and therapeutics of inflammatory bowel disease. Front. Microbiol. 2018, 9, 2247. [Google Scholar] [CrossRef]
  10. Glassner, K.L.; Abraham, B.P.; Quigley, E.M.M. The microbiome and inflammatory bowel disease. J. Allergy Clin. Immunol. 2020, 145, 16–27. [Google Scholar] [CrossRef] [Green Version]
  11. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; Altman, D.; Antes, G.; Atkins, D.; Barbour, V.; Barrowman, N.; Berlin, J.A.; et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e1000097. [Google Scholar] [CrossRef] [Green Version]
  12. Macfarlane, S.; Furrie, E.; Cummings, J.H.; Macfarlane, G.T. Chemotaxonomic Analysis of Bacterial Populations Colonizing the Rectal Mucosa in Patients with Ulcerative Colitis. Clin. Infect. Dis. 2004, 38, 1690–1699. [Google Scholar]
  13. Lepage, P.; Seksik, P.; Sutren, M.; de la Cochetière, M.F.; Jian, R.; Marteau, P.; Doré, J. Biodiversity of the mucosa-associated microbiota is stable along the distal digestive tract in healthy individuals and patients with IBD. Inflamm. Bowel Dis. 2005, 11, 473–480. [Google Scholar] [CrossRef]
  14. Manichanh, C.; Bonnaud, E.; Gloux, K.; Pelletier, E.; Frangeul, L.; Nalin, R.; Jarrin, C.; Chardon, P.; Marteau, P.; Roca, J.; et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 2006, 55, 205–211. [Google Scholar] [CrossRef] [Green Version]
  15. Bibiloni, R.; Mangold, M.; Madsen, K.L.; Fedorak, R.N.; Tannock, G.W. The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn’s disease and ulcerative colitis patients. J. Med. Microbiol. 2006, 55, 1141–1149. [Google Scholar] [CrossRef] [Green Version]
  16. Sokol, H.; Lepage, P.; Seksik, P.; Dore, J.; Marteau, P. Temperature Gradient Gel Electrophoresis of Fecal 16S rRNA Reveals Active Escherichia coli in the Microbiota of Patients with Ulcerative Colitis. J. Clin. Microbiol. 2006, 44, 3172–3177. [Google Scholar] [CrossRef] [Green Version]
  17. Gophna, U.; Sommerfeld, K.; Gophna, S.; Doolittle, W.F.; Zanten, S.J.O.V. Van Differences between Tissue-Associated Intestinal Microfloras of Patients with Crohn ’ s Disease and Ulcerative Colitis. J. Clin. Microbiol. 2006, 44, 4136–4141. [Google Scholar] [CrossRef] [Green Version]
  18. Scanlan, P.D.; Shanahan, F.; Mahony, C.O.; Marchesi, J.R. Culture-Independent Analyses of Temporal Variation of the Dominant Fecal Microbiota and Targeted Bacterial Subgroups in Crohn ’ s Disease. J. Clin. Microbiol. 2006, 44, 3980–3988. [Google Scholar] [CrossRef] [Green Version]
  19. Zhang, M.; Liu, B.; Zhang, Y.; Wei, H.; Lei, Y.; Zhao, L. Structural shifts of mucosa-associated lactobacilli and Clostridium leptum subgroup in patients with ulcerative colitis. J. Clin. Microbiol. 2007, 45, 496–500. [Google Scholar] [CrossRef] [Green Version]
  20. Sepehri, S.; Kotlowski, R.; Bernstein, C.N.; Krause, D.O. Microbial diversity of inflamed and noninflamed gut biopsy tissues in inflammatory bowel disease. Inflamm. Bowel Dis. 2007, 13, 675–683. [Google Scholar] [CrossRef]
  21. Andoh, A.; Sakata, S.; Koizumi, Y.; Mitsuyama, K.; Fujiyama, Y.; Benno, Y. Terminal restriction fragment length polymorphism analysis of the diversity of fecal microbiota in patients with ulcerative colitis. Inflamm. Bowel Dis. 2007, 13, 955–962. [Google Scholar] [CrossRef]
  22. Frank, D.N.; Amand, A.L.S.; Feldman, R.A.; Boedeker, E.C.; Harpaz, N.; Pace, N.R. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci. USA 2007, 104, 13780–13785. [Google Scholar] [CrossRef] [Green Version]
  23. Ott, S.J.; Plamondon, S.; Hart, A.; Begun, A.; Rehman, A.; Kamm, M.A.; Schreiber, S. Dynamics of the mucosa-associated flora in ulcerative colitis patients during remission and clinical relapse. J. Clin. Microbiol. 2008, 46, 3510–3513. [Google Scholar] [CrossRef] [Green Version]
  24. Ott, S.J.; Kühbacher, T.; Musfeldt, M.; Rosenstiel, P.; Hellmig, S.; Rehman, A.; Drews, O.; Weichert, W.; Timmis, K.N.; Schreiber, S. Fungi and inflammatory bowel diseases: Alterations of composition and diversity. Scand. J. Gastroenterol. 2008, 43, 831–841. [Google Scholar] [CrossRef]
  25. Martinez, C.; Antolin, M.; Santos, J.; Torrejon, A.; Casellas, F.; Borruel, N.; Guarner, F.; Malagelada, J.R. Unstable composition of the fecal microbiota in ulcerative colitis during clinical remission. Am. J. Gastroenterol. 2008, 103, 643–648. [Google Scholar] [CrossRef] [PubMed]
  26. Dicksved, J.; Halfvarson, J.; Rosenquist, M.; Järnerot, G.; Tysk, C.; Apajalahti, J.; Engstrand, L.; Jansson, J.K. Molecular analysis of the gut microbiota of identical twins with Crohn’s disease. ISME J. 2008, 2, 716–727. [Google Scholar] [CrossRef]
  27. Kuehbacher, T.; Rehman, A.; Lepage, P.; Hellmig, S.; Fölsch, U.R.; Schreiber, S.; Ott, S.J. Intestinal TM7 bacterial phylogenies in active inflammatory bowel disease. J. Med. Microbiol. 2008, 57, 1569–1576. [Google Scholar] [CrossRef] [Green Version]
  28. Andoh, A.; Tsujikawa, T.; Sasaki, M.; Mitsuyama, K.; Suzuki, Y.; Matsui, T.; Matsumoto, T.; Benno, Y.; Fujiyama, Y. Faecal microbiota profile of Crohn’s disease determined by terminal restriction fragment length polymorphism analysis. Aliment. Pharmacol. Ther. 2008, 29, 75–82. [Google Scholar] [CrossRef]
  29. Nishikawa, J.; Kudo, T.; Sakata, S.; Benno, Y.; Sugiyama, T. Diversity of mucosa-associated microbiota in active and inactive ulcerative colitis. Scand. J. Gastroenterol. 2009, 44, 180–186. [Google Scholar] [CrossRef]
  30. Willing, B.; Halfvarson, J.; Dicksved, J.; Rosenquist, M.; Järnerot, G.; Engstrand, L.; Tysk, C.; Jansson, J.K. Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn’s disease. Inflamm. Bowel Dis. 2009, 15, 653–660. [Google Scholar] [CrossRef]
  31. Andoh, A.; Ida, S.; Tsujikawa, T.; Benno, Y.; Fujiyama, Y. Terminal restriction fragment polymorphism analyses of fecal microbiota in five siblings including two with ulcerative colitis. Clin. J. Gastroenterol. 2009, 2, 343–345. [Google Scholar] [CrossRef] [PubMed]
  32. Gillevet, P.; Sikaroodi, M.; Keshavarzian, A.; Mutlu, E.A. Quantitative Assessment of the Human Gut Microbiome using Multitag Pyrosequencing. Chem. Biodivers. 2010, 7, 1065–1075. [Google Scholar] [CrossRef]
  33. Rehman, A.; Lepage, P.; Nolte, A.; Hellmig, S.; Schreiber, S.; Ott, S.J. Transcriptional activity of the dominant gut mucosal microbiota in chronic inflammatory bowel disease patients. J. Med. Microbiol. 2010, 59, 1114–1122. [Google Scholar] [CrossRef] [PubMed]
  34. Kang, S.; Denman, S.E.; Morrison, M.; Yu, Z.; Dore, J.; Leclerc, M.; McSweeney, C.S. Dysbiosis of fecal microbiota in Crohn’s disease patients as revealed by a custom phylogenetic microarray. Inflamm. Bowel Dis. 2010, 16, 2034–2042. [Google Scholar] [CrossRef]
  35. Rowan, F.; Docherty, N.G.; Murphy, M.; Murphy, B.; Coffey, J.C.; O’Connell, P.R. Desulfovibrio Bacterial Species Are Increased in Ulcerative Colitis. Dis. Colon Rectum 2010, 53, 1530–1536. [Google Scholar] [CrossRef]
  36. Andoh, A.; Imaeda, H.; Aomatsu, T.; Inatomi, O.; Bamba, S.; Sasaki, M.; Saito, Y.; Tsujikawa, T.; Fujiyama, Y. Comparison of the fecal microbiota profiles between ulcerative colitis and Crohn’s disease using terminal restriction fragment length polymorphism analysis. J. Gastroenterol. 2011, 46, 479–486. [Google Scholar] [CrossRef]
  37. Mondot, S.; Kang, S.; Furet, J.P.; Aguirre De Carcer, D.; McSweeney, C.; Morrison, M.; Marteau, P.; Doré, J.; Leclerc, M. Highlighting new phylogenetic specificities of Crohn’s disease microbiota. Inflamm. Bowel Dis. 2011, 17, 185–192. [Google Scholar] [CrossRef] [Green Version]
  38. Joossens, M.; Huys, G.; Cnockaert, M.; De Preter, V.; Verbeke, K.; Rutgeerts, P.; Vandamme, P.; Vermeire, S. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut 2011, 60, 631–637. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Lepage, P.; Hösler, R.; Spehlmann, M.E.; Rehman, A.; Zvirbliene, A.; Begun, A.; Ott, S.; Kupcinskas, L.; Doré, J.; Raedler, A.; et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 2011, 141, 227–236. [Google Scholar] [CrossRef]
  40. Benjamin, J.L.; Hedin, C.R.H.; Koutsoumpas, A.; Ng, S.C.; McCarthy, N.E.; Prescott, N.J.; Pessoa-Lopes, P.; Mathew, C.G.; Sanderson, J.; Hart, A.L.; et al. Smokers with active Crohn’s disease have a clinically relevant dysbiosis of the gastrointestinal microbiota. Inflamm. Bowel Dis. 2012, 18, 1092–1100. [Google Scholar] [CrossRef]
  41. Hotte, N.S.C.; Salim, S.Y.; Tso, R.H.; Albert, E.J.; Bach, P.; Walker, J.; Dieleman, L.A.; Fedorak, R.N.; Madsen, K.L. Patients with inflammatory bowel disease exhibit dysregulated responses to microbial DNA. PLoS ONE 2012, 7, e37932. [Google Scholar] [CrossRef] [Green Version]
  42. Pistone, D.; Marone, P.; Pajoro, M.; Fabbi, M.; Vicari, N.; Daffara, S.; Dalla Valle, C.; Gabba, S.; Sassera, D.; Verri, A.; et al. Mycobacterium avium paratuberculosis in Italy: Commensal or emerging human pathogen? Dig. Liver Dis. 2012, 44, 461–465. [Google Scholar] [CrossRef] [PubMed]
  43. Andoh, A.; Kuzuoka, H.; Tsujikawa, T.; Nakamura, S. Multicenter analysis of fecal microbiota profiles in Japanese patients with Crohn ’ s disease. J Gastroenterol. 2012, 47, 1298–1307. [Google Scholar] [CrossRef]
  44. Li, Q.; Wang, C.; Tang, C.; Li, N.; Li, J. Molecular-phylogenetic characterization of the microbiota in ulcerated and non-ulcerated regions in the patients with crohn’s disease. PLoS ONE 2012, 7, e34939. [Google Scholar] [CrossRef] [PubMed]
  45. Nemoto, H.; Kataoka, K.; Ishikawa, H.; Ikata, K.; Arimochi, H.; Iwasaki, T.; Ohnishi, Y.; Kuwahara, T.; Yasutomo, K. Reduced diversity and imbalance of fecal microbiota in patients with ulcerative colitis. Dig. Dis. Sci. 2012, 57, 2955–2964. [Google Scholar] [CrossRef]
  46. Vigsnæs, L.K.; Brynskov, J.; Steenholdt, C.; Wilcks, A.; Licht, T.R. Gram-negative bacteria account for main differences between faecal microbiota from patients with ulcerative colitis and healthy controls. Benef. Microbes 2012, 3, 287–297. [Google Scholar] [CrossRef]
  47. De Souza, H.L.; De Carvalho, V.R.; Romeiro, F.G.; Sassaki, L.Y.; Keller, R.; Rodrigues, J. Mucosa-associated but not luminal Escherichia coli is augmented in Crohn’s disease and ulcerative colitis. Gut Pathog. 2012, 4, 1–8. [Google Scholar] [CrossRef] [Green Version]
  48. Duboc, H.; Rajca, S.; Rainteau, D.; Benarous, D.; Maubert, M.A.; Quervain, E.; Thomas, G.; Barbu, V.; Humbert, L.; Despras, G.; et al. Connecting dysbiosis, bile-acid dysmetabolism and Gut inflammation in inflammatory bowel diseases. Gut 2012, 62, 531–539. [Google Scholar] [CrossRef]
  49. Sha, S.; Xu, B.; Wang, X.; Zhang, Y.; Wang, H.; Kong, X.; Zhu, H.; Wu, K. The biodiversity and composition of the dominant fecal microbiota in patients with inflammatory bowel disease. Diagn. Microbiol. Infect. Dis. 2013, 75, 245–251. [Google Scholar] [CrossRef]
  50. Kabeerdoss, J.; Sankaran, V.; Pugazhendhi, S.; Ramakrishna, B.S. Clostridium leptum group bacteria abundance and diversity in the fecal microbiota of patients with inflammatory bowel disease: A case – control study in India. BMC Gastroenterol. 2013, 13, 1. [Google Scholar] [CrossRef] [Green Version]
  51. Varela, E.; Manichanh, C.; Gallart, M.; Torrejon, A.; Borruel, N.; Casellas, F.; Guarner, F.; Antolin, M. Colonisation by Faecalibacterium prausnitzii and maintenance of clinical remission in patients with ulcerative colitis. Aliment. Pharmacol. Ther. 2013, 38, 151–161. [Google Scholar] [CrossRef]
  52. Midtvedt, T.; Zabarovsky, E.; Norin, E.; Bark, J.; Gizatullin, R.; Kashuba, V.; Ljungqvist, O.; Zabarovska, V.; Möllby, R.; Ernberg, I. Increase of Faecal Tryptic Activity Relates to Changes in the Intestinal Microbiome: Analysis of Crohn’s Disease with a Multidisciplinary Platform. PLoS ONE 2013, 8, e66074. [Google Scholar] [CrossRef] [PubMed]
  53. Fujimoto, T.; Imaeda, H.; Takahashi, K.; Kasumi, E.; Bamba, S.; Fujiyama, Y.; Andoh, A. Decreased abundance of Faecalibacterium prausnitzii in the gut microbiota of Crohn’s disease. J. Gastroenterol. Hepatol. 2013, 28, 613–619. [Google Scholar] [CrossRef]
  54. Fite, A.; Macfarlane, S.; Furrie, E.; Bahrami, B.; Cummings, J.H.; Steinke, D.T.; MacFarlane, G.T. Longitudinal analyses of gut mucosal microbiotas in ulcerative colitis in relation to patient age and disease severity and duration. J. Clin. Microbiol. 2013, 51, 849–856. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Rajilić-Stojanović, M.; Shanahan, F.; Guarner, F.; De Vos, W.M. Phylogenetic analysis of dysbiosis in ulcerative colitis during remission. Inflamm. Bowel Dis. 2013, 19, 481–488. [Google Scholar] [CrossRef]
  56. Kumari, R.; Ahuja, V.; Paul, J. Fluctuations in butyrate-producing bacteria in ulcerative colitis patients of North India. World J. Gastroenterol. 2013, 19, 3404–3414. [Google Scholar] [CrossRef]
  57. Hedin, C.R.; McCarthy, N.E.; Louis, P.; Farquharson, F.M.; McCartney, S.; Taylor, K.; Prescott, N.J.; Murrells, T.; Stagg, A.J.; Whelan, K.; et al. Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn’s disease and their unaffected siblings. Gut 2014, 63, 1578–1586. [Google Scholar] [CrossRef] [PubMed]
  58. Lennon, G.; Balfe, Á.; Bambury, N.; Lavelle, A.; Maguire, A.; Docherty, N.G.; Coffey, J.C.; Winter, D.C.; Sheahan, K.; O’Connell, P.R. Correlations between colonic crypt mucin chemotype, inflammatory grade and Desulfovibrio species in ulcerative colitis. Color. Dis. 2014, 16, 161–169. [Google Scholar] [CrossRef] [PubMed]
  59. Machiels, K.; Joossens, M.; Sabino, J.; De Preter, V.; Arijs, I.; Eeckhaut, V.; Ballet, V.; Claes, K.; Van Immerseel, F.; Verbeke, K.; et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 2014, 63, 1275–1283. [Google Scholar] [CrossRef]
  60. Wang, W.; Chen, L.; Zhou, R.; Wang, X.; Song, L.; Huang, S.; Wang, G.; Xia, B. Increased Proportions of Bifidobacterium and the Lactobacillus Group and Loss of Butyrate-Producing Bacteria in Inflammatory Bowel. J. Clin. Microbiol. 2014, 52, 398–406. [Google Scholar] [CrossRef] [Green Version]
  61. Blais Lecours, P.; Marsolais, D.; Cormier, Y.; Berberi, M.; Hache, C.; Bourdages, R.; Duchaine, C. Increased Prevalence of Methanosphaera stadtmanae in Inflammatory Bowel Diseases. PLoS ONE 2014, 9, e87734. [Google Scholar] [CrossRef]
  62. Fukuda, K.; Fujita, Y. Determination of the discriminant score of intestinal microbiota as a biomarker of disease activity in patients with ulcerative colitis. BMC Gastroenterol. 2014, 14, 49. [Google Scholar] [CrossRef] [Green Version]
  63. Li, Q.; Wang, C.; Tang, C.; He, Q.; Li, N.; Li, J. Dysbiosis of gut fungal microbiota is associated with mucosal inflammation in crohn’s disease. J. Clin. Gastroenterol. 2014, 48, 513–523. [Google Scholar] [CrossRef] [Green Version]
  64. Andoh, A.; Kobayashi, T.; Kuzuoka, H.; Tsujikawa, T.; Suzuki, Y.; Hirai, F.; Matsui, T.; Nakamura, S.; Matsumoto, T.; Fujiyama, Y. Characterization of gut microbiota profiles by disease activity in patients with Crohn’s disease using data mining analysis of terminal restriction fragment length polymorphisms. Biomed. Rep. 2014, 2, 370–373. [Google Scholar] [CrossRef]
  65. Wisittipanit, N.; Rangwala, H.; Sikaroodi, M.; Keshavarzian, A.; Mutlu, E.A.; Gillevet, P. Classification methods for the analysis of LH-PCR data associated with inflammatory bowel disease patients. Int. J. Bioinform. Res. Appl. 2015, 11, 111–129. [Google Scholar] [CrossRef]
  66. Kabeerdoss, J.; Jayakanthan, P.; Pugazhendhi, S.; Ramakrishna, B.S. Alterations of mucosal microbiota in the colon of patients with inflammatory bowel disease revealed by real time polymerase chain reaction amplification of 16S ribosomal ribonucleic acid. Indian J. Med. Res. 2015, 23–33. [Google Scholar]
  67. Takeshita, K.; Mizuno, S.; Mikami, Y.; Sujino, T.; Saigusa, K.; Matsuoka, K.; Naganuma, M.; Sato, T.; Takada, T.; Tsuji, H.; et al. A single species of clostridium Subcluster XIVa decreased in ulcerative colitis patients. Inflamm. Bowel Dis. 2016, 22, 2802–2810. [Google Scholar] [CrossRef] [Green Version]
  68. Zhang, J.; Chen, S.L.; Li, L.B. Correlation between intestinal flora and serum inflammatory factors in patients with Crohn’s disease. Eur. Rev. Med. Pharmacol. Sci. 2017, 21, 4913–4917. [Google Scholar]
  69. Vrakas, S.; Mountzouris, K.C.; Michalopoulos, G.; Karamanolis, G.; Papatheodoridis, G.; Tzathas, C.; Gazouli, M. Intestinal bacteria composition and translocation of bacteria in inflammatory bowel disease. PLoS ONE 2017, 12, e0170034. [Google Scholar] [CrossRef] [Green Version]
  70. Zamani, S.; Hesam Shariati, S.; Zali, M.R.; Asadzadeh Aghdaei, H.; Sarabi Asiabar, A.; Bokaie, S.; Nomanpour, B.; Sechi, L.A.; Feizabadi, M.M. Detection of enterotoxigenic Bacteroides fragilis in patients with ulcerative colitis. Gut Pathog. 2017, 9, 53. [Google Scholar] [CrossRef] [Green Version]
  71. Ghavami, S.B.; Rostami, E.; Sephay, A.A.; Shahrokh, S.; Balaii, H.; Aghdaei, H.A.; Zali, M.R. Alterations of the human gut Methanobrevibacter smithii as a biomarker for inflammatory bowel diseases. Microb. Pathog. 2018, 117, 285–289. [Google Scholar] [CrossRef]
  72. Le Baut, G.; O’brien, C.; Pavli, P.; Roy, M.; Seksik, P.; Tréton, X.; Nancey, S.; Barnich, N.; Bezault, M.; Auzolle, C.; et al. Prevalence of Yersinia Species in the Ileum of Crohn’s Disease Patients and Controls. Front. Cell. Infect. Microbiol. 2018, 8, 336. [Google Scholar] [CrossRef] [Green Version]
  73. Al-Bayati, L.; Fasaei, B.N.; Merat, S.; Bahonar, A. Longitudinal analyses of Gut-associated bacterial microbiota in ulcerative colitis patients. Arch. Iran. Med. 2018, 21, 578–584. [Google Scholar] [PubMed]
  74. Heidarian, F.; Alebouyeh, M.; Shahrokh, S.; Balaii, H.; Zali, M.R. Altered fecal bacterial composition correlates with disease activity in inflammatory bowel disease and the extent of IL8 induction. Curr. Res. Transl. Med. 2019, 67, 41–50. [Google Scholar] [CrossRef] [PubMed]
  75. Vatn, S.; Carstens, A.; Kristoffersen, A.B.; Bergemalm, D.; Casén, C.; Moen, A.E.F.; Tannaes, T.M.; Lindstrøm, J.; Detlie, T.E.; Olbjørn, C.; et al. Faecal microbiota signatures of IBD and their relation to diagnosis, disease phenotype, inflammation, treatment escalation and anti-TNF response in a European Multicentre Study (IBD-Character). Scand. J. Gastroenterol. 2020, 55, 1146–1156. [Google Scholar] [CrossRef]
  76. Willing, B.P.; Dicksved, J.; Halfvarson, J.; Andersson, A.F.; Lucio, M.; Zheng, Z.; Järnerot, G.; Tysk, C.; Jansson, J.K.; Engstrand, L. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 2010, 139, 1844–1854. [Google Scholar] [CrossRef]
  77. Rausch, P.; Rehman, A.; Künzel, S.; Häsler, R.; Ott, S.J.; Schreiber, S.; Rosenstiel, P.; Franke, A.; Baines, J.F. Colonic mucosa-associated microbiota is influenced by an interaction of crohn disease and FUT2 (Secretor) genotype. Proc. Natl. Acad. Sci. USA 2011, 108, 19030–19035. [Google Scholar] [CrossRef] [Green Version]
  78. Walker, A.W.; Sanderson, J.D.; Churcher, C.; Parkes, G.C.; Hudspith, B.N.; Rayment, N.; Brostoff, J.; Parkhill, J.; Dougan, G.; Petrovska, L. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 2011, 11, 7. [Google Scholar] [CrossRef] [Green Version]
  79. Erickson, A.R.; Cantarel, B.L.; Lamendella, R.; Darzi, Y.; Mongodin, E.F.; Pan, C.; Shah, M.; Halfvarson, J.; Tysk, C.; Henrissat, B.; et al. Integrated Metagenomics/Metaproteomics Reveals Human Host-Microbiota Signatures of Crohn’s Disease. PLoS ONE 2012, 7, e49138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Morgan, X.C.; Tickle, T.L.; Sokol, H.; Gevers, D.; Devaney, K.L.; Ward, D.V.; Reyes, J.A.; Shah, S.A.; Leleiko, N.; Snapper, S.B.; et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 2012, 13, R79. [Google Scholar] [CrossRef] [PubMed]
  81. Ricanek, P.; Lothe, S.M.; Frye, S.A.; Rydning, A.; Vatn, M.H. Gut bacterial profile in patients newly diagnosed with treatment-naïve Crohn ’ s disease. Clin. Exp. Gastroenterol. 2012, 5, 173–186. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Li, E.; Hamm, C.M.; Gulati, A.S.; Sartor, R.B.; Chen, H.; Wu, X.; Zhang, T.; Rohlf, F.J.; Zhu, W.; Gu, C.; et al. Inflammatory bowel diseases phenotype, C. difficile and NOD2 genotype are associated with shifts in human ileum associated microbial composition. PLoS ONE 2012, 7, e26284. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Tong, M.; Li, X.; Parfrey, L.W.; Roth, B.; Ippoliti, A.; Wei, B.; Borneman, J.; McGovern, D.P.B.; Frank, D.N.; Li, E.; et al. A modular organization of the human intestinal mucosal microbiota and its association with inflammatory bowel disease. PLoS ONE 2013, 8, e80702. [Google Scholar]
  84. Thorkildsen, L.T.; Nwosu, F.C.; Avershina, E.; Ricanek, P.; Perminow, G.; Brackmann, S.; Vatn, M.H.; Rudi, K. Dominant Fecal Microbiota in Newly Diagnosed Untreated Inflammatory Bowel Disease Patients. Gastroenterol. Res. Pract. 2013, 636785. [Google Scholar] [CrossRef]
  85. Prideaux, L.; Kang, S.; Wagner, J.; Buckley, M.; Mahar, J.E.; De Cruz, P.; Wen, Z.; Chen, L.; Xia, B.; Van Langenberg, D.R.; et al. Impact of ethnicity, geography, and disease on the microbiota in health and inflammatory bowel disease. Inflamm. Bowel Dis. 2013, 19, 2906–2918. [Google Scholar] [CrossRef]
  86. Chiodini, R.J.; Dowd, S.E.; Davis, B.; Galandiuk, S.; Chamberlin, W.M.; Kuenstner, J.T.; McCallum, R.W.; Zhang, J. Crohn’s disease may be differentiated into 2 distinct biotypes based on the detection of bacterial genomic sequences and virulence genes within submucosal tissues. J. Clin. Gastroenterol. 2013, 47, 612–620. [Google Scholar] [CrossRef] [Green Version]
  87. Pérez-Brocal, V.; García-López, R.; Vázquez-Castellanos, J.F.; Nos, P.; Beltrán, B.; Latorre, A.; Moya, A. Study of the viral and microbial communities associated with Crohn’s disease: A metagenomic approach. Clin. Transl. Gastroenterol. 2013, 4, e36. [Google Scholar] [CrossRef]
  88. Davenport, M.; Poles, J.; Leung, J.M.; Wolff, M.J.; Abidi, W.M.; Ullman, T.; Mayer, L.; Cho, I.; Loke, P. Metabolic alterations to the mucosal microbiota in inflammatory bowel disease. Inflamm. Bowel Dis. 2014, 20, 723–731. [Google Scholar] [CrossRef] [Green Version]
  89. Chen, L.; Wang, W.; Zhou, R.; Ng, S.C.; Li, J.; Huang, M.; Zhou, F.; Wang, X.; Shen, B.; Kamm, M.A.; et al. Characteristics of fecal and mucosa-associated microbiota in chinese patients with inflammatory bowel disease. Medicine 2014, 93, e51. [Google Scholar] [CrossRef]
  90. Wang, W.; Jovel, J.; Halloran, B.; Wine, E.; Patterson, J.; Ford, G.; O’Keefe, S.; Meng, B.; Song, D.; Zhang, Y.; et al. Metagenomic analysis of microbiome in colon tissue from subjects with inflammatory bowel diseases reveals interplay of viruses and bacteria. Inflamm. Bowel Dis. 2015, 21, 1419–1427. [Google Scholar] [CrossRef]
  91. Lavelle, A.; Lennon, G.; O’Sullivan, O.; Docherty, N.; Balfe, A.; Maguire, A.; Mulcahy, H.E.; Doherty, G.; O’Donoghue, D.; Hyland, J.; et al. Spatial variation of the colonic microbiota in patients with ulcerative colitis and control volunteers. Gut 2015, 64, 1553–1561. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Chiodini, R.J.; Dowd, S.E.; Chamberlin, W.M.; Galandiuk, S.; Davis, B.; Glassing, A. Microbial population differentials between mucosal and submucosal intestinal tissues in advanced Crohn’s disease of the ileum. PLoS ONE 2015, 10, e0134382. [Google Scholar]
  93. Pérez-Brocal, V.; García-López, R.; Nos, P.; Beltrán, B.; Moret, I.; Moya, A. Metagenomic analysis of Crohn’s disease patients identifies changes in the virome and microbiome related to disease status and therapy, and detects potential interactions and biomarkers. Inflamm. Bowel Dis. 2015, 21, 2515–2532. [Google Scholar] [CrossRef]
  94. Vidal, R.; Ginard, D.; Khorrami, S.; Mora-Ruiz, M.; Munoz, R.; Hermoso, M.; Díaz, S.; Cifuentes, A.; Orfila, A.; Rosselló-Móra, R. Crohn associated microbial communities associated to colonic mucosal biopsies in patients of the western Mediterranean. Syst. Appl. Microbiol. 2015, 38, 442–452. [Google Scholar] [CrossRef]
  95. Norman, J.M.; Handley, S.A.; Baldridge, M.T.; Droit, L.; Catherine, Y.; Keller, B.C.; Kambal, A.; Zhao, G.; Stappenbeck, T.S.; Mcgovern, D.P.B.; et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 2015, 160, 447–460. [Google Scholar] [CrossRef] [Green Version]
  96. Eun, C.S.; Kwak, M.J.; Han, D.S.; Lee, A.R.; Park, D.I.; Yang, S.K.; Kim, Y.S.; Kim, J.F. Does the intestinal microbial community of Korean Crohn’s disease patients differ from that of western patients? BMC Gastroenterol. 2016, 16, 28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Chiodini, R.J.; Dowd, S.E.; Galandiuk, S.; Davis, B.; Glassing, A. The predominant site of bacterial translocation across the intestinal mucosal barrier occurs at the advancing disease margin in Crohn’s disease. Microbiology 2016, 162, 1608–1619. [Google Scholar] [CrossRef]
  98. Rehman, A.; Rausch, P.; Wang, J.; Skieceviciene, J.; Kiudelis, G.; Bhagalia, K.; Amarapurkar, D.; Kupcinskas, L.; Schreiber, S.; Rosenstiel, P.; et al. Geographical patterns of the standing and active human gut microbiome in health and IBD. Gut 2016, 65, 238–248. [Google Scholar] [CrossRef]
  99. Takahashi, K.; Nishida, A.; Fujimoto, T.; Fujii, M.; Shioya, M.; Imaeda, H.; Inatomi, O.; Bamba, S.; Andoh, A.; Sugimoto, M. Reduced Abundance of Butyrate-Producing Bacteria Species in the Fecal Microbial Community in Crohn’s Disease. Digestion 2016, 93, 59–65. [Google Scholar] [CrossRef] [PubMed]
  100. Forbes, J.D.; Van Domselaar, G.; Bernstein, C.N. Microbiome survey of the inflamed and noninflamed gut at different compartments within the gastrointestinal tract of inflammatory bowel disease patients. Inflamm. Bowel Dis. 2016, 22, 817–825. [Google Scholar] [CrossRef] [Green Version]
  101. Liguori, G.; Lamas, B.; Richard, M.L.; Brandi, G.; da Costa, G.; Hoffmann, T.W.; Di Simone, M.P.; Calabrese, C.; Poggioli, G.; Langella, P.; et al. Fungal dysbiosis in mucosa-associated microbiota of Crohn’s disease patients. J. Crohn’s Colitis 2016, 10, 296–305. [Google Scholar] [CrossRef]
  102. Mar, J.S.; Lamere, B.J.; Lin, D.L.; Levan, S.; Nazareth, M.; Mahadevan, U.; Lynch, S.V. Disease severity and immune activity relate to distinct interkingdom gut microbiome states in ethnically distinct ulcerative colitis patients. MBio 2016, 7, e01072-16. [Google Scholar] [CrossRef] [Green Version]
  103. Hoarau, G.; Mukherjee, P.K.; Gower-Rousseau, C.; Hager, C.; Chandra, J.; Retuerto, M.A.; Neut, C.; Vermeire, S.; Clemente, J.; Colombel, J.F.; et al. Bacteriome and mycobiome interactions underscore microbial dysbiosis in familial Crohn’s disease. MBio 2016, 7, e01250-16. [Google Scholar] [CrossRef] [Green Version]
  104. Hedin, C.; Van Der Gast, C.J.; Rogers, G.B.; Cuthbertson, L.; McCartney, S.; Stagg, A.J.; Lindsay, J.O.; Whelan, K. Siblings of patients with Crohn’s disease exhibit a biologically relevant dysbiosis in mucosal microbial metacommunities. Gut 2016, 65, 944–953. [Google Scholar] [CrossRef] [Green Version]
  105. Naftali, T.; Reshef, L.; Kovacs, A.; Porat, R.; Amir, I.; Konikoff, F.M.; Gophna, U. Distinct Microbiotas are Associated with Ileum-Restricted and Colon-Involving Crohn’s Disease. Inflamm. Bowel Dis. 2016, 22, 293–302. [Google Scholar] [CrossRef]
  106. Pedamallu, C.S.; Bhatt, A.S.; Bullman, S.; Fowler, S.; Freeman, S.S.; Durand, J.; Jung, J.; Duke, F.; Manzo, V.; Cai, D.; et al. Metagenomic Characterization of Microbial Communities In Situ Within the Deeper Layers of the Ileum in Crohn’s Disease. Cmgh 2016, 2, 563–566.e5. [Google Scholar] [CrossRef] [Green Version]
  107. Sokol, H.; Leducq, V.; Aschard, H.; Pham, H.P.; Jegou, S.; Landman, C.; Cohen, D.; Liguori, G.; Bourrier, A.; Nion-Larmurier, I.; et al. Fungal microbiota dysbiosis in IBD. Gut 2016, 66, 1039–1048. [Google Scholar] [CrossRef] [Green Version]
  108. Santoru, M.L.; Piras, C.; Murgia, A.; Palmas, V.; Camboni, T.; Liggi, S.; Ibba, I.; Lai, M.A.; Orrù, S.; Blois, S.; et al. Cross sectional evaluation of the gut-microbiome metabolome axis in an Italian cohort of IBD patients. Sci. Rep. 2017, 7, 9523. [Google Scholar] [CrossRef] [PubMed]
  109. Pascal, V.; Pozuelo, M.; Borruel, N.; Casellas, F.; Campos, D.; Santiago, A.; Martinez, X.; Varela, E.; Sarrabayrouse, G.; Machiels, K.; et al. A microbial signature for Crohn’s disease. Gut 2017, 66, 813–822. [Google Scholar] [CrossRef]
  110. Chen, G.; Zhang, Y.; Wang, W.; Ji, X.; Meng, F.; Xu, P.; Yang, N.; Ye, F.; Bo, X. Partners of patients with ulcerative colitis exhibit a biologically relevant dysbiosis in fecal microbial metacommunities. World J. Gastroenterol. 2017, 23, 4624–4631. [Google Scholar] [CrossRef]
  111. Hall, A.B.; Yassour, M.; Sauk, J.; Garner, A.; Jiang, X.; Arthur, T.; Lagoudas, G.K.; Vatanen, T.; Fornelos, N.; Wilson, R.; et al. A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients. Genome Med. 2017, 9, 103. [Google Scholar] [CrossRef]
  112. Qiu, X.; Ma, J.; Jiao, C.; Mao, X.; Zhao, X.; Lu, M.; Wang, K.; Zhang, H. Alterations in the mucosa-associated fungal microbiota in patients with ulcerative colitis. Oncotarget 2017, 8, 107577–107588. [Google Scholar] [CrossRef] [Green Version]
  113. Kennedy, N.A.; Lamb, C.A.; Berry, S.H.; Walker, A.W.; Mansfield, J.; Parkes, M.; Simpkins, R.; Tremelling, M.; Nutland, S.; Parkhill, J.; et al. The impact of NOD2 variants on fecal microbiota in Crohn’s disease and controls without gastrointestinal disease. Inflamm. Bowel Dis. 2018, 24, 583–592. [Google Scholar] [CrossRef] [Green Version]
  114. Ji, Y.; Li, X.; Zhu, Y.; Li, N.; Zhang, N.; Niu, M. Faecal microRNA as a biomarker of the activity and prognosis of inflammatory bowel diseases. Biochem. Biophys. Res. Commun. 2018, 503, 2443–2450. [Google Scholar] [CrossRef]
  115. Imhann, F.; Vila, A.V.; Bonder, M.J.; Fu, J.; Gevers, D.; Visschedijk, M.C.; Spekhorst, L.M.; Alberts, R.; Franke, L.; van Dullemen, H.M.; et al. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut 2018, 67, 108–119. [Google Scholar] [CrossRef]
  116. Nishino, K.; Nishida, A.; Inoue, R.; Kawada, Y.; Ohno, M.; Sakai, S.; Inatomi, O.; Bamba, S.; Sugimoto, M.; Kawahara, M.; et al. Analysis of endoscopic brush samples identified mucosa-associated dysbiosis in inflammatory bowel disease. J. Gastroenterol. 2018, 53, 95–106. [Google Scholar] [CrossRef] [Green Version]
  117. Rojas-feria, M.; Romero-garcía, T.; Caballero-rico, J.Á.F.; Ramírez, H.P.; Avilés-recio, M.; Castro-fernandez, M.; Porcuna, N.C.; Romero-gόmez, M.; García, F.; Grande, L.; et al. Modulation of faecal metagenome in Crohn’ s disease: Role of microRNAs as biomarkers. World J. Gastroenterol. 2018, 24, 5223–5233. [Google Scholar] [CrossRef]
  118. Schirmer, M.; Franzosa, E.A.; Lloyd-Price, J.; Mciver, L.J.; Schwager, R.; Poon, T.W.; Ananthakrishnan, A.N.; Andrews, E.; Barron, G.; Lake, K.; et al. Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat. Microbiol. 2018, 3, 337–346. [Google Scholar] [CrossRef]
  119. Chiodini, R.J.; Dowd, S.E.; Barron, J.N.; Galandiuk, S.; Davis, B.; Glassing, A. Transitional and temporal changes in the mucosal and submucosal intestinal microbiota in advanced crohn’s disease of the terminal ileum. J. Med. Microbiol. 2018, 67, 549–559. [Google Scholar] [CrossRef]
  120. Hirano, A.; Umeno, J.; Okamoto, Y.; Shibata, H.; Ogura, Y.; Moriyama, T.; Torisu, T.; Fujioka, S.; Fuyuno, Y.; Kawarabayasi, Y.; et al. Comparison of the microbial community structure between inflamed and non-inflamed sites in patients with ulcerative colitis. J. Gastroenterol. Hepatol. 2018, 33, 1590–1597. [Google Scholar] [CrossRef]
  121. Ma, H.Q.; Yu, T.T.; Zhao, X.J.; Zhang, Y.; Zhang, H.J. Fecal microbial dysbiosis in Chinese patients with inflammatory bowel disease. World J. Gastroenterol. 2018, 24, 1464–1477. [Google Scholar] [CrossRef] [Green Version]
  122. Walujkar, S.A.; Kumbhare, S.V.; Marathe, N.P.; Patangia, D.V.; Lawate, P.S.; Bharadwaj, R.S.; Shouche, Y.S. Molecular profiling of mucosal tissue associated microbiota in patients manifesting acute exacerbations and remission stage of ulcerative colitis. World J. Microbiol. Biotechnol. 2018, 34, 76. [Google Scholar] [CrossRef]
  123. Moen, A.E.F.; Lindstrøm, J.C.; Tannæs, T.M.; Vatn, S.; Ricanek, P.; Vatn, M.H.; Jahnsen, J.; Frengen, A.B.; Dahl, F.A.; You, P.; et al. The prevalence and transcriptional activity of the mucosal microbiota of ulcerative colitis patients. Sci. Rep. 2018, 8, 17278. [Google Scholar] [CrossRef]
  124. Laserna-Mendieta, E.J.; Clooney, A.G.; Carretero-Gomez, J.F.; Moran, C.; Sheehan, D.; Nolan, J.A.; Hill, C.; Gahan, C.G.M.; Joyce, S.A.; Shanahan, F.; et al. Determinants of reduced genetic capacity for butyrate synthesis by the gut microbiome in Crohn’s disease and ulcerative colitis. J. Crohn’s Colitis 2018, 12, 204–216. [Google Scholar] [CrossRef]
  125. Libertucci, J.; Dutta, U.; Kaur, S.; Jury, J.; Rossi, L.; Fontes, M.E.; Shajib, M.S.; Khan, W.I.; Surette, M.G.; Verdu, E.F.; et al. Inflammation-related differences in mucosa-associated microbiota and intestinal barrier function in colonic Crohn’s disease. Am. J. Physiol. Gastrointest. Liver Physiol. 2018, 315, G420–G431. [Google Scholar] [CrossRef]
  126. Moustafa, A.; Li, W.; Anderson, E.L.; Wong, E.H.M.; Dulai, P.S.; Sandborn, W.J.; Biggs, W.; Yooseph, S.; Jones, M.B.; Venter, J.C.; et al. Genetic risk, dysbiosis, and treatment stratification using host genome and gut microbiome in inflammatory bowel disease. Clin. Transl. Gastroenterol. 2018, 9, e132. [Google Scholar] [CrossRef] [PubMed]
  127. O’Brien, C.L.; Kiely, C.J.; Pavli, P. The microbiome of Crohn’s disease aphthous ulcers. Gut Pathog. 2018, 10, 44. [Google Scholar] [CrossRef] [Green Version]
  128. Zakrzewski, M.; Simms, L.A.; Brown, A.; Appleyard, M.; Irwin, J.; Waddell, N.; Radford-Smith, G.L. IL23R-Protective Coding Variant Promotes Beneficial Bacteria and Diversity in the Ileal Microbiome in Healthy Individuals Without Inflammatory Bowel Disease. J. Crohn’s Colitis 2019, 13, 451–461. [Google Scholar] [CrossRef]
  129. Zuo, T.; Lu, X.J.; Zhang, Y.; Cheung, C.P.; Lam, S.; Zhang, F.; Tang, W.; Ching, J.Y.L.; Zhao, R.; Chan, P.K.S.; et al. Gut mucosal virome alterations in ulcerative colitis. Gut 2019, 68, 1169–1179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  130. Altomare, A.; Putignani, L.; Del Chierico, F.; Cocca, S.; Angeletti, S.; Ciccozzi, M.; Tripiciano, C.; Dalla Piccola, B.; Cicala, M.; Guarino, M.P.L. Gut mucosal-associated microbiota better discloses inflammatory bowel disease differential patterns than faecal microbiota. Dig. Liver Dis. 2019, 51, 648–656. [Google Scholar] [CrossRef]
  131. Franzosa, E.A.; Sirota-madi, A.; Avila-pacheco, J.; Fornelos, N.; Haiser, H.J.; Reinker, S.; Vatanen, T.; Hall, A.B.; Mallick, H.; Mciver, L.J.; et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat. Microbiol. 2019, 4, 293–305. [Google Scholar] [PubMed]
  132. Lloyd-Price, J.; Arze, C.; Ananthakrishnan, A.N.; Schirmer, M.; Avila-Pacheco, J.; Poon, T.W.; Andrews, E.; Ajami, N.J.; Bonham, K.S.; Brislawn, C.J.; et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 2019, 569, 655–662. [Google Scholar] [CrossRef] [PubMed]
  133. Imai, T.; Inoue, R.; Kawada, Y.; Morita, Y.; Inatomi, O.; Nishida, A.; Bamba, S.; Kawahara, M.; Andoh, A. Characterization of fungal dysbiosis in Japanese patients with inflammatory bowel disease. J. Gastroenterol. 2019, 54, 149–159. [Google Scholar] [CrossRef] [PubMed]
  134. Li, E.; Zhang, Y.; Tian, X.; Wang, X.; Gathungu, G.; Wolber, A.; Shiekh, S.S.; Sartor, R.B.; Davidson, N.O.; Ciorba, M.A.; et al. Influence of Crohn’s disease related polymorphisms in innate immune function on ileal microbiome. PLoS ONE 2019, 14, e0213108. [Google Scholar] [CrossRef] [PubMed]
  135. Vester-Andersen, M.K.; Mirsepasi-Lauridsen, H.C.; Prosberg, M.V.; Mortensen, C.O.; Träger, C.; Skovsen, K.; Thorkilgaard, T.; Nøjgaard, C.; Vind, I.; Krogfelt, K.A.; et al. Increased abundance of proteobacteria in aggressive Crohn’s disease seven years after diagnosis. Sci. Rep. 2019, 9, 13473. [Google Scholar] [CrossRef] [Green Version]
  136. Clooney, A.G.; Sutton, T.D.S.; Shkoporov, A.N.; Holohan, R.K.; Daly, K.M.; O’Regan, O.; Ryan, F.J.; Draper, L.A.; Plevy, S.E.; Ross, R.P.; et al. Whole-Virome Analysis Sheds Light on Viral Dark Matter in Inflammatory Bowel Disease. Cell Host Microbe 2019, 26, 764–778.e5. [Google Scholar] [CrossRef]
  137. Braun, T.; Di Segni, A.; Benshoshan, M.; Neuman, S.; Levhar, N.; Bubis, M.; Picard, O.; Sosnovski, K.; Efroni, G.; Farage Barhom, S.; et al. Individualized Dynamics in the Gut Microbiota Precede Crohn’s Disease Flares. Am. J. Gastroenterol. 2019, 114, 1142–1151. [Google Scholar] [CrossRef]
  138. Galazzo, G.; Tedjo, D.I.; Wintjens, D.S.J.; Savelkoul, P.H.M.; Masclee, A.A.M.; Bodelier, A.G.L.; Pierik, M.J.; Jonkers, D.M.A.E.; Penders, J. Faecal Microbiota Dynamics and their Relation to Disease Course in Crohn’s Disease. J. Crohn’s Colitis 2019, 13, 1273–1282. [Google Scholar] [CrossRef] [PubMed]
  139. Sun, M.; Du, B.; Shi, Y.; Lu, Y.; Zhou, Y.; Liu, B. Combined signature of the fecal microbiome and plasma metabolome in patients with ulcerative colitis. Med. Sci. Monit. 2019, 25, 3303–3315. [Google Scholar] [CrossRef]
  140. Yilmaz, B.; Juillerat, P.; Øyås, O.; Ramon, C.; Bravo, F.D.; Franc, Y.; Fournier, N.; Michetti, P.; Mueller, C.; Geuking, M.; et al. Microbial network disturbances in relapsing refractory Crohn’s disease. Nat. Med. 2019, 25, 323–336. [Google Scholar] [CrossRef]
  141. Magro, D.O.; Santos, A.; Guadagnini, D.; de Godoy, F.M.; Silva, S.H.M.; Lemos, W.J.F.; Vitulo, N.; Torriani, S.; Pinheiro, L.V.; Martinez, C.A.R.; et al. Remission in Crohn’s disease is accompanied by alterations in the gut microbiota and mucins production. Sci. Rep. 2019, 9, 53. [Google Scholar] [CrossRef] [Green Version]
  142. Zhang, Y.-L.; Cai, L.-T.; Qi, J.-Y.; Lin, Y.-Z.; Dai, Y.-C.; Jiao, N.; Chen, Y.-L.; Zheng, L.; Wang, B.-B.; Zhu, L.-X.; et al. Gut microbiota contributes to the distinction between two traditional Chinese medicine syndromes of ulcerative colitis. World J. Gastroenterol. 2019, 25, 3108–3282. [Google Scholar] [CrossRef]
  143. Alam, M.T.; Amos, G.C.A.; Murphy, A.R.J.; Murch, S.; Wellington, E.M.H.; Arasaradnam, R.P. Microbial imbalance in inflammatory bowel disease patients at different taxonomic levels. Gut Pathog. 2020, 12, 1. [Google Scholar] [CrossRef] [PubMed]
  144. Ryan, F.J.; Ahern, A.M.; Fitzgerald, R.S.; Laserna-Mendieta, E.J.; Power, E.M.; Clooney, A.G.; O’Donoghue, K.W.; McMurdie, P.J.; Iwai, S.; Crits-Christoph, A.; et al. Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease. Nat. Commun. 2020, 11, 1512. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Butera, A.; Di Paola, M.; Vitali, F.; De Nitto, D.; Covotta, F.; Borrini, F.; Pica, R.; De Filippo, C.; Cavalieri, D.; Giuliani, A.; et al. IL-13 mRNA Tissue Content Identifies Two Subsets of Adult Ulcerative Colitis Patients with Different Clinical and Mucosa-Associated Microbiota Profiles. J. Crohn’s Colitis 2020, 14, 369–380. [Google Scholar] [CrossRef]
  146. Boland, K.; Bedrani, L.; Turpin, W.; Kabakchiev, B.; Stempak, J.; Borowski, K.; Nguyen, G.; Steinhart, A.H.; Smith, M.I.; Croitoru, K.; et al. Persistent Diarrhea in Patients With Crohn’s Disease After Mucosal Healing Is Associated With Lower Diversity of the Intestinal Microbiome and Increased Dysbiosis. Clin. Gastroenterol. Hepatol. 2020, 19, 296–304.e3. [Google Scholar] [CrossRef] [PubMed]
  147. Olaisen, M.; Flatberg, A.; van Beelen Granlund, A.; Røyset, E.S.; Martinsen, T.C.; Sandvik, A.K.; Fossmark, R. Bacterial mucosa-associated microbiome in inflamed and proximal noninflamed ileum of patients with Crohn’s disease. Inflamm. Bowel Dis. 2020, 27, 12–24. [Google Scholar] [CrossRef]
  148. Shahir, N.M.; Wang, J.R.; Wolber, E.A.; Schaner, M.S.; Frank, D.N.; Ir, D.; Robertson, C.E.; Chaumont, N.; Sadiq, T.S.; Koruda, M.J.; et al. Crohn’s Disease Differentially Affects Region-Specific Composition and Aerotolerance Profiles of Mucosally Adherent Bacteria. Inflamm. Bowel Dis. 2020, 26, 1843–1855. [Google Scholar] [CrossRef]
  149. Park, S.; Kim, H.-N.; Choi, C.H.; Im, J.P.; Cha, J.M.; Eun, C.S.; Kim, T.-O.; Kang, S.-B.; Bang, K.B.; Kim, H.G.; et al. Differentially Abundant Bacterial Taxa Associated with Prognostic Variables of Crohn’s Disease: Results from the IMPACT Study. J. Clin. Med. 2020, 9, 1748. [Google Scholar] [CrossRef] [PubMed]
  150. Clooney, A.G.; Eckenberger, J.; Laserna-Mendieta, E.; Sexton, K.A.; Bernstein, M.T.; Vagianos, K.; Sargent, M.; Ryan, F.J.; Moran, C.; Sheehan, D.; et al. Ranking microbiome variance in inflammatory bowel disease: A large longitudinal intercontinental study. Gut 2020, 70, 499–510. [Google Scholar] [CrossRef]
  151. Park, Y.M.; Ha, E.; Gu, K.-N.; Shin, G.Y.; Lee, C.K.; Kim, K.; Kim, H.J. Host Genetic and Gut Microbial Signatures in Familial Inflammatory Bowel Disease. Clin. Transl. Gastroenterol. 2020, 11, e00213. [Google Scholar] [CrossRef]
  152. Lo Sasso, G.; Khachatryan, L.; Kondylis, A.; Battey, J.N.D.; Solovyeva, V.V.; Garanina, E.E.; Kitaeva, K.V.; Ivanov, K.Y. Inflammatory bowel disease—Associated changes in the gut: Focus on Kazan patients. Inflamm. Bowel Dis. 2020, 27, 418–433. [Google Scholar] [CrossRef]
  153. Borren, N.Z.; Plichta, D.; Joshi, A.D.; Bonilla, G.; Sadreyev, R.; Vlamakis, H.; Xavier, R.J.; Ananthakrishnan, A.N. Multi-“-Omics” Profiling in Patients With Quiescent Inflammatory Bowel Disease Identifies Biomarkers Predicting Relapse. Inflamm. Bowel Dis. 2020, 26, 1524–1532. [Google Scholar] [CrossRef]
  154. Rubbens, P.; Props, R.; Kerckhof, F.M.; Boon, N.; Waegeman, W. Cytometric fingerprints of gut microbiota predict Crohn’s disease state. ISME J. 2021, 15, 354–358. [Google Scholar] [CrossRef]
  155. Halfvarson, J.; Brislawn, C.J.; Lamendella, R.; Vázquez-Baeza, Y.; Walters, W.A.; Bramer, L.M.; D’Amato, M.; Bonfiglio, F.; McDonald, D.; Gonzalez, A.; et al. Dynamics of the human gut microbiome in Inflammatory Bowel Disease. Nat. Microbiol. 2017, 2, 17004. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Zhou, Y.; Xu, Z.Z.; He, Y.; Yang, Y.; Liu, L.; Lin, Q.; Nie, Y.; Li, M.; Zhi, F.; Liu, S.; et al. Gut Microbiota Offers Universal Biomarkers across Ethnicity in Inflammatory Bowel Disease Diagnosis and Infliximab Response Prediction. mSystems 2018, 3, e00188-17. [Google Scholar] [CrossRef] [Green Version]
  157. Feng, T.; Wang, L.; Schoeb, T.R.; Elson, C.O.; Cong, Y. Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis. J. Exp. Med. 2010, 207, 1321–1332. [Google Scholar] [CrossRef] [PubMed]
  158. Nagao-Kitamoto, H.; Shreiner, A.B.; Gillilland, M.G.; Kitamoto, S.; Ishii, C.; Hirayama, A.; Kuffa, P.; El-Zaatari, M.; Grasberger, H.; Seekatz, A.M.; et al. Functional Characterization of Inflammatory Bowel Disease-Associated Gut Dysbiosis in Gnotobiotic Mice. Cmgh 2016, 2, 468–481. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  159. Ward, N.L.; Phillips, C.D.; Nguyen, D.D.; Shanmugam, N.K.N.; Song, Y.; Hodin, R.; Shi, H.N.; Cherayil, B.J.; Goldstein, A.M. Antibiotic Treatment Induces Long-lasting Changes in the Fecal Microbiota that Protect Against Colitis. Inflamm. Bowel Dis. 2016, 22, 2328–2340. [Google Scholar] [CrossRef]
  160. Khan, K.J.; Ullman, T.A.; Ford, A.C.; Abreu, M.T.; Abadir, A.; Marshall, J.K.; Talley, N.J.; Moayyedi, P. Antibiotic therapy in inflammatory bowel disease: A systematic review and meta-analysis. Am. J. Gastroenterol. 2011, 106, 661–673. [Google Scholar] [CrossRef]
  161. Donaldson, G.P.; Lee, S.M.; Mazmanian, S.K. Gut biogeography of the bacterial microbiota. Nat. Rev. Microbiol. 2015, 14, 20–32. [Google Scholar] [CrossRef] [Green Version]
  162. Doolittle, W.F.; Booth, A. It’s the song, not the singer: An exploration of holobiosis and evolutionary theory. Biol. Philos. 2017, 32, 5–24. [Google Scholar] [CrossRef]
  163. Mobeen, F.; Sharma, V.; Prakash, T. Enterotype Variations of the Healthy Human Gut Microbiome in Different Geographical Regions. Bioinformation 2018, 14, 560–573. [Google Scholar] [CrossRef] [PubMed]
  164. Bäckhed, F.; Fraser, C.M.; Ringel, Y.; Sanders, M.E.; Sartor, R.B.; Sherman, P.M.; Versalovic, J.; Young, V.; Finlay, B.B. Defining a healthy human gut microbiome: Current concepts, future directions, and clinical applications. Cell Host Microbe 2012, 12, 611–622. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Kleessen, B.; Kroesen, A.J.; Buhr, H.J.; Blaut, M. Mucosal and invading bacteria in patients with inflammatory bowel disease compared with controls. Scand. J. Gastroenterol. 2002, 37, 1034–1041. [Google Scholar] [CrossRef] [PubMed]
  166. Sokol, H.; Seksik, P.; Rigottier-gois, L.; Lay, C.; Lepage, P.; Podglajen, I.; Marteau, P. Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm. Bowel Dis. 2006, 12, 106–111. [Google Scholar] [CrossRef]
  167. Sokol, H.; Pigneur, B.; Watterlot, L.; Lakhdari, O.; Bermúdez-Humarán, L.G.; Gratadoux, J.J.; Blugeon, S.; Bridonneau, C.; Furet, J.P.; Corthier, G.; et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. USA 2008, 105, 16731–16736. [Google Scholar] [CrossRef] [Green Version]
  168. Venegas, D.P.; De La Fuente, M.K.; Landskron, G.; González, M.J.; Quera, R.; Dijkstra, G.; Harmsen, H.J.M.; Faber, K.N.; Hermoso, M.A. Short chain fatty acids (SCFAs) mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front. Immunol. 2019, 10, 277. [Google Scholar] [CrossRef] [Green Version]
  169. Underhill, D.M.; Iliev, I.D. The mycobiota: Interactions between commensal fungi and the host immune system. Nat. Rev. Immunol. 2014, 14, 405–416. [Google Scholar] [CrossRef]
  170. McKenzie, H.; Main, J.; Pennington, C.R.; Parratt, D. Antibody to selected strains of Sacharomyces cerevisiae (baker’s and brewer’s yeast) and Candida albicans in Crohn’s disease. Gut 1990, 31, 536–538. [Google Scholar] [CrossRef] [Green Version]
  171. Qin, J.; Li, R.; Raes, J.; Arumugam, M.; Burgdorf, S.; Manichanh, C.; Nielsen, T.; Pons, N.; Yamada, T.; Mende, D.R.; et al. A human gut microbial gene catalog established by metagenomic sequencing. Nature 2010, 464, 59–65. [Google Scholar] [CrossRef] [Green Version]
  172. Shkoporov, A.N.; Clooney, A.G.; Sutton, T.D.S.; Ryan, F.J.; Daly, K.M.; Nolan, J.A.; McDonnell, S.A.; Khokhlova, E.V.; Draper, L.A.; Forde, A.; et al. The human gut virome is highly diverse, stable, and individual specific. Cell Host Microbe 2019, 26, 527–541.e5. [Google Scholar] [CrossRef]
  173. Dridi, B.; Raoult, D.; Drancourt, M. Archaea as emerging organisms in complex human microbiomes. Anaerobe 2011, 17, 56–63. [Google Scholar] [CrossRef] [PubMed]
  174. Mitsuyama, K.; Niwa, M.; Takedatsu, H.; Yamasaki, H.; Kuwaki, K.; Yoshioka, S.; Yamauchi, R.; Fukunaga, S.; Torimura, T. Antibody markers in the diagnosis of inflammatory bowel disease. World J. Gastroenterol. 2016, 22, 1304–1310. [Google Scholar] [CrossRef] [PubMed]
  175. Gisbert, J.P.; Gomollón, F.; Maté, J.; Pajares, J.M. Papel de los anticuerpos anticitoplasma de los neutrófilos (ANCA) y anti-Saccharomyces cerevisiae (ASCA) en la enfermedad inflamatoria intestinal. Gastroenterol. Hepatol. 2003, 26, 312–324. [Google Scholar] [CrossRef]
  176. Li, Y.; Hauenstein, K. New Imaging Techniques in the Diagnosis of Inflammatory Bowel Diseases. Visz. Gastrointest. Med. Surg. 2015, 31, 227–234. [Google Scholar] [CrossRef] [Green Version]
  177. Lopez, R.N.; Leach, S.T.; Lemberg, D.A.; Duvoisin, G.; Gearry, R.B.; Day, A.S. Fecal biomarkers in inflammatory bowel disease. J. Gastroenterol. Hepatol. 2017, 32, 577–582. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  178. Tedjo, D.I.; Smolinska, A.; Savelkoul, P.H.; Masclee, A.A.; Van Schooten, F.J.; Pierik, M.J.; Penders, J.; Jonkers, D.M.A.E. The fecal microbiota as a biomarker for disease activity in Crohn’s disease. Sci. Rep. 2016, 6, 35216. [Google Scholar] [CrossRef] [Green Version]
Microorganisms 09 00977 g001 550
Figure 1. Gut microbiota disturbance in inflammatory bowel disease compared to healthy individuals. Upward arrow indicates increase and downward arrow decrease.
Figure 1. Gut microbiota disturbance in inflammatory bowel disease compared to healthy individuals. Upward arrow indicates increase and downward arrow decrease.
Microorganisms 09 00977 g001
Table
Table 1. Gut microbiome studies in inflammatory bowel disease using non-next-generation sequencing approaches.
Table 1. Gut microbiome studies in inflammatory bowel disease using non-next-generation sequencing approaches.
ReferenceYearTreatmentNo. of ParticipantsDisease StateSpecimenHistologyDesignMicrobiome Analysis MethodFocusMicrobiota Findings
CDUCIBD/IBDUHC/C
Macfarlane et al. [12]2004Not naïveNA9NA10ActiveBiopsyNACross-sectionalCulture, FISHBacteriaUC
▪
Only differences in bifidobacteria were statistically significant.
▪
Peptostreptococci were only present in UC patients.
Lepage et al. [13]2005Not naïve2011NA4Active/InactiveStool and biopsyNon-inflamedCross-sectionalTTGE (16S rDNA V6–V8 region)BacteriaCD and UC
▪
Dominant species differ between the mucosa-associated and fecal microbiota.
▪
The microbiota is relatively stable along the distal digestive tract.
Manichanh et al. [14]2006Not naïve6NANA6InactiveStoolNACross-sectionalCloning, Sequencing (16S rDNA)BacteriaCD
▪
Reduced Firmicutes diversity.
Bibiloni et al. [15]2006Naïve2015NA14ActiveBiopsyInflamed/non-inflamedCross-sectionalDGGE (16S rDNA V3 region) and qPCRBacteriaCD and UC
▪
Bacteria associated with inflamed and non-inflamed tissues did not differ.
▪
UC had more bacteria associated with biopsies than CD.
▪
Bacteroidetes were more prevalent in CD than in UC.
Sokol et al. [16]2006Not naïveNA9NA9ActiveStoolNACross-sectionalTTGE (16S rDNA V6–V8 region)BacteriaUC
▪
Reduced bacterial diversity.
Gophna et al. [17]2006Not naïve65NA5Active/InactiveBiopsyInflamed/non-inflamedCross-sectionalPCR, cloning, sequencing (16S rDNA)BacteriaCD and UC
▪
No significant difference between inflamed and non-inflamed tissues.
▪
In CD, increased Proteobacteria and Bacteroidetes and reduced Clostridia.
▪
No difference between UC and HC.
Scanlan et al. [18]2006Not naïve16NANA6Active/InactiveStoolNALongitudinalDGGE (16S rDNA)BacteriaCD
▪
Lower temporal bacterial stability but higher stability for remission patients.
▪
Lactic acid bacteria spp. varied significantly between the CD groups.
▪
Decrease in Clostridium and Bacteroides spp.
Zhang et al. [19]2007Not naïveNA24NANAActiveBiopsyInflamed/non-inflamedCross-sectionalDGGE (16S rDNA V3 region)BacteriaUC
▪
Lactobacilli and the Clostridium leptum subgroup were significantly different between the inflamed and non-inflamed tissues. They were also affected by UC location.
Sepehri et al. [20]2007Not naïve1015NA16NABiopsyInflamed/non-inflamedCross-sectionalARISA, T-RFLPBacteriaCD and UC
▪
Differences between inflamed and non-inflamed tissues were found.
▪
The non-inflamed tissues form an intermediate population between HC and inflamed tissue for both CD and UC.
Andoh et al. [21]2007Not naïveNA44NA46Active/InactiveStoolNACross-sectionalT-RFLP (16S rDNA)BacteriaUC
▪
Bacterial communities are different between HC and active UC patients and between active and inactive patients.
▪
Eubacterium, and Fusobacterium were predominantly detected in the active patients.
▪
Lactobacillus were more predominant in the inactive patients.
Frank et al. [22]2007Not naïve6861NA61NAResected tissueInflamed/non-inflamedCross-sectionalPCR, cloning, sequencing (16S rDNA)BacteriaCD and UC
▪
Significant differences between the microbiotas of CD and UC and those of non-IBD controls.
▪
Depletion of members of the phyla Firmicutes and Bacteroidetes.
Ott et al. [23]2008Not naïveNA13NA5Active/InactiveBiopsyNALongitudinalPCR, cloning and sequencingBacteriaUC
▪
Temporal instability and bacterial richness decreased in relapsing patients compared to remission.
Ott et al. [24]2008Not naïve3126NA47ActiveBiopsyInflamedCross-sectionalDGGE, clone libraries, sequencing, in situ hybridization (18S rDNA)FungiCD
▪
Increased fungal richness and diversity in CD.
Martinez et al. [25]2008Not naïveNA16NA8InactiveStoolNALongitudinalDGGE (16S rDNA V6–V8 region)BacteriaUC
▪
Temporal instability and reduced diversity in remission patients.
Dicksved et al. [26]2008Not naïve14NANA6Active/InactiveStoolNACross-sectionalT-RFLP, cloning and sequencing (16S rDNA)BacteriaCD
▪
Decreased bacterial diversity.
▪
Decreased Bacteroides uniformis and increased B. ovatus and B. vulgatus.
▪
Ileal CD bacterial communities were significantly different from HC and colonic CD.
Kuehbacher et al. [27]2008Not naïve4231NA33ActiveBiopsyInflamedCross-sectionalClone libraries, sequencing and in situ hybridization (16S rDNA)BacteriaCD and UC
▪
TM7 (subgroup of Gram-positive uncultivable bacteria) were more diverse in CD than in UC and non-IBD controls.
Andoh et al. [28]2008Not naïve34NANA30Active/InactiveStoolNACross-sectionalT-RFLP (16S rDNA)BacteriaCD
▪
Decrease in Clostridium cluster IV, Clostridium cluster XI and subcluster XIVa.
▪
Increase in Bacteroides and Enterobacteriales.
Nishikawa et al. [29]2009Not naïve9NANA11Active/InactiveBiopsyInflamed/non-inflamedLongitudinalT-RFLP (16S rDNA)BacteriaUC
▪
Decreased diversity due to loss of commensals.
▪
Decreased diversity in inactive patients compared to active patients.
Willing et al. [30]2009Not naïve14NANA6Active/InactiveBiopsyInflamed/non-inflamedCross-sectionalT-RFLP, cloning and sequencing, qPCR (16S rDNA)BacteriaCD
▪
Ileal CD had a lower abundance of Faecalibacterium prausnitzii and an increased abundance of Escherichia coli compared to healthy co- twins and colonic CD.
▪
Dysbiosis was significantly correlated to the disease phenotype.
Andoh et al. [31]2009Not naïveNA2NA3UrInactiveStoolNACross-sectionalT-RFLP (16S rDNA)BacteriaUC
▪
Increase in Clostridium cluster IX and decreases in Clostridium cluster XIVa.
Gillevet et al. [32]2010Not naïve42NA4NAStool and biopsyNACross-sectionalLH- PCR, cloning, sequencing, and multitagged pyrosequencing (16S rDNA)BacteriaCD and UC
▪
Mucosal microbiome is distinct from the luminal microbiome in HC.
▪
Mucosal microbiome appears to be dysbiotic in IBD.
Rehman et al. [33]2010Not naïve1010NA10ActiveBiopsyInflamedCross-sectionalPCR, cloning, sequencing (16S rDNA)BacteriaCD and UC
▪
Increase in Escherichia sp.
Kang et al. [34]2010Not naïve6NANA6InactiveStoolNACross-sectionalMicroarray (16S rDNA)BacteriaCD.
▪
Decreased Eubacterium rec- tale, B. fragilis group, B. vulgatus, Ruminococcus albus, R. callidus, R. bromii, and F. prausnitzii.
▪
Increased Enterococcus sp., Clostridium difficile, E. coli, Shigella flexneri, and Listeria sp.
Rowan et al. [35]2010Not naïveNA20NA19Active/InactiveBiopsyNACross-sectionalPCR, qPCR (16S rDNA)BacteriaUC
▪
Increase in Desulfovibrio, more marked in acute phase.
Andoh et al. [36]2011Not naïve3131NA30Active/InactiveStoolNACross-sectionalT-RFLP (16S rDNA V4–V9)BacteriaCD and UC.
▪
Decrease in the Clostridium family in active UC and inactive/active CD.
▪
Increase in Bacteroides.
▪
Inactive UC tended to be closer to that of HC.
Mondot et al. [37]2011Not naïve16NANA16ActiveStoolNACross-sectionalqPCR, RT qPCR (16S rDNA)BacteriaCD
▪
Decrease in F. prausnitzii Ruminococcus bromii, Oscillibacter valericigenes, Bifidobacterium bifidum, and E. rectale.
▪
Increase in E. coli and Enterococcus faecium.
▪
More marked increase in E. coli in ileal CD.
Joossens et al. [38]2011Not naïve68NANA84 Ur + 55InactiveStoolNACross-sectionalDGGE (16S rDNA V3), qPCRBacteriaCD
▪
Decrease in Dialister invisus species of Clostridium cluster XIVa, F. prausnitzii and Bifidobacterium adolescentis.
▪
Increase in R. gnavus.
Lepage et al. [39]2011Not naïveNA8NA54ActiveBiopsyNACross-sectionalPCR, cloning, sequencing (16S rDNA)BacteriaUC.
▪
Decreased bacterial diversity.
▪
Increase in Actinobacteria and Proteobacteria.
▪
Healthy siblings from discordant twins had more bacteria from the Lachnospiraceae and Ruminococcaceae families than twins who were both healthy.
Benjamin et al. [40]2012Not naïve103NANA66ActiveStoolNACross-sectionalFISH (16S rDNA)BacteriaCD
▪
Increase in Bacteroides-Prevotella in smokers (38.4%) compared with nonsmokers (28.1%).
▪
Increase in bifidobacterial and Bacteroides-Prevotella.
▪
Decrease in F. prausnitzii.
Hotte et al. [41]2012Not naïve1514NA21InactiveBiopsyNon-inflamedCross-sectionalT-RFLP (16S rDNA)BacteriaCD and UC
▪
Increase in Proteobacteria compared with HC and UC.
Pistone et al. [42]2012Not naïve3518NA35NABiopsyInflamed/non-inflamedCross-sectionalPCRMycobacterium avium subspecies paratuberculosisCD and UC
▪
Increase in M. avium subspecies paratuberculosis compared to controls.
Andoh et al. [43]2012Not naïve67NANA121Active/InactiveStoolNALongitudinalT-RFLP (16S rDNA V1–V9)BacteriaCD
▪
Decrease in Clostridia in active disease and remission and in Bifidobacterium in active phase but increased during remission.
▪
Increase in Bacteroides genus in active.
▪
Decreased bacterial diversity.
Li et al. [44]2012Not naïve18NANA9ActiveStool and biopsyInflamed/non-inflamedCross-sectionalDGGE (16S rDNA V3 region), sequencingBacteriaCD
▪
Decreased bacterial diversity.
▪
Increase in γ-Proteobacteria (especially E. coli and S. flexneri).
▪
Decrease in reduced Bacteroidetes and Firmicutes.
▪
In ulcerated mucosa, E. coli was increased and F. prausnitzii, Lactobacillus coleohominis, Bacteroides sp and Streptococcus gallolyticus were decreased compared with the non-ulceated.
Nemoto et al. [45]2012Not naïveNA48NA36Active/InactiveStoolNACross-sectionalCulture, T-RFLP, qPCRBacteriaUC
▪
Decreased bacterial diversity.
▪
Decrease in Bacteroides and Clostridium subcluster XIVab.
▪
Increase in Enterococcus.
Vigsnæs et al. [46]2012Not naïveNA12NA6Active/InactiveStoolNACross-sectionalDGGE (16S rDNA, 16S-23S rDNA intergenic spacer region), qPCRBacteriaUC.
▪
Different microbiota in active UC compared to HC but in inactive UC compared to HC.
▪
Decrease in Lactobacillus spp. and Akkermansia muciniphila in active disease.
de Souza et al. [47]2012Not naïve117NA14NAStool and biopsyInflamed/non-inflamedCross-sectionalCultureE. coliCD and UC
▪
Only the mucosa-associated population of E. coli was increased, not in stool. The increase was prominent in the ileal CD and rectum and sigmoid of both UC and CD.
Duboc et al. [48]2013Not naïve1230NA26Active/InactiveStoolNACross-sectionalPCR (rDNA), cultureBacteriaCD and UC
▪
Decrease in the ratio between F. prausntizii and E. coli
Sha et al. [49]2013Not naïve1026NA14Active/InactiveStoolNACross-sectionalDGGE (16S rDNA V6–V8 region), qPCRBacteriaCD and UC.
▪
Decrease in the numbers of Bacteroides–Porphyromonas–Prevotella, Bifidobacterium and B. fragilis in active phase.
▪
Decrease in Helicobacter and Clostridium phylogenetic clusters XI and XIVa in active and inactive phases.
▪
Increase in E. coli in active phases.
Kabeerdoss et al. [50]2013Not naïve2022NA17Active/InactiveStoolNACross-sectionalTTGE (16S rDNA V1–V9), qPCRC. leptum group, F. prausnitziiCD and UC
▪
Decrease in C. leptum group bacteria and F. prausnitzii.
▪
Decreased bacterial diversity.
Varela et al. [51]2013Not naïveNA116NA29 Ur + 31InactiveStoolNACross-sectional and longitudinalPCR (16S rDNA), qPCRF. prausnitziiUC
▪
Decrease in F. prausnitzii in patients and relatives.
▪
Recovery of the F. prausnitzii population after relapse was associated with remission.
Midtvedt et al. [52]2013Not naïve4NANA5ActiveStool and biopsyInflamedCross-sectionalMicroarrayBacteriaCD
▪
Decrease in Bacteroides in both stool and biopsies.
Fujimoto et al. [53]2013Not naïve47NANA20Active/InactiveStoolNACross-sectionalqPCR, PCR (16S rDNA V4–V9), T-RFLPF. prausnitzii and Bilophila wadsworthiaCD
▪
Decrease in Clostridia, including the genus Faecalibacterium.
▪
Decreased bacterial diversity.
Fite et al. [54]2013Not naïveNA33NA18ActiveBiopsyInflamedLongitudinalqPCRBacteriaUC
▪
High clinical activity indices were associated with enterobacteria, desulfovibrios, type E Clostridium perfringens, and Enterococcus faecalis.
▪
Low clinical activity indices were associated with Clostridium butyricum, R. albus, Lactobacillus, bifidobacterium and E. rectale.
Rajilic-Stojanovic et al. [55]2013Not naïveNA15NA15InactiveStoolNALongitudinalMicroarrayBacteriaUC
▪
Decrease in members of the Clostridium cluster IV R. bromii et rel. E. rectale et rel., Roseburia sp., and Akkermansia sp.
▪
Increase in Fusobacterium sp., Peptostreptococcus sp., Helicobacter sp., Campylobacter sp. and C. difficile.
Kumari et al. [56]2013Not naïveNA26NA14Active/InactiveStoolNACross-sectionalFISH, flow cytometry, qPCR (16S rDNA)BacteriaUC
▪
Decrease in C. coccoides and C. leptum clusters.
▪
F. prausnitzii and Roseburia intestinalis were differentially present in patients with different disease activity.
Hedin et al. [57]2014Not naïve22NANA25 + 21UrInactiveStoolNACross-sectionalqPCR (16S rDNA)BacteriaCD
▪
Siblings shared dysbiosis pattern with patients (lower concentrations of F. prausnitzii, Clostridia cluster IV and Roseburia spp.).
Lennon et al. [58]2014Not naïveNA19NA34ActiveBiopsyNACross-sectionalqPCR (16S rDNA)Desulfovibrio speciesUC
▪
No significant differences in Desulfovibrio sp. were found between cohorts or at each sampling region between the cohorts.
Machiels et al. [59]2014Not naïveNA127NA447Active/InactiveStoolNACross-sectionalPCR (16S rDNA V3 region) DGGE, sequencing, qPCRBacteriaUC
▪
Decrease in Roseburia hominis and F. prausnitzii.
▪
R. hominis and F. prausnitzii showed an inverse correlation with disease activity.
Wang et al. [60]2014Not naïve2134NA21Active/InactiveStool and biopsyInflamed/non-inflamedCross-sectionalqPCR (16S rDNA)BacteriaCD and UC
▪
Bifidobacterium was increased in biopsies of active UC patients, and higher in the biopsies than in the fecal samples in active CD patients.
▪
Lactobacillus group was s increased in biopsies of active CD patients.
▪
F. prausnitzii was decreased in both the fecal and biopsy specimens of the active patients.
Blais Lecours et al. [61]2014Not naïve1811NA29Active/InactiveStoolNACross-sectionalqPCRArchaea and bacteriaCD and UC
▪
Increase in Methanosphaera stadtmanae.
Fukuda et al. [62]2014Not naïveNA69NA80UrActive/InactiveStoolNACross-sectionalPCR (16S rDNA, V4–V9 region), T-RFLPBacteriaUC
▪
Development of a Discriminant Score based on selected OTUs.
▪
Five differential clusters were obtained indicating a strong association between the gut microbiota and UC *.
Li et al. [63]2014Not naïve19NANA7ActiveStool and biopsyInflamed/non-inflamedCross-sectionalDGGE (18S rDNA), cloning, sequencingFungiCD
▪
Increase in fungal richness and diversity in the inflamed mucosa compared with the non-inflamed mucosa.
▪
Increase in Candida spp., Gibberella moniliformis, Alternaria brassicicola, and Cryptococcus neoformans.
▪
In stool, increase in fungal diversity and prevalence in Candida albicans, Aspergillus clavatus, and C. neoformans.
Andoh et al. [64]2014Not naïve160NANA121Active/InactiveStoolNALongitudinalT-RFLP (16S rDNA V1–V9)BacteriaCD
▪
Decision tree based on selected OTUs, obtaining 9 groups.
▪
Microbiota profiles may differ according to disease activity.
Wisittipanit et al. [65]2015Not naïve10189NA235Active/InactiveBiopsy and lumen aspirationNACross-sectionalLH-PCR (16S rDNA V1–V2 region)Bacteria
  • ▪ Development of a computational pipeline to characterise the gut microbial communities.
  • ▪ Model could classify IBD from HC at specific locations and based on disease state *.
Kabeerdoss et al. [66]2015Naïve and not naïve2832NA30NABiopsyInflamed/non-inflamedCross-sectionalRT-qPCR (16S rDNA)BacteriaCD and UC
▪
Increase in Bacteroides and Lactobacillus in UC patients compared with controls or CD.
▪
Increase in E. coli in UC compared with controls.
▪
Decrease in C. coccoides group and C. leptum group in CD compared with controls.
▪
Decrease in Firmicutes to Bacteroidetes ratio in UC and CD.
▪
No differences between inflamed and non-inflamed tissues were found, nor between treated and untreated patients.
Takeshita et al. [67]2016Not naïveNA48NA34Active/InactiveStoolNACross-sectionalRT-qPCRBacteriaUC
▪
Decrease bacterial diversity in active phase.
▪
Fusicatenibacter saccharivorans was decreased in active patients and increased in quiescent.
Zhang et al. [68]2017Not naïve132NANA71Active/InactiveStoolNACross-sectionalCultureBacteriaCD
▪
Increase in E. coli and Enterococcus sp. in active phase compared with inactive and controls.
Vrakas et al. [69]2017Naïve and not naïve1220NA20Active/InactiveBiopsyInflamedCross-sectionalRT-qPCR (16S rDNA)BacteriaCD and UC
▪
Increased total bacterial DNA concentration levels in active phase compared to the inactive.
▪
Increase in Bacteroides spp. in active and inactive phases.
▪
Decrease in C. leptum group (IV), and F. prausnitzi in active and inactive phases.
Zamani et al. [70]2017Not naïveNA35NA60ActiveBiopsyInflamedCross-sectionalCulture, qPCRBacteriaUC
▪
No association between B. fragilis and UC.
▪
Enterotoxigenic B. fragilis was more prevalent in UC patients with diarrhea.
Ghavami et al. [71]2018Not naïve945NA47Active/InactiveStoolNACross-sectionalPCR, qPCR (16S rDNA)Bacteria and Methanobrevibacter smithii (Archaea)CD and UC
▪
Decrease in Methanobrevibacter smithii.
▪
More marked increase in Mbb. smithii in remission than in active phase.
Le Baut et al. [72]2018Not naïve262NANA76NAResected tissue and biopsyInflamed/non-inflamedCross-sectionalPCRYersinia SpeciesCD
▪
Increase in Yersinia species.
Al-Bayati et al. [73]2018Not naïveNA40NA40NABiopsyInflamedCross-sectionalCulture, PCR (16S rDNA)BacteriaUC
▪
Decrease in F. prausnitzii, Prevotella, and Peptostreptococcus productus.
Heidarian et al. [74]2019Not naïve722NA29Active/InactiveStoolNACross-sectionalqPCRBacteriaCD and UC
▪
Decrease in Bacteroides, F. prausnitzii, Prevotella spp., and Methanobrevibacterium.
▪
Decrease in Bacteroides spp., F. prausnitzii, and Prevotella spp. in UC patients with disease activity score greater than 4.
▪
Increase in Streptococcus and Haemophilus in the patients who were at flare.
Vatn et al. [75]2020Naïve and not naïve688412160Active/InactiveStoolNACross-sectionalGA-map™ (16S rDNA V3–V9 region)BacteriaCD and UC
▪
Decrease in Firmicutes and Eubacterium hallii.
▪
Increase in Bifidobacterium spp., E. hallii, Actinobacteria and Firmicutes in ulcerative proctitis, compared to extensive colitis.
▪
No association with disease location in CD.
Abbreviations: CD, Crohn’s disease; UC, ulcerative colitis; IBD, inflammatory bowel disease; IBDU, inflammatory bowel disease unclassified; HC, healthy control; C, control; NA, not applicable; FISH, fluorescence in situ hybridization; TTGE, temporal temperature gradient gel electrophoresis; DGGE, denaturing gradient gel electrophoresis; qPCR, quantitative real-time polymerase chain reaction; ARISA, automated ribosomal intergenic spacer analysis; T-RFLP, terminal restriction fragment length polymorphism; Ur, unaffected relatives; LH-PCR, length heterogeneity polymerase chain reaction; OTUs, operational taxonomic unit. * No microorganisms specified.
Table
Table 2. Gut microbiome studies in inflammatory bowel disease using next-generation sequencing approaches.
Table 2. Gut microbiome studies in inflammatory bowel disease using next-generation sequencing approaches.
ReferenceYearTreatmentNo. of ParticipantsDisease StateSpecimenHistologyDesignMicrobiome Analysis MethodFocusMicrobiota Findings
CDUCIBD/IBDUHC/C
Willing et al. [76]2010Not naïve2916NA35Active/InactiveStool and biopsyNon-inflamedCross-sectional16S rDNA sequencingBacteriaCD and UC
▪
Ileal CD differed from colonic CD.
▪
In ileal CD, decrease in Faecalibacterium and Roseburia, and increase in Enterobacteriaceae and Ruminococcus gnavus.
Rausch et al. [77]2011Not naïve29NANA18InactiveBiopsyNon-inflamedCross-sectional16S rDNA V1–V2 region sequencingBacteriaCD
▪
Decrease in bacterial diversity.
▪
Prevotella, Lactobacillus, Coprobacillus, Clostridium, Faecalibacterium, and Stenotrophomonas were only present in HC.
Walker et al. [78]2011Not naïve66NA5ActiveBiopsyInflamed/non-inflamedCross-sectional16S rDNA V1–V8 region sequencingBacteriaCD and UC
▪
Decrease in bacterial diversity.
▪
Decrease in Firmicutes and increase in Bacteroidetes, and in CD only, Enterobacteriaceae.
▪
Differences between inflamed and non-inflamed tissues were found.
Erickson et al. [79]2012Not naïve8NANA4Active/InactiveStoolNACross-sectional16S rDNA V1–V2 region and WGSBacteriaCD
▪
Decrease in bacterial diversity.
▪
Decrease in Firmicutes in ileal CD.
Morgan et al. [80]2012Not naïve12175827Active/InactiveStool and biopsyNACross-sectional16S rDNA V3–V5 region and WGSBacteriaCD and UC
▪
Disease status influenced Firmicutes and Enterobacteriaceae abundances.
Ricanek et al. [81]2012Naïve4NANA1ActiveBiopsyInflamedCross-sectional16S rDNA sequencingBacteriaCD
▪
Microbiota of Norwegian CD patients was found to be similar to that of CD patients in other countries.
Li et al. [82]2012Not naïve5258NA60NABiopsyNon-inflamedCross-sectional16S rDNA V1–V3 and V3–V5 regions sequencing and qPCRBacteriaCD and UC
▪
Decrease in C. coccoides-E. rectales group in ileal CD compared to control non-IBD.
▪
Decrease in F. prausnitzii in CD.
Tong et al. [83]2013Not naïve1616NA32InactiveMucosal lavageNon-inflamedCross-sectional16S rDNA V4 region sequencingBacteriaCD and UC
▪
Decrease in Firmicutes and increase in Proteobacteria and Actinobacteria.
▪
Decrease in microbial diversity
Thorkildsen et al. [84]2013Naïve3033334ActiveStoolNACross-sectional16S rDNA (all regions) sequencingBacteriaCD and UC
▪
Increase in Escherichia/Shigella in CD.
▪
Decrease in Faecalibacterium in CD compared to both UC and controls.
Prideaux et al. [85]2013Not naïve2230NA29 +6Ur (CD)NABiopsyInflamed/non-inflamedCross-sectionalMicroarray, 16S rDNA V1–V3 region sequencingBacteriaCD and UC
▪
Decrease in microbial diversity and in Faecalibacterium, Coprococcus, Dorea, Roseburia, and 2 unclassified gener (from Lachnospiraceae and Clostridiales) in CD.
▪
In UC, diversity was reduced in Chinese subjects.
▪
Actinobacteria was significantly different between the UC groups.
▪
Decrease in Coprococcus and Dorea genera in UC.
Chiodini et al. [86]2013Not naïve14NANA6NAResected tissueNACross-sectional16S rDNA V3–V6 region sequencingBacteriaCD
▪
Separation of the submucosal and mucosal microbiome and existence of a submucosal bacterial population within diseased tissues.
Pérez-Brocal et al. [87]2013Naïve and not naïve11NANA8NAStoolNACross-sectionalViral DNA and 16S rDNA V1–V3 region sequencingBacteria and virusesCD
▪
Decreased bacterial and viral diversity.
▪
Synechococcus phage S CBS1 and Retroviridae family viruses were more represented in CD.
▪
Increase in Proteobacteria and decrease in Tenericutes, the order Bacteroidales and Collinsella aerofaciens.
Davenport et al. [88]2014Not naïve1314NA27NABiopsyInflamedCross-sectional16S rDNA V4 region sequencingBacteriaCD and UC
▪
Decreased bacterial diversity.
▪
No phylum-level significant differences in Firmicutes or Proteobacteria
▪
Bacteroidetes were only increased in CD.
Chen et al. [89]2014Not naïve2641NA21Active/InactiveStool and biopsyInflamed/non-inflamedCross-sectional16S rDNA V1–V3 region sequencingBacteriaCD and UC
▪
Decrease in Roseburia, Coprococcus, and Ruminococcus.
▪
Increase in Escherichia-Shigella and Enterococcus.
▪
Fecal- and mucosa-associated microbiota were similar between CD and UC and differed from HC.
Wang et al. [90]2015Not naïve64NA5NABiopsyNACross-sectionalRNA sequencingBacteria and virusesCD and UC
▪
Increase in bradyrhizobiaceae, enterobacteriaceae, comamonadaceae, and moraxellaceae families.
▪
Human adenovirus and Herpesviridae sequences were predominant in IBD.
Lavelle et al. [91]2015Not naïveNA9NA4NALuminal brush, mucosal biopsy, mucus gel layerInflamed/non-inflamedCross-sectional16S rDNA V4 region sequencingBacteriaUC
▪
Spatial variation between the luminal and mucosal communities in both cohorts.
▪
Decrease in Bacteroidaceae and Akkermanseaceae.
▪
Increase in Clostridiaceae, Peptostreptococcaceae, Enterobacteriaceae, Ruminococcaceae, Bifidobacteriaceae, Actinomycetaceae and FJ440089, an uncultured member of the Prevotellaceae family.
Chiodini et al. [92]2015Not naïve20NANA15NABiopsyInflamedCross-sectional16S rDNA V4 region sequencingBacteriaCD
▪
Distinct sub- mucosal microbiome compared to mucosa and/or fecal material.
▪
Desulfovibrionales were present within the submucosal tissues.
▪
Increase in Firmicutes in the subjacent submucosa as compared to the parallel mucosal tissue.
▪
Increase in Propionibac- terium spp., Cloacibacterium spp., Parasutterella spp. and Methylobacterium spp.
Pérez-Brocal et al. [93]2015Naïve and not naïve20NANA20ActiveStool and biopsyInflamed/non-inflamedCross-sectional16S rDNA V1–V3 region and viral DNA/RNA sequencingBacteria and virusesCD
▪
Decrease bacterial diversity in all CD groups.
▪
Increased richness and diversity were observed in feces compared with biopsies.
▪
Increase in Actinobacteria, Gammaproteobacteria, and Fusobacteria.
Vidal et al. [94]2015Not naïve13NANA7Active/InactiveBiopsyNon-inflamedCross-sectional16S rDNA V1–V5 region sequencingBacteriaCD
▪
Decrease in Clostridia and increase in Bacteroidetes and Proteobacteria.
▪
No detection of F. prausnitzii.
Norman et al. [95]2015Not naïve1842NA12Active/InactiveStoolNACross-sectionalVLP DNA sequencingVirusesCD and UC
▪
Increase in Caudovirales bacteriophages.
▪
It did not appear that expansion and diversification of the enteric virome was secondary to changes in the microbiota.
Eun et al. [96]2016Not naïve35NANA15InactiveStool and biopsyNACross-sectional16S rDNA V1–V3 region sequencingBacteriaCD
▪
Decrease in bacterial diversity.
▪
Increase in Proteobacteria was increased in both fecal and mucosal tissues, and Fusobacteria only in tissue samples.
▪
Increase in Gammaproteobacteria and Fusobacteria in both fecal and mucosal tissue samples in active phase.
Chiodini et al. [97]2016Not naïve20NANA15NABiopsyInflamedCross-sectional16S rDNA V1–V3 region sequencingBacteriaCD
▪
Increase in Sphingomonadaceae, Alicyclobacillaceae, Methylobacteriaceae, Pseudomonadaceae and Prevotellaceae in the submucosa at the advancing disease margin when compared to the superjacent mucosa (translocation).
Rehman et al. [98]2016Not naïve2830NA30InactiveBiopsyNACross-sectional16S rDNA V1–V2 region sequencingBacteriaCD and UC
▪
Proteobacteria decrease in UC compared with CD and HC.
▪
Different microbial pattern based on geographical origin.
Takahashi et al. [99]2016Not naïve68NANA10Active/InactiveStoolNACross-sectionalqPCR and 16S rDNA V3–V4 region sequencingBacteriaCD
▪
Decrease in Bacteroides, Eubacterium, Faecalibacterium and Ruminococcus.
▪
Increase in Actinomyces and Bifidobacterium.
Forbes et al. [100]2016Not naïve1521NA7NABiopsyInflamed/non-inflamedCross-sectional16S rDNA V6 region sequencingBacteriaCD and UC
▪
No difference between inflamed and non-inflamed tissues were found. There were only differences between the inflamed and non-inflamed mucosa between CD and UC.
▪
Increase in Bacteroidetes and Fusobacteria in inflamed CD mucosa than in inflamed UC mucosa.
▪
Proteobacteria and Firmicutes were more frequently in the inflamed UC mucosa.
Liguori et al. [101]2016Not naïve23NANA10Active/InactiveBiopsyInflamed/non-inflamedCross-sectionalqPCR (16S or 18S rDNA) 16S rDNA V3–V4 region and ITS2 sequencingBacteria and fungiCD and UC
▪
Decrease in bacterial diversity.
▪
Increase in Proteobacteria and Fusobacteria.
▪
Increase in fungal load in active phase. Cystofilobasidiaceae family and Candida glabrata species were overrepresented.
Mar et al. [102]2016Not naïveNA30NA13NAStoolNACross-sectional16S rDNA V3–V4 region and ITS2 sequencingBacteria and fungiUC
▪
Decrease in bacterial diversity.
▪
Decrease in Bacteroides and Prevotella species and Alternaria alternata, Aspergillus flavus, Aspergillus cibarius, and Candida sojae.
▪
Increase in Streptococcus, Bifidobacterium, and Enterococcus and Candida albicans and Debaryomyces.
Hoarau et al. [103]2016Not naïve20NANA21 + 28UrActive/InactiveStoolNACross-sectional16S rDNA V4 region and ITS1 sequencingBacteria and fungiCD
▪
Increase in Serratia marcescens and E. coli, and Candida tropicalis.
Hedin et al. [104]2016Not naïve21NANA19+17UrInactiveBiopsyNACross-sectional16S rDNA V1–V3 region sequencingBacteriaCD
▪
Decrease in bacterial diversity.
▪
Decrease in F. prausnitzii.
Naftali et al. [105]2016Not naïve31NANA5Active/InactiveBiopsyInflamedCross-sectional16S rDNA V1–V3 region sequencingBacteriaCD
▪
Difference between ileal CD compared with colonic CD. This separation was unaffected by the biopsy’s location, its inflammatory state or disease state.
▪
Faecalibacterium was strongly reduced in ileal CD compared with colonic CD, whereas Enterobacteriaceae were more abundant in the former.
Pedamallu et al. [106]2016Not naïve12NANA12NAResected tissueNACross-sectionalWGSBacteriaCD
▪
Decrease in Bacteroidetes and Clostridia.
▪
Enrichment of enterotoxigenic Staphylococcus aureus and an environmental Mycobacterium species within deeper layers of the ileum.
Sokol et al. [107]2016Not naïve14986NA38Active/InactiveStoolNACross-sectional16S rDNA V3–V5 region and ITS2 sequencingBacteria and fungiCD and UC
▪
Increase in Basidiomycota/Ascomycota ratio and C. albicans.
▪
Decrease in Saccharomyces cerevisiae.
▪
Correlations between bacterial and fungal components.
Santoru et al. [108]2017Not naïve5082NA51Active/InactiveStoolNACross-sectional16S rDNA V3–V4 region sequencing, qPCRBacteriaCD and UC
▪
Increase in Firmicutes, Proteobacteria, Verrucomicrobia, and Fusobacteria.
▪
Decrease in Bacteroidetes and Cyanobacteria.
Pascal et al. [109]2017Not naïve3433NA40 + 71UrActive/InactiveStoolNALongitudinal16S rDNA V4 region sequencingBacteriaCD and UC
▪
Dysbiosis was greater in CD than UC, as shown by a more reduced diversity, a less stable microbial community.
Chen et al. [110]2017Not naïveNA8NA8NAStoolNACross-sectional16S rDNA V3–V4 region sequencingBacteriaUC
▪
Decrease in Firmicutes, (Blautia, Clostridium, Coprococcus and Roseburia).
▪
Decreased bacterial diversity.
Hall et al. [111]2017Not naïve910112Active/InactiveStoolNALongitudinalWGSBacteriaCD and UC
▪
Increase in facultative anaerobes.
▪
Increase in R. gnavus, often co-occurring with increased disease activity.
Qiu et al. [112]2017Not naïveNA14NA15ActiveBiopsyInflamedCross-sectional18S rDNA sequencingFungiUC
▪
Increase in Wickerhamomyces, unidentified genus of Saccharomycetales, Aspergillus, Sterigmatomyces, and Candida.
▪
Decrease in Exophiala, Alternaria, Emericella, Epicoccum, Acremonium, Trametes, and Penicillium.
Kennedy et al. [113]2018Not naïve37NANA54InactiveStoolNACross-sectional16S rDNA V1–V2 region sequencingBacteriaCD
▪
Decrease in bacterial diversity.
▪
Decrease in Ruminococcaceae, Rikenellaceae, and Christensenellaceae.
▪
Increase in Enterobacteriaceae.
Ji et al. [114]2018Not naïve5166NA66Active/InactiveStoolNACross-sectional16S rDNA V4 region sequencingBacteriaCD and UC
▪
Results were different between HC and IBD patients and between active and inactive patients.
Imhann et al. [115]2018Not naïve18810718582Active/InactiveStoolNACross-sectional16S rDNA V4 region sequencingBacteriaCD and UC
▪
Colonic CD was different from that of patients with ileal CD, with a decrease in alpha diversity associated with ileal CD.
▪
Decrease in the genus Roseburia was associated with higher IBD risk score.
Nishino et al. [116]2018Not naïve2643NA14Active/InactiveMucosal brushNon-inflamedCross-sectional16S rDNA V3–V4 region sequencingBacteriaCD and UC
▪
No significant difference among anatomical sites within individuals.
▪
Increase in Proteobacteria and decrease in Firmicutes and Bacteroidetes in CD.
▪
Greater abundance of Escherichia, Ruminococcus (R. gnavus), Clostridium, Cetobacterium, Peptostreptococcus in CD, and the Faecalibacterium, Blautia, Bifidobacterium, Roseburia and Citrobacter in UC.
Rojas-Feria et al. [117]2018Naïve13NANA16OnsetStoolNACross-sectional16S rDNA V1–V3 region sequencingBacteriaCD
▪
Decrease in bacterial diversity.
▪
Decrease in Firmicutes and an increase in Bacteroidetes.
Schirmer et al. [118]2018Naïve and not naïve3021NA11Active/InactiveStoolNALongitudinalWGSBacteriaCD and UC
▪
Decrease in bacterial diversity.
▪
Decrease in Firmicutes and increase in Enterobacteriaceae.
▪
Longitudinal profiles showed taxonomic shifts in community composition over time that coincided with changes in disease severity.
Chiodini et al. [119] 2018Not naïve20NANA15NAResected tissueInflamedCross-sectional16S rDNA V1–V3 region sequencingBacteriaCD
▪
Increase in bacterial richness.
▪
Bacterial translocation, with two bacterial families (Comamonadaceae and Xanthomonadaceae), having penetrated the mucosal surfaces.
Hirano et al. [120]2018Not naïveNA14NA14ActiveBiopsyInflamed/non-inflamedCross-sectional16S rDNA V4 region sequencingBacteriaUC
▪
Decrease in bacterial diversity.
▪
Increase in Cloacibacterium and the Tissierellaceae and decrease in Neisseria in inflamed site when compared to the non-inflamed site.
Ma et al. [121]2018Not naïve1514NA13Active/InactiveStoolNACross-sectional16S rDNA V4 region sequencingBacteriaCD and UC
▪
Increase in Proteobacteria.
▪
Decrease in Bacteroidetes in the active CD compared to inactive CD.
▪
Bacteroidetes showed a negative correlation with the CD activity index scores.
Walujkar et al. [122]2018Not naïveNA12NA7ActiveBiopsyInflamedLongitudinal16S rDNA V4 region sequencingBacteriaUC
▪
Increase in bacterial count in active UC.
▪
Increase in Stenotrophomonas, Parabacteroides, Elizabethkingia, Pseudomonas, Micrococcus, Ochrobactrum and Achromobacter in active UC.
Moen et al. [123]2018NaïveNA44NA35OnsetBiopsyInflamed/non-inflamedCross-sectional16S rDNA V4 region sequencingBacteriaUC
▪
No difference in bacterial diversity.
▪
Proteobacteria were higher in the inflamed tissue compared with the non-inflamed.
Laserna-Mendieta et al. [124]2018Not naïve7158NA75Active/InactiveStoolNACross-sectional16S rDNA V3–V4 region sequencingBacteriaCD and UC
▪
Decreased bacterial diversity.
▪
Decrease in Clostridium cluster IV, Roseburia, and F. prausnitzii only in CD.
Libertucci et al. [125]2018Not naïve43NANA10Active/InactiveBiopsyInflamed/non-inflamedCross-sectional16S rDNA V3 region and ITS2 sequencingBacteria and fungiCD
▪
Increase in Escherichia and a decrease in Firmicutes in inflamed tissue.
▪
Bacterial diversity did not correlate with inflammation.
Moustafa et al. [126]2018Not naïve4541NA146Active/InactiveStoolNACross-sectionalWGSBacteriaCD and UC
▪
Decreased bacterial diversity.
▪
Increase in Proteobacteria and decrease in Bacteroidetes and Firmicutes.
O’Brien et al. [127]2018Not naïve24NANA17NABiopsyInflamed/non-inflamedCross-sectional16S rDNA V1–V3 region sequencingBacteriaCD
▪
No bacterial imbalance or reduced diversity in CD aphthous ulcers and adjacent mucosa, relative to control biopsies.
Zakrzewski et al. [128]2019Not naïve15NANA58ActiveBiopsyInflamed/non-inflamedCross-sectional16S rDNA V3–V4 region sequencingBacteria
  • ▪ Decrease in bacterial diversity and richness.
  • ▪ Decrease in F. prausnitzii.
Zuo et al. [129]2019Not naïveNA91NA76Active/InactiveBiopsyInflamed/non-inflamedCross-sectionalVLP and 16S rDNA sequencingVirusesUC
▪
Increase in Caudovirales bacteriophages, but decrease in mucosa Caudovirales diversity, richness and evenness.
▪
Virome correlated with intestinal inflammation.
▪
Increase in Escherichia phage and Enterobacteria phage.
Altomare et al. [130]2019Not naïve104NA11Active/InactiveStool and biopsyInflamed/non-inflamedCross-sectional16S rDNA V1–V3 region sequencingBacteriaCD and UC
▪
Fecal microbiota was more similar to controls than mucosal microbiota.
▪
In the colon district some specific bacterial biomarkers were identified: Enterobacteriaceae for IBD stools, Bacteroides for IBD biopsies.
Franzosa et al. [131]2019Not naïve6853NA34Active/InactiveStoolNACross-sectionalWGSBacteriaCD and UC
▪
Decreased bacterial diversity.
▪
Decrease in Firmicutes and increase in Proteobacteria.
▪
Disease localization did not have a significant effect among CD subjects.
Lloyd-Price et al. [132]2019Not naïve6738NA27Active/InactiveStool and biopsyNALongitudinal16S rDNA sequencing and WGSBacteria and virusesCD and UC
▪
Increase in facultative anaerobes at the expense of obligate anaerobes.
▪
Periods of disease activity were marked by increases in temporal taxonomic variability.
Imai et al. [133]2019Not naïve2018NA20InactiveStoolNACross-sectional16S rDNA V3–V4 region and ITS sequencingBacteria and fungiCD and UC
▪
Decrease in bacterial diversity in CD compared to HC and UC.
▪
No difference in fungal diversity.
▪
Increase in Candida in CD compared to HC and UC.
Li et al. [134]2019Not naïve106NA8889NAResected tissueInflamed/non-inflamedLongitudinal16S rDNA V3–V5 region sequencing, qPCRBacteriaCD
▪
Proteobacteria was positively associated with ileal CD and more marked in non-inflamed tissue.
Vester-Andersen et al. [135]2019Not naïve5882NA30Active/InactiveStoolNACross-sectional16S rDNA V3–V4 region sequencingBacteriaCD and UC
▪
Decrease in richness, diversity and Firmicutes in active and in aggressive CD.
▪
Increase in Proteobacteria in CD.
Clooney et al. [136]2019Not naïve2782NA61Active/InactiveStoolNALongitudinalWhole-virome analysis and 16S rDNA V3–V4 region sequencingBacteria and virusesCD and UC
▪
No changes in viral richness.
▪
Increase in Caudovirales.
▪
Changes in virome reflected alterations bacteriome.
Braun et al. [137]2019Not naïve45NANA22InactiveStoolNALongitudinal16S rDNA V4 region sequencingBacteriaCD
▪
Decrease in bacterial diversity.
▪
Inactive patients preceding flare showed a decrease in Christensenellaceae and S24.7, and increase in Gemellaceae compared with those in remission.
Galazzo et al. [138]2019Not naïve57NANA15Active/InactiveStoolNALongitudinal16S rDNA V4 region sequencingBacteriaCD
▪
Decrease in bacterial diversity and richness.
▪
Microbial community structure was less stable over time.
Sun et al. [139]2019Not naïveNA58NA30Active/InactiveStoolNACross-sectional16S rDNA V3–V4 region sequencingBacteriaUC
▪
Decreased bacterial diversity.
▪
Firmicutes and Bacteroidetes, were the most abundant active UC and inactive UC, respectively.
▪
Increase in Proteobacteria and Fusobacteria and decrease in Firmicutes and Bacteroidetes in active UC.
Yilmaz et al. [140]2019Not naïve270232NA573Active/InactiveBiopsyInflamed/non-inflamedLongitudinal16S rDNA V5–V6 region sequencingBacteriaCD and UC
▪
Decrease in diversity in CD compared with UC and HC.
▪
Firmicutes were higher than Bacteroidetes in UC compared with CD.
Magro et al. [141]2019Not naïve18NANA18InactiveStoolNACross-sectional16S rDNA V3–V4 region sequencingBacteriaUC
▪
Decrease in bacterial diversity.
▪
Increase in Proteobacteria and decrease in the Deltaproteobacteria, Akkermansia, Oscillospira and Saccharomyces cerevisiae.
Zhang et al. [142]2019Not naïveNA63NA30Active/InactiveStoolNACross-sectional16S rDNA V4 region sequencingBacteriaUC
▪
Decrease in Porphyromonadaceae, Rikeneliaceae, and Lachnospiraceae and increase in Enterococcus and Streptococcus.
Alam et al. [143]2020Not naïve911NA10NAStoolNACross-sectional16S rDNA V1–V3 region sequencingBacteriaCD and UC
▪
Decrease in bacterial diversity.
▪
Increase in Firmicutes Prevotellaceae and decrease Bacteroidetes in UC.
▪
Increase in Prevotellaceae and decrease in Bacteroidetes in CD.
Ryan et al. [144]2020Not naïve8050NA31Active/InactiveBiopsyInflamed/non-inflamedCross-sectional16S rDNA V3–V4 region sequencingBacteriaCD and UC
▪
Difference in inflamed and non-inflamed colonic segments in both CD and UC.
▪
Inflammatory status did not appear to affect diversity.
Butera et al. [145]2020No naïveNA88NA24ActiveBiopsyInflamed/non-inflamedCross-sectional16S rDNA V3–V4 region sequencingBacteriaUC
▪
High IL-13mRNA patients are younger at diagnosis and show higher prevalence of extensive colitis than low IL-13mRNA patients.
▪
Increase in Prevotella in patients with high IL-13mRNA tissue content and Sutterella and Acidaminococcus in patients with low IL-13mRNA tissue content.
Boland et al. [146]2020No naïve101991548Active/InactiveBiopsyNACross-sectional16S rDNA V4 region sequencingBacteriaCD and UC
▪
CD mucosal biopsy who achieved mucosal healing had lower diversity than biopsies from patients with UC or HC.
▪
Diversity was differently related to mucosal healing in CD and UC.
Olaisen et al. [147]2020No naïve51NANA40Active/InactiveBiopsyInflamed/non-inflamedCross-sectional16S rDNA V3–V4 region sequencingBacteriaCD
▪
Decreased bacterial diversity.
▪
Overrepresentation of Tyzzerella 4.
▪
No difference in diversity in inflamed and non-inflamed ileal mucosa.
Shahir et al. [148]2020No naïve125NANA23NABiopsyInflamed/non-inflamedCross-sectional16S rDNA V1–V2 region sequencingBacteriaCD
▪
Decreased bacterial diversity. Distinct profile in colon and ileum.
▪
Increase in obligate anaerobes in the ileum, B. fragilis was dramatically increased.
Park et al. [149]2020No naïve370NANA740Active/InactiveStoolNALongitudinal16S rDNA V3–V4 region sequencingBacteriaCD
▪
Diversity was more decreased in patients with worse prognosis.
▪
E. coli might be causally involved in CD progression.
Clooney et al. [150]2020No naïve303228NA161Active/InactiveStoolNALongitudinal16S rDNA V3–V4 region sequencingBacteriaCD and UC
▪
Decrease in bacterial diversity but increase in variability.
▪
Reduced temporal microbiota stability, particularly in patients with changes in disease activity.
Park et al. [151]2020No naïve106NA9UrInactiveStoolNACross-sectional16S rDNA V3–V4 region sequencingBacteriaCD and UC
▪
Decrease in bacterial diversity.
▪
Different diversity and identification of differentially abundant taxa in affected IBD relatives.
Lo Sasso et al. [152]2020No naïve4143NA42ActiveStoolNACross-sectional16S rDNA V4 region and WGSBacteriaCD and UC
▪
Increase in Proteobacteria, Actinobacteria, and Fusobacteria
▪
Decrease in Firmicutes, Bacteroidetes, and Verrucomicrobia.
Borren et al. [153]2020No naïve10856NANAInactiveStoolNALongitudinalWGSBacteriaCD and UC
▪
Increase in Proteobacteria and Fusobacteria and, at the species level, Lachnospiraceae_ bacterium_2_1_58FAA in relapse.
▪
Potential microbial biomarker to identify proinflammatory state in quiescent IBD that predisposes to clinical relapse.
Rubbens et al. [154]2020No naïve29NANA66InactiveStoolNACross-sectionalFlow cytometry and 16S rDNA sequencingBacteriaCD
▪
Decrease in bacterial diversity.
▪
Potential of flow cytometry to perform rapid diagnostics of microbiome profile.
Abbreviations: CD, Crohn’s disease; UC, ulcerative colitis; IBD, inflammatory bowel disease; IBDU, inflammatory bowel disease unclassified; HC, healthy control; C, control; NA, not applicable; Ur, unaffected relatives; WGS, whole-genome shotgun sequencing; qPCR, quantitative real-time polymerase chain reaction; VLP, virus-like particle; ITS, internal transcribed spacer.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Aldars-García, L.; Chaparro, M.; Gisbert, J.P. Systematic Review: The Gut Microbiome and Its Potential Clinical Application in Inflammatory Bowel Disease. Microorganisms 2021, 9, 977. https://doi.org/10.3390/microorganisms9050977

AMA Style

Aldars-García L, Chaparro M, Gisbert JP. Systematic Review: The Gut Microbiome and Its Potential Clinical Application in Inflammatory Bowel Disease. Microorganisms. 2021; 9(5):977. https://doi.org/10.3390/microorganisms9050977

Chicago/Turabian Style

Aldars-García, Laila, María Chaparro, and Javier P. Gisbert. 2021. "Systematic Review: The Gut Microbiome and Its Potential Clinical Application in Inflammatory Bowel Disease" Microorganisms 9, no. 5: 977. https://doi.org/10.3390/microorganisms9050977

APA Style

Aldars-García, L., Chaparro, M., & Gisbert, J. P. (2021). Systematic Review: The Gut Microbiome and Its Potential Clinical Application in Inflammatory Bowel Disease. Microorganisms, 9(5), 977. https://doi.org/10.3390/microorganisms9050977

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop