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Gut Microbiome Stability in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (20 February 2026) | Viewed by 8231

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Prof. Dr. Tomomi Kuwahara

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Guest Editor

Department of Molecular Microbiology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
Interests: gut microbiome
Special Issues, Collections and Topics in MDPI journals

Dr. Yoshitohi Ogura

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Guest Editor

Division of Microbiology, Department of Infectious Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
Interests: gut microbiota; metagenomic; metabolomic; gut microbiomes

Special Issue Information

Dear Colleagues,

Omics analysis, represented by metagenomics or metabolomics in the gut microbiome, has been accumulating evidence for its close association with human health. Gut microbial instability affects intestinal permeability and the immune response, predisposing hosts to certain types of disease, such as obesity and inflammatory bowel diseases. Along with the pathological changes in gut microbiome composition, defined as dysbiosis, being extensively studied, the molecular basis that establishes gut microbiome stability at various stages of human life (infant to elderly) is a future avenue for addressing how host–microbe and microbe–microbe interactions keep the homeostasis of the gut. Novel insights into the molecular mechanisms causing gut microbiome stability provide valuable information with which to develop new strategies for preventing the diseases induced by gut microbiome dysbiosis.

This Special Issue will highlight recent advances in the research on the molecular mechanisms establishing gut microbiome stability. We welcome original research papers, reviews, short communications, and discussion papers that address the molecular mechanisms of gut microbiome stability from unique approaches and various points of view.

Prof. Dr. Tomomi Kuwahara
Dr. Yoshitohi Ogura
Guest Editors

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Keywords

gut microbiome stability
immune system
epithelial cell
mucous layer
antibiotics
diet
inflammatory bowel disease
gut microbial metabolites

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Published Papers (5 papers)

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Research

19 pages, 1617 KB

Open AccessArticle

Gut Microbiome Signatures Distinguish Susceptibility from Disease Development in Type 2 Diabetes

by Chen Ifrach, Ruth Levy-Turgeman, Amir Szitenberg, Inbar Kesten, Milena Pitashny, Nomy Levin-Iaina, Yael Segev and Yoram Yagil

Int. J. Mol. Sci. 2026, 27(7), 3160; https://doi.org/10.3390/ijms27073160 - 31 Mar 2026

Viewed by 433

Abstract

Individuals may be prone or resistant to the development of type 2 diabetes. The basis for susceptibility is in part genetic, but environmental factors are likely to come into play. The gut microbiome stands at the interface of genetics and the host microenvironment. Its role in mediating susceptibility to diabetes, however, has not been resolved. Here we investigated whether the gut microbial composition contributes to susceptibility to diabetes, as distinct from disease development. We hypothesized that distinct microbial signatures modulate sensitivity or resistance to a diabetogenic diet (DD) and that separate signatures are linked to disease development. To test this hypothesis, we studied the Cohen diabetic rat model, comprising a diabetes-sensitive strain (CDs/y) and a diabetes-resistant strain (CDr/y). When exposed to DD, diabetes develops in CDs/y but not in CDr/y rats; on a regular diet (RD), both strains remain metabolically normal. To establish the contribution of the gut microbiome to susceptibility, we studied the fecal microbial composition in young, metabolically healthy CDs/y and CDr/y rats, using 16S rRNA gene sequencing, measures of α- and β-diversity, and differential taxonomic abundance. We found distinct, strain-specific gut microbiota profiles that differentiated diabetes-sensitive from -resistant animals, indicating an association between microbial composition and susceptibility. To test causality, we co-housed sensitive and resistant animals to allow passive microbial cross-transfer and fed the animals with DD. Co-housing led to partial convergence of microbial communities and significantly attenuated the diabetic phenotype in CDs/y rats, supporting a contributory and causal role for the gut microbiome in modulating sensitivity to diabetes. The resistance phenotype, on the other hand, remained unchanged. To distinguish between the contribution of the gut microbiome to susceptibility to diabetes as opposed to the development of the disease, we studied the gut microbial profiles across strains after feeding with DD or RD and the development of diabetes in CDs/y but not in CDr/y. We found distinct taxonomic signatures that differentiated diabetic from non-diabetic animals. These findings demonstrate that the gut microbiome contributes to susceptibility to diabetes with separate pathways from those linked to the development of diabetes and may represent an important modifiable determinant of diabetes risk and a target for early intervention. Full article

(This article belongs to the Special Issue Gut Microbiome Stability in Health and Disease)

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21 pages, 3189 KB

Open AccessArticle

Gut Microbiota-Derived Propionic Acid Mediates ApoA-I-Induced Amelioration of MASLD via Activation of GPR43–Ca²⁺–CAMKII–ATGL Hepatic Lipolysis

by Mengyuan Liu, Yutong Wang and Haixia Huang

Int. J. Mol. Sci. 2026, 27(1), 468; https://doi.org/10.3390/ijms27010468 - 1 Jan 2026

Cited by 1 | Viewed by 988

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread hepatic condition characterised by hepatic lipid accumulation and inflammation. Emerging research highlights the contribution of the intestinal microbiota and its metabolic byproducts to the pathogenesis of MASLD through the gut–liver axis. Apolipoprotein A-I (apoA-I), the principal structural component of high-density lipoprotein (HDL), is linked to various metabolic disorders; however, its function in MASLD has not yet been clearly elucidated. This study sought to examine whether apoA-I protects against MASLD, with a focus on the possible role of the gut microbiota and propionic acid (PPA). The contribution of the gut microbiota was evaluated using faecal microbiota transplantation (FMT) and antibiotic cocktail (ABX)-mediated depletion. Microbial composition was assessed via 16S rRNA sequencing, and concentrations of short-chain fatty acids (SCFAs) were quantified. The effects of PPA on MASLD were examined using in vivo and in vitro models. The results showed that apoA-I overexpression alleviated MASLD in a gut microbiota-dependent manner, restored microbial homeostasis, and elevated PPA levels. PPA supplementation improved MASLD phenotypes. Mechanistically, PPA treatment was associated with the activation of the GPR43–Ca²⁺–CAMKII–ATGL pathway, suggesting that PPA plays a role in stimulating hepatic lipolysis and enhancing mitochondrial β-oxidation. These findings reveal a novel pathway through which apoA-I ameliorates MASLD by modulating the gut microbiota and increasing PPA levels, which activate a hepatic lipolysis cascade. The apoA-I–microbiota–PPA axis represents a promising therapeutic target for MASLD intervention. Full article

(This article belongs to the Special Issue Gut Microbiome Stability in Health and Disease)

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19 pages, 3434 KB

Open AccessArticle

Reactivity of Autologous Serum IgG to Gut Microbes in Pediatric Ulcerative Colitis

by Nafisa Tabassum, Haruyuki Nakayama-Imaohji, Emmanuel Munyeshyaka, Ayano Tada, Takeo Kondo, Sonoko Kondo, Takashi Kusaka and Tomomi Kuwahara

Int. J. Mol. Sci. 2025, 26(17), 8196; https://doi.org/10.3390/ijms26178196 - 23 Aug 2025

Cited by 1 | Viewed by 1439

Abstract

Ulcerative colitis (UC) is caused by an excessive immune response to gut microbiota. A recent study reported that the population of IgG-coated gut microbes increases with disease severity in patients with UC, but the role of these IgG-coated microbes in UC pathology is unclear. Serum, feces and colonoscopic lavage fluids (CLFs) were collected from pediatric UC (n = 13) and non-inflammatory bowel disease (IBD) patients (n = 15). Gut microbes were isolated from feces. Serum IgG reactivity to microbial cells and CLF-derived proteins was evaluated by Western blotting. Complement activation by the bacteria–IgG complexes was also assessed. Serum IgG reactivity to gut microbial extracts was highly variable in patients with active UC and increased with mucosal inflammation. IgG reactivity and clinical condition were inversely associated depending on disease activity. Non-IBD patients showed a similar degree of serum IgG response as that seen for patients whose UC was in remission. Lactobacillaceae bound higher amounts of IgG than other gut microbes tested and absorbed IgG to other bacteria. Lacticaseibacillus paracasei suppressed complement activation by Escherichia coli—IgG immune complexes. Appropriate IgG responses to luminal microbes might play a key role in gut microbiota stability by reducing excessive mucosal inflammation. Full article

(This article belongs to the Special Issue Gut Microbiome Stability in Health and Disease)

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24 pages, 8766 KB

Open AccessArticle

Perilla frutescens Seed Residue Extract Restores Gut Microbial Balance and Enhances Insulin Function in High-Fat Diet and Streptozotocin-Induced Diabetic Rats

by Pattharaphong Deethai, Chatsiri Siriwathanakul, Pornsiri Pitchakarn, Arisa Imsumran, Ariyaphong Wongnoppavich, Sivamoke Dissook and Teera Chewonarin

Int. J. Mol. Sci. 2025, 26(17), 8176; https://doi.org/10.3390/ijms26178176 - 22 Aug 2025

Cited by 3 | Viewed by 2648

Abstract

The seed residue of Perilla frutescens possesses diverse biological properties and is rich in bioactive phytochemicals, including luteolin, rosmarinic acid, and apigenin. The aim of this study was to investigate the anti-diabetic effects of perilla seed residue crude extract (PCE) and its impact on the composition of the gut microbiome in rats with diabetes induced by a high-fat diet (HFD) and streptozotocin (STZ). Forty male Wistar rats were fed on an HFD for six weeks before receiving an injection of STZ injection to induce diabetes. These rats were then treated for four weeks with metformin (100 mg/kg bw) or PCE (100 and 1000 mg/kg bw) alongside a control group maintained on a normal diet. The results showed that PCE treatment improved metabolic parameters in diabetic rats, as evidenced by reduced water and food intake, increased body weight gain, lower blood glucose levels, and enhanced insulin secretion effects, especially at the 100 mg/kg bw dosage. PCE also promoted the regeneration of pancreatic β-cells and improved utilization of glucose. PCE also suppressed inflammation and oxidative stress, enhanced antioxidant capacity, and reduced circulating triglyceride levels. Most notably, PCE administration increased gut microbial diversity and shifted the microbiome closer to that of healthy controls, demonstrating its prebiotic effect. It promoted the abundance of beneficial bacteria that are linked to improved glucose metabolism and reduced inflammation—specifically, Bacteroides fragilis, Lactobacillus, Clostridium, and Akkermansia. Harmful bacteria associated with inflammation and poor glycemic control were reduced. Collectively, these results suggest that PCE not only helps restore a balanced gut microbiome but also offers metabolic benefits that could improve diabetic outcomes. These findings position PCE as a promising supplement for the management of diabetes and encourage further exploration of the mechanisms associated with its actions. Full article

(This article belongs to the Special Issue Gut Microbiome Stability in Health and Disease)

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12 pages, 272 KB

Open AccessArticle

Identification of Non-Invasive Diagnostic Markers for Oral Squamous Cell Carcinoma Through Salivary Microbiome and Gene Expression Analysis

by Mitsuhiro Hishida, Kosuke Nomoto, Kengo Hashimoto, Sei Ueda and Shuji Nomoto

Int. J. Mol. Sci. 2025, 26(16), 8104; https://doi.org/10.3390/ijms26168104 - 21 Aug 2025

Viewed by 1816

Abstract

Oral squamous cell carcinoma (OSCC) is a malignancy with a poor prognosis, and early diagnosis is essential for improving patient survival and quality of life. This study aimed to develop a non-invasive screening method based on salivary gene expression and microbiome analysis. Unstimulated saliva samples were collected from patients with OSCC, patients with oral potentially malignant disorders, and healthy controls. Microbiome profiling was performed using 16S ribosomal RNA gene sequencing. The OSCC group showed a significant increase in Fusobacterium and Bacteroidetes and a decrease in Streptococcus. LEfSe analysis indicated microbial changes associated with disease progression. Receiver operating characteristic analysis demonstrated high diagnostic accuracy when multiple bacterial species were combined. An increase in Fusobacteria was also associated with a higher risk of recurrence. Gene expression analysis revealed that NUS1, RCN1, CPLANE1, and CCL20 were significantly upregulated in OSCC, as confirmed by qRT-PCR and tissue expression data. Notably, CCL20 expression positively correlated with Fusobacterium abundance. These findings suggest that integrated analysis of the salivary microbiome and gene expression may offer a useful non-invasive approach for early OSCC detection and disease monitoring. Furthermore, we integrated current evidence from the literature to provide a comprehensive overview. Full article

(This article belongs to the Special Issue Gut Microbiome Stability in Health and Disease)

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