Next Article in Journal
Evaluation of Left Atrial Electromechanical Delay and Left Atrial Phasic Functions in Patients Undergoing Treatment with Cardiotoxic Chemotherapeutic Agents
Previous Article in Journal
Increased Dose in Spine Stereotactic Radiosurgery for Metastatic Disease: Are We Underestimating the Risks?
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Medicina
Volume 60
Issue 9
10.3390/medicina60091515
medicina-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 thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Insights into the Two Most Common Cancers of Primitive Gut-Derived Structures and Their Microbial Connections

by
Amitabha Ray
1,*,
Thomas F. Moore
2,
Dayalu S. L. Naik
3 and
Daniel M. Borsch
4
1
School of Health Professions, D’Youville University, 320 Porter Ave, Buffalo, NY 14201, USA
2
College of Health Sciences, Glenville State University, Glenville, WV 26351, USA
3
ICMR National Institute of Traditional Medicine, Belagavi 590010, India
4
Lake Erie College of Osteopathic Medicine at Seton Hill, Greensburg, PA 15601, USA
*
Author to whom correspondence should be addressed.
Medicina 2024, 60(9), 1515; https://doi.org/10.3390/medicina60091515
Submission received: 5 August 2024 / Revised: 11 September 2024 / Accepted: 14 September 2024 / Published: 18 September 2024
(This article belongs to the Section Oncology)
Browse Figures
Versions Notes

Abstract

:
The gastrointestinal and respiratory systems are closely linked in different ways, including from the embryological, anatomical, cellular, and physiological angles. The highest number (and various types) of microorganisms live in the large intestine/colon, and constitute the normal microbiota in healthy people. Adverse alterations of the microbiota or dysbiosis can lead to chronic inflammation. If this detrimental condition persists, a sequence of pathological events can occur, such as inflammatory bowel disease, dysplasia or premalignant changes, and finally, cancer. One of the most commonly identified bacteria in both inflammatory bowel disease and colon cancer is Escherichia coli. On the other hand, patients with inflammatory bowel disease are at risk of several other diseases—both intestinal (such as malnutrition and intestinal obstruction, besides cancer) and extraintestinal (such as arthritis, bronchiectasis, and cancer risk). Cancers of the lung and colon are the two most common malignancies occurring worldwide (except for female breast cancer). Like the bacterial role in colon cancer, many studies have shown a link between chronic Chlamydia pneumoniae infection and lung cancer. However, in colon cancer, genotoxic colibactin-producing E. coli belonging to the B2 phylogroup may promote tumorigenesis. Furthermore, E. coli is believed to play an important role in the dissemination of cancer cells from the primary colonic site. Currently, seven enteric pathogenic E. coli subtypes have been described. Conversely, three Chlamydiae can cause infections in humans (C. trachomatis may increase the risk of cervical and ovarian cancers). Nonetheless, striking genomic plasticity and genetic modifications allow E. coli to constantly adjust to the surrounding environment. Consequently, E. coli becomes resistant to antibiotics and difficult to manage. To solve this problem, scientists are thinking of utilizing suitable lytic bacteriophages (viruses that infect and kill bacteria). Several bacteriophages of E. coli and Chlamydia species are being evaluated for this purpose.

1. Introduction

The gastrointestinal and respiratory systems are closely connected anatomically and physiologically. Our respiratory system develops about the third week of embryonic life, when an outgrowth appears from the ventral wall of the primitive foregut. The endodermal cells of the foregut invade the surrounding mesenchyme and sequentially form the trachea, bronchial tree, and lobules [1]. Therefore, one can observe many similarities and cooperation between the respiratory and gastrointestinal systems. Apart from the pharynx, which belongs to both systems, other essential functions include the maintenance of cellular metabolism and survival by the constant supply of oxygen and nutrients, participation in the elimination of waste products such as carbon dioxide and undigested food materials, and support in the immune response. Of note, the gut-associated lymphatic tissue (GALT), including Peyer’s patches of the ileum, as well as the bronchus-associated lymphatic tissue (BALT) and other lymphatic tissue of the respiratory system, are located in the lamina propria and submucosa, in both diffuse and nodular forms. Histologically, a sizable portion of both gastrointestinal and respiratory tracts are lined by columnar cells and mucous-secreting cells/Goblet cells. Interestingly, a small proportion of the cell population (less than 1%) are neuroendocrine cells, such as small granule cells (Kulchitsky cells) of the respiratory system and enteroendocrine cells of the gastrointestinal system, which are present individually all over the gastrointestinal epithelium and in accumulations in the pancreatic islets of Langerhans [2]. Neoplastic transformation of these cells could release hormonal substances and result in distinct clinical syndromes.
The majority of neuroendocrine neoplasms originate from the gastrointestinal (~70%) and respiratory (~20%) systems; hence, these neoplasms from the two sites account for roughly 90% of all neuroendocrine neoplasms, which overall represent about 0.5% of all malignancies [3,4]. However, aggressive malignancies are more common in the respiratory system [4]. Among pulmonary neuroendocrine neoplasms, small-cell lung carcinoma accounts for approximately 15% of lung primary cancers [5]. Like the association between cigarette smoking and small-cell lung carcinoma, recent reports have shown a connection between gastrointestinal neuroendocrine neoplasms and inflammatory bowel disease [6,7,8,9].
Inflammatory bowel disease, which primarily refers to ulcerative colitis and Crohn’s disease, is a chronic inflammatory disorder of idiopathic origin. Many investigators have reported that patients with inflammatory bowel disease are at risk of the development of malignancies in several sites—both intestinal and extraintestinal, e.g., the colon (colorectal), oral cavity, breast, uterine cervix, skin, and lung [10,11,12,13]. It is worth mentioning that in inflammatory bowel disease, other non-cancerous extraintestinal manifestations may include respiratory tract involvement, such as bronchiectasis, chronic bronchitis, and interstitial pneumonia [14]. Nevertheless, it is believed that inflammatory bowel disease has a link to a number of pathological factors—for instance, genetic susceptibility, environmental elements, abnormal immune response, and alterations in intestinal microbiota (dysbiosis). From this perspective, researchers have categorized several suspected bacterial species, including Clostridium difficile, Mycobacterium avium paratuberculosis, Escherichia coli, Klebsiella pneumoniae, Campylobacter spp., and Chlamydia spp. [15,16].
The prevalence of inflammatory bowel disease is increasing worldwide, particularly in newly industrialized nations [10]. Similarly, an increasing incidence rate is observed globally for another condition, i.e., proctitis/proctocolitis due to lymphogranuloma venereum, which may mimic inflammatory bowel disease [17,18,19]. Lymphogranuloma venereum, caused by Chlamydia trachomatis, is a sexually transmitted disease, and relevant proctocolitis is diagnosed specifically in homosexual patients. In a study in Switzerland, the investigators analyzed inflamed biopsy specimens from patients with Crohn’s disease (n = 39) and ulcerative colitis (n = 13) [20]. In Crohn’s disease-inflamed tissue specimens, significantly more Chlamydia pneumoniae DNA was detected compared with specimens from unaffected areas. A study from New Zealand identified C. pneumoniae DNA from 21.4% of biopsy specimens from Crohn’s disease (9/42), 15.3% of biopsies from ulcerative colitis (9/59), and 11.4% of biopsies from subjects without inflammatory bowel disease (control, 14/122) [21]. Interestingly, Chlamydiae in humans and many animals colonize the gastrointestinal tract, which could be a reservoir for reinfection [22,23].
As mentioned earlier, inflammatory bowel disease is linked to several pathophysiological events, e.g., dietary factors, the compromise of gut mucus tissue integrity, and host immune responses, as well as alterations in microbial diversity and their metabolites [24,25] (Table 1 [26,27,28,29,30,31,32,33]). Among the pathogenic bacteria in this dysbiosis–inflammation–dysplasia–carcinogenesis process, E. coli perhaps plays an important role [24,34]. A recent report, which analyzed E. coli genomes from patients with Crohn’s disease, ulcerative colitis, a pouch (caused by ileoanal anastomosis in ulcerative colitis), and healthy persons, observed that no strains were unique to inflammatory bowel disease, while E. coli B2 phylogenetic group/lineage was more prevalent in ulcerative colitis than in other subjects [35]. Furthermore, E. coli strains isolated from ulcerative colitis encoded more genotoxic colibactin, which could increase cancer risk.
In this review, an attempt has been made to discuss the pathological impacts of E. coli and Chlamydia in two major neoplastic diseases—colon cancer and lung cancer, respectively (Figure 1). As stated before, tissues of these two sites share the same embryonic origin. Of note, the colon originates from the middle (midgut) and caudal (hindgut) segments of the primitive gut. In addition, relevant antimicrobial resistance and the prospect of phage therapy will be addressed briefly. Unlike E. coli, which is a common Gram-negative bacillus and can survive in an open environment, Chlamydia is deficient in several biosynthetic/metabolic components, which must be acquired from the host cell.
In this review, an electronic literature search was carried out primarily using PubMed, and, initially, papers published between 2000 and the current year (i.e., 2024) were considered. However, during our comprehensive search and examination of cross-references, we found a few interesting articles that were either published before 2000 or not in English. We utilized the Google system to translate those articles into English. In this process, we also included information from two books and an article that was identified through a Google search. Two authors independently screened the articles/studies, assessed their quality, and extracted the necessary information. The majority of the articles cited in this review were published within the last five years, constituting roughly 59% of the references. This review comprises four main sections: Introduction, E. coli-related pathologies, Chlamydial infections, and Bacteriophage aspects. We selected relevant articles for each section to ensure a coherent and rational discussion. Overall, our study on both lung and colon cancers has found that microbiota communities play a significant role in human health, including homeostasis and immune function.

2. The Large Intestine: E. coli and Cancer

E. coli is a highly diverse bacterial species—from a commensal organism (without causing any harm to its hosts) to a pathogen for a range of diseases, e.g., infections of the gastrointestinal tract, urinary tract, central nervous system, and bloodstream (Figure 2). Of note, E. coli is the most common cause of urinary tract infections. The organism has striking genomic plasticity, which is responsible for its large variability [36]. Genetic modifications such as horizontal gene transfer, point mutations, and DNA rearrangements allow the bacterium to continually adapt to the surrounding environment. Interestingly, within the classical E. coli, hybrid- and hetero-pathogenic E. coli have been described as indicating a unique arrangement of virulence factors; for instance, Shiga toxin-producing E. coli (STEC, which was traditionally not documented) [37]. It may be worth mentioning that multidrug-resistant E. coli strains are prevalent in different parts of the world. For example, in Asia, CTX-M-producing and New Delhi metallo-β-lactamase (NDM)-producing E. coli strains become a serious concern [38]. Notably, CTX-M is an enzyme under the extended-spectrum β-lactamases (ESBLs), which can hydrolyze β-lactam antibiotics such as cephalosporins and monobactams. On the other hand, many investigators believe that E. coli could play a significant role in colon cancer [39,40,41]. Several bacterial characteristics, e.g., induction of chronic inflammation, intracellular parasitism, and production of colibactin, as well as the ability to cause DNA damage and accumulate mutations in host cells, may promote cancer development [34,41,42].
It is commonly mentioned that colibactin-producing E. coli can incite carcinogenesis in the colon. Colibactin can cause DNA damage, and this genotoxic metabolite is encoded by 19 genes in a 54 kb polyketide synthase (pks) pathogenicity island frequently harbored by E. coli from the B2 phylogroup. A Japanese study on 413 patients with colon cancer showed that pks+ E. coli was more pronounced in tumor tissue from early disease stages [43]. The investigators concluded that pks+ E. coli may participate in the initial tumor development, but not in tumor progression. In the same manner, the results of the study conducted by Chen et al. have supported the role of pks+ E. coli in early tumorigenesis [44]. Furthermore, they noticed that their findings might denote additional contributing factors for colon carcinogenesis. It is notable that the development of colon cancer is influenced by a number of risk factors, including some modifiable/lifestyle-related factors, for example, consumption of red meats and processed meats, saturated fat, and alcohol, smoking, insulin resistance/hyperinsulinemia, obesity, and medical interventions such as cholecystectomy [45,46]. A recent study in China documented the fact that pks+ E. coli was enhanced in patients with cholelithiasis or cholecystectomy [47]. Another study in France showed that colibactin-producing E. coli was linked to alterations in the lipid metabolism of cancer cells, which could create an immune-suppressive tumor microenvironment and disease recurrence [48]. The accumulation of lipids in the tumor region might change the intracellular signaling systems, leading to cell proliferation and resistance to chemotherapeutic agents. Interestingly, colibactin-producing E. coli has been reported to display resistance to different antibiotics and induce the emergence of tumor cells that exhibit resistance to chemotherapeutic drugs [49,50].
A study that analyzed mucosal E. coli isolates from 61 colon cancer patients, along with 20 healthy controls, noticed a trend of a higher rate of colibactin-producing E. coli among cancer patients in comparison with controls, but the significance was borderline [51]. However, the investigators of this study observed a higher prevalence of other genes that encode virulence factors such as S-fimbriae, siderophore receptor, invasin, and uropathogenic-specific protein/genotoxin in E. coli from cancer patients’ mucosal biopsies. It may be noteworthy that phylogroup B2 E. coli also releases other virulence factors collectively called cyclomodulins, which include cytotoxic necrotizing factor, cytolethal distending toxin, and cycle inhibiting factor (apart from colibactin), as well as cyclooxygenase–2 [52,53]. On the other hand, in an in vitro study using colorectal adenocarcinoma Caco-2 cells, the investigators found that oxidative DNA lesions could be triggered by enterohemorrhagic E. coli (EHEC or STEC) [54]. Of note, E. coli strains such as enterohemorrhagic E. coli and enteropathogenic E. coli can cause the formation of attaching and effacing (A/E) intestinal lesions, which is dependent on the bacterial type III secretion system (T3SS), and the development of DNA lesions. In a recent report, a significantly higher prevalence of enteropathogenic E. coli was detected among colon cancer patients compared to healthy participants [55]. Intriguingly, it is believed that E. coli might be involved in impairing the gut–vascular barrier at the site of neoplastic lesions, which could create a favorable condition for disseminating cancer cells or distant metastasis [56]. It is worth noting that E. coli was one of the initial bacteria that were thought to be connected with colon cancer pathology [Table 2].

3. Challenges with E. coli Management

Regarding the global antimicrobial resistance problem, the World Health Organization has specifically listed certain drug-resistant bacteria as serious public health threats; one of them is E. coli. Obviously, the epidemiology of the human–animal antimicrobial resistance relationship is exceptionally intricate. In the environment, antibiotic residues and E. coli, along with other bacteria, are commonly spread primarily with manure from food-animal production industrial farms. Logically, these byproducts affect the environmental bacteria, including microorganisms in wild fauna, which can be a source (or reservoirs) of drug-resistant bacteria [67]. In a study conducted in Italy, the investigators collected ESBL-producing E. coli isolates from humans and food-producing animals [68]. They observed that CTX-M was the most common type in human and animal isolates. Nevertheless, they concluded that ESBL gene transfer is possible from animals to humans. Another study in Tanzania analyzed the samples of feces from households and adjacent livestock, as well as soil and water in urban and peri-urban areas [69]. In 52% of household–livestock clusters, ampicillin- and tetracycline-resistant E. coli isolates were detected. The transfer of fecal bacteria among humans, cattle, soil, and water near livestock farms might happen frequently. Similarly, a study in Ethiopia found genetically similar E. coli (O157, a Shiga toxin-producing strain) in cattle, beef, and humans [70].
A research group in India collected samples from poultry farms (fecal matter, litter, and neighboring agricultural soil) and patients with urinary tract infections [71]. Interestingly, E. coli isolates from patients and poultry environments showed a similar resistance pattern for antibiotics such as amikacin, amoxicillin, ampicillin, and ofloxacin. Another study in the Netherlands, which analyzed ESBL E. coli isolates from broilers and staff of broiler farms, observed the transmission of bacterial strains, along with horizontal plasmid and gene transfer among broilers, workers, and their family members [72]. On the other hand, a study in New Zealand revealed that transmission within the same household (persons and pets) might contribute to the spread of ESBL- or AmpC beta-lactamase (ACBL)-producing E. coli in the community [73]. Moreover, Marchetti et al. concluded that E. coli isolates from dogs in Argentina could be a potential source of antibiotic resistance [74].
For the features mentioned above, it is evident that E. coli has highly complex cellular mechanisms and a great capacity for adaptation. Consequently, antimicrobial stewardship programs (ASPs) in certain places showed mixed results [75,76]. Wang et al. evaluated bacterial resistance data from 350,699 patients during the 2011–2016 period, and they observed that the resistance rates of E. coli to fluoroquinolones (levofloxacin and ciprofloxacin) declined as a result of antimicrobial stewardship, while the resistance rates to carbapenems (imipenem and meropenem) increased [75]. However, in an ASP on ESBL-producing E. coli, conducted in 214 primary health centers in Spain during 2012–2017, the intervention revealed a significant decrease in ESBL-producing E. coli infections along with an improvement in the use of antibiotics [77]. Similarly, another ASP in Spain, in 104 cases, recorded a favorable clinical outcome in urinary tract infections caused by ESBL-producing E. coli [78]. Furthermore, a study in Israel that included 6001 patients showed that ASP positively affected the antibiotic resistance rates of E. coli [79].
E. coli is widely present in the environment and in all mammals. Therefore, the ‘One Health’ approach is required for an effective ASP. With regard to this connection, functional cooperation is needed between several experts and regulatory bodies, e.g., veterinarians, physicians, pharmacists, food safety professionals, farmers, and environment/wildlife experts, as well as the relevant legal authorities at the national and international levels.

4. Link between Chlamydia and Lung Cancer Risk

Chlamydiae are Gram-negative obligate intracellular bacteria that maintain their life cycle in two phases: the infectious extracellular elementary body and the non-infectious intracellular reticulate body, which is a metabolically active replicative form (Figure 3). Chlamydia was initially thought of as a member of protozoa, subsequently a virus, and finally, it was discovered to be more analogous to Rickettsia, another Gram-negative obligate intracellular bacterium [80]. Although Chlamydia and Rickettsia are phylogenetically different, both share certain lifestyle characteristics, e.g., their intracellular survival, and have a wide range of hosts such as reptiles, birds, and mammals, which may result in zoonoses (Table 3). For this reason, many authors have tried to correlate these two groups of bacteria in different manners—for instance, genetic makeup, functions of a specific molecule, and utilization of cholesterol/lipids [81,82,83]. Nevertheless, Chlamydiae are unable to produce several essential biomolecules including ATP and components of nucleic acid and amino acid biosynthesis pathways; but a number of bacteria-associated molecules function as virulence factors, such as major outer membrane protein, polymorphic membrane proteins, lipopolysaccharide, and type III secretion systems [84]. In addition, Chlamydia infections can cause activation of various molecules/pathways, e.g., epidermal growth factor receptor, NF-κB pathway, IL-6 phosphatidylinositol 3-kinase, and mitogen-activated protein kinase, which are also connected with neoplastic pathological processes.
Early studies documented a connection between chronic C. pneumoniae infection and lung cancer [85,86,87]. In the cohort of Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, two serum samples were collected at a 3-year interval to detect C. pneumoniae infection before the diagnosis of lung cancer [85]. In this study, 230 male smokers with lung cancer, along with matched controls, were selected. The presence of chronic C. pneumoniae infection was detected in 52% of cases and 45% of controls. The incidence was specifically noticed in subjects younger than 60 years of age [85]. In the pathogenesis of lung cancer, smoking and chronic C. pneumoniae infection possibly act collaboratively [87,88,89,90]. On the other hand, a study on non-smoking women in China recorded that nearly 62% of patients with lung cancer (n = 192) and around 29% of healthy controls (n = 90) were immunoglobulin G (IgG) seropositive for C. pneumoniae [91]. In general, it has been observed that IgG and/or IgA seropositive titers against C. pneumoniae are a risk factor for lung cancer [92,93]. Interestingly, a case-control study in the USA on 593 lung cancer cases and 671 controls showed that elevated antibody titers for Chlamydial heat shock protein-60 (hsp60) were associated with an increased risk of lung cancer [94].
In a study in Austria, Aigelsreiter et al. examined the presence of Chlamydiae in five cases of lymphoma of mucosa-associated lymphoid tissue (MALT lymphomas) of the lung; all cases were positive for Chlamydia psittaci [95]. In another study in Greece, the investigators assessed surgically removed lung cancer tissue samples from 32 cases for the presence of Chlamydia muridarum and C. trachomatis [96]. In this study, 12.5% of cases were positive for Chlamydia. Of note, C. muridarum is a pathogen for mice. Interestingly, in a recent study on C. muridarum infection in knockout mice (Il12rb2 KO and STAT1 KO), a urothelial papilloma was developed in connection with this pathogen [97]. In another in vivo study, Wistar rats were divided into four groups; excepting the control group (n = 40) and carcinogenic benzo[a]pyrene group (BP, n = 46), the other two groups received repeated intratracheal administration of C. pneumoniae (only bacteria- n = 48, and with BP- n = 43) [98]. Incidences of lung cancer in the latter two groups were 14.6% and 44.2%, respectively, and 10.9% in the BP group. On the other hand, C. pneumoniae infection in pulmonary mesothelial cells (Mes1 cells) revealed induction of different cancer-linked genes, such as calretinin, Wilms tumor 1, and matrix metalloproteinase-2 [99]. Therefore, C. pneumoniae infection may favor the transformation of cells.
It is believed that the proliferation of C. pneumoniae in monocytes and macrophages in the lungs initiates pathogenesis by releasing elevated concentrations of different pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), IL-1β, IL-8, as well as reactive oxygen species (ROS) [92,93]. For this reason, chronic C. pneumoniae infection and tobacco smoking could act synergistically to increase cancer risk. Nevertheless, pro-inflammatory cytokines and ROS can bring about chronic inflammation, which leads to cell injury and DNA damage. As a result, defects in the repairing process of cells might enhance the risk of mutation, which could also aggravate the risk of cancer [92,93]. In addition to the plausible role in tumorigenesis, C. pneumoniae perhaps affects the disease course. A study on patients with advanced non-small-cell lung cancer (stages III and IV) showed favorable results when treated with azithromycin in addition to chemotherapeutic agents, viz. paclitaxel and cisplatin [100]. Azithromycin is one of the commonly used antibiotics for the management of Chlamydial infections. A prospective hospital-based study evaluated 82 patients with primary lung cancer [101]. In this study, 75.6% of patients were positive for IgG antibodies against C. pneumoniae, 45.1% were positive for IgA, and seropositivity for both IgG and IgA was detected in 41.5% of cases. However, the study concluded that pre-treatment for C. pneumoniae infection may modify the health-related quality of life. On the other hand, a report demonstrated alterations in the levels of cytokines during treatment, depending on the status of C. pneumoniae infection [102]. For instance, there was a gradual increase in the concentration of transforming growth factor beta (TGF-β) during radiotherapy. Finally, after radiotherapy, TGF-β displayed a significantly higher concentration among C. pneumoniae IgG-positive patients with lung cancer, compared to the IgG-negative group.

5. Antimicrobial Issues with Chlamydia

Chlamydial infection is associated with the highest incidence of sexually transmitted bacterial disease worldwide. The World Health Organization estimated 128.5 million new infections with the Chlamydial pathogen in 2020 among adults (15–49 years). In addition, a high recurrence rate has been observed in cases of Chlamydial infection [103]. However, it is not clear whether this high rate of recurrence is caused by reinfection or persistent infection by antibiotic-resistant bacteria. In a report from China, higher rates of 23S rRNA gene mutations were found in the azithromycin treatment-failure group [104]. In addition, recent studies indicated antimicrobial resistance in C. psittaci and C. trachomatis (lymphogranuloma venereum) strains [105,106]. In contrast, several observations were not able to detect any treatment-resistant Chlamydial strains in clinical samples [107,108,109,110]. In a recent study from Thailand, a group of researchers identified antimicrobial resistance genes from Chlamydia in semiaquatic reptiles [111]. Specifically, there are a number of reports on the tetracycline-resistant Chlamydia suis in pigs and the possible horizontal transfer of resistance genes to other Chlamydial species [112,113,114]. In pig farms, tetracycline is used routinely, and this practice is responsible for the homotypic resistance to tetracycline (homotypic: where most organisms display resistance). Nevertheless, this type of resistance gene transmission was either undetected or inconclusive in wild boar populations [115,116].
In general, the determination of antibiotic resistance and the identification of relevant genes are performed in the laboratory/in vitro by serial passage of Chlamydial strains in sub-inhibitory (i.e., lower) concentrations of antibiotics. Nonetheless, the clinical implications of these in vitro findings are not clear [103]. Among patients, the variations in clinical outcomes could be due to other factors that are unrelated to antimicrobial resistance, such as hypoxia, interferon-gamma (INF-γ), IL-8, and macrophages [117,118,119].
Due to obligate intracellular parasitism, Chlamydial infections are generally diagnosed by certain complex methods such as cell culture, antigen-based detection techniques, or nucleic acid amplification tests (NAATs) [108]. However, there is no uniform methodology for antimicrobial susceptibility testing for Chlamydiae. Different laboratories use various cell lines, e.g., McCoy, HeLa (cervical cancer cells), and HEp-2, as well as BGMK and Vero (monkey kidney) cell lines. Although the McCoy cell line is commonly used, a number of these cells in many laboratories are mouse fibroblasts, not the original McCoy cells derived from human synovial tissue [120]. Similarly, the HEp-2 cell line which originally derived from laryngeal cancer cells was reported to be contaminated by HeLa cells [121]. It may be worth mentioning that there are cell line-dependent differences in in vitro antimicrobial susceptibility [122]. Nevertheless, the Chlamydial genes, which are linked with antimicrobial resistance in vitro, have been summarized in Table 4 [123,124].

6. Potential Prevention Aspect: Bacteriophages

Evidence suggests that C. trachomatis may increase the risk of cervical and ovarian cancers, in addition to causing other sexually transmitted diseases [125,126,127]. The situation has become more complicated due to the emergence of multidrug-resistant sexually transmitted infections all over the world. Along with Neisseria gonorrhea, growing antibiotic resistance problems have also been documented for other bacteria such as Haemophilus ducreyi, Mycoplasma genitalium, Treponema pallidum, and C. trachomatis [128]. Interestingly, both in vitro (using McCoy cells) and in vivo (in female BALB/c mice) studies showed an inhibitory effect of capsid protein Vp1 of chlamydiaphage φCPG1 on C. trachomatis serovar E strain [129]. Of note, φCPG1 is a lytic bacteriophage for Chlamydia caviae, which primarily causes inclusion conjunctivitis in guinea pigs. Currently, there are six known bacteriophages for different Chlamydia species, and they belong to the Microviridae family (chlamydiaphages Chp1–4, φCPG1, and ϕCPAR39—under the subfamily Gokushovirinae, and distantly related to E. coli bacteriophage ϕX174) [130]. These phages may have an extended host range; for example, ϕCPAR39 can infect C. pneumoniae, C. caviae, C. abortus (which causes miscarriages in ewes), and C. pecorum (which causes a wide variety of diseases in various animals) [130,131]. In one study, C. pneumoniae was grown in HeLa cells and infected with ϕCPAR39 [132]. The study recorded that ϕCPAR39 infection suppressed various protein syntheses of C. pneumoniae. In the same way, bacterial cell lysis was observed when C. abortus was cultured in BGMK cells and infected by chlamydiaphage Chp2 [133]. In another study, HeLa cells were used to grow C. trachomatis, which was subsequently infected with φCPG1 [134]. As expected, φCPG1 was able to inhibit the growth of C. trachomatis in a dose-dependent manner. These findings are fascinating, and perhaps the use of bacteriophages could be a potential method for future antimicrobial therapeutic strategies.
Since the initial discoveries around the early 1900s by Ernest H. Hankin (1865–1939), Frederick W. Twort (1877–1950), and Felix d’Herelle (1873–1949), scientists are now again thinking seriously about the issues of bacteriophages and methods to utilize them, either in combination with currently available antibiotics or alone, to manage the problem of multidrug-resistant bacterial infections. The first field trials of phage therapy were conducted in rural France against fowl typhoid, caused by Gram-negative Salmonella gallinarum, in 1919, as prophylactic measures [135]. Subsequently, phage therapy became popular during the 1930s, i.e., before the clinical use of penicillin among the masses. Although the discovery of antibiotics and their accessibility for people halted the interest in bacteriophage research and relevant therapeutic use, the study of bacteriophages and phage therapy was started in the Soviet Union when Felix d’Herelle moved to Tbilisi in 1934 and worked with his friend George Eliava (1892–1937) [135]. In the 1930s and 1940s, many research papers from the Soviet Union were dedicated to the topic of phage therapy in a wide variety of bacterial infections [136]. However, these studies were generally not accepted appropriately by the Western world. In recent times, particularly in the last decade, the situation has changed rapidly, due to the speedy emergence of multidrug-resistant bacteria across the globe, along with a decline in the process of new antibacterial discovery [137].
With regard to phage therapy, bacteriophages should have certain specific characteristics [138]. For example, only lytic bacteriophages can be considered in treating bacterial infections. Of note, in the case of a lytic (or virulent) group, new virions are released with the lysis of bacterial cells, whereas in the lysogenic (or temperate) group, viral genetic material is integrated with the host genome. On the other hand, unlike antibiotics, bacteriophages are able to kill only the specific bacteria that they recognize (i.e., without damaging commensal/symbiotic microorganisms). Lastly, administration of bacteriophages is easy, and only a few doses are needed, due to virus proliferation after the initial administration. However, it is necessary to resolve some important issues, e.g., proper identification of a useful bacteriophage for treatment, prevention of possible bacterial resistance against bacteriophages or phage-mediated antibiotic resistance (i.e., for lysogenic phages), and avoidance of an immune response against therapeutic bacteriophages [138,139]. Nevertheless, phage therapy could be an important component of ASPs in the near future.
Perhaps bacteriophages can efficiently kill bacteria in easily accessible zones, such as the body surface. In a recent study in a mouse model, lytic phage Tequatrovirus YZ2 therapy has been shown to significantly enhance the healing of E. coli-infected skin wounds [140]. The study also noticed that the phage’s action was helpful in creating a favorable environment of cytokines, such as a decrease in IL-1β and TNF-α and an increase in the level of vascular endothelial growth factor. In an experiment during milk fermentation, coliphages DT1 and DT6, either individually or in combination, effectively reduced Shiga toxigenic E. coli without compromising lactic starter Streptococcus thermophilus [141]. On the other hand, the bactericidal effects of phages inside the body systems are not satisfactory thus far, possibly due to shortcomings in delivery techniques. An oral coliphage clinical trial using a T4 phage cocktail in acute bacterial diarrhea did not demonstrate any positive results, although there were no noticeable adverse effects [142]. The study included 11 T4-like phages, and 60% of the cases suffered from E. coli infections—the most common was enterotoxigenic E. coli. Of note, the group of T4 and related phages is considered a potential candidate in the treatment of infections with various E. coli strains [143]. Currently, seven enteric pathogenic E. coli have been described: enteroinvasive E. coli, enteropathogenic E. coli, enterohemorrhagic E. coli, enterotoxigenic E. coli, enteroaggregative E. coli, diffusely adherent E. coli, and adherent-invasive E. coli (AIEC) [144].
In the CEABAC10 transgenic mice whose intestine was colonized with the AIEC strain LF82, oral administration of the cocktail of three bacteriophages (LF82_P2, LF82_P6, and LF82_P8) significantly reduced the quantity of AIEC from the intestine [145]. Enterocytes of this transgenic mouse express CEACAM6 glycoprotein, and LF82 can bind with it. In another study, the investigators induced colitis with the AIEC strain LF82 in BALB/cYJ mice [146]. The investigators collected AIEC strains from clinical samples, as well as non-E. coli bacteria that are associated with a healthy microbiome. In this study, a cocktail of seven phages (LF82_P2, LF82_P8, ECML-119, ECML-123-2, ECML-359, ECML-363, and CLB_P2) was administered twice a day for 15 days, and the regimen prevented inflammation. It is worth mentioning that AIEC is frequently associated with inflammatory bowel disease.

7. Conclusions

Primitive gut-derived structures are the sites for a number of important cancers, and a few of them are thought to be connected with bacterial pathologies. For instance, among the derivatives of the primitive foregut, Helicobacter pylori is often associated with gastric pre-cancerous changes, and plays an etiological role in both adenocarcinomas and MALT lymphomas. In addition, except for a supposed relationship between chronic C. pneumoniae infection and lung cancer, Salmonella typhi may promote the risk of gallbladder cancer. In recent times, several lytic phages have been isolated against the abovementioned bacteria. The suitable therapeutic use of these bacteriophages, which may include appropriate genetic modifications, could be a promising strategy in preventive medicine/oncology. On the other hand, the situation in inflammatory bowel disease or colon cancer development is more intricate, due to the possible involvement of several bacterial species, e.g., C. difficile, E. coli, Campylobacter spp., Chlamydia spp., B. fragilis, and Fusobacterium spp. In this type of condition, perhaps the cocktail of various suitable bacteriophages could be evaluated for efficacy. Furthermore, as per the concept of the gut–lung axis, this kind of biological (nonantibiotic) therapeutic approach may confer the necessary requirements for a healthy lung. Of note, the gut–lung axis concept proposes a significantly influential role of intestinal microbiota communities and their alterations on pulmonary conditions, possibly through different immune cells and relevant cytokines. For the same reason, there is a need to develop prebiotics (such as inulin and pectin) and probiotics (such as Lactobacillus and Bifidobacterium) appropriately, i.e., other biological methods for disease prevention. Nevertheless, proper lifestyle changes such as healthy diets and avoiding tobacco use, along with the reduction in harmful bacterial growth by a nonantibiotic strategy, might be useful in lowering the incidences and management of a sizable number of cancers.

Author Contributions

Conceptualization, A.R.; resources and data curation, A.R. and D.S.L.N.; software and visualization D.S.L.N.; validation and formal analysis, A.R. and D.M.B.; writing—original draft preparation, A.R.; writing—review and editing, T.F.M. and D.M.B.; supervision and project administration, D.M.B. All authors have read and agreed to the published version of the manuscript.

Funding

This work received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Joshi, S.; Kotecha, S. Lung growth and development. Early Hum. Dev. 2007, 83, 789–794. [Google Scholar] [CrossRef] [PubMed]
  2. Pawlina, W. Histology, 9th ed.; Wolters Kluwer: Philadelphia, PA, USA, 2024. [Google Scholar]
  3. Taal, B.G.; Visser, O. Epidemiology of neuroendocrine tumours. Neuroendocrinology 2004, 80 (Suppl. S1), 3–7. [Google Scholar] [CrossRef]
  4. Kasajima, A.; Klöppel, G. Neuroendocrine neoplasms of lung, pancreas and gut: A morphology-based comparison. Endocr. Relat. Cancer 2020, 27, R417–R432. [Google Scholar] [CrossRef] [PubMed]
  5. Rekhtman, N. Lung neuroendocrine neoplasms: Recent progress and persistent challenges. Mod. Pathol. 2022, 35 (Suppl. S1), 36–50. [Google Scholar] [CrossRef] [PubMed]
  6. Yu, J.; Refsum, E.; Perrin, V.; Helsingen, L.M.; Wieszczy, P.; Løberg, M.; Bretthauer, M.; Adami, H.O.; Ye, W.; Blom, J.; et al. Inflammatory bowel disease and risk of adenocarcinoma and neuroendocrine tumors in the small bowel. Ann. Oncol. 2022, 33, 649–656. [Google Scholar] [CrossRef]
  7. Festa, S.; Zerboni, G.; Derikx, L.A.A.P.; Ribaldone, D.G.; Dragoni, G.; Buskens, C.; van Dijkum, E.N.; Pugliese, D.; Panzuto, F.; Krela-Kaźmierczak, I.; et al. Gastroenteropancreatic neuroendocrine neoplasms in patients with inflammatory bowel disease: An ECCO CONFER multicentre case series. J. Crohns Colitis 2022, 16, 940–945. [Google Scholar] [CrossRef]
  8. Vitale, G.; Dicitore, A.; Barrea, L.; Sbardella, E.; Razzore, P.; Campione, S.; Faggiano, A.; Colao, A.; Albertelli, M.; Altieri, B.; et al. From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell? Rev. Endocr. Metab. Disord 2021, 22, 511–525. [Google Scholar] [CrossRef]
  9. West, N.E.; Wise, P.E.; Herline, A.J.; Muldoon, R.L.; Chopp, W.V.; Schwartz, D.A. Carcinoid tumors are 15 times more common in patients with Crohn’s disease. Inflamm. Bowel Dis. 2007, 13, 1129–1134. [Google Scholar] [CrossRef]
  10. Porter, R.J.; Arends, M.J.; Churchhouse, A.M.D.; Din, S. Inflammatory bowel disease-associated colorectal cancer: Translational risks from mechanisms to medicines. J. Crohns Colitis 2021, 15, 2131–2141. [Google Scholar] [CrossRef]
  11. Gao, H.; Zheng, S.; Yuan, X.; Xie, J.; Xu, L. Causal association between inflammatory bowel disease and 32 site-specific extracolonic cancers: A Mendelian randomization study. BMC Med. 2023, 21, 389. [Google Scholar] [CrossRef]
  12. Kim, J.; Jung, J.H.; Jo, H.; Kim, M.H.; Kang, D.R.; Kim, H.M. Risk of uterine cervical cancer in inflammatory bowel disease: A systematic review and meta-analysis. Scand. J. Gastroenterol. 2023, 58, 1412–1421. [Google Scholar] [CrossRef] [PubMed]
  13. Lo, B.; Zhao, M.; Vind, I.; Burisch, J. The risk of extraintestinal cancer in inflammatory bowel disease: A systematic review and meta-analysis of population-based cohort studies. Clin. Gastroenterol. Hepatol. 2021, 19, 1117–1138.e19. [Google Scholar] [CrossRef] [PubMed]
  14. Cavalli, C.A.M.; Gabbiadini, R.; Dal Buono, A.; Quadarella, A.; De Marco, A.; Repici, A.; Bezzio, C.; Simonetta, E.; Aliberti, S.; Armuzzi, A. Lung involvement in inflammatory bowel diseases: Shared pathways and unwanted connections. J. Clin. Med. 2023, 12, 6419. [Google Scholar] [CrossRef] [PubMed]
  15. Lobatón, T.; Domènech, E. Bacterial intestinal superinfections in inflammatory bowel diseases beyond clostridum difficile. Inflamm. Bowel Dis. 2016, 22, 1755–1762. [Google Scholar] [CrossRef]
  16. Chen, Y.; Cui, W.; Li, X.; Yang, H. Interaction between commensal bacteria, immune response and the intestinal barrier in inflammatory bowel disease. Front. Immunol. 2021, 12, 761981. [Google Scholar] [CrossRef]
  17. Neri, B.; Stingone, C.; Romeo, S.; Sena, G.; Gesuale, C.; Compagno, M.; De Cristofaro, E.; Baciorri, F.; Del Vecchio Blanco, G.; Palmieri, G.; et al. Inflammatory bowel disease versus Chlamydia trachomatis infection: A case report and revision of the literature. Eur. J. Gastroenterol. Hepatol. 2020, 32, 454–457. [Google Scholar] [CrossRef]
  18. Córdova, A.; Quera, R.; Contreras, L.; Catalán, P.; Quezada, F.; Tinoco, J. Infectious proctitis and perianal disease: A gaze beyond inflammatory bowel disease. Rev. Chilena Infectol. 2021, 38, 820–823. [Google Scholar] [CrossRef]
  19. Smolarczyk, K.; Mlynarczyk-Bonikowska, B.; Majewski, S.; Rudnicka, E.; Unemo, M.; Fiedor, P. Lymphogranuloma venereum: An emerging problem in Poland. Postepy Dermatol. Alergol. 2022, 39, 587–593. [Google Scholar] [CrossRef]
  20. Müller, S.; Arni, S.; Varga, L.; Balsiger, B.; Hersberger, M.; Maly, F.; Seibold, F. Serological and DNA-based evaluation of Chlamydia pneumoniae infection in inflammatory bowel disease. Eur. J. Gastroenterol. Hepatol. 2006, 18, 889–894. [Google Scholar] [CrossRef]
  21. Chen, W.; Li, D.; Wilson, I.; Chadwick, V.S. Detection of Chlamydia pneumoniae by polymerase chain reaction-enzyme immunoassay in intestinal mucosal biopsies from patients with inflammatory bowel disease and controls. J. Gastroenterol. Hepatol. 2002, 17, 987–993. [Google Scholar] [CrossRef]
  22. Howe, S.E.; Shillova, N.; Konjufca, V. Dissemination of Chlamydia from the reproductive tract to the gastro-intestinal tract occurs in stages and relies on Chlamydia transport by host cells. PLoS Pathog. 2019, 15, e1008207. [Google Scholar] [CrossRef] [PubMed]
  23. Zhong, G. Chlamydia overcomes multiple gastrointestinal barriers to achieve long-lasting colonization. Trends Microbiol. 2021, 29, 1004–1012. [Google Scholar] [CrossRef] [PubMed]
  24. Quaglio, A.E.V.; Grillo, T.G.; De Oliveira, E.C.S.; Di Stasi, L.C.; Sassaki, L.Y. Gut microbiota, inflammatory bowel disease and colorectal cancer. World J. Gastroenterol. 2022, 28, 4053–4060. [Google Scholar] [CrossRef] [PubMed]
  25. Lopez, L.R.; Ahn, J.H.; Alves, T.; Arthur, J.C. Microenvironmental factors that shape bacterial metabolites in inflammatory bowel disease. Front. Cell. Infect. Microbiol. 2022, 12, 934619. [Google Scholar] [CrossRef] [PubMed]
  26. Bengtsson, J.; Adlerberth, I.; Östblom, A.; Saksena, P.; Öresland, T.; Börjesson, L. Effect of probiotics (Lactobacillus plantarum 299 plus Bifidobacterium Cure21) in patients with poor ileal pouch function: A randomised controlled trial. Scand. J. Gastroenterol. 2016, 51, 1087–1092. [Google Scholar] [CrossRef]
  27. Fan, H.; Du, J.; Liu, X.; Zheng, W.W.; Zhuang, Z.H.; Wang, C.D.; Gao, R. Effects of pentasa-combined probiotics on the microflora structure and prognosis of patients with inflammatory bowel disease. Turk. J. Gastroenterol. 2019, 30, 680–685. [Google Scholar] [CrossRef]
  28. Fedorak, R.N.; Feagan, B.G.; Hotte, N.; Leddin, D.; Dieleman, L.A.; Petrunia, D.M.; Enns, R.; Bitton, A.; Chiba, N.; Paré, P.; et al. The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn’s disease. Clin. Gastroenterol. Hepatol. 2015, 13, 928–935.e2. [Google Scholar]
  29. Groeger, D.; O’Mahony, L.; Murphy, E.F.; Bourke, J.F.; Dinan, T.G.; Kiely, B.; Shanahan, F.; Quigley, E.M. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes 2013, 4, 325–339. [Google Scholar] [CrossRef]
  30. Matsuoka, K.; Uemura, Y.; Kanai, T.; Kunisaki, R.; Suzuki, Y.; Yokoyama, K.; Yoshimura, N.; Hibi, T. Efficacy of Bifidobacterium breve fermented milk in maintaining remission of ulcerative colitis. Dig. Dis. Sci. 2018, 63, 1910–1919. [Google Scholar] [CrossRef]
  31. Palumbo, V.D.; Romeo, M.; Marino Gammazza, A.; Carini, F.; Damiani, P.; Damiano, G.; Buscemi, S.; Lo Monte, A.I.; Gerges-Geagea, A.; Jurjus, A.; et al. The long-term effects of probiotics in the therapy of ulcerative colitis: A clinical study. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 2016, 160, 372–377. [Google Scholar] [CrossRef]
  32. Shadnoush, M.; Hosseini, R.S.; Khalilnezhad, A.; Navai, L.; Goudarzi, H.; Vaezjalali, M. Effects of probiotics on gut microbiota in patients with inflammatory bowel disease: A double-blind, placebo-controlled clinical trial. Korean J. Gastroenterol. 2015, 65, 215–221. [Google Scholar] [CrossRef] [PubMed]
  33. Tamaki, H.; Nakase, H.; Inoue, S.; Kawanami, C.; Itani, T.; Ohana, M.; Kusaka, T.; Uose, S.; Hisatsune, H.; Tojo, M.; et al. Efficacy of probiotic treatment with Bifidobacterium longum 536 for induction of remission in active ulcerative colitis: A randomized, double-blinded, placebo-controlled multicenter trial. Dig. Endosc. 2016, 28, 67–74. [Google Scholar] [CrossRef] [PubMed]
  34. Khan, A.A.; Khan, Z.; Malik, A.; Kalam, M.A.; Cash, P.; Ashraf, M.T.; Alshamsan, A. Colorectal cancer-inflammatory bowel disease nexus and felony of Escherichia coli. Life Sci. 2017, 180, 60–67. [Google Scholar] [CrossRef] [PubMed]
  35. Dubinsky, V.; Reshef, L.; Rabinowitz, K.; Wasserberg, N.; Dotan, I.; Gophna, U. Escherichia coli strains from patients with inflammatory bowel diseases have disease-specific genomic adaptations. J. Crohns Colitis 2022, 16, 1584–1597. [Google Scholar] [CrossRef] [PubMed]
  36. Leimbach, A.; Hacker, J.; Dobrindt, U.E. coli as an all-rounder: The thin line between commensalism and pathogenicity. Curr. Top. Microbiol. Immunol. 2013, 358, 3–32. [Google Scholar]
  37. Santos, A.C.M.; Santos, F.F.; Silva, R.M.; Gomes, T.A.T. Diversity of hybrid- and hetero-pathogenic Escherichia coli and their potential implication in more severe diseases. Front. Cell. Infect Microbiol. 2020, 10, 339. [Google Scholar] [CrossRef]
  38. Sidjabat, H.E.; Paterson, D.L. Multidrug-resistant Escherichia coli in Asia: Epidemiology and management. Expert Rev. Anti Infect. Ther. 2015, 13, 575–591. [Google Scholar] [CrossRef]
  39. Martin, H.M.; Campbell, B.J.; Hart, C.A.; Mpofu, C.; Nayar, M.; Singh, R.; Englyst, H.; Williams, H.F.; Rhodes, J.M. Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer. Gastroenterology 2004, 127, 80–93. [Google Scholar] [CrossRef]
  40. Magdy, A.; Elhadidy, M.; Abd Ellatif, M.E.; El Nakeeb, A.; Abdallah, E.; Thabet, W.; Youssef, M.; Khafagy, W.; Morshed, M.; Farid, M. Enteropathogenic Escherichia coli (EPEC): Does it have a role in colorectal tumourigenesis? A prospective cohort study. Int. J. Surg. 2015, 18, 169–173. [Google Scholar] [CrossRef]
  41. Yoshikawa, Y.; Tsunematsu, Y.; Matsuzaki, N.; Hirayama, Y.; Higashiguchi, F.; Sato, M.; Iwashita, Y.; Miyoshi, N.; Mutoh, M.; Ishikawa, H.; et al. Characterization of colibactin-producing Escherichia coli isolated from Japanese patients with colorectal cancer. Jpn. J. Infect. Dis. 2020, 73, 437–442. [Google Scholar] [CrossRef]
  42. Nouri, R.; Hasani, A.; Shirazi, K.M.; Alivand, M.R.; Sepehri, B.; Sotoodeh, S.; Hemmati, F.; Rezaee, M.A. Escherichia coli and colorectal cancer: Unfolding the enigmatic relationship. Curr. Pharm. Biotechnol. 2022, 23, 1257–1268. [Google Scholar] [PubMed]
  43. Miyasaka, T.; Yamada, T.; Uehara, K.; Sonoda, H.; Matsuda, A.; Shinji, S.; Ohta, R.; Kuriyama, S.; Yokoyama, Y.; Takahashi, G.; et al. Pks-positive Escherichia coli in tumor tissue and surrounding normal mucosal tissue of colorectal cancer patients. Cancer Sci. 2024, 115, 1184–1195. [Google Scholar] [CrossRef] [PubMed]
  44. Chen, B.; Ramazzotti, D.; Heide, T.; Spiteri, I.; Fernandez-Mateos, J.; James, C.; Magnani, L.; Graham, T.A.; Sottoriva, A. Contribution of pks(+) E. coli mutations to colorectal carcinogenesis. Nat. Commun. 2023, 14, 7827. [Google Scholar] [CrossRef] [PubMed]
  45. Lin, O.S. Acquired risk factors for colorectal cancer. Methods Mol. Biol. 2009, 472, 361–372. [Google Scholar]
  46. Giovannucci, E. Modifiable risk factors for colon cancer. Gastroenterol. Clin. N. Am. 2002, 31, 925–943. [Google Scholar] [CrossRef]
  47. Pan, S.Y.; Zhou, C.B.; Deng, J.W.; Zhou, Y.L.; Liu, Z.H.; Fang, J.Y. The effects of pks(+) Escherichia coli and bile acid in colorectal tumorigenesis among people with cholelithiasis or cholecystectomy. J. Gastroenterol. Hepatol. 2024, 39, 868–879. [Google Scholar] [CrossRef]
  48. de Oliveira Alves, N.; Dalmasso, G.; Nikitina, D.; Vaysse, A.; Ruez, R.; Ledoux, L.; Pedron, T.; Bergsten, E.; Boulard, O.; Autier, L.; et al. The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance. Gut Microbes 2024, 16, 2320291. [Google Scholar] [CrossRef]
  49. Akinduti, P.A.; Izevbigie, O.O.; Akinduti, O.A.; Enwose, E.O.; Amoo, E.O. Fecal carriage of colibactin-encoding Escherichia coli associated with colorectal cancer among a student populace. Open Forum Infect. Dis. 2024, 11, ofae106. [Google Scholar] [CrossRef]
  50. Dalmasso, G.; Cougnoux, A.; Faïs, T.; Bonnin, V.; Mottet-Auselo, B.; Nguyen, H.T.; Sauvanet, P.; Barnich, N.; Jary, M.; Pezet, D.; et al. Colibactin-producing Escherichia coli enhance resistance to chemotherapeutic drugs by promoting epithelial to mesenchymal transition and cancer stem cell emergence. Gut Microbes 2024, 16, 2310215. [Google Scholar] [CrossRef]
  51. Bosák, J.; Kohoutová, D.; Hrala, M.; Křenová, J.; Morávková, P.; Rejchrt, S.; Bureš, J.; Šmajs, D. Escherichia coli from biopsies differ in virulence genes between patients with colorectal neoplasia and healthy controls. Front. Microbiol. 2023, 14, 1141619. [Google Scholar] [CrossRef]
  52. Wassenaar, T.M. E. coli and colorectal cancer: A complex relationship that deserves a critical mindset. Crit. Rev. Microbiol. 2018, 44, 619–632. [Google Scholar] [CrossRef] [PubMed]
  53. Qu, R.; Zhang, Y.; Ma, Y.; Zhou, X.; Sun, L.; Jiang, C.; Zhang, Z.; Fu, W. Role of the gut microbiota and its metabolites in tumorigenesis or development of colorectal cancer. Adv. Sci. 2023, 10, e2205563. [Google Scholar] [CrossRef] [PubMed]
  54. Fang, Y.; Fu, M.; Li, X.; Zhang, B.; Wan, C. Enterohemorrhagic Escherichia coli effector EspF triggers oxidative DNA lesions in intestinal epithelial cells. Infect. Immun. 2024, 92, e0000124. [Google Scholar] [CrossRef] [PubMed]
  55. Nouri, R.; Hasani, A.; Shirazi, K.M.; Sefiadn, F.Y.; Mazraeh, F.N.; Sattarpour, S.; Rezaee, M.A. Colonization of the gut mucosa of colorectal cancer patients by pathogenic mucosa-associated Escherichia coli strains. Diagn. Microbiol. Infect. Dis. 2024, 109, 116229. [Google Scholar] [CrossRef]
  56. Ayabe, R.I.; White, M.G. Metastasis and the microbiome: The impact of bacteria in disseminated colorectal cancer. Front. Biosci. Landmark Ed. 2024, 29, 152. [Google Scholar] [CrossRef]
  57. Butt, J.; Jenab, M.; Werner, J.; Fedirko, V.; Weiderpass, E.; Dahm, C.C.; Tjønneland, A.; Olsen, A.; Boutron-Ruault, M.C.; Rothwell, J.A.; et al. Association of pre-diagnostic antibody responses to Escherichia coli and Bacteroides fragilis toxin proteins with colorectal cancer in a European cohort. Gut Microbes 2021, 13, 1–14. [Google Scholar] [CrossRef]
  58. He, T.; Cheng, X.; Xing, C. The gut microbial diversity of colon cancer patients and the clinical significance. Bioengineered 2021, 12, 7046–7060. [Google Scholar] [CrossRef]
  59. Iwasaki, M.; Kanehara, R.; Yamaji, T.; Katagiri, R.; Mutoh, M.; Tsunematsu, Y.; Sato, M.; Watanabe, K.; Hosomi, K.; Kakugawa, Y.; et al. Association of Escherichia coli containing polyketide synthase in the gut microbiota with colorectal neoplasia in Japan. Cancer Sci. 2022, 113, 277–286. [Google Scholar] [CrossRef]
  60. Iyadorai, T.; Mariappan, V.; Vellasamy, K.M.; Wanyiri, J.W.; Roslani, A.C.; Lee, G.K.; Sears, C.; Vadivelu, J. Prevalence and association of pks+ Escherichia coli with colorectal cancer in patients at the University Malaya Medical Centre, Malaysia. PLoS ONE 2020, 15, e0228217. [Google Scholar] [CrossRef]
  61. Kamali Dolatabadi, R.; Fazeli, H.; Emami, M.H.; Karbasizade, V.; Maghool, F.; Fahim, A.; Rahimi, H. Phenotypic and genotypic characterization of clinical isolates of intracellular adherent-invasive Escherichia coli among different stages, family history, and treated colorectal cancer patients in Iran. Front. Cell. Infect. Microbiol. 2022, 12, 938477. [Google Scholar] [CrossRef]
  62. López-Siles, M.; Camprubí-Font, C.; Gómez Del Pulgar, E.M.; Sabat Mir, M.; Busquets, D.; Sanz, Y.; Martinez-Medina, M. Prevalence, abundance, and virulence of adherent-invasive Escherichia coli in ulcerative colitis, colorectal cancer, and coeliac disease. Front. Immunol. 2022, 13, 748839. [Google Scholar] [CrossRef] [PubMed]
  63. Messaritakis, I.; Vogiatzoglou, K.; Tsantaki, K.; Ntretaki, A.; Sfakianaki, M.; Koulouridi, A.; Tsiaoussis, J.; Mavroudis, D.; Souglakos, J. The prognostic value of the detection of microbial translocation in the blood of colorectal cancer patients. Cancers 2020, 12, 1058. [Google Scholar] [CrossRef] [PubMed]
  64. Mirzarazi, M.; Bashiri, S.; Hashemi, A.; Vahidi, M.; Kazemi, B.; Bandehpour, M. The OmpA of commensal Escherichia coli of CRC patients affects apoptosis of the HCT116 colon cancer cell line. BMC Microbiol. 2022, 22, 139. [Google Scholar] [CrossRef] [PubMed]
  65. Rondepierre, F.; Meynier, M.; Gagniere, J.; Deneuvy, V.; Deneuvy, A.; Roche, G.; Baudu, E.; Pereira, B.; Bonnet, R.; Barnich, N.; et al. Preclinical and clinical evidence of the association of colibactin-producing Escherichia coli with anxiety and depression in colon cancer. World J. Gastroenterol. 2024, 30, 2817–2826. [Google Scholar] [CrossRef] [PubMed]
  66. Wachsmannova, L.; Majek, J.; Zajac, V.; Stevurkova, V.; Ciernikova, S. The study of bacteria in biopsies from Slovak colorectal adenoma and carcinoma patients. Neoplasma 2018, 65, 644–648. [Google Scholar] [CrossRef] [PubMed]
  67. Wegener, H.C. Antibiotic resistance—Linking human and animal health. In Improving Food Safety through a One Health Approach; Institute of Medicine (US)/The National Academies Press: Washington, DC, USA, 2012; A15; pp. 331–349. [Google Scholar]
  68. Giufrè, M.; Mazzolini, E.; Cerquetti, M.; Brusaferro, S.; CCM2015 One-Health ESBL-Producing Escherichia coli Study Group. Extended-spectrum β-lactamase-producing Escherichia coli from extraintestinal infections in humans and from food-producing animals in Italy: A ‘One Health’ study. Int. J. Antimicrob. Agents 2021, 58, 106433. [Google Scholar] [CrossRef]
  69. Lupindu, A.M.; Dalsgaard, A.; Msoffe, P.L.; Ngowi, H.A.; Mtambo, M.M.; Olsen, J.E. Transmission of antibiotic-resistant Escherichia coli between cattle, humans and the environment in peri-urban livestock keeping communities in Morogoro, Tanzania. Prev. Vet. Med. 2015, 118, 477–482. [Google Scholar] [CrossRef]
  70. Gutema, F.D.; Rasschaert, G.; Agga, G.E.; Jufare, A.; Duguma, A.B.; Abdi, R.D.; Duchateau, L.; Crombe, F.; Gabriël, S.; De Zutter, L. Occurrence, molecular characteristics, and antimicrobial resistance of Escherichia coli O157 in cattle, beef, and humans in Bishoftu Town, Central Ethiopia. Foodborne Pathog. Dis. 2021, 18, 1–7. [Google Scholar] [CrossRef]
  71. Sebastian, S.; Tom, A.A.; Babu, J.A.; Joshy, M. Antibiotic resistance in Escherichia coli isolates from poultry environment and UTI patients in Kerala, India: A comparison study. Comp. Immunol. Microbiol. Infect. Dis. 2021, 75, 101614. [Google Scholar] [CrossRef]
  72. van Hoek, A.H.A.M.; Dierikx, C.; Bosch, T.; Schouls, L.; van Duijkeren, E.; Visser, M. Transmission of ESBL-producing Escherichia coli between broilers and humans on broiler farms. J. Antimicrob. Chemother. 2020, 75, 543–549. [Google Scholar] [CrossRef]
  73. Toombs-Ruane, L.J.; Benschop, J.; French, N.P.; Biggs, P.J.; Midwinter, A.C.; Marshall, J.C.; Chan, M.; Drinković, D.; Fayaz, A.; Baker, M.G.; et al. Carriage of extended-spectrum-beta-lactamase- and AmpC beta-lactamase-producing Escherichia coli strains from humans and pets in the same households. Appl. Environ. Microbiol. 2020, 86, e01613-20. [Google Scholar] [CrossRef] [PubMed]
  74. Marchetti, L.; Buldain, D.; Gortari Castillo, L.; Buchamer, A.; Chirino-Trejo, M.; Mestorino, N. Pet and stray dogs as reservoirs of antimicrobial-resistant Escherichia coli. Int. J. Microbiol. 2021, 2021, 6664557. [Google Scholar] [CrossRef] [PubMed]
  75. Wang, H.; Wang, H.; Yu, X.; Zhou, H.; Li, B.; Chen, G.; Ye, Z.; Wang, Y.; Cui, X.; Zheng, Y.; et al. Impact of antimicrobial stewardship managed by clinical pharmacists on antibiotic use and drug resistance in a Chinese hospital, 2010–2016: A retrospective observational study. BMJ Open 2019, 9, e026072. [Google Scholar] [CrossRef] [PubMed]
  76. Aliabadi, S.; Anyanwu, P.; Beech, E.; Jauneikaite, E.; Wilson, P.; Hope, R.; Majeed, A.; Muller-Pebody, B.; Costelloe, C. Effect of antibiotic stewardship interventions in primary care on antimicrobial resistance of Escherichia coli bacteraemia in England (2013-18): A quasi-experimental, ecological, data linkage study. Lancet Infect. Dis. 2021, 21, 1689–1700. [Google Scholar] [CrossRef] [PubMed]
  77. Peñalva, G.; Fernández-Urrusuno, R.; Turmo, J.M.; Hernández-Soto, R.; Pajares, I.; Carrión, L.; Vázquez-Cruz, I.; Botello, B.; García-Robredo, B.; Cámara-Mestres, M.; et al. Long-term impact of an educational antimicrobial stewardship programme in primary care on infections caused by extended-spectrum β-lactamase-producing Escherichia coli in the community: An interrupted time-series analysis. Lancet Infect. Dis. 2020, 20, 199–207. [Google Scholar] [CrossRef]
  78. Esteve-Palau, E.; Grau, S.; Herrera, S.; Sorlí, L.; Montero, M.; Segura, C.; Durán, X.; Horcajada, J.P. Impact of an antimicrobial stewardship program on urinary tract infections caused by extended-spectrum β-lactamase-producing Escherichia coli. Rev. Esp. Quimioter. Span. J. Chemother. 2018, 31, 110–117. [Google Scholar]
  79. Ziv-On, E.; Friger, M.D.; Saidel-Odes, L.; Borer, A.; Shimoni, O.; Nikonov, A.; Nesher, L. Impact of an antibiotic stewardship program on the incidence of resistant Escherichia coli: A quasi-experimental study. Antibiotics 2021, 10, 179. [Google Scholar] [CrossRef]
  80. Vanrompay, D.; Nguyen, T.L.A.; Cutler, S.J.; Butaye, P. Antimicrobial resistance in Chlamydiales, Rickettsia, Coxiella, and other intracellular pathogens. Microbiol. Spectr. 2018, 6, 10–128. [Google Scholar] [CrossRef]
  81. Zomorodipour, A.; Andersson, S.G. Obligate intracellular parasites: Rickettsia prowazekii and Chlamydia trachomatis. FEBS. Lett. 1999, 452, 11–15. [Google Scholar] [CrossRef]
  82. Schmitz-Esser, S.; Linka, N.; Collingro, A.; Beier, C.L.; Neuhaus, H.E.; Wagner, M.; Horn, M. ATP/ADP translocases: A common feature of obligate intracellular amoebal symbionts related to Chlamydiae and Rickettsiae. J. Bacteriol. 2004, 186, 683–691. [Google Scholar] [CrossRef]
  83. Samanta, D.; Mulye, M.; Clemente, T.M.; Justis, A.V.; Gilk, S.D. Manipulation of host cholesterol by obligate intracellular bacteria. Front. Cell. Infect. Microbiol. 2017, 7, 165. [Google Scholar] [CrossRef] [PubMed]
  84. Ray, A.; Moore, T.F.; Pandit, R.; Burke, A.D.; Borsch, D.M. An overview of selected bacterial infections in cancer, their virulence factors, and some aspects of infection management. Biology 2023, 12, 963. [Google Scholar] [CrossRef]
  85. Laurila, A.L.; Anttila, T.; Läärä, E.; Bloigu, A.; Virtamo, J.; Albanes, D.; Leinonen, M.; Saikku, P. Serological evidence of an association between Chlamydia pneumoniae infection and lung cancer. Int. J. Cancer 1997, 74, 31–34. [Google Scholar] [CrossRef]
  86. Koyi, H.; Brandén, E.; Gnarpe, J.; Gnarpe, H.; Arnholm, B.; Hillerdal, G. Chlamydia pneumoniae may be associated with lung cancer. Preliminary report on a seroepidemiological study. APMIS 1999, 107, 828–832. [Google Scholar] [CrossRef] [PubMed]
  87. Jackson, L.A.; Wang, S.P.; Nazar-Stewart, V.; Grayston, J.T.; Vaughan, T.L. Association of Chlamydia pneumoniae immunoglobulin A seropositivity and risk of lung cancer. Cancer Epidemiol. Biomark. Prev. 2000, 9, 1263–1266. [Google Scholar]
  88. Kocazeybek, B. Chronic Chlamydophila pneumoniae infection in lung cancer, a risk factor: A case-control study. J. Med. Microbiol. 2003, 52 Pt 8, 721–726. [Google Scholar] [CrossRef]
  89. Xu, X.; Liu, Z.; Xiong, W.; Qiu, M.; Kang, S.; Xu, Q.; Cai, L.; He, F. Combined and interaction effect of Chlamydia pneumoniae infection and smoking on lung cancer: A case-control study in Southeast China. BMC Cancer 2020, 20, 903. [Google Scholar] [CrossRef]
  90. Chebak, M.; Azzouzi, M.; Chaibi, H.; Fakhkhari, M.; Benamri, I.; Mguil, M.; Hajjout, K.; Zegmout, A.; Tiresse, N.; Rhorfi, I.A.; et al. Assessment of the association of Chlamydia e pneumoniae infection with lung cancer in a Moroccan patients’ cohort. Asian Pac. J. Cancer Prev. 2023, 24, 659–665. [Google Scholar] [CrossRef]
  91. Liu, Z.; Su, M.; Yu, S.C.; Yin, Z.H.; Zhou, B.S. Association of Chlamydia pneumoniae immunoglobulin G antibodies with the risk of lung cancer among non-smoking women in Liaoning, China. Thorac. Cancer 2010, 1, 126–129. [Google Scholar] [CrossRef]
  92. Drokow, E.K.; Effah, C.Y.; Agboyibor, C.; Budu, J.T.; Arboh, F.; Kyei-Baffour, P.A.; Xiao, Y.; Zhang, F.; Wu, I.X. Microbial infections as potential risk factors for lung cancer: Investigating the role of human papillomavirus and chlamydia pneumoniae. AIMS Public Health 2023, 10, 627–646. [Google Scholar] [CrossRef]
  93. Premachandra, N.M.; Jayaweera, J.A.A.S. Chlamydia pneumoniae infections and development of lung cancer: Systematic review. Infect. Agent. Cancer 2022, 17, 11. [Google Scholar] [CrossRef] [PubMed]
  94. Chaturvedi, A.K.; Gaydos, C.A.; Agreda, P.; Holden, J.P.; Chatterjee, N.; Goedert, J.J.; Caporaso, N.E.; Engels, E.A. Chlamydia pneumoniae infection and risk for lung cancer. Cancer Epidemiol. Biomark. Prev. 2010, 19, 1498–1505. [Google Scholar] [CrossRef] [PubMed]
  95. Aigelsreiter, A.; Gerlza, T.; Deutsch, A.J.; Leitner, E.; Beham-Schmid, C.; Beham, A.; Popper, H.; Borel, N.; Pospischil, A.; Raderer, M.; et al. Chlamydia psittaci Infection in nongastrointestinal extranodal MALT lymphomas and their precursor lesions. Am. J. Clin. Pathol. 2011, 135, 70–75. [Google Scholar] [CrossRef] [PubMed]
  96. Apostolou, P.; Tsantsaridou, A.; Papasotiriou, I.; Toloudi, M.; Chatziioannou, M.; Giamouzis, G. Bacterial and fungal microflora in surgically removed lung cancer samples. J. Cardiothorac. Surg. 2011, 6, 137. [Google Scholar] [CrossRef] [PubMed]
  97. Mishkin, N.; Miranda, I.C.; Carrasco, S.E.; Cheleuitte-Nieves, C.; Arbona, R.R.J.; Wingert, C.; Sun, J.C.; Lipman, N.S. Chlamydia muridarum associated pulmonary and urogenital disease and pathology in a colony of enzootically infected Il12rb2 deficient and Stat1 knockout mice. Comp. Med. 2024, 74, 121–129. [Google Scholar] [CrossRef]
  98. Chu, D.J.; Guo, S.G.; Pan, C.F.; Wang, J.; Du, Y.; Lu, X.F.; Yu, Z.Y. An experimental model for induction of lung cancer in rats by Chlamydia pneumoniae. Asian Pac. J. Cancer Prev. 2012, 13, 2819–2822. [Google Scholar] [CrossRef]
  99. Rizzo, A.; Carratelli, C.R.; De Filippis, A.; Bevilacqua, N.; Tufano, M.A.; Buommino, E. Transforming activities of Chlamydia pneumoniae in human mesothelial cells. Int. Microbiol. 2014, 17, 185–193. [Google Scholar]
  100. Chu, D.J.; Yao, D.E.; Zhuang, Y.F.; Hong, Y.; Zhu, X.C.; Fang, Z.R.; Yu, J.; Yu, Z.Y. Azithromycin enhances the favorable results of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer. Genet. Mol. Res. 2014, 13, 2796–2805. [Google Scholar] [CrossRef]
  101. Chen, Z.; Zhuang, J.; Liu, M.; Xu, X.; Liu, Y.; Yang, S.; Xie, J.; Lin, N.; Lai, F.; He, F. Longitudinal analysis of quality of life in primary lung cancer patients with chlamydia pneumoniae infection: A time-to-deterioration model. BMC Pulm. Med. 2024, 24, 36. [Google Scholar] [CrossRef]
  102. Zhang, W.; Qiao, T.; Zhou, D.; Yuan, S. Correlation between Chlamydia pneumoniae IgG positive in lung cancer patients and cytokines related to radiation-induced pulmonary lesion. Zhongguo Fei Ai Za Zhi Chin. J. Lung Cancer 2011, 14, 132–136. [Google Scholar]
  103. Zele-Starcević, L.; Plecko, V.; Budimir, A.; Kalenić, S. Choice of antimicrobial drug for infections caused by Chlamydia trachomatis and Chlamydophila pneumoniae. Acta Med. Croat. 2004, 58, 329–333. [Google Scholar]
  104. Shao, L.; You, C.; Cao, J.; Jiang, Y.; Liu, Y.; Liu, Q. High treatment failure rate is better explained by resistance gene detection than by minimum inhibitory concentration in patients with urogenital Chlamydia trachomatis infection. Int. J. Infect. Dis. 2020, 96, 121–127. [Google Scholar] [CrossRef] [PubMed]
  105. Lu, H.; Yuan, J.; Wu, Z.; Wang, L.; Wu, S.; Chen, Q.; Zhang, Z.; Chen, Z.; Zou, X.; Hu, Q.; et al. Distribution of drug-resistant genes in alveolar lavage fluid from patients with psittacosis and traceability analysis of causative organisms. Front. Microbiol. 2023, 14, 1182604. [Google Scholar] [CrossRef] [PubMed]
  106. Borges, V.; Isidro, J.; Correia, C.; Cordeiro, D.; Vieira, L.; Lodhia, Z.; Fernandes, C.; Rodrigues, A.M.; Azevedo, J.; Alves, J.; et al. Transcontinental Dissemination of the L2b/D-Da Recombinant Chlamydia trachomatis lymphogranuloma venereum (LGV) Strain: Need of broad multi-country molecular surveillance. Clin. Infect. Dis. 2021, 73, e1004–e1007. [Google Scholar] [CrossRef] [PubMed]
  107. Pitt, R.; Doyle, R.; Theilgaard Christiansen, M.; Horner, P.; Hathorn, E.; Alexander, S.; Woodford, N.; Cole, M.; Breuer, J. Whole-genome sequencing of Chlamydia trachomatis isolates from persistently infected patients. Int. J. STD AIDS 2022, 33, 442–446. [Google Scholar] [CrossRef]
  108. Páez-Canro, C.; Alzate, J.P.; González, L.M.; Rubio-Romero, J.A.; Lethaby, A.; Gaitán, H.G. Antibiotics for treating urogenital Chlamydia trachomatis infection in men and non-pregnant women. Cochrane Database Syst. Rev. 2019, 1, CD010871. [Google Scholar] [CrossRef]
  109. O’Brien, K.S.; Emerson, P.; Hooper, P.J.; Reingold, A.L.; Dennis, E.G.; Keenan, J.D.; Lietman, T.M.; Oldenburg, C.E. Antimicrobial resistance following mass azithromycin distribution for trachoma: A systematic review. Lancet Infect. Dis. 2019, 19, e14–e25. [Google Scholar] [CrossRef]
  110. Maldonado-Calderón, J.L.; López-Márquez, F.C.; Ruiz-Flores, P. Azithromycin as a treatment for Chlamydia trachomatis? Gac. Med. Mex. 2018, 154, 689–692. [Google Scholar]
  111. Chaiwattanarungruengpaisan, S.; Thongdee, M.; Arya, N.; Paungpin, W.; Sirimanapong, W.; Sariya, L. Diversity and genetic characterization of Chlamydia isolated from Siamese crocodiles (Crocodylus siamensis). Acta Trop. 2024, 253, 107183. [Google Scholar] [CrossRef]
  112. Marti, H.; Suchland, R.J.; Rockey, D.D. The impact of lateral gene transfer in Chlamydia. Front. Cell. Infect. Microbiol. 2022, 12, 861899. [Google Scholar] [CrossRef]
  113. Unterweger, C.; Schwarz, L.; Jelocnik, M.; Borel, N.; Brunthaler, R.; Inic-Kanada, A.; Marti, H. Isolation of tetracycline-resistant Chlamydia suis from a pig herd affected by reproductive disorders and conjunctivitis. Antibiotics 2020, 9, 187. [Google Scholar] [CrossRef] [PubMed]
  114. Bommana, S.; Polkinghorne, A. Mini review: Antimicrobial control of Chlamydial infections in animals: Current practices and issues. Front. Microbiol. 2019, 10, 113. [Google Scholar] [CrossRef] [PubMed]
  115. Wahdan, A.; Rohner, L.; Marti, H.; Bacciarini, L.N.; Menegatti, C.; Di Francesco, A.; Borel, N. Prevalence of Chlamydiaceae and tetracycline resistance genes in wild boars of Central Europe. J. Wildl. Dis. 2020, 56, 512–522. [Google Scholar] [CrossRef] [PubMed]
  116. Di Francesco, A.; Morandi, F.; Marti, H.; Santagati, C.; Borel, N. Chlamydia suis and tetracycline resistance genes in Italian wild boar (Sus scrofa). Vet. Ital. 2021, 57, 151–154. [Google Scholar] [CrossRef]
  117. Shima, K.; Coopmeiners, J.; Graspeuntner, S.; Dalhoff, K.; Rupp, J. Impact of micro-environmental changes on respiratory tract infections with intracellular bacteria. FEBS Lett. 2016, 590, 3887–3904. [Google Scholar] [CrossRef]
  118. Matsuo, J.; Sakai, K.; Okubo, T.; Yamaguchi, H. Chlamydia pneumoniae enhances Interleukin 8 (IL-8) production with reduced azithromycin sensitivity under hypoxia. APMIS 2019, 127, 131–138. [Google Scholar] [CrossRef]
  119. Harvie, M.C.; Carey, A.J.; Armitage, C.W.; O’Meara, C.P.; Peet, J.; Phillips, Z.N.; Timms, P.; Beagley, K.W. Chlamydia-infected macrophages are resistant to azithromycin treatment and are associated with chronic oviduct inflammation and hydrosalpinx development. Immunol. Cell Biol. 2019, 97, 865–876. [Google Scholar] [CrossRef]
  120. Fong, C.K.; Yang-Feng, T.L.; Lerner-Tung, M.B. Re-examination of the McCoy cell line for confirmation of its mouse origin: Karyotyping, electron microscopy and reverse transcriptase assay for endogenous retrovirus. Clin. Diagn. Virol. 1994, 2, 95–103. [Google Scholar] [CrossRef]
  121. Gorphe, P. A comprehensive review of Hep-2 cell line in translational research for laryngeal cancer. Am. J. Cancer Res. 2019, 9, 644–649. [Google Scholar]
  122. Wang, S.A.; Papp, J.R.; Stamm, W.E.; Peeling, R.W.; Martin, D.H.; Holmes, K.K. Evaluation of antimicrobial resistance and treatment failures for Chlamydia trachomatis: A meeting report. J. Infect. Dis. 2005, 191, 917–923. [Google Scholar] [CrossRef]
  123. Mestrovic, T.; Ljubin-Sternak, S. Molecular mechanisms of Chlamydia trachomatis resistance to antimicrobial drugs. Front. Biosci. Landmark Ed. 2018, 23, 656–670. [Google Scholar] [CrossRef] [PubMed]
  124. Benamri, I.; Azzouzi, M.; Sanak, K.; Moussa, A.; Radouani, F. An overview of genes and mutations associated with Chlamydiae species’ resistance to antibiotics. Ann. Clin. Microbiol. Antimicrob. 2021, 20, 59. [Google Scholar] [CrossRef] [PubMed]
  125. Koskela, P.; Anttila, T.; Bjørge, T.; Brunsvig, A.; Dillner, J.; Hakama, M.; Hakulinen, T.; Jellum, E.; Lehtinen, M.; Lenner, P.; et al. Chlamydia trachomatis infection as a risk factor for invasive cervical cancer. Int. J. Cancer 2000, 85, 35–39. [Google Scholar] [CrossRef]
  126. Bhuvanendran Pillai, A.; Mun Wong, C.; Dalila Inche Zainal Abidin, N.; Fazlinda Syed Nor, S.; Fathulzhafran Mohamed Hanan, M.; Rasidah Abd Ghani, S.; Afzan Aminuddin, N.; Safian, N. Chlamydia infection as a risk factor for cervical cancer: A systematic review and meta-analysis. Iran. J. Public Health 2022, 51, 508–517. [Google Scholar] [CrossRef] [PubMed]
  127. Idahl, A.; Le Cornet, C.; González Maldonado, S.; Waterboer, T.; Bender, N.; Tjønneland, A.; Hansen, L.; Boutron-Ruault, M.C.; Fournier, A.; Kvaskoff, M.; et al. Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: Results from the EPIC cohort. Int. J. Cancer 2020, 147, 2042–2052. [Google Scholar] [CrossRef]
  128. Krupp, K.; Madhivanan, P. Antibiotic resistance in prevalent bacterial and protozoan sexually transmitted infections. Indian J. Sex. Transm. Dis. AIDS 2015, 36, 3–8. [Google Scholar]
  129. Wang, S.; Guo, R.; Guo, Y.L.; Shao, L.L.; Liu, Y.; Wei, S.J.; Liu, Y.J.; Liu, Q.Z. Biological effects of chlamydiaphage phiCPG1 capsid protein Vp1 on chlamydia trachomatis in vitro and in vivo. J. Huazhong Univ. Sci. Technol. Med. Sci. 2017, 37, 115–121. [Google Scholar] [CrossRef]
  130. Rosenwald, A.G.; Murray, B.; Toth, T.; Madupu, R.; Kyrillos, A.; Arora, G. Evidence for horizontal gene transfer between Chlamydophila pneumoniae and Chlamydia phage. Bacteriophage 2014, 4, e965076. [Google Scholar] [CrossRef]
  131. Śliwa-Dominiak, J.; Suszyńska, E.; Pawlikowska, M.; Deptuła, W. Chlamydia bacteriophages. Arch. Microbiol. 2013, 195, 765–771. [Google Scholar] [CrossRef]
  132. Hoestgaard-Jensen, K.; Christiansen, G.; Honoré, B.; Birkelund, S. Influence of the Chlamydia pneumoniae AR39 bacteriophage CPAR39 on chlamydial inclusion morphology. FEMS Immunol. Med. Microbiol. 2011, 62, 148–1456. [Google Scholar] [CrossRef]
  133. Salim, O.; Skilton, R.J.; Lambden, P.R.; Fane, B.A.; Clarke, I.N. Behind the chlamydial cloak: The replication cycle of chlamydiaphage Chp2, revealed. Virology 2008, 377, 440–445. [Google Scholar] [CrossRef] [PubMed]
  134. Wei, S.; Liu, Q.; Lian, T.; Shao, L. The phiCPG1 chlamydiaphage can infect Chlamydia trachomatis and significantly reduce its infectivity. Virus Res. 2019, 267, 1–8. [Google Scholar] [CrossRef] [PubMed]
  135. Summers, W.C. The strange history of phage therapy. Bacteriophage 2012, 2, 130–133. [Google Scholar] [CrossRef] [PubMed]
  136. Chanishvili, N. Phage therapy--history from Twort and d’Herelle through Soviet experience to current approaches. Adv. Virus Res. 2012, 83, 3–40. [Google Scholar]
  137. Brives, C.; Pourraz, J. Phage therapy as a potential solution in the fight against AMR: Obstacles and possible futures. Palgrave Commun. 2020, 6, 100. [Google Scholar] [CrossRef]
  138. Principi, N.; Silvestri, E.; Esposito, S. Advantages and limitations of bacteriophages for the treatment of bacterial infections. Front. Pharmacol. 2019, 10, 513. [Google Scholar] [CrossRef]
  139. Sharma, S.; Chatterjee, S.; Datta, S.; Prasad, R.; Dubey, D.; Prasad, R.K.; Vairale, M.G. Bacteriophages and its applications: An overview. Folia Microbiol. 2017, 62, 17–55. [Google Scholar] [CrossRef]
  140. Wang, X.; Xu, Z.; Xia, Y.; Chen, Z.; Zong, R.; Meng, Q.; Wang, W.; Zhuang, W.; Meng, X.; Chen, G. Characterization of an Escherichia coli phage Tequatrovirus YZ2 and its application in bacterial wound infection. Virology 2024, 597, 110155. [Google Scholar] [CrossRef]
  141. Tomat, D.; Mercanti, D.; Balagué, C.; Quiberoni, A. Phage biocontrol of enteropathogenic and Shiga toxin-producing Escherichia coli during milk fermentation. Lett. Appl. Microbiol. 2013, 57, 3–10. [Google Scholar] [CrossRef]
  142. Sarker, S.A.; Sultana, S.; Reuteler, G.; Moine, D.; Descombes, P.; Charton, F.; Bourdin, G.; McCallin, S.; Ngom-Bru, C.; Neville, T.; et al. Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: A randomized trial in children from Bangladesh. EBioMedicine 2016, 4, 124–137. [Google Scholar] [CrossRef]
  143. Nikulin, N.; Nikulina, A.; Zimin, A.; Aminov, R. Phages for treatment of Escherichia coli infections. Prog. Mol. Biol. Transl. Sci. 2023, 200, 171–206. [Google Scholar] [PubMed]
  144. Pakbin, B.; Brück, W.M.; Rossen, J.W.A. Virulence factors of enteric pathogenic Escherichia coli: A review. Int. J. Mol. Sci. 2021, 22, 9922. [Google Scholar] [CrossRef] [PubMed]
  145. Galtier, M.; De Sordi, L.; Sivignon, A.; de Vallée, A.; Maura, D.; Neut, C.; Rahmouni, O.; Wannerberger, K.; Darfeuille-Michaud, A.; Desreumaux, P.; et al. Bacteriophages targeting adherent invasive Escherichia coli strains as a promising new treatment for Crohn’s disease. J. Crohns Colitis 2017, 11, 840–847. [Google Scholar] [CrossRef]
  146. Titécat, M.; Rousseaux, C.; Dubuquoy, C.; Foligné, B.; Rahmouni, O.; Mahieux, S.; Desreumaux, P.; Woolston, J.; Sulakvelidze, A.; Wannerberger, K.; et al. Safety and efficacy of an AIEC-targeted bacteriophage cocktail in a mice colitis model. J. Crohns Colitis 2022, 16, 1617–1627. [Google Scholar] [CrossRef] [PubMed]
Medicina 60 01515 g001
Figure 1. An overview of the global cancer burden and relevant adult derivatives of the primitive gut tube. * Source: The World Health Organization (News release: 1 February 2024). The midgut-hindgut junction is situated between the right two-thirds and the left third of the transverse colon (which extends from the hepatic or right colic flexure to the left colic flexure).
Figure 1. An overview of the global cancer burden and relevant adult derivatives of the primitive gut tube. * Source: The World Health Organization (News release: 1 February 2024). The midgut-hindgut junction is situated between the right two-thirds and the left third of the transverse colon (which extends from the hepatic or right colic flexure to the left colic flexure).
Medicina 60 01515 g001
Medicina 60 01515 g002
Figure 2. Gram-negative Escherichia coli and different surface structures. (A) Microscopic view of E. coli (100×, oil-immersion). (B) Magnification of a part of the microscopic view of (A) by the camera system (10 times). (C) Enlargement of an E. coli to show bacterial appendages (manual expansion and placed obliquely, according to the position of hand-drawn E. coli in (D)). (D) Sketch of an E. coli.
Figure 2. Gram-negative Escherichia coli and different surface structures. (A) Microscopic view of E. coli (100×, oil-immersion). (B) Magnification of a part of the microscopic view of (A) by the camera system (10 times). (C) Enlargement of an E. coli to show bacterial appendages (manual expansion and placed obliquely, according to the position of hand-drawn E. coli in (D)). (D) Sketch of an E. coli.
Medicina 60 01515 g002
Medicina 60 01515 g003
Figure 3. The life cycle of Chlamydia—development of the elementary and reticulate bodies.
Figure 3. The life cycle of Chlamydia—development of the elementary and reticulate bodies.
Medicina 60 01515 g003
Table 1. Results of different clinical trials that showed the plausible role of probiotics (mainly Lactobacilli and Bifidobacterium) in the modification of gut microbiota and overall disease course among patients with inflammatory bowel disease.
Table 1. Results of different clinical trials that showed the plausible role of probiotics (mainly Lactobacilli and Bifidobacterium) in the modification of gut microbiota and overall disease course among patients with inflammatory bowel disease.
InvestigatorsStudy DesignFindings
Bengtsson et al., 2016 (Sweden) [26]Patients with poor pouch function after restorative operative procedure for ulcerative colitis: probiotic group (n = 17, Lactobacillus plantarum and Bifidobacterium infantis) and placebo (n = 16).There was no statistically significant difference between the two groups—probiotics did not improve pouch-associated dysfunction.
Fan et al., 2019 (China) [27]40 patients with IBD: control group (n = 19, treatment with mesalazine) and probiotic group (n = 21, mesalazine + probiotics).After treatment, fecal bacterial counts decreased significantly in both groups, but the number of Lactobacilli and Bifidobacterium increased significantly only in the probiotic group, which also showed lower levels of inflammatory markers (IL-6 and hs-CRP).
Fedorak et al., 2015 (Canada) [28]Patients with Crohn’s disease within 1 month of ileocolonic resection and re-anastomosis: probiotic group (n = 59; received Lactobacillus—4 strains, Bifidobacterium—3 strains, and Streptococcus salivarius—thermophilus), and placebo (n = 60).At day 90, there were no statistical differences between the probiotic and placebo groups. However, lower mucosal levels of inflammatory cytokines (e.g., IL-1β and IL-8) and a lower rate of recurrence in the probiotic group were noted.
Groeger et al., 2013 (Ireland) [29]Probiotic feeding: ulcerative colitis (n = 22) for 6 weeks; psoriasis (n = 26), chronic fatigue syndrome (n = 48), healthy subjects with probiotic intake (n = 10), and healthy subjects with placebo (n = 12) for 8 weeks.Probiotic consumption (Bifidobacterium infantis) resulted in diminished blood CRP levels in all disorders compared to placebo. Blood levels of IL-6 were decreased in ulcerative colitis.
Matsuoka et al., 2018 (Japan) [30]195 patients with ulcerative colitis: placebo (n = 97) and probiotic group (n = 98, Bifidobacterium breve and Lactobacillus acidophilus).There were no significant differences between the two groups. However, regardless of treatment, there was a significant reduction in Bifidobacterium species before relapse.
Palumbo et al., 2016 (Italy) [31]Ulcerative colitis: 30 patients—mesalazine treatment, 30 patients—mesalazine + probiotics (Lactobacillus acidophilus, Lactobacillus salivarius, and Bifidobacterium bifidus). The treatment was continued for 2 years.Patients with combination treatment displayed better improvement in comparison with the mesalazine group.
Shadnoush et al., 2015 (Iran) [32]105 IBD patients with probiotic yogurt, 105 IBD patients with placebo, and 95 healthy persons with yogurt (intervention for 8 weeks).The mean numbers of Lactobacillus, Bifidobacterium, and Bacteroides in the stool specimens among IBD patients receiving yogurt were significantly increased.
Tamaki et al., 2016 (Japan) [33]Patients with active ulcerative colitis: probiotic group (n = 24, Bifidobacterium longum) and placebo (n = 23)—clinical trial for 8 weeks.Probiotic supplementation decreased UCDAI scores.
IBD: Inflammatory bowel disease, Mesalazine (5-aminosalicylic acid): anti-inflammatory drug primarily used in ulcerative colitis, IL: Interleukin, hs-CRP: high-sensitivity–C-reactive protein, UCDAI: Ulcerative Colitis Disease Activity Index, which considers stool frequency, rectal bleeding, mucosal appearance, and clinical assessment (higher scores → severe disease).
Table 2. Selected recent studies that showed a link between E. coli infections and colon cancer development or associated clinicopathologic events.
Table 2. Selected recent studies that showed a link between E. coli infections and colon cancer development or associated clinicopathologic events.
Investigators, Place of Study, and Study PlanResults in Brief
Butt et al., 2021 (6 Western European countries) [57]
The European Prospective Investigation into Nutrition and Cancer (EPIC) study—pre-diagnostic serum samples from incident colon cancer cases and matched controls (n = 442 pairs).		Immunoglobulin A (IgA) seropositivity to E. coli protein Ag43 and IgG seropositivity to enterotoxigenic Bacteroides fragilis toxin BFT-1 were significantly associated with higher odds of developing cancer.
He et al., 2021 (China) [58]
Fecal samples from 61 colon cancer patients and 72 normal persons were analyzed to evaluate the microbial diversity and composition.		In comparison to the normal control group, the numbers of E. coli, along with Prevetella copri, were significantly higher among cancer patients.
Iwasaki et al., 2022 (Japan) [59]
543 participants with colonic growth (22 cancer and 521 adenomas) and 425 participants with normal colon (controls). The study aimed to assess the prevalence of E. coli containing polyketide synthase (pks).		The percentage of pks+ E coli was 32.6% among cases (cancer and adenoma) and 30.8% among controls. There was no statistically significant association between pks+ E coli and colonic lesions.
Iyadorai et al., 2020 (Malaysia) [60]
Fresh tissue samples from 48 colon cancer patients (both malignant and nearby non-malignant tissues) and 23 healthy controls (normal colon tissues) were collected for the detection of pks+ E coli.		8 colon cancer patients (16.7%) and 1 healthy control (4.3%) were found to be positive for pks+ E. coli.
Kamali Dolatabadi et al., 2022 (Iran) [61]
Colorectal tissue samples were collected from 150 subjects during colonoscopy: 30 subjects with normal results, 30 subjects with normal results but a positive family history of colon cancer, 30 subjects with normal results but a history of colon cancer, 30 patients with adenocarcinoma-in-situ, and 30 patients with adenocarcinoma.		74 intracellular E. coli were isolated from all subjects (among them, there were 24 adherent-invasive E. coli/AIEC strains). The majority were isolated from rectal specimens (31/74). AIEC strains generally belonged to B2 and D phylogenetic groups.
López-Siles et al., 2022 (Spain) [62]
AIEC phenotype was examined in 4233 E. coli isolated from the ileum and colon biopsy samples from 14 ulcerative colitis and 15 colon cancer patients.		Regarding the prevalence of AIEC, one cancer patient had AIEC-like isolates (6.7%), whereas 5 patients with ulcerative colitis harbored AIEC-like isolates (35.7%). All AIEC-like strains belonged to the B1 phylogroup except one, which was isolated from an ulcerative colitis patient.
Messaritakis et al., 2020 (Greece) [63]
Microbial DNA fragments in peripheral blood were analyzed for the β-galactosidase gene of E. coli (along with the glutamine synthase gene of B. fragilis and DNA coding for 5.8S rRNA of Candida albicans) from 397 colon cancer patients and 32 healthy blood donors.		E. coli β-galactosidase gene was detected in 104 patients (26.2%). Detection of these microbial fragments was significantly associated with metastatic disease and prognosis.
Mirzarazi et al., 2022 (Iran) [64]
Fecal samples were collected from 20 newly diagnosed colon cancer patients (before treatment) and 50 healthy persons.		55% of E.coli isolates from patients’ samples, and 26% of E. coli from healthy persons belonged to the B2 phylogenetic group. Moreover, the outer membrane protein A (OmpA) was overexpressed in the E. coli B2 phylogenetic group isolated from cancer patients, compared to the control group. The protein significantly decreased the expression of pro-apoptotic genes (Bax and Bak) and p53.
Rondepierre et al., 2024 (France) [65]
Patients with colon cancer were evaluated for present and lifetime psychiatric problems. Out of 64 suitable patients, 12 participated. In this limited cohort, patients were followed up after surgery.		All patients with colonization by colibactin-producing E. coli presented with psychiatric disorders several years before cancer diagnosis.
Wachsmannova et al., 2018 (Slovakia) [66]
Analysis was performed to identify the presence of intracellular bacteria in colorectal biopsy samples that were collected from 10 colon cancer patients, 10 cases with adenomas, and 9 healthy controls.		The noticeable increase in intracellular E. coli in patients with carcinoma and colorectal adenomas was statistically significant in comparison to biopsy tissue samples from controls.
Table 3. Two extensively studied Gram-negative obligate intracellular bacteria and associated diseases.
Table 3. Two extensively studied Gram-negative obligate intracellular bacteria and associated diseases.
BacteriaSpeciesDiseases
ChlamydiaeChlamydia trachomatisTrachoma biovar (serovars- A, B, Ba, C)Trachoma: chronic conjunctivitis, visual impairment, blindness
Genital tract biovar (serovars- D, E, F, G, H, I, J, K)Non-specific urethritis, prostatitis, epididymitis, infertility, cervicitis, pelvic inflammatory disease, ectopic pregnancy, premature delivery, inclusion conjunctivitis, neonatal pneumonia; can promote HIV infection and cervical cancer pathogenesis
LGV biovar (serovars- L1, L2, L3)Lymphogranuloma venereum
Chlamydia pneumoniaePharyngitis, sinusitis, ear infection, laryngitis, bronchitis, pneumonia; may contribute to asthma, arthritis, atherosclerosis, myocarditis and encephalitis
Chlamydia psittaciRespiratory infection (psittacosis), pneumonia; can initiate complications such as hepatitis, endocarditis, and inflammation of the nerves/brain
Spread by (vectors)
RickettsiaeRickettsia rickettsiiTicksRocky Mountain spotted fever
Rickettsia akariMouse miteRickettsialpox
Rickettsia conoriiTicksMediterranean spotted fever or Boutonneuse fever (ssp. Conorii, spread by dog tick); Indian tick typhus (ssp. Indica); Israeli spotted fever (ssp. Israelensis)
Rickettsia sibiricaTicksNorth Asian or Siberian tick typhus
Rickettsia australisTicksAustralian tick typhus or Queensland tick typhus
Rickettsia felisFleaPseudotyphus of California
Rickettsia japonicaTicksJapanese spotted fever
Rickettsia africaeTicksAfrican tick bite fever
Rickettsia prowazekiiBody liceEpidemic typhus or sylvatic typhus (contact with flying squirrels)
Rickettsia typhiFleasEndemic typhus or murine typhus
Orientia tsutsugamushi (family Rickettsiaceae)MitesScrub typhus
HIV: human immunodeficiency virus; ssp.: subspecies. Musca flies can be a vector for trachoma (due to their capability to spread Chlamydia trachomatis). The trachoma biovar remains at the mucosal surface, whereas LGV infects the lymphatic system. Psittacosis is a zoonotic disease.
Table 4. Chlamydial genes that may negatively influence the effectiveness of antibiotic treatment.
Table 4. Chlamydial genes that may negatively influence the effectiveness of antibiotic treatment.
Antimicrobial AgentsChlamydia SpeciesMutated Genes
Macrolides (azithromycin, erythromycin)C. trachomatis23S rRNA, rplD, rplV
C. psittaci23S rRNA
Tetracyclines (tetracycline, doxycycline, minocycline)C. trachomatistetA, tetR, rpoB
Fluoroquinolone (ciprofloxacin, ofloxain, sparfloxacin)C. trachomatisgyrA, parC, ygeD
C. pneumoniaegyrA
Rifamycins (rifampin)C. trachomatis, C. pneumoniaerpoB
Aminoglycosides (gentamicin, streptomycin, kasugamycin)C. trachomatisksgA
C. psittaci16S rRNA, rpoB
LincomycinC. trachomatis23S rRNA
FosfomycinC. trachomatismurA
TrimethoprimC. trachomatisfolA
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Ray, A.; Moore, T.F.; Naik, D.S.L.; Borsch, D.M. Insights into the Two Most Common Cancers of Primitive Gut-Derived Structures and Their Microbial Connections. Medicina 2024, 60, 1515. https://doi.org/10.3390/medicina60091515

AMA Style

Ray A, Moore TF, Naik DSL, Borsch DM. Insights into the Two Most Common Cancers of Primitive Gut-Derived Structures and Their Microbial Connections. Medicina. 2024; 60(9):1515. https://doi.org/10.3390/medicina60091515

Chicago/Turabian Style

Ray, Amitabha, Thomas F. Moore, Dayalu S. L. Naik, and Daniel M. Borsch. 2024. "Insights into the Two Most Common Cancers of Primitive Gut-Derived Structures and Their Microbial Connections" Medicina 60, no. 9: 1515. https://doi.org/10.3390/medicina60091515

APA Style

Ray, A., Moore, T. F., Naik, D. S. L., & Borsch, D. M. (2024). Insights into the Two Most Common Cancers of Primitive Gut-Derived Structures and Their Microbial Connections. Medicina, 60(9), 1515. https://doi.org/10.3390/medicina60091515

Article Metrics

Back to TopTop