Stratification of human gut microbiomes by succinotype is associated with inflammatory bowel disease status.

BACKGROUND: The human gut microbiome produces and consumes a variety of compounds that interact with the host and impact health. Succinate is of particular interest as it intersects with both host and microbiome metabolism. However, which gut bacteria are most responsible for the consumption of intestinal succinate is poorly understood. RESULTS: We build upon an enrichment-based whole fecal sample culturing approach and identify two main bacterial taxa that are responsible for succinate consumption in the human intestinal microbiome, Phascolarctobacterium and Dialister. These two taxa have the hallmark of a functional guild and are strongly mutual exclusive across 21,459 fecal samples in 94 cohorts and can thus be used to assign a robust "succinotype" to an individual. We show that they differ with respect to their rate of succinate consumption in vitro and that this is associated with higher concentrations of fecal succinate. Finally, individuals suffering from inflammatory bowel disease (IBD) are more likely to have the Dialister succinotype compared to healthy subjects. CONCLUSIONS: We identified that only two bacterial genera are the key succinate consumers in human gut microbiome, despite the fact that many more intestinal bacteria encode for the succinate pathway. This highlights the importance of phenotypic assays in functionally profiling intestinal microbiota. A stratification based on "succinotype" is to our knowledge the first function-based classification of human intestinal microbiota. The association of succinotype with IBD thus builds a bridge between microbiome function and IBD pathophysiology related to succinate homeostasis. Video Abstract.

Beyond bacteria: Role of non-bacterial gut microbiota species in inflammatory bowel disease and colorectal cancer progression.

This letter emphasizes the need to expand discussions on gut microbiome's role in inflammatory bowel disease (IBD) and colorectal cancer (CRC) by including the often-overlooked non-bacterial components of the human gut flora. It highlights how viral, fungal and archaeal inhabitants of the gut respond towards gut dys-biosis and contribute to disease progression. Viruses such as bacteriophages target certain bacterial species and modulate the immune system. Other viruses found associated include Epstein-Barr virus, human papillomavirus, John Cunningham virus, cytomegalovirus, and human herpes simplex virus type 6. Fungi such as Candida albicans and Malassezia contribute by forming tissue-invasive filaments and producing inflammatory cytokines, respectively. Archaea, mainly metha-nogens are also found altering the microbial fermentation pathways. This corres-pondence, thus underscores the significance of considering the pathological and physiological mechanisms of the entire spectrum of the gut microbiota to develop effective therapeutic interventions for both IBD and CRC.

Dual-targeted treatment for inflammatory bowel disease: Whether fecal microbiota transplantation can be an important part of it.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disease. With the emergence of biologics and other therapeutic methods, two biologics or one biologic combined with a novel small-molecule drug has been proposed in recent years to treat IBD. Although treatment strategies for IBD are being optimized, their efficacy and risks still warrant further consideration. This editorial explores the current risks associated with dual-targeted treatment for IBD and the great potential that fecal microbiota transplantation (FMT) may have for use in combination therapy for IBD. We are focused on addressing refractory IBD or biologically resistant IBD based on currently available dual-targeted treatment by incorporating FMT as part of this dual-targeted treatment. In this new therapy regimen, FMT represents a promising combination therapy.

Gut microbiome therapy: fecal microbiota transplantation vs live biotherapeutic products.

The human intestine hosts a complex ecosystem of various microorganisms, collectively known as the gut microbiome, which significantly impacts human health. Disruptions in the gut microbiome are linked to various disorders, including gastrointestinal diseases, such as Clostridioides difficile infection and inflammatory bowel disease, as well as metabolic, neurological, oncologic conditions. Fecal microbiota transplantation (FMT) and live biotherapeutic products (LBPs) have emerged as prospective therapeutic procedures to restore microbial and metabolic balance in the gut. This review assesses the latest advancements, challenges, and therapeutic efficacy of FMT and LBPs, highlighting the need for standardization, safety, and long-term evaluation to optimize their clinical application.

Dysbiotic signatures and diagnostic potential of gut microbial markers for inflammatory bowel disease in Korean population.

Fecal samples were collected from 640 individuals in Korea, including 523 patients with IBD (223 with Crohn's disease [CD] and 300 with ulcerative colitis [UC]) and 117 healthy controls. The samples were subjected to cross-sectional gut metagenomic analysis using 16 S rRNA sequencing and bioinformatics analysis. Patients with IBD, particularly those with CD, exhibited significantly lower alpha diversities than the healthy subjects. Differential abundance analysis revealed dysbiotic signatures, characterized by an expansion of the genus Escherichia-Shigella in patients with CD. Functional annotations showed that functional pathways related to bacterial pathogenesis and production of hydrogen sulfide (H2S) were strongly upregulated in patients with CD. A dysbiosis score, calculated based on functional characteristics, highly correlated with disease severity. Markers distinguishing between healthy subjects and patients with IBD showed accurate classification based on a small number of microbial taxa, which may be used to diagnose ambiguous cases. These findings confirm the taxonomic and functional dysbiosis of the gut microbiota in patients with IBD, especially those with CD. Taxa indicative of dysbiosis may have significant implications for future clinical research on the management and diagnosis of IBD.

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

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.

Follicular Skin Disorders, Inflammatory Bowel Disease, and the Microbiome: A Systematic Review.

Follicular skin disorders, including hidradenitis suppurativa (HS), frequently coexist with systemic autoinflammatory diseases, such as inflammatory bowel disease (IBD) and its subtypes, Crohn's disease and ulcerative colitis. Previous studies suggest that dysbiosis of the human gut microbiome may serve as a pathogenic link between HS and IBD. However, the role of the microbiome (gut, skin, and blood) in the context of IBD and various follicular disorders remains underexplored. Here, we performed a systematic review to investigate the relationship between follicular skin disorders, IBD, and the microbiome. Of the sixteen included studies, four evaluated the impact of diet on the microbiome in HS patients, highlighting a possible link between gut dysbiosis and yeast-exclusion diets. Ten studies explored bacterial colonization and HS severity with specific gut and skin microbiota, including Enterococcus and Veillonella. Two studies reported on immunological or serological biomarkers in HS patients with autoinflammatory disease, including IBD, and identified common markers including elevated cytokines and T-lymphocytes. Six studies investigated HS and IBD patients concurrently. Our systematic literature review highlights the complex interplay between the human microbiome, IBD, and follicular disorders with a particular focus on HS. The results indicate that dietary modifications hold promise as a therapeutic intervention to mitigate the burden of HS and IBD. Microbiota analyses and the identification of key serological biomarkers are crucial for a deeper understanding of the impact of dysbiosis in these conditions. Future research is needed to more thoroughly delineate the causal versus associative roles of dysbiosis in patients with both follicular disorders and IBD.

Antibiotics damage the colonic mucus barrier in a microbiota-independent manner.

Antibiotic use is a risk factor for development of inflammatory bowel diseases (IBDs). IBDs are characterized by a damaged mucus layer, which does not separate the intestinal epithelium from the microbiota. Here, we hypothesized that antibiotics affect the integrity of the mucus barrier, which allows bacterial penetrance and predisposes to intestinal inflammation. We found that antibiotic treatment led to breakdown of the colonic mucus barrier and penetration of bacteria into the mucus layer. Using fecal microbiota transplant, RNA sequencing followed by machine learning, ex vivo mucus secretion measurements, and antibiotic treatment of germ-free mice, we determined that antibiotics induce endoplasmic reticulum stress in the colon that inhibits colonic mucus secretion in a microbiota-independent manner. This antibiotic-induced mucus secretion flaw led to penetration of bacteria into the colonic mucus layer, translocation of microbial antigens into circulation, and exacerbation of ulcerations in a mouse model of IBD. Thus, antibiotic use might predispose to intestinal inflammation by impeding mucus production.

Vitamin B12 ameliorates gut epithelial injury via modulating the HIF-1 pathway and gut microbiota.

Inflammatory bowel diseases (IBDs) are immune chronic diseases characterized by recurrent episodes, resulting in continuous intestinal barrier damage and intestinal microbiota dysbiosis. Safe strategies aimed at stabilizing and reducing IBDs recurrence have been vigorously pursued. Here, we constructed a recurrent intestinal injury Drosophila model and found that vitamin B12 (VB12), an essential co-factor for organism physiological functions, could effectively protect the intestine and reduce dextran sulfate sodium-induced intestinal barrier disruption. VB12 also alleviated microbial dysbiosis in the Drosophila model and inhibited the growth of gram-negative bacteria. We demonstrated that VB12 could mitigate intestinal damage by activating the hypoxia-inducible factor-1 signaling pathway in injured conditions, which was achieved by regulating the intestinal oxidation. In addition, we also validated the protective effect of VB12 in a murine acute colitis model. In summary, we offer new insights and implications for the potential supportive role of VB12 in the management of recurrent IBDs flare-ups.

Integrating multi-omics to unravel host-microbiome interactions in inflammatory bowel disease.

The gut microbiome is crucial for nutrient metabolism, immune regulation, and intestinal homeostasis with changes in its composition linked to complex diseases like inflammatory bowel disease (IBD). Although the precise host-microbial mechanisms in disease pathogenesis remain unclear, high-throughput sequencing have opened new ways to unravel the role of interspecies interactions in IBD. Systems biology-a holistic computational framework for modeling complex biological systems-is critical for leveraging multi-omics datasets to identify disease mechanisms. This review highlights the significance of multi-omics data in IBD research and provides an overview of state-of-the-art systems biology resources and computational tools for data integration. We explore gaps, challenges, and future directions in the research field aiming to uncover novel biomarkers and therapeutic targets, ultimately advancing personalized treatment strategies. While focusing on IBD, the proposed approaches are applicable for other complex diseases, like cancer, and neurodegenerative diseases, where the microbiome has also been implicated.

A disturbed metabolite-GPCR axis is associated with microbial dysbiosis in IBD patients: Potential role of GPR109A in macrophages.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract characterized by disrupted immune function. Indeed, gut microbiota dysbiosis and metabolomic profile alterations, are hallmarks of IBD. In this scenario, metabolite-sensing G-protein coupled receptors (GPCRs), involved in several biological processes, have emerged as pivotal players in the pathophysiology of IBD. The aim of this study was to characterize the axis microbiota-metabolite-GPCR in intestinal surgical resections from IBD patients. Results showed that UC patients had a lower microbiota richness and bacterial load, with a higher proportion of the genus Cellulosimicrobium and a reduced proportion of Escherichia, whereas CD patients showed a decreased abundance of Enterococcus. Furthermore, metabolomic analysis revealed alterations in carboxylic acids, fatty acids, and amino acids in UC and CD samples. These patients also exhibited upregulated expression of most metabolite-sensing GPCRs analysed, which positively correlated with pro-inflammatory and pro-fibrotic markers. The role of GPR109A was studied in depth and increased expression of this receptor was detected in epithelial cells and cells from lamina propria, including CD68+ macrophages, in IBD patients. The treatment with ß-hydroxybutyrate increased gene expression of GPR109A, CD86, IL1B and NOS2 in U937-derived macrophages. Besides, when GPR109A was transiently silenced, the mRNA expression and secretion of IL-1ß, IL-6 and TNF-α were impaired in M1 macrophages. Finally, the secretome from siGPR109A M1 macrophages reduced the gene and protein expression of COL1A1 and COL3A1 in intestinal fibroblasts. A better understanding of metabolite-sensing GPCRs, such as GPR109A, could establish their potential as therapeutic targets for managing IBD.

Effect of diet on the gut mycobiome and potential implications in inflammatory bowel disease.

The gut microbiome is a complex, unique entity implicated in the prevention, pathogenesis, and progression of common gastrointestinal diseases. While largely dominated by bacterial populations, advanced sequencing techniques have identified co-inhabiting fungal communities, collectively referred to as the mycobiome. Early studies identified that gut inflammation is associated with altered microbial composition, known as gut dysbiosis. Altered microbial profiles are implicated in various pathological diseases, such as inflammatory bowel disease (IBD), though their role as a cause or consequence of systemic inflammation remains the subject of ongoing research. Diet plays a crucial role in the prevention and management of various diseases and is considered to be an essential regulator of systemic inflammation. This review compiles current literature on the impact of dietary modulation on the mycobiome, showing that dietary changes can alter the fungal architecture of the gut. Further research is required to understand the impact of diet on gut fungi, including the metabolic pathways and enzymes involved in fungal fermentation. Additionally, investigating whether dietary modulation of the gut mycobiome could be utilized as a therapy in IBD is essential.

Cultured fecal microbial community and its impact as fecal microbiota transplantation treatment in mice gut inflammation.

The fecal microbiome is identical to the gut microbial communities and provides an easy access to the gut microbiome. Therefore, fecal microbial transplantation (FMT) strategies have been used to alter dysbiotic gut microbiomes with healthy fecal microbiota, successfully alleviating various metabolic disorders, such as obesity, type 2 diabetes, and inflammatory bowel disease (IBD). However, the success of FMT treatment is donor-dependent and variations in gut microbes cannot be avoided. This problem may be overcome by using a cultured fecal microbiome. In this study, a human fecal microbiome was cultured using five different media; growth in brain heart infusion (BHI) media resulted in the highest microbial community cell count. The microbiome (16S rRNA) data demonstrated that the cultured microbial communities were similar to that of the original fecal sample. Therefore, the BHI-cultured fecal microbiome was selected for cultured FMT (cFMT). Furthermore, a dextran sodium sulfate (DSS)-induced mice-IBD model was used to confirm the impact of cFMT. Results showed that cFMT effectively alleviated IBD-associated symptoms, including improved gut permeability, restoration of the inflamed gut epithelium, decreased expression of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1, IL-6, IL-12, and IL-17), and increased expression of anti-inflammatory cytokines (IL-4 and IL-10). Thus, study's findings suggest that cFMT can be a potential alternative to nFMT. KEY POINTS: • In vitro fecal microbial communities were grown in a batch culture using five different media. • Fecal microbial transplantation was performed on DSS-treated mice using cultured and normal fecal microbes. • Cultured fecal microbes effectively alleviated IBD-associated symptoms.

Fecal let-7b and miR-21 directly modulate the intestinal microbiota, driving chronic inflammation.

Inflammatory bowel diseases (IBD) etiology is multifactorial. Luminal microRNAs (miRNAs) have been suspected to play a role in the promotion of chronic inflammation, but the extent to which fecal miRNAs are interacting with the intestinal ecosystem in a way that contribute to diseases, including IBD, remains unknown. Here, fecal let-7b and miR-21 were found elevated, associated with inflammation, and correlating with multiple bacteria in IBD patients and IL-10-/- mice, model of spontaneous colitis. Using an in vitro microbiota modeling system, we revealed that these two miRNAs can directly modify the composition and function of complex human microbiota, increasing their proinflammatory potential. In vivo investigations revealed that luminal increase of let-7b drastically alters the intestinal microbiota and enhances macrophages' associated proinflammatory cytokines (TNF, IL-6, and IL-1ß). Such proinflammatory effects are resilient and dependent on the bacterial presence. Moreover, we identified that besides impairing the intestinal barrier function, miR-21 increases myeloperoxidase and antimicrobial peptides secretion, causing intestinal dysbiosis. More importantly, in vivo inhibition of let-7b and miR-21 with anti-miRNAs significantly improved the intestinal mucosal barrier function and promoted a healthier host-microbiota interaction in the intestinal lining, which altogether conferred protection against colitis. In summary, we provide evidence of the functional significance of fecal miRNAs in host-microbiota communication, highlighting their therapeutic potential in intestinal inflammation and dysbiosis-related conditions, such as IBD.

A Comprehensive Review of the Triangular Relationship among Diet-Gut Microbiota-Inflammation.

The human gastrointestinal tract hosts a complex and dynamic community of microorganisms known as the gut microbiota, which play a pivotal role in numerous physiological processes, including digestion, metabolism, and immune function. Recent research has highlighted the significant impact of diet on the gut microbiota composition and functionality, and the consequential effects on host health. Concurrently, there is growing evidence linking the gut microbiota to inflammation, a key factor in many chronic diseases such as inflammatory bowel disease (IBD), obesity, diabetes, and cardiovascular diseases (CVDs). This review explores how dietary components influence the gut microbiota composition, how these microbial changes affect inflammatory pathways, and the therapeutic implications of modulating this axis for chronic inflammatory disease prevention and management. Beneficial dietary patterns, such as the Mediterranean diet (MD) and plant-based diets, promote a diverse and balanced gut microbiota composition, supporting anti-inflammatory pathways. Conversely, the Western diet (WD), high in saturated fats and refined sugars, is associated with dysbiosis and increased inflammation. With all the links between the three variables considered, this review attempts to offer a thorough examination of the triangle formed by inflammation, the gut microbiota, and food.

The Role of Host Genetics and Intestinal Microbiota and Metabolome as a New Insight into IBD Pathogenesis.

Inflammatory bowel disease (IBD) is an incurable, chronic disorder of the gastrointestinal tract whose incidence increases every year. Scientific research constantly delivers new information about the disease and its multivariate, complex etiology. Nevertheless, full discovery and understanding of the complete mechanism of IBD pathogenesis still pose a significant challenge to today's science. Recent studies have unanimously confirmed the association of gut microbial dysbiosis with IBD and its contribution to the regulation of the inflammatory process. It transpires that the altered composition of pathogenic and commensal bacteria is not only characteristic of disturbed intestinal homeostasis in IBD, but also of viruses, parasites, and fungi, which are active in the intestine. The crucial function of the microbial metabolome in the human body is altered, which causes a wide range of effects on the host, thus providing a basis for the disease. On the other hand, human genomic and functional research has revealed more loci that play an essential role in gut homeostasis regulation, the immune response, and intestinal epithelial function. This review aims to organize and summarize the currently available knowledge concerning the role and interaction of crucial factors associated with IBD pathogenesis, notably, host genetic composition, intestinal microbiota and metabolome, and immune regulation.

A Novel Microbial Dysbiosis Index and Intestinal Microbiota-Associated Markers as Tools of Precision Medicine in Inflammatory Bowel Disease Paediatric Patients.

Recent evidence indicates that the gut microbiota (GM) has a significant impact on the inflammatory bowel disease (IBD) progression. Our aim was to investigate the GM profiles, the Microbial Dysbiosis Index (MDI) and the intestinal microbiota-associated markers in relation to IBD clinical characteristics and disease state. We performed 16S rRNA metataxonomy on both stools and ileal biopsies, metabolic dysbiosis tests on urine and intestinal permeability and mucosal immunity activation tests on the stools of 35 IBD paediatric patients. On the GM profile, we assigned the MDI to each patient. In the statistical analyses, the MDI was correlated with clinical parameters and intestinal microbial-associated markers. In IBD patients with high MDI, Gemellaceae and Enterobacteriaceae were increased in stools, and Fusobacterium, Haemophilus and Veillonella were increased in ileal biopsies. Ruminococcaceae and WAL_1855D were enriched in active disease condition; the last one was also positively correlated to MDI. Furthermore, the MDI results correlated with PUCAI and Matts scores in ulcerative colitis patients (UC). Finally, in our patients, we detected metabolic dysbiosis, intestinal permeability and mucosal immunity activation. In conclusion, the MDI showed a strong association with both severity and activity of IBD and a positive correlation with clinical scores, especially in UC. Thus, this evidence could be a useful tool for the diagnosis and prognosis of IBD.

Oral Anti-Inflammatory and Symbiotic Effects of Fermented Lingonberry Juice-Potential Benefits in IBD.

Microbial dysbiosis may manifest as inflammation both orally and in the gastrointestinal tract. Altered oral and gut microbiota composition and decreased diversity have been shown in inflammatory bowel disease (IBD) and periodontal disease (PD). Recent studies have verified transmission of oral opportunistic microbes to the gut. Prebiotics, probiotics, or dietary interventions are suggested to alleviate IBD symptoms in addition to medicinal treatment. Lingonberries contain multiple bioactive molecules, phenolics, which have a broad spectrum of effects, including antimicrobial, anti-inflammatory, antioxidant, anti-proteolytic, and anti-cancer properties. An all-natural product, fermented lingonberry juice (FLJ), is discussed as a potential natural anti-inflammatory substance. FLJ has been shown in clinical human trials to promote the growth of oral lactobacilli, and inhibit growth of the opportunistic oral pathogens Candida, Streptococcus mutans, and periodontopathogens, and decrease inflammation, oral destructive proteolysis (aMMP-8), and dental microbial plaque load. Lactobacilli are probiotic and considered also beneficial for gut health. Considering the positive outcome of these oral studies and the fact that FLJ may be swallowed safely, it might be beneficial also for the gut mucosa by balancing the microbiota and reducing proteolytic inflammation.

The causal relationship between cholecystectomy and IBD/IBS and the role of bile acids and gut microbiota: a two-sample Mendelian randomization study.

OBJECTIVE: This study aims to explore the causal relationship between cholecystectomy and inflammatory bowel disease (IBD)/irritable bowel syndrome (IBS) and the role of serum bile acids and gut microbiota in this context. METHODS: Utilizing genetic variant data from previous Genome-Wide Association Studies (GWAS), this study employed a two-sample MR approach to assess the causal effect of cholecystectomy on IBD/IBS. RESULTS: The MR analysis suggested a potential negative causal relationship between cholecystectomy and UC (p = 0.0233, OR 0.9773, 95%CI 0.9581-0.9969) and a positive causal relationship between cholecystectomy and IBS (p = 0.0395, OR 4.077, 95%CI 1.0699-15.5362). Various sensitivity analyses reinforced the reliability of the causal relationship. However, the analysis did not find definitive results between serum bile acids or gut microbiota and cholecystectomy or IBD/IBS, possibly due to insufficient statistical power. MVMR find a causal relationship between bile acids and IBS (p = 0.0015, b = 0.4085) and UC (p = 0.0198, b = 0.0029). CONCLUSION: This study provides evidence of a causal relationship between cholecystectomy and IBD/IBS, highlighting the potential risk reduction for UC and increased risk for IBS following cholecystectomy. The role of bile acids and gut microbiota in this relationship remains unclear, necessitating further research to validate the causality and explore underlying mechanisms.

Proteolytic bacteria expansion during colitis amplifies inflammation through cleavage of the external domain of PAR2.

Imbalances in proteolytic activity have been linked to the development of inflammatory bowel diseases (IBD) and experimental colitis. Proteases in the intestine play important roles in maintaining homeostasis, but exposure of mucosal tissues to excess proteolytic activity can promote pathology through protease-activated receptors (PARs). Previous research implicates microbial proteases in IBD, but the underlying pathways and specific interactions between microbes and PARs remain unclear. In this study, we investigated the role of microbial proteolytic activation of the external domain of PAR2 in intestinal injury using mice expressing PAR2 with a mutated N-terminal external domain that is resistant to canonical activation by proteolytic cleavage. Our findings demonstrate the key role of proteolytic cleavage of the PAR2 external domain in promoting intestinal permeability and inflammation during colitis. In wild-type mice expressing protease-sensitive PAR2, excessive inflammation leads to the expansion of bacterial taxa that cleave the external domain of PAR2, exacerbating colitis severity. In contrast, mice expressing mutated protease-resistant PAR2 exhibit attenuated colitis severity and do not experience the same proteolytic bacterial expansion. Colonization of wild-type mice with proteolytic PAR2-activating Enterococcus and Staphylococcus worsens colitis severity. Our study identifies a previously unknown interaction between proteolytic bacterial communities, which are shaped by inflammation, and the external domain of PAR2 in colitis. The findings should encourage new therapeutic developments for IBD by targeting excessive PAR2 cleavage by bacterial proteases.