[The Oral Microbiome in the Development of Oral Cancer].

Oral cancer is an aggressive and rapidly progressive disease. The oral cavity is home to over 700 species of microorganisms that regulate metabolism, immune function, and health. There are three types of mechanisms by which bacteria may participate in carcinogenesis. First, bacteria cause chronic inflammation, which stimulates the production of cytokines, including interleukins, interferons, and tumor necrosis factor. Second, bacteria can interact directly with host cells by secreting toxins or by binding to membrane receptors. Finally, the production of metabolites by bacteria may also contribute to carcinogenesis. The importance of the bacteria level and composition in the transition of oral precancerous lesions to cancer has been demonstrated. The relationships of changes in microbiome composition with smoking, inflammation in healthy individuals, as well as with the development of oral cancer in patients, have been studied.

Correlation between the neuroendocrine axis, microbial species, inflammatory response, and gastrointestinal symptoms in irritable bowel syndrome.

BACKGROUND: This study examines the complex relationships among the neuroendocrine axis, gut microbiome, inflammatory responses, and gastrointestinal symptoms in patients with irritable bowel syndrome (IBS). The findings provide new insights into the pathophysiology of IBS and suggest potential therapeutic targets for improving patient outcomes. AIM: To investigate the interactions between the neuroendocrine axis, gut microbiome, inflammation, and gastrointestinal symptoms in patients with IBS. METHODS: Patients diagnosed with IBS between January 2022 and January 2023 were selected for the study. Healthy individuals undergoing routine check-ups during the same period served as the control group. Data were collected on neuroendocrine hormone levels, gut microbiome profiles, inflammatory biomarkers, and gastrointestinal symptomatology to analyze their interrelations and their potential roles in IBS pathogenesis. RESULTS: IBS patients exhibited significant dysregulation of the neuroendocrine axis, with altered levels of cortisol, serotonin, and neuropeptides compared to healthy controls. The gut microbiome of IBS patients showed reduced diversity and specific alterations in bacterial genera, including Bifidobacterium, Lactobacillus, and Faecalibacterium, which were associated with neuroendocrine disturbances. Additionally, elevated levels of inflammatory markers, such as C-reactive protein, interleukin-6, and tumor necrosis factor-α, were observed and correlated with the severity of gastrointestinal symptoms like abdominal pain, bloating, and altered bowel habits. CONCLUSION: The findings suggest that targeting the neuroendocrine axis, gut microbiome, and inflammatory pathways may offer novel therapeutic strategies to alleviate symptoms and improve the quality of life in IBS patients.

Pediatric migraine is characterized by traits of ecological and metabolic dysbiosis and inflammation.

BACKGROUND: Recently, there has been increasing interest in the possible role of the gut microbiota (GM) in the onset of migraine. Our aim was to verify whether bacterial populations associated with intestinal dysbiosis are found in pediatric patients with migraine. We looked for which metabolic pathways, these bacteria were involved and whether they might be associated with gut inflammation and increased intestinal permeability. METHODS: Patients aged between 6 and 17 years were recruited. The GM profiling was performed by the 16S rRNA metataxonomics of faecal samples from 98 patients with migraine and 98 healthy subjects. Alpha and beta diversity analyses and multivariate and univariate analyses were applied to compare the gut microbiota profiles between the two group. To predict functional metabolic pathways, we used phylogenetic analysis of communities. The level of indican in urine was analyzed to investigate the presence of metabolic dysbiosis. To assess gut inflammation, increased intestinal permeability and the mucosal immune activation, we measured the plasmatic levels of lipopolysaccharide, occludin and IgA, respectively. RESULTS: The α-diversity analysis revealed a significant increase of bacterial richness in the migraine group. The ß-diversity analysis showed significant differences between the two groups indicating gut dysbiosis in patients with migraine. Thirty-seven metabolic pathways were increased in the migraine group, which includes changes in tryptophan and phenylalanine metabolism. The presence of metabolic dysbiosis was confirmed by the increased level of indican in urine. Increased levels of plasmatic occludin and IgA indicated the presence of intestinal permeability and mucosal immune activation. The plasmatic LPS levels showed a low intestinal inflammation in patients with migraine. CONCLUSIONS: Pediatric patients with migraine present GM profiles different from healthy subjects, associated with metabolic pathways important in migraine.

Aggregatibacter is inversely associated with inflammatory mediators in sputa of patients with chronic airway diseases and reduces inflammation in vitro.

BACKGROUND: Chronic airway disease (CAD) is characterized by chronic airway inflammation and colonization of the lungs by pro-inflammatory pathogens. However, while various other bacterial species are present in the lower airways, it is not fully understood how they influence inflammation. We aimed to identify novel anti-inflammatory species present in lower airway samples of patients with CAD. METHODS: Paired sputum microbiome and inflammatory marker data of adults with CAD across three separate cohorts (Australian asthma and bronchiectasis, Scottish bronchiectasis) was analyzed using Linear discriminant analysis Effect Size (LEfSE) and Spearman correlation analysis to identify species associated with a low inflammatory profile in patients. RESULTS: We identified the genus Aggregatibacter as more abundant in patients with lower levels of airway inflammatory markers in two CAD cohorts (Australian asthma and bronchiectasis). In addition, the relative abundance of Aggregatibacter was inversely correlated with sputum IL-8 (Australian bronchiectasis) and IL-1ß levels (Australian asthma and bronchiectasis). Subsequent in vitro testing, using a physiologically relevant three-dimensional lung epithelial cell model, revealed that Aggregatibacter spp. (i.e. A. actinomycetemcomitans, A. aphrophilus) and their cell-free supernatant exerted anti-inflammatory activity without influencing host cell viability. CONCLUSIONS: These findings suggest that Aggregatibacter spp. might act to reduce airway inflammation in CAD patients.

Cardiovascular Disease May Be Triggered by Gut Microbiota, Microbial Metabolites, Gut Wall Reactions, and Inflammation.

Cardiovascular disease (CVD) may be inherited, as recently shown with the identification of single nucleotide polymorphisms (SNPs or "snips") on a 250 kb DNA fragment that encodes 92 proteins associated with CVD. CVD is also triggered by microbial dysbiosis, microbial metabolites, metabolic disorders, and inflammatory intestinal epithelial cells (IECs). The epithelial cellular adhesion molecule (Ep-CAM) and trefoil factor 3 (TFF3) peptide keeps the gut wall intact and healthy. Variations in Ep-CAM levels are directly linked to changes in the gut microbiome. Leptin, plasminogen activator inhibitor 1 (PAI1), and alpha-1 acid glycoprotein 1 (AGP1) are associated with obesity and may be used as biomarkers. Although contactin 1 (CNTN1) is also associated with obesity and adiposity, it regulates the bacterial metabolism of tryptophan (Trp) and thus appetite. A decrease in CNTN1 may serve as an early warning of CVD. Short-chain fatty acids (SCFAs) produced by gut microbiota inhibit pro-inflammatory cytokines and damage vascular integrity. Trimethylamine N-oxide (TMAO), produced by gut microbiota, activates inflammatory Nod-like receptors (NLRs) such as Nod-like receptor protein 3 (NLRP3), which increase platelet formation. Mutations in the elastin gene (ELN) cause supra valvular aortic stenosis (SVAS), defined as the thickening of the arterial wall. Many of the genes expressed by human cells are regulated by gut microbiota. The identification of new molecular markers is crucial for the prevention of CVD and the development of new therapeutic strategies. This review summarizes the causes of CVD and identifies possible CVD markers.

Sex-specific post-inflammatory dysbiosis mediates chronic visceral pain in colitis.

BACKGROUND: Despite achieving endoscopic remission, over 20% of inflammatory bowel disease (IBD) patients experience chronic abdominal pain. Visceral pain and the microbiome exhibit sex-dependent interactions, while visceral pain in IBD shows a sex bias. Our aim was to evaluate whether post-inflammatory microbial perturbations contribute to visceral hypersensitivity in a sex-dependent manner. METHODS: Males, cycling females, ovariectomized, and sham-operated females were given dextran sodium sulfate to induce colitis and allowed to recover. Germ-free recipients received sex-appropriate and cross-sex fecal microbial transplants (FMT) from post-inflammatory donor mice. Visceral sensitivity was assessed by recording visceromotor responses to colorectal distention. The composition of the microbiota was evaluated via 16S rRNA gene V4 amplicon sequencing, while the metabolome was assessed using targeted (short chain fatty acids - SCFA) and semi-targeted mass spectrometry. RESULTS: Post-inflammatory cycling females developed visceral hyperalgesia when compared to males. This effect was reversed by ovariectomy. Both post-inflammatory males and females exhibited increased SCFA-producing species, but only males had elevated fecal SCFA content. FMT from post-inflammatory females transferred visceral hyperalgesia to both males and females, while FMT from post-inflammatory males could only transfer visceral hyperalgesia to males. CONCLUSIONS: Female sex, hormonal status as well as the gut microbiota play a role in pain modulation. Our data highlight the importance of considering biological sex in the evaluation of visceral pain.

Akkermansia muciniphila as a Potential Guardian against Oral Health Diseases: A Narrative Review.

The oral microbiome is a diverse ecosystem containing a community of symbiotic, commensal, and pathogenic microorganisms. One key microorganism linked to periodontal disease (PD) is Porphyromonas gingivalis (P. gingivalis), a Gram-negative anaerobic bacterium known to have several virulence factors that trigger inflammation and immune evasion. On the other hand, Akkermansia muciniphila (A. muciniphila), a symbiotic bacterium, has been recently shown to play an important role in mitigating inflammation and reducing periodontal damage. In vivo and in vitro studies have shown that A. muciniphila decreases inflammatory mediators and improves immune responses, suggesting its role in mitigating PD and related inflammatory systemic conditions such as diabetes, hypertension, and obesity. This review discusses the anti-inflammatory effects of A. muciniphila, its impact on periodontal health, and its potential role in managing systemic diseases. The overall aim is to elucidate how this bacterium might help reduce inflammation, improve oral health, and influence broader health outcomes.

Reducing the excessive inflammation after burn injury in aged mice by maintaining a healthier intestinal microbiome.

One in six people are projected to be 65 years or older by 2050. As the population ages, better treatments for injuries that disproportionately impact the aged population will be needed. Clinical studies show that people aged 65 and older experience higher rates of morbidity and mortality after burn injury, including a greater incidence of pulmonary complications when compared to younger burn injured adults, which we and others believe is mediated, in part, by inflammation originating in the intestines. Herein, we use our clinically relevant model of scald burn injury in young and aged mice to determine whether cohousing aged mice with young mice or giving aged mice oral gavage of fecal material from young mice is sufficient to alter the microbiome of the aged mice and protect them from inflammation in the ileum and the lungs. Aged burn injured mice have less DNA expression of Bacteroidetes in the feces and an unhealthy Firmicutes/Bacteroidetes ratio. Both Bacteroidetes and the ratio of these two phyla are restored in aged burn injured by prior cohousing for a month with younger mice but not fecal transfer from young mice. This shift in the microbiome coincides with heightened expression of danger-associated molecular patterns (DAMP), and pro-inflammatory cytokine interleukin-6 (il6) in the ileum and lung of aged, burn injured mice, and heightened antimicrobial peptide camp in the lung. Cohousing reverses DAMP expression in the ileum and lung, and cathelicidin-related antimicrobial peptide protein (camp) in the lung, while fecal transfer heightened DAMPs while reducing camp in the lung, and also increased IL-6 protein in the lungs. These results highlight the importance of the intestinal microbiome in mediating inflammation within the gut-lung axis, giving insights into potential future treatments in the clinic.

[Association of Gut and Oral Microbiota with Cerebral Aneurysms].

In recent years, the association of the microbiome with various diseases has been reported. The oral and gut microbiomes have been linked to cerebral aneurysms and are involved in the systemic inflammatory response, which is mediated mainly via the immune system. Chronic inflammation plays an important role in the pathogenesis and rupture of cerebral aneurysms, and the microbiome is potentially involved in this process. Moreover, the gut microbiome is involved in acute brain injury following subarachnoid hemorrhage. Thus, further studies on microbiome-targeted treatments for cerebral aneurysm are required.

Sexual behavior is linked to changes in gut microbiome and systemic inflammation that lead to HIV-1 infection in men who have sex with men.

Pathogenic changes in gut microbial composition precede the onset of HIV-1 infection in men who have sex with men (MSM). This process is associated with increased levels of systemic inflammatory biomarkers and risk for AIDS development. Using mediation analysis framework, in this report we link the effects of unprotected receptive intercourse among MSM prior to primary HIV-1 infection to higher levels of proinflammatory cytokines sCD14 and sCD163 in plasma and a significant decrease in the abundance of A. muciniphila, B. caccae, B. fragilis, B. uniformis, Bacteroides spp., Butyricimonas spp., and Odoribacter spp., and a potential increase in the abundance of Dehalobacterium spp. and Methanobrevibacter spp. in stools of MSM with the highest number of sexual partners. These differences in microbiota, together with a reduction in the pairwise correlations among commensal and short-chain fatty acid-producing bacteria with a number of sexual partners, support an increase in gut dysbiosis with the number of sexual partners. These results demonstrate the interconnectedness of sexual behavior, immune response, and microbiota composition, notably among MSM participating in high-risk sexual behaviors.

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.

Insights into Gut Dysbiosis: Inflammatory Diseases, Obesity, and Restoration Approaches.

The gut microbiota is one of the most critical factors in human health. It involves numerous physiological processes impacting host health, mainly via immune system modulation. A balanced microbiome contributes to the gut's barrier function, preventing the invasion of pathogens and maintaining the integrity of the gut lining. Dysbiosis, or an imbalance in the gut microbiome's composition and function, disrupts essential processes and contributes to various diseases. This narrative review summarizes key findings related to the gut microbiota in modern multifactorial inflammatory conditions such as ulcerative colitis or Crohn's disease. It addresses the challenges posed by antibiotic-driven dysbiosis, particularly in the context of C. difficile infections, and the development of novel therapies like fecal microbiota transplantation and biotherapeutic drugs to combat these infections. An emphasis is given to restoration of the healthy gut microbiome through dietary interventions, probiotics, prebiotics, and novel approaches for managing gut-related diseases.

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.

Microbiota and Lipotoxicity.

Gut microbiota is an indispensable commensal partner of human superorganism. The wealth of genetic repertoire provided by these microorganisms extends host's substrate processing capability. Energy and nutrient harvesting machinery primarily depends on the proper function of these organisms. However, the dynamic composition of microbiota changes with age, lifestyle, stress factors, infections, medications, and host pathophysiological conditions. Host immune system is primarily responsible for shaping up the microbial community and sustaining the symbiotic state. This involves controlling the delicate balance between agility toward pathobionts and tolerance toward symbionts. When things go wrong with this crosstalk, dysbiosis may arise.Metabolic syndrome is a multisystemic, low-grade chronic inflammatory disease that involves dyslipidemia, glucose intolerance, insulin resistance, and central obesity. Excess caloric intake with high-sugar and high-fat diet promote high energy harvesting and lipogenesis. The secretion of adipokines accompanies lipid spillover from fat cells, which contribute to insulin resistance and the expansion of adipose tissue in ectopic sites. Proinflammatory cytokines from adipose tissue macrophages increase the extent of adipose dysfunction.The inflammatory nature of obesity and metabolic syndrome recall the connection between dysbiosis and immune dysfunction. A remarkable association exits between obesity, inflammatory bowel disease, gluten-sensitive enteropathy, and dysbiosis. These conditions compromise the gut mucosa barrier and allow lipopolysaccharide to enter circulation. Unresolved chronic inflammation caused by one condition may overlap or trigger the other(s). Experimental studies and therapeutic trials of fecal microbiota transplantation promise limited improvement in some of these conditions.Typically, metabolic syndrome is considered as a consequence of overnutrition and the vicious cycle of lipogenesis, lipid accumulation, and chronic low-level inflammation. Because of the complex nature of this disorder, it remains inconclusive whether dysbiosis is a cause or consequence of obesity and metabolic syndrome.

Commensal consortia decolonize Enterobacteriaceae via ecological control.

Persistent colonization and outgrowth of potentially pathogenic organisms in the intestine can result from long-term antibiotic use or inflammatory conditions, and may perpetuate dysregulated immunity and tissue damage1,2. Gram-negative Enterobacteriaceae gut pathobionts are particularly recalcitrant to conventional antibiotic treatment3,4, although an emerging body of evidence suggests that manipulation of the commensal microbiota may be a practical alternative therapeutic strategy5-7. Here we isolated and down-selected commensal bacterial consortia from stool samples from healthy humans that could strongly and specifically suppress intestinal Enterobacteriaceae. One of the elaborated consortia, comprising 18 commensal strains, effectively controlled ecological niches by regulating gluconate availability, thereby re-establishing colonization resistance and alleviating Klebsiella- and Escherichia-driven intestinal inflammation in mice. Harnessing these activities in the form of live bacterial therapies may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant Enterobacteriaceae infection.

The Salmonella Effector SspH2 Facilitates Spatially Selective Ubiquitination of NOD1 to Enhance Inflammatory Signaling.

As part of its pathogenesis, Salmonella enterica serovar Typhimurium delivers effector proteins into host cells. One effector is SspH2, a member of the so-called novel E3 ubiquitin ligase family, that interacts with and enhances, NOD1 pro-inflammatory signaling, though the underlying mechanisms are unclear. Here, we report that SspH2 interacts with multiple members of the NLRC family to enhance pro-inflammatory signaling by targeted ubiquitination. We show that SspH2 modulates host innate immunity by interacting with both NOD1 and NOD2 in mammalian epithelial cell culture via the NF-κB pathway. Moreover, purified SspH2 and NOD1 directly interact, where NOD1 potentiates SspH2 E3 ubiquitin ligase activity. Mass spectrometry and mutational analyses identified four key lysine residues in NOD1 that are required for its enhanced activation by SspH2, but not its basal activity. These critical lysine residues are positioned in the same region of NOD1 and define a surface on the receptor that appears to be targeted by SspH2. Overall, this work provides evidence for post-translational modification of NOD1 by ubiquitin and uncovers a unique mechanism of spatially selective ubiquitination to enhance the activation of an archetypal NLR.

Pseudomonas aeruginosa Infection and Inflammation in Cystic Fibrosis: A Pilot Study With Lung Explants and a Novel Histopathology Scoring System.

PURPOSE: Pseudomonas aeruginosa is the predominant bacterial pathogen colonizing the cystic fibrosis (CF) lung. Mixed populations of nonmucoid and mucoid variants of P. aeruginosa have been isolated from the CF airway. While the association between mucoid variants and pulmonary function decline is well-established, their impact on inflammation and tissue damage in advanced CF lung disease remains unclear. METHODS: This pilot study utilized 1 non-CF and 3 CF lung explants to examine lobar distribution, inflammation, and histopathology related to nonmucoid and mucoid P. aeruginosa infection. To study tissue damage, we developed a novel lung histopathology scoring system, the first applied to human CF lung biopsies, which is comprised of five indicators: bronchiolar epithelial infiltrate, luminal inflammation, peribronchial/bronchiolar infiltrate, peribronchiolar fibrosis, and alveolar involvement. RESULTS: Mucoid P. aeruginosa variants were distributed throughout the CF lung but associated with greater concentrations of proinflammatory cytokines, IL-1ß, TNF-α, IL-6, IL-8, and IFN-γ, and one anti-inflammatory cytokine, IL-10, compared to nonmucoid variants. CF lung explants exhibited higher histopathology scores compared to a non-CF lung control. In mixed-variant infection, nonmucoid constituents associated with increased bronchiolar epithelial infiltration, one indicator of histopathology. CONCLUSION: This pilot study suggests ongoing interplay between host and bacterial elements in late-stage CF pulmonary disease. Mucoid P. aeruginosa infection correlates with inflammation regardless of lung lobe, whereas nonmucoid P. aeruginosa is associated with increased inflammatory cell infiltration. The development of a novel lung histopathology scoring system lays the groundwork for future large-cohort investigations.

Balancing the mind: Toward a complete picture of the interplay between gut microbiota, inflammation and major depressive disorder.

The intricate interplay existing between gut microbiota and homeostasis extends to the realm of the brain, where emerging research underscores the significant impact of the microbiota on mood regulation and overall neurological well-being and vice-versa, with inflammation playing a pivotal role in mediating these complex interactions. This comprehensive review explores the complex interplay between inflammation, alterations in gut microbiota, and their impact on major depressive disorder (MDD). It provides a cohesive framework for the puzzle pieces of this triad, emphasizing recent advancements in understanding the gut microbiota and inflammatory states' contribution to the depressive features. Two directions of communication between the gut and the brain in depression are discussed, with inflammation serving as a potential modulator. Therapeutic implications were discussed as well, drawing insights from interventional studies on the effects of probiotics on gut bacterial composition and depressive symptoms. Ultimately, this review will attempt to provide a complete and valuable framework for future research and therapeutic interventions in MDD.

Fecal microbiota from patients with Parkinson's disease intensifies inflammation and neurodegeneration in A53T mice.

AIMS: We evaluated the potential of Parkinson's disease (PD) fecal microbiota transplantation to initiate or exacerbate PD pathologies and investigated the underlying mechanisms. METHODS: We transplanted the fecal microbiota from PD patients into mice by oral gavage and assessed the motor and intestinal functions, as well as the inflammatory and pathological changes in the colon and brain. Furthermore, 16S rRNA gene sequencing combined with metabolomics analysis was conducted to assess the impacts of fecal delivery on the fecal microbiota and metabolism in recipient mice. RESULTS: The fecal microbiota from PD patients increased intestinal inflammation, deteriorated intestinal barrier function, intensified microglia and astrocyte activation, abnormal deposition of α-Synuclein, and dopaminergic neuronal loss in the brains of A53T mice. A mechanistic study revealed that the fecal microbiota of PD patients stimulated the TLR4/NF-κB/NLRP3 pathway in both the brain and colon. Additionally, multiomics analysis found that transplantation of fecal microbiota from PD patients not only altered the composition of the gut microbiota but also influenced the fecal metabolic profile of the recipient mice. CONCLUSION: The fecal microbiota from PD patients intensifies inflammation and neurodegeneration in A53T mice. Our findings demonstrate that imbalance and dysfunction in the gut microbiome play significant roles in the development and advancement of PD.

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.