Regulation of Bacteroides acidifaciens by the aryl hydrocarbon receptor in IL-22-producing immune cells has sex-dependent consequential impact on colitis.

Introduction: Colitis is an inflammatory bowel disease (IBD) characterized by immune cell dysregulation and alterations in the gut microbiome. In our previous report, we showed a natural product in cruciferous vegetables and ligand of the aryl hydrocarbon receptor (AhR), indole-3-carbinol (I3C), was able to reduce colitis-induced disease severity and microbial dysbiosis in an interleukin-22 (IL-22) dependent manner. Methods: In the current study, we performed single-cell RNA sequencing (scRNAseq) from colonocytes during colitis induction and supplementation with I3C and show how this treatment alters expression of genes involved in IL-22 signaling. To further define the role of IL-22 signaling in I3C-mediated protection during colitis and disease-associated microbial dysbiosis, we generated mice with AhR deficiency in RAR-related orphan receptor c (Rorc)-expressing cells (AhR ΔRorc ) which depletes this receptor in immune cells involved in production of IL-22. Colitis was induced in wildtype (WT), AhR ΔRorc , and littermate (LM) mice with or without I3C treatment. Results: Results showed AhR ΔRorc mice lost the efficacy effects of I3C treatment which correlated with a loss of ability to increase IL-22 by innate lymphoid type 3 (ILC3s), not T helper 22 (Th22) cells. 16S rRNA microbiome profiling studies showed AhR ΔRorc mice were unable to regulate disease-associated increases in Bacteroides, which differed between males and females. Lastly, inoculation with a specific disease-associated Bacteroides species, Bacteroides acidifaciens (B. acidifaciens), was shown to exacerbate colitis in females, but not males. Discussion: Collectively, this report highlights the cell and sex-specific role of AhR in regulating microbes that can impact colitis disease.

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.

Roseburia intestinalis-derived extracellular vesicles ameliorate colitis by modulating intestinal barrier, microbiome, and inflammatory responses.

Inflammatory bowel disease (IBD) is a chronic disorder characterized by recurrent gastrointestinal inflammation, lacking a precise aetiology and definitive cure. The gut microbiome is vital in preventing and treating IBD due to its various physiological functions. In the interplay between the gut microbiome and human health, extracellular vesicles secreted by gut bacteria (BEVs) are key mediators. Herein, we explore the role of Roseburia intestinalis (R)-derived EVs (R-EVs) as potent anti-inflammatory mediators in treating dextran sulfate sodium-induced colitis. R was selected as an optimal BEV producer for IBD treatment through ANCOM analysis. R-EVs with a 76 nm diameter were isolated from R using a tangential flow filtration system. Orally administered R-EVs effectively accumulated in inflamed colonic tissues and increased the abundance of Bifidobacterium on microbial changes, inhibiting colonic inflammation and prompting intestinal recovery. Due to the presence of Ile-Pro-Ile in the vesicular structure, R-EVs reduced the DPP4 activity in inflamed colonic tissue and increased the active GLP-1, thereby downregulating the NFκB and STAT3 via the PI3K pathway. Our results shed light on the impact of BEVs on intestinal recovery and gut microbiome alteration in treating IBD.

Chronic binge drinking-induced susceptibility to colonic inflammation is microbiome-dependent.

Alterations in intestinal permeability and the gut microbiome caused by alcohol abuse are associated with alcoholic liver disease and with worsening of inflammatory bowel diseases (IBD) symptoms. To resolve the direct effects of chronic ethanol consumption on the colon and its microbiome in the absence of acute or chronic alcohol-induced liver disease, we developed a mouse model of chronic binge drinking that uncovers how alcohol may enhance susceptibility to colitis via the microbiota. Employing daily ethanol gavage, we recapitulate key features of binge ethanol consumption. We found that binge ethanol drinking worsens intestinal infection, colonic injury and inflammation, and this effect persists beyond the drinking period. Using gnotobiotics, we showed that alcohol-driven susceptibility to colitis is microbiota-dependent and transferable to ethanol-naïve mice by microbiome transplantation. Allobaculum spp. expanded in binge drinking mice, and administration of Allobaculum fili was sufficient to enhance colitis in non-drinking mice. Our study provides a model to study binge drinking-microbiota interactions and their effects on host disease and reinforces the pathogenic function of Allobaculum spp. as colitogenic bacteria. Our findings illustrate how chronic binge drinking-induced alterations of the microbiome may affect susceptibility to IBD onset or flares.

Mouse adaptation of human inflammatory bowel diseases microbiota enhances colonization efficiency and alters microbiome aggressiveness depending on the recipient colonic inflammatory environment.

BACKGROUND: Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. RESULTS: Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. CONCLUSIONS: Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract.

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.

Class A1 scavenger receptor antibody improves murine colitis by influencing macrophage and gut microbiota.

This study aimed to investigate whether class A1 scavenger receptor (SR-A1) regulated macrophage polarization and gut microbial alteration during intestinal inflammation of colitis. A murine colitis model was established by feeding with dextran sulfate sodium (DSS), and treatment groups were injected intravenously with SR-A1 antibody. Results showed a preventive effect on colitis symptoms and fewer inflammatory cell infiltrates in treatment groups. Down-regulation of inflammatory cytokines and up-regulation of anti-inflammatory cytokine related to macrophages were seen in murine PBMC and LPMC after injected with SR-A1 antibody. The percentage of M2 macrophages was also elevated in treatment groups. In addition, SR-A1 antibody treatment resulted in the decreased apoptosis and increased proliferation of colonic epithelial cells. Other findings indicated that SR-A1 antibody injection could mediate its anti-inflammatory effect via inhibiting TLR4-MyD88-NF-kB signaling pathway and alterating the gut microbiota composition. Our research identified SR-A1 as a potential therapeutic target in inflammatory bowel disease (IBD).

Immunomodulatory Effects of a Probiotic Mixture: Alleviating Colitis in a Mouse Model through Modulation of Cell Activation Markers and the Gut Microbiota.

Ulcerative colitis (UC) is a persistent inflammatory intestinal disease that consistently affects the colon and rectum. Its exact cause remains unknown. UC causes a considerable challenge in healthcare, prompting research for novel therapeutic strategies. Although probiotics have gained popularity as possible candidates for managing UC, studies are still ongoing to identify the best probiotics or probiotic mixtures for clinical applications. This study aimed to determine the efficacy of a multi-strain probiotic mixture in mitigating intestinal inflammation in a colitis mouse model induced by dextran sulfate sodium. Specifically, a multi-strain probiotic mixture consisting of Tetragenococcus halophilus and Eubacterium rectale was used to study its impact on colitis symptoms. Anti-inflammatory effects were evaluated using ELISA and flow cytometry. The configuration of gut microbial communities was determined using 16S rRNA metagenomic analysis. According to this study, colitis mice treated with the probiotic mixture experienced reduced weight loss and significantly less colonic shortening compared to untreated mice. Additionally, the treated mice exhibited increased levels of forkhead box P3 (Foxp3) and interleukin 10, along with decreased expression of dendritic cell activation markers, such as CD40+, CD80+, and CD83+, in peripheral blood leukocytes and intraepithelial lymphocytes. Furthermore, there was a significant decrease in the frequencies of CD8+N.K1.1+ cells and CD11b+Ly6G+ cells. In terms of the gut microbiota, probiotic-mixture treatment of colitis mice significantly increased the abundance of the phyla Actinobacteria and Verrucomicrobia (p < 0.05). These results provide valuable insights into the therapeutic promise of multi-strain probiotics, shedding light on their potential to alleviate colitis symptoms. This research contributes to the ongoing exploration of effective probiotic interventions for managing inflammatory bowel disease.

Characterization of Eurotium cristatum Fermented Thinned Young Apple and Mechanisms Underlying Its Alleviating Impacts on Experimental Colitis.

A hundred million tons of young apples are thinned and discarded in the orchard per year, aiming to increase the yield and quality of apples. We fermented thinned young apples using a potential probiotic fungus, Eurotium cristatum, which notably disrupted the microstructure of raw samples, as characterized by the scanning electron microscope. Fermentation substantially altered the metabolite profiles of samples, which are predicted to alleviate colitis via regulating inflammatory response and response to lipopolysaccharide by using network pharmacology analysis. In vivo, oral gavage of water extracts of E. cristatum fermented young apples (E.YAP) effectively alleviated DSS-induced colitis, restored the histopathology damage, reduced the levels of inflammatory cytokines, and promoted colonic expressions of tight junction proteins. Moreover, E.YAP ameliorated gut dysbacteriosis by increasing abundances of Lactobacillus,Blautia, Muribaculaceae, and Prevotellaceae_UCG-001 while inhibiting Turicibacter, Alistipes, and Desulfovibrio. Importantly, E.YAP increased colonic bile acids, such as CA, TCA, DCA, TUDCA, and LCA, thereby alleviating colitis via PXR/NF-κB signaling. Furthermore, a synbiotic combination with Limosilactobacillus reuteri WX-94, a probiotic strain isolated from feces of healthy individuals with anti-inflammatory properties, augmented anticolitis capacities of E.YAP. Our findings demonstrate that E.YAP could be a novel, potent, food-based anti-inflammatory prebiotic for relieving inflammatory injuries.

Insoluble polysaccharides produced in plant cell cultures protect from Clostridioides difficile colitis.

Clostridioides difficile infection (CDI) poses a significant health threat due to high recurrence rates. Antimicrobial agents are commonly used to manage CDI-related diarrhoea; however, by aggravating intestinal dysbiosis, antibiotics enable C. difficile spores germination and production of toxins, the main virulence factors. Therefore, the binding of exotoxins using adsorbents represents an attractive alternative medication for the prevention and treatment of relapses. In this study, we provided evidence that the natural insoluble polysaccharides, named ABR119, extracted by plant cell cultures, effectively trap C. difficile toxins. In our experiments, ABR119 exhibited no cytotoxicity in vitro and was safely administered in vivo. In the animal model of C. difficile-associated colitis, ABR119 (50 mg/kg body weight) significantly reduced the colonic myeloperoxidase activity and severity of inflammation, preventing body weight loss. These effects were not evident when we treated animals with wheat bran polysaccharides. We did not detect bacterial killing effects of ABR119 against C. difficile nor against bacterial species of the normal gut microbiota. Moreover, ABR119 did not interfere in vitro with the antimicrobial activities of most clinically used antibiotics. In summary, ABR119 holds promise for treating and preventing C. difficile colitis by trapping the bacterial toxins, warranting further studies to assess the ABR119 potential in human infections caused by C. difficile.

Ovomucin and its hydrolysates differentially influenced colitis severity in Citrobacter rodentium-infected mice.

Egg white protein ovomucin and its hydrolysates were previously reported to exhibit anti-inflammatory and anti-adhesive activities. However, their potential to regulate pathogen colonization and disease severity has not been fully characterized. To investigate the effects of ovomucin (OVM) and its hydrolysates including ovomucin-Protex 26L (OP) and -pepsin/pancreatin (OPP) on host resistance to pathogen infection, a well-documented colitis model in mice for attaching and effacing E. coli pathogens, Citrobacter rodentium, was used in the current study. C57Bl/6J female mice were fed on a basal diet supplemented with OVM or its hydrolysates for 3 weeks prior to the C. rodentium challenge, with the dietary treatments continued for seven days. Body weight was not affected throughout the experimental period. OP supplementation resulted in lower (P < 0.05) pathogen loads at 7 dpi. Attenuated colitis severity was observed in mice that received OVM and OP, as indicated by reduced colonic pathological scores and pro-inflammatory responses compared with the infected control group. In contrast, OPP consumption resulted in enhanced C. rodentium colonization and disease severity. Notably, reduced microbial diversity indices of the gut microbiota were observed in the OPP-supplemented mice compared with the OVM- and OP-supplemented groups. This study showed the potential of OVM and OP to alleviate the severity of colitis induced by infection while also suggesting the opposite outcome of OPP in mitigating enteric infection.

Anti-inflammation mechanisms of a homogeneous polysaccharide from Phyllanthus emblica L. on DSS induced colitis mice via the gut microbiota and metabolites alteration.

Phyllanthus emblica L. offers promising therapeutic potential for inflammatory diseases. This study revealed the molecular structure of a homogeneous polysaccharide purified from Phyllanthus emblica L. (PEP-1) and evaluated its anti-inflammatory effects on ulcerative colitis (UC) in mice. In the in vivo experiment, administered in varying dosages to dextran sulfate sodium (DSS)-induced UC models, PEP-1 significantly alleviated colonic symptoms, histological damages and reshaped the gut microbiota. Notably, it adjusted the Firmicutes/Bacteroidetes ratio and reduced pro-inflammatory species, closely aligning with shifts in the fecal metabolites and metabolic pathways such as the metabolism of pyrimidine, beta-alanine, and purine. These findings underscore the potential of PEP-1 as a therapeutic agent for UC, providing insights into the mechanisms through gut microbiota and metabolic modulation.

Coumarin derivatives ameliorate the intestinal inflammation and pathogenic gut microbiome changes in the model of infectious colitis through antibacterial activity.

Coumarin, a phenolic compound, is a secondary metabolite produced by plants such as Tanga and Lime. Coumarin derivatives were prepared via Pechmann condensation. In this study, we performed in vitro and in vivo experiments to determine the antimicrobial and gut immune-regulatory functions of coumarin derivatives. For the in vitro antimicrobial activity assay, coumarin derivatives C1 and C2 were selected based on their pathogen-killing activity against various pathogenic microbes. We further demonstrated that the selected coumarin derivatives disrupted bacterial cell membranes. Next, we examined the regulatory function of the coumarin derivatives in gut inflammation using an infectious colitis model. In an in vivo infectious colitis model, administration of selected C1 coumarin derivatives reduced pathogen loads, the number of inflammatory immune cells (Th1 cells and Th17 cells), and inflammatory cytokine levels (IL-6 and IL-1b) in the intestinal tissue after pathogen infection. In addition, we found that the administration of C1 coumarin derivatives minimized abnormal gut microbiome shift-driven pathogen infection. Potential pathogenic gut microbes, such as Enterobacteriaceae and Staphylococcaceae, were increased by pathogen infection. However, this pathogenic microbial expansion was minimized and beneficial bacteria, such as Ligilactobacillus and Limosilactobacillus, increased with C1 coumarin derivative treatment. Functional gene enrichment assessment revealed that the relative abundance of genes associated with lipid and nucleotide metabolism was reduced by pathogen infection; however, this phenomenon was not observed in C1 coumarin derivative-treated animals. Collectively, our data suggest that C1 coumarin derivative is effective antibacterial agents that minimize pathogen-induced gut inflammation and abnormal gut microbiome modulation through their antibacterial activity.

Potential of using an engineered indole lactic acid producing Escherichia coli Nissle 1917 in a murine model of colitis.

The gut microbiome is a significant factor in the pathophysiology of ulcerative colitis (UC), prompting investigations into the use of probiotic therapies to counter gastrointestinal inflammation. However, while much attention has been given to the therapeutic potential of microbes at the species and strain level, the discovery and application of their metabolic products may offer more precise and controlled solutions in battling disease. In this work, we examined the therapeutic potential of indole lactic acid (ILA) to alleviate inflammation in a murine model of colitis. A previously constructed ILA-producing Escherichia coli Nissle 1917 strain (EcN aldh) and its isogenic non-ILA producing counterpart (EcN) were studied in a murine model of Dextran Sodium Sulfate (DSS) induced colitis. The colitic animals suffered from severe colitic symptoms, with no differentiation between the groups in body weight loss and disease activity index. However, three days after cessation of DSS treatment the EcN aldh-treated mice showed signs of reduced intestinal inflammation, as manifested by lower concentrations of fecal lipocalin-2. Additionally, expression analysis of the inflamed tissue revealed distinct effects of the EcN aldh strain on proteins associated with intestinal health, such as TFF3, occludin and IL-1ß expression. These results show no impact of EcN or EcN aldh on acute DSS-induced colitis, but suggest that in particular EcN aldh may assist recovery from intestinal inflammation.

Intestinal epithelial Cldn-7 regulates intestinal inflammation by altering the gut microbiota.

BACKGROUND AND AIM: Tight junctions maintain gut homeostasis by forming a physical barrier that protects the gut from invasion by microbiota. Cldn-7 is an important component involved in this protection, but the relationship between Cldn-7, intestinal inflammation, and gut microbiota has not been clarified. Here, we hypothesize that Cldn-7 depletion affects intestinal inflammation by altering the gut microbiota. METHODS: Based on the induced intestinal condition of Cldn-7 knockout mice (Cldn7fl/fl;villin-CreaERT2), we established the intestinal flora depletion model and colitis model by antibiotic drinking and feeding with dextran sodium sulfate (DSS). The environment of Cldn-7 gene deletion mice was changed by co-housing experiment. AB-PAS staining and Muc2 were used to detect the effect of co-housing and Cldn-7 deficiency on the mucus layer after flora depletion. qRT-PCR was used to detect the expression of intestinal inflammatory factors and AMPs in mice. Feces were collected and proportions of microbiota were analyzed by 16 S rRNA amplicon sequencing. RESULTS: Mice in the co-housing experiment had altered intestinal microbiota, including diversity, composition, and functional prediction, compared to controls. Intestinal inflammation was restored to some extent following altered intestinal microbiota. The intestinal inflammation caused by Cldn-7 deficiency and susceptibility to DSS could be reduced after antibiotic administration compared to controls, in terms of phenotype, pathological changes, inflammatory factors, mucus barrier, and expression of AMPs. CONCLUSIONS: In analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal disruption of Cldn-7, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. Cldn-7might therefore be an important mediator of host-microbiome interactions. Our research has revealed that Cldn-7 plays an indispensable role in maintaining intestinal homeostasis by regulating the gut microbiota and impacting intestinal inflammation. These findings provide new insights into the pathogenesis of ulcerative colitis.

Lactobacillus rhamnosus GG coating with nanocomposite ameliorates intestinal inflammation.

The steady increase in the prevalence of inflammatory bowel disease (IBD) is regarded as a worldwide health issue. Gut microorganisms could modulate host immune and metabolic status and are associated with health effects. Probiotics, Lactobacillus rhamnosus GG (LGG), are beneficial microorganisms that ameliorate disease and exert advantageous effects on intestinal homeostasis. However, the viability of probiotics will suffer from various risk factors in the digestive tract. In this view, we developed a probiotic coating with nanocomposite using tannic acid (TA) and casein phosphopeptide (CPP) through layer-by-layer technology to overcome the challenges after oral administration. LGG showed an improved survival rate in simulated gastrointestinal conditions after coated. The coating (LGG/TA-Mg2+/CPP) had potent reactive oxygen species (ROS) scavenging ability and improved the survival rate of colorectal epithelial cells after H2O2 stimulation. In DSS-induced colitis, administration of LGG/TA-Mg2+/CPP ameliorated intestinal inflammation and reduced the disruption of barrier function. Furthermore, LGG/TA-Mg2+/CPP increased the abundance and diversity of the gut microbiota. In the mouse model of DSS colitis, LGG/TA-Mg2+/CPP can better activate the EGFR/AKT signaling pathway, thereby protecting the epithelial barrier function of the colon epithelium. In conclusion, the probiotic coating with nanocomposite may become a delivery platform for probiotics applied to IBD.

Disruption of intestinal oxygen balance in acute colitis alters the gut microbiome.

The juxtaposition of well-oxygenated intestinal colonic tissue with an anerobic luminal environment supports a fundamentally important relationship that is altered in the setting of intestinal injury, a process likely to be relevant to diseases such as inflammatory bowel disease. Herein, using two-color phosphorometry to non-invasively quantify both intestinal tissue and luminal oxygenation in real time, we show that intestinal injury induced by DSS colitis reduces intestinal tissue oxygenation in a spatially defined manner and increases the flux of oxygen from the tissue into the gut lumen. By characterizing the composition of the microbiome in both DSS colitis-affected gut and in a bioreactor containing a stable human fecal community exposed to microaerobic conditions, we provide evidence that the increased flux of oxygen into the gut lumen augments glycan degrading bacterial taxa rich in glycoside hydrolases which are known to inhabit gut mucosal surface. Continued disruption of the intestinal mucus barrier through such a mechanism may play a role in the perpetuation of the intestinal inflammatory process.

Enhancing recovery from gut microbiome dysbiosis and alleviating DSS-induced colitis in mice with a consortium of rare short-chain fatty acid-producing bacteria.

The human gut microbiota is a complex community comprising hundreds of species, with a few present in high abundance and the vast majority in low abundance. The biological functions and effects of these low-abundant species on their hosts are not yet fully understood. In this study, we assembled a bacterial consortium (SC-4) consisting of B. paravirosa, C. comes, M. indica, and A. butyriciproducens, which are low-abundant, short-chain fatty acid (SCFA)-producing bacteria isolated from healthy human gut, and tested its effect on host health using germ-free and human microbiota-associated colitis mouse models. The selection also favored these four bacteria being reduced in abundance in either Ulcerative Colitis (UC) or Crohn's disease (CD) metagenome samples. Our findings demonstrate that SC-4 can colonize germ-free (GF) mice, increasing mucin thickness by activating MUC-1 and MUC-2 genes, thereby protecting GF mice from Dextran Sodium Sulfate (DSS)-induced colitis. Moreover, SC-4 aided in the recovery of human microbiota-associated mice from DSS-induced colitis, and intriguingly, its administration enhanced the alpha diversity of the gut microbiome, shifting the community composition closer to control levels. The results showed enhanced phenotypes across all measures when the mice were supplemented with inulin as a dietary fiber source alongside SC-4 administration. We also showed a functional redundancy existing in the gut microbiome, resulting in the low abundant SCFA producers acting as a form of insurance, which in turn accelerates recovery from the dysbiotic state upon the administration of SC-4. SC-4 colonization also upregulated iNOS gene expression, further supporting its ability to produce an increasing number of goblet cells. Collectively, our results provide evidence that low-abundant SCFA-producing species in the gut may offer a novel therapeutic approach to IBD.

Diminished Immune Response and Elevated Abundance in Gut Microbe Dubosiella in Mouse Models of Chronic Colitis with GBP5 Deficiency.

Guanylate binding protein 5 (GBP5) is an emerging immune component that has been increasingly recognized for its involvement in autoimmune diseases, particularly inflammatory bowel disease (IBD). IBD is a complex disease involving inflammation of the gastrointestinal tract. Here, we explored the functional significance of GBP5 using Gbp5 knockout mice and wildtype mice exposed to dextran sulfate sodium (DSS) to generate chronic colitis model. We found that Gbp5 deficiency protected mice from DSS-induced chronic colitis. Transcriptome analysis of colon tissues showed reduced immune responses in Gbp5 knockout mice compared to those in corresponding wildtype mice. We further observed that after repeated DSS exposure, the gut microbiota was altered, both in wildtype mice and Gbp5 knockout mice; however, the gut microbiome health index was higher in the Gbp5 knockout mice. Notably, a probiotic murine commensal bacterium, Dubosiella, was predominantly enriched in these knockout mice. Our findings suggest that GBP5 plays an important role in promoting inflammation and dysbiosis in the intestine, the prevention of which might therefore be worth exploring in regards to IBD treatment.