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Irisin attenuates inflammation in a mouse model of ulcerative colitis by altering the intestinal microbiota.

ABSTRACT: Evidence has demonstrated that the gut microbiota, which consists of probiotics and pathogenic microorganisms, is involved in the initiation of ulcerative colitis (UC) via the dysregulation of intestinal microflora and normal immune interactions, which ultimately leads to intestinal mucosal dysfunction. Irisin is released from muscle cells and displays anti-inflammatory effects; however, the mechanisms underlying irisin-mediated anti-inflammatory effects in UC have not been previously reported. In the present study, mice were divided into the following four groups: i) Control; ii) irisin; iii) dextran sulfate sodium (DSS) salt; and iv) DSS + irisin. Subsequently, the effects of irisin were investigated by observing alterations in intestinal microbes. Irisin significantly reduced the degree of inflammation in UC by reversing alterations to the macroscopic score, histological score, number of CD64⁺ cells and inflammatory cytokine alterations (P<0.05). Analysis of the microbial diversity in the stools of mice with active UC indicated that the five bacteria that displayed the greatest alterations in relative abundance were Alloprevotella, Bacteroides, Lachnospiraceae-UCG-001, Prebotellaceae-UCG-001 and Rikenellaceae-RCB-gut-group. Furthermore, Bactoroides were positively correlated with the histopathological score (P=0.001; R=0.977) and interleukin (IL)-23 levels (P=0.008; R=0.924). Alloprevotella (P=0.001; R=-0.943), Lachnospiraceae-UCG-001 (P=0.000; R=-0.973) and Rikenollaceae-RC8-gut-group (P=0.001; R=-0.971) were negatively correlated with the histopathological score. Furthermore, Lachnospiraceae-UCG-001 (P=0.01; R=-0.873) and Rikenollaceae-RC8-gut-group (P=0.049; R=-0.814) were negatively correlated with IL-23 levels. In summary, the results of the present study suggested that irisin improved inflammation in a UC mouse model potentially via altering the gut microbiota.

SUBMITTER: Huangfu LX

PROVIDER: S-EPMC8543469 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Irisin attenuates inflammation in a mouse model of ulcerative colitis by altering the intestinal microbiota.

Huangfu Lu Xin LX Cai Xin Tong XT Yang Jing Nan JN Wang Hui Chao HC Li Yu Xia YX Dai Zhi Feng ZF Yang Rui Lin RL Lin Xu Hong XH

Experimental and therapeutic medicine 20211011 6

Evidence has demonstrated that the gut microbiota, which consists of probiotics and pathogenic microorganisms, is involved in the initiation of ulcerative colitis (UC) via the dysregulation of intestinal microflora and normal immune interactions, which ultimately leads to intestinal mucosal dysfunction. Irisin is released from muscle cells and displays anti-inflammatory effects; however, the mechanisms underlying irisin-mediated anti-inflammatory effects in UC have not been previously reported. ...[more]

PMID: 34707714

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Project description:Susceptibility to Clostridioides difficile infection (CDI) typically follows the administration of antibiotics. Patients with inflammatory bowel disease (IBD) have increased incidence of CDI, even in the absence of antibiotic treatment. However, the mechanisms underlying this susceptibility are not well understood. To explore the intersection between CDI and IBD, we recently described a mouse model where colitis triggered by the murine gut bacterium, Helicobacter hepaticus, in IL-10-/- mice led to susceptibility to C. difficile colonization without antibiotic administration. The current work disentangles the relative contributions of inflammation and gut microbiota in colonization resistance to C. difficile in this model. We show that inflammation drives changes in microbiota composition, which leads to CDI susceptibility. Decreasing inflammation with an anti-p40 monoclonal antibody promotes a shift of the microbiota back toward a colonization-resistant state. Transferring microbiota from susceptible and resistant mice to germfree animals transfers the susceptibility phenotype, supporting the primacy of the microbiota in colonization resistance. These findings shine light on the complex interactions between the host, microbiota, and C. difficile in the context of intestinal inflammation, and may form a basis for the development of strategies to prevent or treat CDI in IBD patients. IMPORTANCE Patients with inflammatory bowel disease (IBD) have an increased risk of developing C. difficile infection (CDI), even in the absence of antibiotic treatment. Yet, mechanisms regulating C. difficile colonization in IBD patients remain unclear. Here, we use an antibiotic-independent mouse model to demonstrate that intestinal inflammation alters microbiota composition to permit C. difficile colonization in mice with colitis. Notably, treating inflammation with an anti-p40 monoclonal antibody, a clinically relevant IBD therapeutic, restores microbiota-mediated colonization resistance to the pathogen. Through microbiota transfer experiments in germfree mice, we confirm that the microbiota shaped in the setting of IBD is the primary driver of susceptibility to C. diffiicile colonization. Collectively, our findings provide insight into CDI pathogenesis in the context of intestinal inflammation, which may inform methods to manage infection in IBD patients. More broadly, this work advances our understanding of mechanisms by which the host-microbiota interface modulates colonization resistance to C. difficile.

Project description:ObjectiveTo explore the composition of the intestinal microbiota in ulcerative colitis (UC) patients and to identify differences in the microbiota between patients with active disease and those in remission.MethodsBetween September 2020 and June 2021, we enrolled into our study, and collected stool samples from, patients with active UC or in remission and healthy control subjects. The diagnosis of UC was based on clinical, endoscopic, radiological, and histological findings. The composition of the intestinal microbiota was determined by sequencing of the 16S rRNA V3-V4 region and by bioinformatic methods. The functional composition of the intestinal microbiota was predicted using PICRUSt 2 (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) software.ResultsWe found that the intestinal flora was significantly less rich and diverse in UC patients than in healthy control subjects. Beta diversity analysis revealed notable differences in the intestinal flora compositions among the three groups, but there was no statistical difference in alpha diversity between UC patients with active disease and those in remission. At the phylum level, the relative abundances of Proteobacteria and Patescibacteria were significantly higher, and the relative abundances of Desulfobacterota and Verrucomicrobiota were lower, in UC patients with active disease than in the healthy control group. Higher levels of potential pathogens and lower levels of butyrate-producing bacteria were also detected in UC patients with active disease. Linear discriminant analysis Effect Size (LefSe) revealed that 71 bacterial taxa could serve as biomarkers, with 26 biomarkers at the genus level. In addition, network analysis showed that there was a positive correlation between Roseburia and Lachnospira. Functional predictions indicated that gene functions involving the metabolism of some substances, such as methane, lipopolysaccharide, geraniol, and ansamycins, were significantly different among the three groups.ConclusionThe richness and diversity of the intestinal microbiota differed significantly among the three groups. Richness describes the state of being rich in number of intestinal bacteria, whereas diversity is the number of different species of intestinal bacteria. Different bacterial taxa could be used as biomarkers, expanding our understanding of the relationship between the intestinal microbiota microenvironment and UC in the future.

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Irisin attenuates inflammation in a mouse model of ulcerative colitis by altering the intestinal microbiota.

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Irisin attenuates inflammation in a mouse model of ulcerative colitis by altering the intestinal microbiota.

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