GLP‐1 receptor agonists alleviate colonic inflammation by modulating intestinal microbiota and the function of group 3 innate lymphoid cells

Mar 28, 2024Immunology

GLP-1 receptor agonists reduce colon inflammation by changing gut bacteria and immune cell activity

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Abstract

GLP-1 receptor agonists may improve colitis induced by dextran sulfate sodium in mice.

GLP-1 receptor agonists are associated with reduced symptoms of colitis in both wild-type and T/B-cell-deficient mice.
The protective effects of these drugs may involve the modulation of group 3 innate lymphoid cells (ILC3s), which help regulate intestinal immunity.
Treatment with GLP-1 receptor agonists promotes the production of IL-22 by ILC3s, critical for intestinal health.
The beneficial effects of GLP-1 receptor agonists on colitis may depend on the gut microbiota.
These drugs increase beneficial bacteria in the gut, such as Lactobacillus reuteri, while decreasing harmful bacteria.
An endogenous metabolite, N,N-dimethylsphingosine (DMS), is enriched in fecal samples from GLP-1 receptor agonist-treated mice and may also help alleviate colitis.

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Glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are drugs used for treating type 2 diabetes, have been reported to exert anti-inflammatory effects on inflammatory bowel disease (IBD), the mechanism of which remains elusive. Here, we report that GLP-1RAs ameliorate dextran sulfate sodium (DSS)-induced colitis in both wild-type and T/B-cell-deficient mice through modulating group 3 innate lymphoid cells (ILC3s), a subset of innate lymphoid cells that regulate intestinal immunity. GLP-1RAs promote IL-22 production by ILC3, and the protective effect of GLP-1RAs on DSS-induced colitis was abrogated in ILC3-deficient RORgtmice. Furthermore, the treatment effect of GLP-RAs on colitis, as well as the generation of IL-22-producing ILC3s by GLP-RAs, is dependent on the gut microbiota. GLP-1RAs increase the abundance of Firmicutes and Proteobacteria in the gut, particularly beneficial bacteria such as Lactobacillus reuteri, and decrease the abundance of enteropathogenic Staphylococcus bacteria. The untargeted gas chromatography (GC)/liquid chromatography (LC)-mass spectrometry (MS) of faecal metabolites further revealed enrichment of N,N-dimethylsphingosine (DMS), an endogenous metabolite derived from sphingosine, in the GLP-1RA-treated group. Strikingly, DMS ameliorates colitis while promoting intestinal IL-22-producing ILC3s. Taken together, our findings show that GLP-1RAs exert a therapeutic effect on colitis possibly by regulating the microbiota-DMS-IL-22ILC3 axis, highlighting the potential beneficial role of GLP-RAs in inflammatory intestinal disorders with diabetes complications. gfp/gfp +

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GLP‐1 receptor agonists alleviate colonic inflammation by modulating intestinal microbiota and the function of group 3 innate lymphoid cells

Abstract

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