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Metformin Targets Intestinal Immune System Signaling Pathways in High-Fat Diet-Induced Type 2 Diabetes Mouse Model

ABSTRACT: Research findings of the past decade have highlighted the gut as the main site of action of the oral antihyperglycemic agent metformin despite its pharmacological role in the liver. Extensive evidence supports metformin’s modulatory effect on the composition and function of gut microbiota, nevertheless, the underlying mechanisms of the host responses remain elusive. Our study aimed to evaluate metformin-induced alterations in the intestinal transcriptome profiles at different metabolic states. The high-fat diet-induced type 2 diabetes mouse model of both sexes was developed in a randomized block experiment and bulk RNA-Seq of the ileum tissue was the method of choice for comparative transcriptional profiling after metformin intervention for ten weeks. We found a prominent transcriptional effect of the diet itself with comparatively fewer genes responding to metformin intervention. The overrepresentation of immune-related genes was observed, including pronounced metformin-induced upregulation of immunoglobulin heavy-chain variable regioncoding Ighv1-7 gene in both high-fat diet and control diet-fed animals, supporting the contribution of intestinal immunoglobulin responses. Finally, we provide evidence of the downregulation NF-kappa B signaling pathway in the small intestine of both hyperglycemic and normoglycemic animals after metformin treatment. Moreover, our data pinpoint the gut microbiota as a crucial component in the metformin-mediated downregulation of NF-kappaB signaling evidenced by a positive correlation between the Rel and Rela gene expression levels and abundances of Parabacteroides distasonis, Bacteroides spp., and Lactobacillus spp. in the gut microbiota of the same animals.

ORGANISM(S): Mus musculus

PROVIDER: GSE240206 | GEO | 2023/08/12

REPOSITORIES: GEO

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