Metformin targets intestinal immune system signaling pathways in a high-fat diet-induced mouse model of obesity and insulin resistance

Abstract

IntroductionResearch 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. MethodsThe high-fat diet-induced mouse model of obesity and insulin resistance 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. ResultsWe 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 region coding Ighv1-7 gene in both high-fat diet and control diet-fed animals. Moreover, we provide evidence of the downregulation NF-kappa B signaling pathway in the small intestine of both obese and insulin-resistant animals as well as control animals after metformin treatment. Finally, our data pinpoint the gut microbiota as a crucial component in the metformin-mediated downregulation of NF-kappa B 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. DiscussionOur study supports the immunomodulatory effect of metformin in the ileum of obese and insulin-resistant C57BL/6N mice contributed by intestinal immunoglobulin responses, with a prominent emphasis on the downregulation of NF-kappa B signaling pathway, associated with alterations in the composition of the gut microbiome.

Comprehensive analysis of key host gene-microbe networks in the cecum tissues of the obese rabbits induced by a high-fat diet

“…Similarly, the mechanism of insulin resistance stems from the interaction between gut microbiota and host genes. Previous studies reported that the lipid diet-induced gut microbiota, including Parabacteroides distasonis , Bacteroides spp., and Lactobacillus spp., could reduce the NF-κB gene expression level as well as the levels of pro-inflammatory Th17 cells in the gut tissues ( Ang et al., 2020 ; Brīvība et al., 2023 ). The current study found that the cecal host genes involved in the calcium signaling pathway and PI3K-Akt signaling pathway were upregulated, while those involved in the NF-κB signaling pathway and T cell receptor signaling pathway were downregulated.…”

Understanding the action mechanisms of metformin in the gastrointestinal tract

“…Additionally, metformin has demonstrated anti-inflammatory effects through the inhibition of IL-18 expression, which is linked to alterations in the intestinal microbiome (Lee et al, 2019). Another study found that treatment with metformin can regulate the immune response in the intestines of mice by altering the composition of the gut microbiome, particularly through the downregulation of the NF-κB signaling pathway (Brīvība et al, 2023). Therefore, metformin potentially enhances immune responses by modulating the gut microbiota.…”