Mesenchymal stem cell-derived exosome mitigates colitis via the modulation of the gut metagenomics-metabolomics-farnesoid X receptor axis.

Inflammatory bowel disease (IBD) is associated with chronic gut immune dysregulation and altered microbiome and metabolite composition. Bile acids and their receptors such as the farnesoid X receptor (FXR) form a crucial component of the chemical communications between the intestinal microbiota and the host immune system; thus, alterations in the bile acid pool affect intestinal homeostasis and exacerbate IBD. Considering the promising therapeutic effect of mesenchymal stem cell-derived exosomes (MSC-Ex) on IBD, this study assessed the regulatory effect of MSC-Ex on the gut bacteria composition and diversity, metabolites, and their related functions and pathways, as well as key inflammatory and anti-inflammatory cytokines during the mitigation of IBD. The dextran sulfate sodium (DSS)-induced IBD model of BABL/C mice was established, consisting of three groups: control, DSS, and MSC-Ex groups. Post administration of MSC-Ex, the effect was evaluated via hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), qRT-PCR, and western blotting. Mice fecal samples were obtained for metagenomics and metabolomics analysis via 16S rRNA gene sequencing and UHPLC/Q-TOF-MS respectively. Results showed that MSC-Ex mitigated colitis by significantly relieving the macroscopic and microscopic features of inflammation, modulating the gut metagenomics and metabolomics profile, and increasing colonic FXR. MSC-Ex improved the gut microbiota composition by significantly restoring the structure of OTUs and colitis-induced reduction in α-diversity, increasing the abundance of 'healthy' bacteria, decreasing disease-associated bacteria, decreasing detrimental functions, and enhancing other vital cellular functions. For the first time, we demonstrate that MSC-Ex mitigates colitis in mice by modulating the gut metagenomics-metabolomics-FXR axis, thus providing potential therapeutic targets.