Empagliflozin restores colonic fatty acid metabolism and ameliorates fibrotic signalling despite gut dysbiosis in Western diet-fed mice

Gut dysbiosis and an altered host colonic transcriptomic contribute to Western diet (WD) induced metabolic deterioration. In this pilot study we investigated the effect of empagliflozin on intestinal transcriptomics and microbiome. CL57BL/6J mice were fed a WD or control-diet with or without empagliflozin supplementation for 10 weeks. Colon and stool samples were used for transcriptomics and 16 S amplicon sequencing. An additive model with global drug and diet effects was compared to a full interaction model. Colon transcriptomics data suggested an interaction effect between drug and diet ( p = 0.001; PERMANOVA). From overall 1136 interacting genes, gene ontology analysis revealed two major biological processes being involved: In WD fed mice empagliflozin activated fatty acid metabolism and protected against fibrosis related genes. The drug-diet interaction was also found in representative regulators Peroxisome proliferator-activated receptor alpha and Nuclear factor kappa B subunit p65 ( p < 0.05). In microbiome analysis WD significantly reduced alpha diversity and distinct clustering with regards to beta-diversity. In conclusion, WD but not empagliflozin treatment altered gut microbiome suggesting microbiome-independent effects of empagliflozin on the colonic transcriptome. Upregulation of fatty acid metabolism, and protection against fibrosis related genes in gut dysbiosis represent novel mechanisms of actions with SGLT2 inhibition.