{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE318nnn/GSE318754/"]},"type":"primary"},"statusCodeValue":200,"statusCode":"OK"}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE318754"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Empagliflozin restores colonic fatty acid metabolism and ameliorates fibrotic signalling despite gut dysbiosis in Western diet-fed mice","description":"Aims Gut dysbiosis and an altered host colonic transcriptomic response are significant contributors to metabolic deterioration with westernization of the diet. Despite the wide usage of SGLT2 inhibitors in patients with type 2 diabetes, chronic kidney disease and/or heart failure, intestinal effects of SGLT-2 inhibitors are largely unknown. Here we aimed to investigate diet-dependent effects of empagliflozin on microbiome and colonic transcriptome. Methods C57BL/6j mice were fed a high-sucrose, high-fat Western Diet (WD) with or without supplementation of empagliflozin for 10 weeks. A control diet (CD) was used to evaluate potential drug-diet interactions. C57/Bl6j mice were fed either a Western diet or standard diet and treated with empagliflozin for 10 weeks. Mice on standard or Western diet without empagliflozin treatment served as controls. A control diet was used to evaluate potential drug-diet interactions. Metabolic phenotyping was performed and already published. Here, colon and stool samples were used for transcriptomics and 16S metagenomics. An additive model with global drug and diet effects was compared to a full interaction model. Results Colon transcriptomics data suggested an interaction effect between drug and diet (PERMANOVA; p for interaction = 0.001). Overall, 1136 genes showed significant interactions when compared to an additive model. 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. Mechanistically, the drug-diet interaction was also found in respective master regulators Ppara (Peroxisome proliferator-activated receptor alpha) (p for interaction < 0.001) and Rela (Nuclear factor kappa B subunit p65) (p for interaction = 0.014). In 16S metagenomics WD led to a significantly reduced microbial alpha diversity (two-way-anova; p < 0.001) and distinct clustering with regards to beta-diversity (PERMANOVA, p = 0.001), empagliflozin did not reverse colonic bacterial composition, despite protection against metabolic deterioration on whole-body level. Conclusions Western diet but not empagliflozin treatment altered colonic bacterial composition suggesting microbiome-independent effects of empagliflozin on the colonic transcriptome. When taking drug-diet interactions into account, a vast regulatory influence of empagliflozin on colonic transcriptome is apparent. Upregulation of fatty acid metabolism only when needed, and protection against fibrosis related genes in gut dysbiosis represent novel mechanisms of actions with SGLT2 inhibition.","dates":{"publication":"2026/10/05"},"accession":"GSE318754","cross_references":{"GSM":["GSM9502667","GSM9502668","GSM9502669","GSM9502658","GSM9502659","GSM9502670","GSM9502671","GSM9502660","GSM9502661","GSM9502672","GSM9502662","GSM9502673","GSM9502674","GSM9502663","GSM9502664","GSM9502675","GSM9502676","GSM9502665","GSM9502677","GSM9502666"],"GPL":["24247"],"GSE":["318754"],"taxon":["Mus musculus"]}}