Diabetes-Associated Alterations in the Cecal Microbiome and Metabolome are Independent of Diet or Environment in the UC Davis Type 2-Diabetes Mellitus Rat Model

The composition of the gut microbiome is altered in obesity and type 2 diabetes; however, it is not known whether these alterations are mediated by dietary factors or related to declines in metabolic health. To address this, cecal contents were collected from age-matched, chow-fed male UCD-T2DM rats before the onset of diabetes (pre-diabetic PD, n=15); 2 wk recently-diabetic (RD, n=10); 3 mo (D3M, n=11); and 6 mo (D6M, n=8) post-onset of diabetes. Bacterial species and functional gene counts were assessed by shotgun metagenomic sequencing of bacterial DNA in cecal contents, while metabolites were identified by GC-QTOF-MS. Metagenomic analysis showed a shift from Firmicutes species in early stages of diabetes (PD+RD) towards an enrichment of Bacteroidetes species in later stages of diabetes (D3M+D6M). In total, 45 bacterial species discriminated early and late stages of diabetes with 25 of these belonging to either Bacteroides or Prevotella genera. Furthermore, 61 bacterial gene clusters discriminated early and later stages of diabetes with elevations of enzymes related to stress response (e.g., glutathione and glutaredoxin), and amino acid, carbohydrate, and bacterial cell wall metabolism. Twenty-five metabolites discriminated early vs late stages of diabetes, with the largest differences observed in abundances of dehydroabietic acid and phosphate. Alterations in the gut microbiota and cecal metabolome track diabetes progression in UCD-T2DM rats when controlling for diet, age, and housing environment. Results suggest that diabetes-specific host signals impact the ecology and end-product metabolites of the gut microbiome when diet is held constant.