Reductions in Intestinal Taurine-Conjugated Bile Acids and Short-Chain Fatty Acid-Producing Bacteria Might be Novel Mechanisms of Type 2 Diabetes Mellitus in Otsuka Long-Evans Tokushima Fatty Rats.

BACKGROUND: The pathogenesis of spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, among the best models for human type 2 diabetes mellitus (T2DM), remains poorly defined. Therefore, we investigated the dynamic changes in taurine-conjugated bile acids (T-BAs) and intestinal microbiota during T2DM development in OLETF rats. METHODS: OLETF rats and corresponding diabetes-resistant Long Evans Tokushima Otsuka (LETO) rats were fed a normal baseline diet. The progress of T2DM was divided into four phases, including normal glycemia-normal insulinemia (baseline), normal glycemia-hyperinsulinemia, impaired glucose tolerance, and DM. Body weight, liver function, blood lipids, fasting plasma glucose, fasting plasma insulin, fasting plasma glucagon-like peptide (GLP)-1 and GLP-2, serum and fecal T-BAs, and gut microbiota were analyzed during the entire course of T2DM development. RESULTS: There were reductions in fecal T-BAs and short-chain fatty acids (SCFAs)-producing bacteria including Phascolarctobacterium and Lactobacillus in OLETF rats compared with those in LETO rats at baseline, and low levels of fecal T-BAs and SCFAs-producing bacteria were maintained throughout the whole course of the development of T2DM among OLETF rats compared with those in corresponding age-matched LETO rats. Fecal taurine-conjugated chenodeoxycholic acid correlated positively with Phascolarctobacterium. Fecal taurine-conjugated deoxycholic acid correlated positively with Lactobacillus and fasting plasma GLP-1 and inversely with fasting plasma glucose. CONCLUSION: The fecal BAs profiles and microbiota structure among OLETF rats were different from those of LETO rats during the entire course of T2DM development, indicating that reductions in intestinal T-BAs and specific SCFA-producing bacteria may be potential mechanisms of T2DM in OLETF rats.