Improvement of glucose homeostasis during leptin treatment does not alter the intestinal microbiome in male diabetic UC Davis type-2 diabetes mellitus rats.

Gut dysbiosis contributes to type 2 diabetes mellitus (T2DM) progression according to the preclinical evidence. Alterations in gut microbiome, energy metabolism, and barrier function were observed in individuals with obesity and insulin resistance. However, it remains unclear whether therapeutic interventions can reverse these alterations. This study aimed to evaluate whether improvements of glucose homeostasis resulting from leptin administration can lead to changes in colonic epithelial metabolism and barrier function in male UC Davis type 2 diabetic mellitus (UCD-T2DM) rats. Male UCD-T2DM rats (age: 173 ± 41 days) with 6 wk postonset of diabetes were randomized to receive daily subcutaneous injections of either phosphate buffer solution (control; n = 12) or recombinant leptin (0.5 mg/kg; n = 12) for 4 wk. Metabolic and intestinal outcomes were assessed, including glucose tolerance, insulin sensitivity, glucagon-like protein 1 levels, gut permeability, microbiota composition, short-chain fatty acids content, colon epithelial hypoxia, intestinal morphology, and gene/protein expression. Leptin treatment significantly reduced food intake and improved glucose homeostasis and insulin sensitivity without affecting body weight. No changes were observed in microbiome composition, gut permeability, or colon epithelial hypoxic gradients. Ileal villus height was decreased, whereas colonic crypt depth was not different between leptin-treated rats and control rats. Butyric, isocaproic, and valeric acids levels were increased in colonic content, colonic gene expression of Pparg and Ldha was downregulated, whereas PHD2 and Occludin protein levels were upregulated in leptin-treated compared with control. Despite improvements of glucose homeostasis, chronic leptin treatment did not modify gut microbiota or barrier function markers and colonic metabolic gene expression showed no clear adaptive shift.NEW & NOTEWORTHY Our data indicate that chronic administration of recombinant leptin in diabetic UCD-T2DM rats does not change the gut microbiome, despite improvements in food intake, glucose homeostasis, and insulin sensitivity.