Global Sirt5 deletion reshapes gut microbiota and impairs glucose metabolism in high-fat diet-induced obese mice.

Defects in sirtuins (SIRTs) signaling contribute to disrupted glycolipid metabolism, resulting in obesity, type 2 diabetes (T2D) and other metabolic diseases. Sirtuin 5 (Sirt5) has been implicated in regulating multiple metabolic pathways. Given the roles of gut microbiota dysbiosis and β cells dysfunction in T2D pathogenesis, we investigated whether Sirt5 modulates intestinal microbiota composition, β cells function, and systemic glucose metabolism. In this study, adopting whole-body Sirt5-deficient mice fed a chow diet or high-fat diet (HFD), we revealed that systemic lack of Sirt5 facilitated gut microbial dysbiosis, characterized by increased abundance of opportunistic pathogens and decreased levels of beneficial bacteria. Moreover, global Sirt5 loss also augmented non-fasting and fasting blood glucose levels, triggered the exacerbation of glucose intolerance and attenuation of insulin sensitivity, suppressed glucose-stimulated insulin secretion (GSIS) of islet β cells, and reduced β cells mass in HFD-fed mice. Correlation analysis demonstrated that the increment of blood glucose levels induced by Sirt5 deficiency was closely pertinent to the alteration of gut microbiota. Additionally, the impaired GSIS initiated by Sirt5 ablation correlated negatively with glycaemia and positively with genus Rikenalla. Overall, Sirt5 exerts crucial roles in ameliorating glucose metabolism and mitigating T2D progression partially through sustaining β cells function and gut microbiota homeostasis.