The Microbial Metabolite 4-Cresol Improves Glucose Homeostasis and Enhances β-Cell Function

Gut microbiota changes are associated with increased risk of Type 2 diabetes (T2D) and obesity. Through serum metabolome profiling in patients with cardiometabolic disease (CMD) we identified significant inverse correlation between the microbial metabolite 4-cresol and T2D. Chronic administration of non toxic dose of 4-cresol in two complementary preclinical models of CMD reduced adiposity, glucose intolerance and liver triglycerides, and enhanced insulin secretion in vivo , which may be explained by markedly increased pancreas weight, augmented islet density and size, and enhanced vascularisation suggesting activated islet neogenesis. Incubation of isolated islets with 4-cresol enhanced insulin secretion, insulin content and cell proliferation. In both CMD models 4-cresol treatment in vivo was associated with altered expression of SIRT1 and the kinase DYRK1A, which may contribute to mediate its biological effects. Our findings identify 4-cresol as an effective regulator of β-cell function and T2D endophenotypes, which opens therapeutic perspectives in syndromes of insulin deficiency.