Early life stress induces type 2 diabetes-like features in ageing mice

•Maternal separation is a risk factor for glucose intolerance in ageing mice.•Maternal separation induces microbiota dysbiosis in favor to pathobionts.•Maternal separation-induced glucose intolerance is associated with decrease of intestinal IL-17 and IL-22 responses. Early life stress is known to impair intestinal barrier through induction of intestinal hyperpermeability, low-grade inflammation and microbiota dysbiosis in young adult rodents. Interestingly, those features are also observed in metabolic disorders (obesity and type 2 diabetes) that appear with ageing. Based on the concept of Developmental Origins of Health and Diseases, our study aimed to investigate whether early life stress can trigger metabolic disorders in ageing mice. Maternal separation (MS) is a well-established model of early life stress in rodent. In this study, MS increased fasted blood glycemia, induced glucose intolerance and decreased insulin sensitivity in post-natal day 350 wild type C3H/HeN male mice fed a standard diet without affecting body weight. MS also triggered fecal dysbiosis favoring pathobionts and significantly decreased IL-17 and IL-22 secretion in response to anti-CD3/CD28 stimulation in small intestine lamina propria. Finally, IL-17 secretion in response to anti-CD3/CD28 stimulation was also diminished at systemic level (spleen). For the first time, we demonstrate that early life stress is a risk factor for metabolic disorders development in ageing wild type mice under normal diet.