Maternal Treatment with Metformin Persistently Ameliorates High-Fat Diet-Induced Metabolic Symptoms and Modulates Gut Microbiota in Rat Offspring

Abstract

A maternal high-fat (HF) diet has long-term deleterious effect on offspring. This study aims to evaluate whether maternal metformin (MT) treatment ameliorates the adverse effects of maternal HF diet on offspring and the role of gut microbiota in it. Pregnant Sprague-Dawley rats were randomly assigned to a HF diet (60% fat) or a standard chow diet (11.8% fat) group, and part of the HF diet group rats were co-treated with MT via drinking water (300 mg/kg/day), resulting in three groups according to maternal diet and MT treatment during gestation and lactation. All offspring were weaned on a chow diet. A maternal HF diet showed a significant deleterious effect on offspring’s metabolic phenotype and induced colonic inflammation and gut-barrier disruption through the reshaped gut microbiota. The daily oral administration of MT to HF-fed dams during gestation and lactation reversed the dysbiosis of gut microbiota in both dams and adult offspring. The hypothalamic TGR5 expression and plasma bile acids composition in adult male offspring was restored by maternal MT treatment, which could regulate hypothalamic appetite-related peptides expression and alleviate inflammation, thereby improving male offspring’s metabolic phenotype. The present study indicates that targeting the gut–brain axis through the mother may be an effective strategy to control the metabolic phenotype of offspring.