Offspring metabolic programming via the maternal diet increases susceptibility to metabolic dysregulation.

BACKGROUND: Maternal nutrition during critical developmental windows is crucial for offspring metabolic programming. Methionine, an essential amino acid, is crucial in pancreatic differentiation. However, the impact of a maternal methionine-deficiency (MD) diet on offspring during the critical stage of embryonic pancreatic differentiation remains unclear. METHODS: We used an in vitro human induced pluripotent stem cell (hiPSC) differentiation model and in vivo mouse and rat models to assess the impact of short-term maternal MD during pancreatic development. Offspring metabolic outcomes were evaluated under control or high-fat diet conditions. Multi-omics analyses were performed to explore mechanistic pathways, and Ruminococcus flavefaciens supplementation was used to assess microbiota-metabolite-host interactions. FINDINGS: During foetal pancreatic development in mice, a two-day maternal MD diet induced long-term metabolic perturbations in offspring. MD disrupted pancreatic progenitor differentiation in vitro and altered offspring glucose homeostasis, pancreatic function, and gut microbiota composition in vivo. Male offspring showed impaired glucose tolerance, enhanced pancreatic differentiation, and increased susceptibility to diet-induced obesity in adulthood. These metabolic impairments were evident early in life, with MD neonates displaying altered metabolic profiles and pancreatic gene expression. We identified an association between maternal MD diet, gut microbiota-dependent R. flavefaciens abundance, and elevated creatine levels in both mothers and offspring. R. flavefaciens supplementation in mice recapitulates the observed metabolic dysregulation. INTERPRETATION: Short-term maternal MD during foetal pancreatic development can induce lasting metabolic reprogramming in offspring. Gut microbiota-dependent creatine dysregulation may serve as a key mediator linking maternal diet to offspring metabolic susceptibility. These findings highlight the developmental impact of transient maternal nutrient imbalance and role of the microbiota-metabolite axis in shaping offspring health. FUNDING: See Acknowledgements.