INVESTIGATION INTO THE MECHANISMS UNDERLYING THE TRANSGENERATIONAL EFFECTS OF MATERNAL HIGH-FAT DIET-INDUCED DYSBIOSIS ON OFFSPRING BRAIN AND METABOLISM

Genetic and environmental factors, and their interactions, contribute to the etiology and pathophysiology of neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD). The clinical heterogeneity and phenotypic variability in patients with NDDs have made identification of causal mechanisms contributing to their onset difficult. Yet, unraveling the underlying causes of NDDs is essential to the development of appropriate preventive/therapeutic strategies. Maternal obesity is considered one of the main nongenetic risk factors for NDDs in progeny. We and others have found that high-fat (HF) obesogenic diets in both humans and animal models induce significant modifications in maternal gut microbiome composition (dysbiosis), which are causally related to detrimental health outcomes in offspring, including ASD-like social deficits. Given the increasing prevalence of obesity and overweight in women of childbearing age, further investigation into the mechanisms by which maternal obesity impacts offspring health is needed. Here, working in a mouse model, we aimed to determine in whether vertical transmission of maternal high-fat diet (MHFD)-induced obese-type gut microbiota could serve as the primary driver of cognitive and metabolic dysfunction in offspring, identify the underlying mechanisms, and test the efficacy of prenatal modulation of the maternal gut microbiome on preventing behavioral and metabolic dysfunction in offspring. In a second study, we tested the hypothesis that MHFD-induced dysbiosis of the gut microbiome and related social dysfunction persists across generations and are therefore propagated in generations beyond the first, even in the absence of direct exposure to MHFD. We anticipate that our studies have the potential to revolutionize antenatal care for women of overweight and obese status and could lead to the development of innovative preventative and therapeutic strategies, such as prenatal probiotic administration, to improve the health of children affected by maternal diet-induced obesity in utero.