MaterHypoBiota · MaterHypoBiota: Exploring the role of maternal gut microbiota on hypothalamic neurodevelopment and metabolic programming in offspring.

The alarmingly high incidence of obesity, particularly in children, highlights the need to better understand the factors and mechanisms involved in the early development of this pathological condition. Accumulating evidence, including work from the host lab, support the idea that the maternal nutritional environment could influence the offspring’s susceptibility to develop obesity and related comorbidities in later life. In particular, there is growing appreciation that developmental malprogramming of hypothalamic neuroendocrine system by the perinatal environment represents a possible cause for these diseases. However, the mechanisms by which the maternal environment affects hypothalamic development and predisposition to obesity are still largely unknown. We hypothesize that the maternal gut microbiota (mGM) conditions, in the offspring, the development of hypothalamic structures with lifelong metabolic consequences. We will test this novel hypothesis by using two complementary animal models of impaired mGM: germ-free dams and dams with antibiotic-induced alteration of gut microbiota during pregnancy and lactation. We will assess neuroanatomical organization of hypothalamic feeding circuits, structural and functional development of blood-brain barrier as well as metabolic outcomes in the offspring. Finally, we will examine the cause and effect relationship between mGM and hypothalamic development and function by determining whether i) maternal fecal material transplant and ii) dams’ supplementation with specifically identified microbial metabolites prevent offspring’s neuroanatomical and metabolic alterations. Completion of this project will i) shed light on a new vertical role of mGM on hypothalamic neurodevelopment and metabolic programming and ii) identify new potential drivers leading to early-life metabolic disorders. Given the high prevalence of maternal antibiotic use and childhood obesity, this project could have a potential impact on public health.