The role of microbe-epithelial interactions on primate enteroneuroactivity in response to maternal high fat diet

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Neurochemical messengers like serotonin, dopamine, and gamma-aminobutyric acid have been linked to anxiety for decades, and yet these compounds are largely produced in the gut, both by intestinal cells and by gut microbes (aka enteroneuroactivity). However, the extent to which the gut contributes to the mechanism of neurotransmitter dysregulation in child anxiety remains poorly understood. The long-term goal of this project is to investigate the microbiome-gut-brain axis, how it is shaped in childhood, and how it contributes to early life neurodevelopment. The overall objective is to elucidate the effect of microbe-epithelial interactions on the form and function of gut epithelia in juvenile non-human primates (NHPs) that display anxiety-like behavior induced by maternal high fat diet (mHFD). Preliminary data in mHFD-exposed NHP juveniles demonstrate a) altered serotonin and dopamine in the brain, b) reduced serotonin in mHFD-microbe treated gut epithelia, and c) a persistently-altered gut microbiome. The central hypothesis is that ongoing microbe-epithelial interactions are required to perpetuate the altered enteroneuroactive function in the mHFD-exposed NHP gut. To better understand the in vivo associative data, the rationale for this project is to generate mechanistic data in vitro through the cultivation of enteroids and colonoids derived from control and mHFD-exposed NHPs. The central hypothesis will be tested by pursing two specific aims that will characterize the cellular enteroneuroactive functional status and compositional form of enteroids/colonoids in the absence and presence of reintroduced gut microbes. Under the first aim, enteroids/colonoids derived from control and mHFD-exposed NHPs will be cultured with and without microbes and compared for enteroneuroactive compound and enzyme levels (function). For the second aim, enteroids/colonoids will be compared for enteroneuroactive cell types and receptors (form). Together this analysis will determine if the enteroneuroactive profile witnessed in vivo is replicated in vitro with or without microbes. The trainee’s environment is perfectly primed to accomplish these aims via the enteroid core of Baylor College of Medicine, the metabolomics laboratory of the Texas Children’s Microbiome Center, and the longstanding NHP model of the Aagaard lab. The research proposed in this application is aimed to enhance the trainee’s career path towards a dynamic, multidisciplinary specialization in the fields of microbiology, gastroenterology, and neurology with the goal of becoming an academic pediatrician- scientist. The proposed research is significant because it is expected to determine the necessity of ongoing microbial-host interactions on the form and function of enteroneuroactivity in the context of anxiety. Ultimately, such knowledge has the potential to identify the critical components involved in childhood neurobehavioral development.