Role of Microbial Metabolites in Regulating Hypothalamic Pathways Involved in Feeding Behavior

Funding Summary

The probiotic supplement, BPL1, shows promise improving metabolism and behavior in people with PWS, but more work is needed to understand how this gut microbiome intervention can be optimized. This project aims to understand how probiotic supplementation improves metabolic and mental health in individuals with PWS by influencing brain circuits regulating energy balance.

Dr. Theresa Strong, Director of Research Programs, explains the details of this project in this video clip. 

Lay Abstract

The gastrointestinal tract is colonized by microorganisms commonly known as the gut microbiome, whose composition influences human health. Probiotic supplementation alters the microbiome and the production of bioactive metabolites that influence appetite and energy homeostasis. Indeed, microbial metabolites are key players in the cross-communication between gut and brain, regulating a range of symptoms, including satiety and anxiety. Targeting the microbiome is actively investigated as a therapeutic strategy for a wide range of diseases, including obesity, depression, and autism. Among all gut bacteria, Bifidobacterium animalis spp. lactis (BPL1) showed promises in reducing body weight and improve metabolic function. Positive results have been reported in subjects with PWS, with reduced adiposity and improved insulin sensitivity and cognitive function. However, the mechanisms underlying these effects are still unknown. This proposal aims to understand how probiotic supplementation improves metabolic and mental health in individuals with PWS by influencing brain circuitries regulating energy homeostasis. For that, we are combining interdisciplinary laboratory and clinical expertise. For the clinical part, we will take advantage of an ongoing clinical trial in which subjects with PWS are being treated with the probiotic BPL1. Plasma and feces are being taken and we will determine the gut microbiome composition and metabolite concentrations. Changes in gut microbiome and metabolome will be correlated with clinical data to identify the microbial metabolites that potentially mediate the beneficial effect of BPL1. In the lab, we will recreate a key brain structure involved in appetite sensing deeply affected in subjects with PWS named the arcuate nucleus (ARC) of hypothalamus. For that, we will tissue engineering to create organ-like tissue structures, or organoids, resembling this part of the human brain from stem cell models of PWS harboring the paternal deletion of 15q11.2-13 region. In follow-up studies, this model will be used as a reliable platform to assess the impact of the most relevant BPL1 metabolites, crossing the blood-brain barrier (BBB), in hypothalamic functioning. With this project, we hope to decipher the molecular mechanisms regulating energy homeostasis through which probiotic supplementation improves metabolic and mental health in individuals with PWS.