PROBE: Probiotic Regulation Of Gut-Microbiome-Brain Interactions in Obesity and Eating Behaviors - PROJECT SUMMARY/ABSTRACT One specific area that has garnered attention is the microbiome-gut-brain (MGB) axis - a bidirectional signaling system between the gut and the brain. While targeting the microbiome in obesity has demonstrated some efficacy in improving insulin sensitivity and adiposity, the involvement of “gut-brain interactions” in these processes is unclear. This is because few studies have examined the role of the microbiome in modulating the reward network, the brainstem and its associated nuclei after a targeted gut-directed treatment (e.g., probiotics), especially in humans. Obesity continues to represent a major health epidemic, with a very high financial burden and with implications for the development of preventable chronic disease. This translates to an urgent need for therapeutic strategies that complement existing approaches, preferably interventions that can be personalized, are cost effective, and easy to implement. Moreover, because obesity is so heterogeneous we need to focus on treating the phenotype of obesity, which in turn increases treatment responses. Understanding the underlying MGB pathways will offer viable targets to address these unmet needs. Therefore, in response to NOT-AT-24- 041, we will perform a randomized, double-blind, placebo-controlled mechanistic clinical study, treating 250 participants (200 with obesity, 50 controls without obesity) with a probiotic blend, consisting of Akkermansia mucinphila and Bacteroides thetaiotamicron, that individually have known effects on tryptophan metabolism, glucagon-like-peptide [GLP-1] production, insulin sensitivity, weight, and waist circumference, and evaluate the MGB response. We will use a novel 7 Tesla (7T) parallel transmit/receive coil capable of simultaneously imaging the brainstem and cortex at ultra-high fields, providing a unique opportunity to obtain imaging with both higher spatial resolution and significantly increased sensitivity. We will focus on obese individuals with reward-based eating and high cravings, which presents a more homogeneous phenotype. We posit that probiotics (a targeted gut intervention) will alter the gut microbiome and metabolites (Aim A) leading to normalization of brain activity within the brainstem (key link between the brain and gut, an interoception hub, and the point of origin of the vagus nerve that regulates the gastrointestinal tract) and the extended reward network (key brain regions involved in regulating obesity and disrupted eating behaviors) (Aim B). Studying the gut and brain simultaneously is crucial for elucidating the role of MGB interactions in response to a targeted gut intervention in obesity (Aim C). Interrogating the MGB system after the probiotic intervention via high-resolution 7T MRI of the cortex and brainstem with concurrent gut microbiome analyses will provide vital insights into gut-brain pathways and ultimately guide optimized, precise, novel obesity treatments and prevention strategies, and microbiome-based drug discovery.
