Title of project

Gut barrier function as a therapeutic target in obesity

Abstract

Obesity is a global health concern and is associated with systemic low-grade inflammation and a range of chronic metabolic diseases. There is increasing evidence that abdominal fat is associated with systemic low-grade inflammation and a higher risk of cardiometabolic diseases through a complex relationship between the mucosal layers of the intestines, gut microbiota, metabolic pathways, and the immune system. The gut barrier plays a critical role in regulating digestion, nutrient absorption, and inflammation, and a chronic excessive food intake, particularly high in fat and low in fibre, can reduce gut barrier function. This reduction in gut barrier function is thought to contribute to systemic low-grade inflammation and the development of chronic metabolic diseases. Additionally, the blood-brain barrier (BBB) is affected in a state of systemic low-grade inflammation which contributes to neuroinflammation and potentially neurodegenerative diseases. To investigate the mechanisms regulating gut barrier function and its relationship to systemic low-grade inflammation, BBB integrity, and neuroinflammation, we propose an interdisciplinary research format with a focus on interventions and unbiased target discovery.

This project aims to:

1. Explore transcriptomic and proteomic data of intestinal mucosa biopsies, and gut and blood microbiomes in individuals experiencing substantial weight loss after undergoing Rouxen-Y gastric bypass (RYGB), individuals with type 2 diabetes, and healthy individuals. Further, the inflammatory response to gut microbiota of individuals undergoing RYGB is explored with the use of specialized reporter cell lines.
2. Conduct a cross-sectional study of 20 obese individuals and 20 lean, healthy, age-matched controls to determine gut barrier and BBB integrity and their interrelationship in the context of body weight and metabolic status.

Our expected outcomes include a better understanding of the mechanisms regulating gut barrier function in obesity and its relationship to systemic low-grade inflammation and neuroinflammation. We also anticipate the discovery of new pharmacotherapeutic targets related to gut barrier function for obesity and associated disorders, ultimately increasing the chances of future effective preventive measures and interventions than can relieve both the individual and societal burden of obesity-associated morbidity and mortality.