Neuro-immune mechanisms of early-life stress-induced gastrointestinal disorders

Early-life adversity is a major risk factor for the later-life development and severity of major GI diseases including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) in adulthood.

The overall objective of this research is to understand the mechanisms by which early-life stress triggers long-lasting defects in intestinal epithelial barrier function.

The proposed studies will investigate the interactive signaling between the enteric cholinergic nervous system, intestinal mast cells, and the intestinal epithelial barrier utilizing novel pig and murine model systems. In addition, we aim to test the influence of sex on ENS development and mast cell function.

The project, based on previous studies and recent preliminary data, will test the hypothesis that early-life stress-associated GI disease is caused by a multi-step mechanism in which long-term sensitization and increased abundance of cholinergic enteric nerves triggers persistent mast cell activation and subsequent intestinal barrier dysfunction in a sex-dependent manner.

Understanding the early-life signaling pathways that trigger long-lasting intestinal barrier dysfunction and GI disease susceptibility will be critical in the development of new health management practices and therapies for important human GI diseases associated with early-life adversity.

At the same time, these studies will have significant relevance to understanding and treating GI diseases of agricultural animals, such as pigs, which undergo early-life production stressors that have long-lasting, deleterious influence on disease resistance, growth rate, and feed efficiency throughout the animal's production lifespan.