Stressful, traumatic events are a well-recognized trigger leading to acute and chronic gastrointestinal (GI) disease like Irritable Bowel Syndrome (IBS) or Inflammatory Bowel Disease (IBD). Two major types of stress which are pervasive within the world population are early life adversity and depression, both of which are strongly associated with GI disease throughout life. Though much of the underlying pathology in IBS and IBD has been described, the underlying mechanisms explain how stress may trigger onset or increased symptom severity in these chronic disease is poorly understood. The enteric cholinergic nervous system is a major regulator of GI homeostasis with broad regulatory roles over epithelial barrier permeability, epithelial cell secretion, smooth muscle contraction and motility, and immune activation. Though a role of the enteric nervous system has been describe in acute stress induced GI dysfunction, little is known about the role of this system in chronic stress, early life adversity, or in infectious models. The objective of this dissertation was to determine if the enteric cholinergic nervous system contributed to GI disease under different types of environmental challenges including early life adversity, chronic stress and pathogen challenge. To answer these questions, we utilized several different small and large animal models in combination with pharmacological agonists and antagonist of the cholinergic system. The results presented here demonstrate that different types of stressors differentially impact the enteric cholinergic system. Following early life adversity, we observed a persistent upregulation of the enteric cholinergic system, which predisposes individuals to increased intestinal secretion, permeability, motility, and upregulation of stress related genes. In a pathogen challenge model, we observed an upregulation of a non-neuronal component of the enteric cholinergic system which correlated positively with disease severity. Finally we observed that chronic stress in adulthood results in a strong down regulation of the enteric cholinergic nervous system with reduced cholinergic mediated functional secretion. Combined these findings demonstrated that different modes of stress have dichotomous impacts the enteric cholinergic system, which differentially impact GI function. Future work should focus on the precise factors impacting the function and expression of the cholinergic system in order to develop better therapies to cope with stress induced GI disease.
Read
