Gastrointestinal (GI) health is essential for overall body health. Inflammatory insults to the GI mucosa often cause profound and irreversible changes of GI homeostasis, including disrupted enteric neural regulation and subsequent alteration of GI function. Mucosal inflammation causes irreversible structural changes of the enteric nervous system (ENS), demonstrating a strong linkage between inflammation and GI innervation. Understanding of the cellular and molecular mechanisms that link mucosal inflammation with the loss/regeneration of enteric neurons are the focus of this proposal.
We characterized a phenotypically and transcriptionally distinct subset of intestinal macrophages that reside along the neural fibers of enteric neurons and are particularly enriched at the level of myenteric neural plexus of the ENS; we discovered a novel mechanism of crosstalk between these macrophages with enteric neurons. By using infectious and non-infectious murine models of transient mucosal inflammation and state of the art immunological and physiological techniques we will determine the role of mucosal inflammation, ENS-associated macrophages and the factors that they produce in regulation of homeostasis and function of enteric neurons during mucosal inflammation. The proposed studies will substantially advance our understanding of the pathophysiology of post-inflammatory enteric neuropathy known as irritable bowel syndrome (IBS) common in patients with IBD.