Cholinergic modulation of intestinal immune homeostasis: implications for Inflammatory Bowel Disease

The gastrointestinal (GI) tract is continuously exposed to vast amounts of foreign antigens, mainly of dietary and bacterial origin. Although the intestinal mucosa creates a tight barrier against intraluminal proteins and bacteria, it remains highly vulnerable to pathogenic infection. In order to deal with this constant threat, the GI tract is equipped by a potent and efficient defense mechanism provided by the innate immune system, in particular by macrophages and dendritic cells (DC) residing in the submucosa and the gut associate lymphoid tissue. In recent years, it has become clear that the mucosal immune system has developed an ingenious mechanism, referred to as oral tolerance, to avoid unnecessary inflammation reactions and collateral tissue damage. Loss of tolerance towards commensal bacteria is believed to underlie chronic inflammation of the intestine, as seen in inflammatory bowel disease (IBD). The pathogenesis of IBD is, up to now, not completely understood, although the chronic relapsing inflammation is thought to be result from a dysregulated, aberrant immune response to intestinal flora in a context of genetic predisposition. In the past few decades, diverse immune-regulatory mechanisms crucial to maintain intestinal immune homeostasis have been revealed. Recent evidence from our Lab supports the idea that an additional actor, i.e. the enteric nervous system through neural input mainly from the vagus nerve, may play a role in modulating the intestinal microenvironment, thereby modulating immune cell activation and preventing chronic intestinal immune activation. In the present project, I will explore the hypothesis that the cholinergic tone generated by the vagal/enteric nervous system axis represents a key player in generating the tolerogenic microenvironment in the intestinal submucosa by interacting with the resident macrophages, and thereby preventing activation of chronic intestinal immune response resulting in colitis. In addition, I will investigate whether electrical stimulation of the vagus nerve might present a therapeutic tool for the prevention and/or treatment of colitis in experimental murine models.

Jaar van publicatie:2018

Toegankelijkheid:Open