Cholinergic stimulation enhances intestinal antimicrobial activity and prevents systemic dissemination of pathogenic bacteria

Abstract

Abstract Inflammation constitutes an important component of host defense against pathogenic bacteria. This innate immune response is crucial for clearance of pathogens and survival of the host. However, unrestrained inflammatory reaction may result in systemic manifestations with dire consequences to the host. The extent of activation of the inflammatory response is tightly regulated through immunological and neural pathways. We have previously demonstrated that cholinergic stimulation, by administration of acetylcholinesterase inhibitors, confers enhanced protection in experimental animals orally infected with virulent Salmonella typhymurium. In this study, we investigated the mechanism by which AChE inhibition modulates the immune response to Salmonella infection. Enhanced host survival following oral infection correlated with significantly reduced bacterial dissemination to target organs, including livers and spleens. This protection was not due to increased gut motility or rapid bacterial clearance from the gastrointestinal tract. Moreover, protection was lost when the animals were infected systemically, suggesting that acetylcholine-mediated protective effect was mostly confined to gut mucosal tissue. In vivo imaging demonstrated more localized infection and delay in bacterial dissemination into systemic organs in mice pre-treated with AChE inhibitors. Morphological analysis of small intestine (ileum) showed that AChE inhibition induced degranulation of goblet cells and Paneth cells, two specialized secretory cells involved in innate immunity. Our findings demonstrate a crucial pathway between neural and immune systems that acts at the mucosal interface to protect the host against invading pathogens.