The role of the enteric nervous system in the pathogenesis of Clostridioides difficile infection

Abstract

Clostridioides difficile is the leading cause of antibiotic-associated diarrhoea worldwide. In the USA, C. difficile infection (CDI) is the eighth leading cause for hospital readmission and seventh for mortality among all gastrointestinal disorders. Gastrointestinal dysmotility and/or diarrhoea occurs after the acute phase of CDI, but persistent gastrointestinal dysfunction post-infection supports contributions of neuroplasticity in the enteric nervous system (ENS), which has a key role in regulating intestinal motility and secretion, in the natural course of CDI. Here, our goal is to provide an up-to-date summary of how the ENS and extrinsic innervation of the gut are affected by CDI and how ENS responses contribute to CDI pathogenesis and outcomes. Enteric neurons and glia are targets of C. difficile toxins in humans and in preclinical model, and changes to the ENS and extrinsic innervation contribute to intestinal inflammation, damage and secretory diarrhoea. These findings suggest possible bidirectional interaction between CDI and the ENS. More studies focusing on understanding how various neurotransmitters and mediators released by the ENS and extrinsic neurons modulate immune responses to CDI could provide insight into novel pharmacological approaches to balance the host response, improve the management of CDI and prevent gastrointestinal dysfunction post-infection. This Perspective highlights emerging evidence of an interaction between Clostridiodes difficile and the enteric nervous system (ENS) during infection, discussing underlying mechanisms and how the ENS and extrinsic innervation are affected by C. difficile infection and toxins and how ENS responses contribute to pathogenesis and disease outcomes.