Vasoactive intestinal polypeptide plays a key role in the microbial-neuroimmune control of intestinal motility

Background and aims: Although chronic diarrhea and constipation are common, the treatment is symptomatic as their pathophysiology is poorly understood. Accumulating evidence suggests that the microbiota modulates gut function but the underlying mechanisms are unknown. We therefore investigated the pathways by which microbiota modulates gastrointestinal motility in different sections of the alimentary tract. Methods: Gastric emptying, intestinal transit, muscle contractility, acetylcholine release, gene expression and vasoactive intestinal polypeptide (VIP) immunoreactivity were assessed in wild-type and Myd88-/-Trif-/- mice in germ-free, gnotobiotic and SPF conditions. Effects of transient colonization and antimicrobials, as well as immune cell blockade were investigated. VIP levels were assessed in human full thickness biopsies by Western blot. Results: Germ-free mice had similar gastric emptying but slower intestinal transit compared with SPF mice, or mice monocolonized with Lactobacillus rhamnosus or Escherichia coli, the latter having stronger effects. While muscle contractility was unaffected, its neural control was modulated by microbiota by upregulating jejunal VIP, which co-localized with and controlled cholinergic nerve function. This process was responsive to changes in the microbial composition and load, and mediated through TLR signaling, with enteric glia cells playing a key role. Jejunal VIP was lower in patients with chronic intestinal pseudo-obstruction compared with control subjects. Conclusion: Microbial control of gastrointestinal motility is both region- and bacteria-specific, it reacts to environmental changes, and is mediated by innate immunity-neural system interactions. Small intestinal VIP, by regulating cholinergic nerves, plays a key role in this process, thus providing a new therapeutic target for patients with motility disorders.