Bile acids induce visceral hypersensitivity via mucosal mast cell–to–nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis

Abstract

Increased colonic bile acid (BA) exposure, frequent in diarrhea‐predominant irritable bowel syndrome (IBS‐D), can affect gut function. Nerve growth factor (NGF) is implicated in the development of visceral hyper‐sensitivity (VH). In this study, we tested the hypothesis that BAs cause VH via mucosal mast cell (MMC)‐to‐nociceptor signaling, which involves the farnesoid X receptor (FXR)/NGF/transient receptor potential vanilloid (TRPV)1 axis. BAs were intracolonically administered to rats for 15 d. Visceral sensitivity to colorectal distention and colonic NGF expression were examined. BAs caused VH, an effect that involved MMC‐derived NGF and was accompanied by enhanced TRPV1 expression in the dorsal root ganglia. Anti‐NGF treatment and TRPV1 antagonism inhibited BA‐induced VH. BAs induced NGF mRNA and protein expression and release in cultured mast cells. Colonic supernatants from patients with IBS‐D with elevated colonic BA content transcriptionally induced NGF expression. In FXR−/− mice, visceral sensitivity and colonic NGF expression were unaltered after BA treatment. Pharmacological antagonism and FXR silencing suppressed BA‐induced NGF expression and release in mast cells. Mitogen‐activated protein kinase kinase (MKK) 3/6/p38 MAPK/NF‐κB signaling was mechanistically responsible for FXR‐mediated NGF expression and secretion. The findings show an MMC‐dependent and FXR‐mediated pronociceptive effect of BAs and identify the BA/FXR/NGF/TRPV1 axis as a key player in MMC‐to‐neuron communication during pain processing in IBS.—Li, W.‐T., Luo, Q.‐Q., Wang, B., Chen, X., Yan, X.‐J., Qiu, H.‐Y., Chen, S.‐L. Bile acids induce visceral hypersensitivity via mucosal mast cell–to–nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis. FASEB J. 33, 2435–2450 (2019). http://www.fasebj.org

The Role of Transient Receptor Potential Vanilloid 1 in Common Diseases of the Digestive Tract and the Cardiovascular and Respiratory System

“…BA-stimulated, MMC-derived NGF mainly acts on the TrkA/TRPV1 axis in DRG neurons. BAs induce VH via mucosal mast cell-to-nociceptor signaling, which involves the farnesoid X receptor-nerve growth factor-transient receptor potential vanilloid 1 axis (Li et al, 2019).…”

The role of intestinal mast cell infiltration in irritable bowel syndrome

“…Previous studies have ascertained that mediators released by MCs induced visceral hyperalgesia through activating submucosal neurons, 47,48 suggesting that MCs may play a role in IBS through interacting with the central and peripheral nervous systems. Structural change has also been identified.…”

Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases

“…BA species and concentrations in different portions of the gastrointestinal tract can result in increased side effects including increased intestinal permeability and BA-induced diarrhea (78). Elevated hydrophobic BAs in the colon are capable of inducing inflammation which is reduced following CDCA treatment alleviating the increased toxicity from insoluble BA concentrations and mast cell secretory factors (i.e., histamine or nerve growth factor NGF) (78,79).…”

“…Removal of commensal gut microbiota in Mdr2 −/− mice resulted in increased serum liver enzyme levels, cholangiocyte senescence, and circulating primary BAs (37). Alternatively, Li et al discovered a depletion of BA induced damage to the colon and reduced mast cell activation and degranulation in FXR −/− mice or Z-guggulsterone treated mast cells (79).…”