Cysteinyl leukotrienes and acetylcholine are biliary tuft cell cotransmitters

Abstract

The gallbladder stores bile between meals and empties into the duodenum upon demand and is thereby exposed to the intestinal microbiome. This exposure raises the need for antimicrobial factors, among them, mucins produced by cholangiocytes, the dominant epithelial cell type in the gallbladder. The role of the much less frequent biliary tuft cells is still unknown. We here show that propionate, a major metabolite of intestinal bacteria, activates tuft cells via the short-chain free fatty acid receptor 2 and downstream signaling involving the cation channel transient receptor potential cation channel subfamily M member 5. This results in corelease of acetylcholine and cysteinyl leukotrienes from tuft cells and evokes synergistic paracrine effects upon the epithelium and the gallbladder smooth muscle, respectively. Acetylcholine triggers mucin release from cholangiocytes, an epithelial defense mechanism, through the muscarinic acetylcholine receptor M3. Cysteinyl leukotrienes cause gallbladder contraction through their cognate receptor CysLTR1, prompting emptying and closing. Our results establish gallbladder tuft cells as sensors of the microbial metabolite propionate, initiating dichotomous innate defense mechanisms through simultaneous release of acetylcholine and cysteinyl leukotrienes.

Abstract

Sensing of propionate by gallbladder tuft cells triggers innate responses by corelease of acetylcholine and cysteinyl leukotrienes.

Bacterial sensing by biliary tuft cells

The mucosal surfaces of the gallbladder and biliary tract are potentially vulnerable to bacterial infection ascending from the intestine. Innate effector mechanisms that protect the biliary tract from infection include mucus secretion and gallbladder emptying after smooth muscle contraction. Keshavarz et al . used optogenetic stimulation of chemosensory tuft cells in the mouse gallbladder epithelium to show that tuft cell activation releases both acetylcholine and cysteinyl leukotrienes, leading to mucus secretion and smooth muscle contraction, respectively. The short-chain fatty acid propionate was identified as a product of bacterial metabolism capable of eliciting tuft cell release of inflammatory mediators after sensing by the free fatty acid receptor FFAR2. These findings uncover how the innate sentinel functions of biliary tuft cells are regulated via a sensory receptor.