Tuft cell-derived acetylcholine regulates epithelial fluid secretion

Abstract

Tuft cells are solitary chemosensory epithelial cells that can sense lumenal stimuli at mucosal barriers and secrete effector molecules to regulate the physiology and immune state of their surrounding tissue. In the small intestine, tuft cells detect parasitic worms (helminths) and microbe-derived succinate, and signal to immune cells to trigger a Type 2 immune response that leads to extensive epithelial remodeling spanning several days. Acetylcholine (ACh) from airway tuft cells has been shown to stimulate acute changes in breathing and mucocilliary clearance, but its function in the intestine is unknown. Here we show that tuft cell chemosensing in the intestine leads to release of ACh, but that this does not contribute to immune cell activation or associated tissue remodeling. Instead, tuft cell-derived ACh triggers immediate fluid secretion from neighboring epithelial cells into the intestinal lumen. This tuft cell-regulated fluid secretion is amplified during Type 2 inflammation, and helminth clearance is delayed in mice lacking tuft cell ACh. The coupling of the chemosensory function of tuft cells with fluid secretion creates an epithelium-intrinsic response unit that effects a physiological change within seconds of activation. This response mechanism is shared by tuft cells across tissues, and serves to regulate the epithelial secretion that is both a hallmark of Type 2 immunity and an essential component of homeostatic maintenance at mucosal barriers.

Gut microbiota gate host exposure to metabolites from dietary Solanums

“…In the colon where we found SGAs to significantly accumulate, acetylcholine is additionally a key regulator of multiple processes including chloride secretion 56 , epithelial proliferation 57 , fluid secretion 58 , and intestinal propulsion 59 . Considering the role of ACh in these diverse physiological processes, we suspect that AChE inhibition by SGAs may impact colonic physiology through a myriad of mechanisms beyond overt toxicity.…”

Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation

“…Tuft cells from neonatal mice housed in an SOPF facility free of Tritrichomonas expressed Il25 as soon as they emerged in the small intestinal epithelium [7]. Constitutive expression of Il25 transcript might reflect the anticipatory state in which tuft cells are engaged, marked also by concurrent expression of the enzymatic machinery for production of leukotrienes and acetylcholine [6, 8, 35, 36]. The constant de novo differentiation of tuft cells from the pool of LGR5 + stem cells, coupled with their short life span in the villus epithelium, likely requires such a state of preparedness to facilitate immediate and meaningful responses to luminal signals [28, 37].…”

“…Small intestinal tuft cells may employ similar mechanisms to produce IL-25. Whether small intestinal tuft cells also depend on IP3R2 for TRPM5-mediated acetylcholine release and fluid secretion, or for helminth-induced leukotriene mobilization, requires further study [35, 36]. A recent report showing impaired helminth-evoked type 2 responses in mice lacking Lrmp, an ER-resident protein and possible interaction partner of IP3Rs, suggests that IP3R2 activation may indeed be a central signaling step downstream of multiple tuft cell stimuli [40].…”

Intestinal Tuft Cells: Morphology, Function, and Implications for Human Health

“…Another ubiquitous tuft cell marker across tissues is ChAT, an enzyme that synthesizes the cholinergic neurotransmitter ACh ( 103 , 112 , 130 ). In the intestinal epithelium, tuft cells are the exclusive source of ACh, which is an important regulator of WNT signaling that supports the intestinal stem cell niche ( 86 , 131 , 132 ). ACh also mediates intestinal contraction in weep and sweep responses that are important for helminth clearance ( 133 ).…”