Adolescent is more susceptible to tuft cell hyperplasia with increased mast cell infiltration and enhanced FFA2/5-HT mediated anion secretion in mouse duodenum and jejunum

Abstract

Though one of the primary functions of intestinal tuft cells us the sensing of the luminal content, the contribution of tuft cells to epithelial secretion has not been previously studied. We have found that in adult mice, induced tuft cell hyperplasia enhances the secretory responses to luminal short-chain fatty acids (SCFA) due to increased jejunal cholinergic signaling, whereas mast cell-mediated serotonergic signaling is predominant in the duodenum. Since mast cell density is higher in children with functional dyspepsia (FD) than in adults, we hypothesized that mast cell density and 5-HT signals may be increased by tuft cell hyperplasia more in adolescent (7-week-old; 7 wk) than in adult mice (15-week-old; 15 wk). Tuft cell hyperplasia was induced by oral sodium succinate (NaSuc, 100 mM) in the drinking water for 7 days in 7 wk or 15 wk mice, then assessed at 8 or 16 wk (8 w/16 w). Using Ussing chambers mounted with muscle-stripped mouse proximal duodenum or jejunum, the succinate receptor agonist cis-epoxy succinic acid (cESA, 1-30 mM) was applied to the mucosal bath whereas the selective free fatty acid receptor 2 (FFA2) agonist 4-CMTB (10 μM) was added to the serosal bath. Tuft cell doublecortin-like kinase 1 (DCLK1), mast cell protease 1 (MCPT1), and tryptophan hydroxylase 1 (TPH1/5-HT), used to measure tuft cell, mast cell, and enterochromaffin (EC) cell density, respectively, were assessed by real-time PCR and immunostaining.NaSuc treatment significantly increased the number of DCLK1-positive tuft cells and MCPT1-positive mast cells with no change in EC cell density in the duodenal and jejunal villi; density was higher at 8 w than at 16 w. mRNA expression of DCLK1 was increased in the duodenal and jejunal mucosa at both ages, whereas MCPT1, TPH1 and FFA2 were increased in both mucosæ at 8 w, but choline acetyltransferase (ChAT) was increased in the jejunal mucosa at 16 w. Luminal cESA increased atropine-inhibitable Isc in the jejunal mucosa, whereas 4-CMTB increased 5-HT3/5-HT4-mediated duodenal Isc. The Isc response to cESA in jejunum was enhanced at 16 w, whereas the response to 4-CMTB was enhanced at 8 w.These results suggest that NaSuc differentially enhances secretory responses, with jejunal serotonergic signals predominating at 8 w and cholinergic signals at 16 w. These data suggest that younger mice are more susceptible to tuft cell hyperplasia with resultant enhanced 5-HT signals with mast cell infiltration, consistent with clinical data. Supported by VA Merit Review This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.