Commensal-derived succinate enhances tuft cell specification and suppresses ileal inflammation

Abstract

Lead contactLongitudinal analysis of Crohn's disease (CD) incidence has identified an inverse correlation with helminth infestation and recent studies have revealed that intestinal tuft cell hyperplasia is critical for helminth response. Tuft cell frequency was decreased in the inflamed ilea of CD patients and a mouse model of TNFα-induced Crohn's-like ileitis (TNFΔARE). Single-cell RNA sequencing paired with unbiased differential trajectory analysis of the tuft cell lineage in a genetic model of tuft cell hyperplasia (AtohKO) demonstrated that the tuft cell lineage had increased tricarboxylic acid (TCA) cycle gene signatures. Commensal microbiome-derived succinate was detected in the ileal lumen of these animals while microbiome depletion suppressed tuft cell hyperplasia. Therapeutic succinate treatment in TNFΔARE animals reduced pathology in correlation with induced tuft cell specification. We provide evidence implicating the modulatory role of intestinal tuft cells in chronic intestinal inflammation, which could facilitate leveraging this rare and elusive cell type for CD treatment.

Possible connection between intestinal tuft cells, ILC2s and obesity

“…While investigating ulcerative colitis (UC), the researchers noticed a reduction in TCs along with inflammation and tissue damage. However, when they treated UC mice with succinate, they observed an improvement of chronic intestinal inflammation, accompanied by an increase in the number of intestinal TCs (6). TCs are characterized by their apical microvilli and orchestrate the mucosal immune response (7), such as parasite immunity (8)(9)(10).…”