Diet-induced changes in tuft cell dynamics couple with type 2 immune response modulation and energy metabolism

Purpose: To examine the temporal changes in intestinal tuft cell number and activity in response to intake of a high fat diet and investigate the relation to whole-body energy metabolism and the immune phenotype of the small intestine and epididymal white adipose tissue (eWAT). Methods: C57BL/6J mice were fed either a low fat reference diet (RFD, 10 % kcal fat) or a high fat diet (HFD, 60% kcal fat) for 9 or 22 weeks, followed by characterization of whole-body metabolic parameters, transcription profiles of sorted intestinal tuft cells, and immune phenotypes of tissues. Results: HFD feeding was associated with reductions in the overall number of small intestinal epithelial cells and tuft cells and reduced expression of the intestinal type 2 tuft cell markers Il25 and Tslp. Amongst >1,700 diet-regulated genes in tuft cells identified by RNA-seq, we observed an early association between body mass expansion and increased expression of Serpini1, which encodes the serine protease inhibitor neuroserpin. By contrast, tuft cell expression of genes encoding the GABA-receptors linked to reduced body mass gain. Although we observed a HFD-induced change in the eWAT inflammatory profile, the small intestinal lamina propria displayed a consistent non-inflammatory phenotype, and small intestinal tuft cell-derived transcripts were found to correlate with whole body metabolic features independently of intestinal immune cell involvement. Conclusion: Our These findings point to a role for small intestinal tuft cells in systems-wide metabolic regulation. We here aimed to characterize the functional aspects of small intestinal tuft cells in response to HFD feeding with a focus on their role in relaying immune-metabolic signals. Additionally, we explored how HFD-associated effects on small intestinal tuft cells coupled with small intestinal and eWAT immune profiles as well as whole-body metabolic parameters