Abstract
ABSTRACTThe gastrointestinal epithelium constitutes a chemosensory system for microbiota-derived metabolites such as Short Chain Fatty Acids (SCFA). In this study, we investigated spatial distribution of Olfr78, one of the SCFA receptors, in the mouse intestine and studied the transcriptome of colon enteroendocrine cells expressing Olfr78. The receptor is principally detected in the enterochromaffin and L subtypes in the proximal and distal colon, respectively. Using the Olfr78-GFP and VilCre/Olfr78flox transgenic mouse lines, we reveal that loss of epithelial Olfr78 results in impaired enterochromaffin cell differentiation, blocking cells in an undefined secretory lineage state. This is accompanied by dysbiosis, characterized by an increasedFirmicutes/Bacteroidetes ratio, as well as a less efficient antioxidant system in colon crypts. Using organoid cultures, we further show that maintenance of enterochromaffin cells involves activation of the Olfr78 receptor via the SCFA ligand acetate. Altogether, this work provides evidence that Olfr78 contributes to colon homeostasis by regulating enterochromaffin cell differentiation.
Publisher
Cold Spring Harbor Laboratory
Reference46 articles.
1. A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor;Frontiers in Oncology,2018
2. Asle, B. W. , Turvey, M. , Larina, O. , Thorn, P. , Skepper, J. , Morton, A. J. , & Edwardson, J. M. (2005). Syncollin is required for efficient zymogen granule exocytosis. In Biochem. J (Vol. 385).
3. The Exploration-Exploitation Dilemma: A Multidisciplinary Framework
4. Induced Quiescence of Lgr5+ Stem Cells in Intestinal Organoids Enables Differentiation of Hormone-Producing Enteroendocrine Cells
5. Enterochromaffin Cells Are Gut Chemosensors that Couple to Sensory Neural Pathways