Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling

Vertical sleeve gastrectomy (VSG) results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium; however, the mechanism remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the nuclear bile acid receptor farne...

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Bibliographic Details
Published in:JCI insight 2022-06, Vol.7 (11)
Main Authors: Kim, Ki-Suk, Peck, Bailey Ce, Hung, Yu-Han, Koch-Laskowski, Kieran, Wood, Landon, Dedhia, Priya H, Spence, Jason R, Seeley, Randy J, Sethupathy, Praveen, Sandoval, Darleen A
Format: Article
Language:English
Subjects:
Animals
Bile Acids and Salts
Cell biology
Cell Differentiation
Gastrectomy - methods
Glucagon-Like Peptide 1 - metabolism
Metabolism
Mice
Stem Cells - metabolism
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Summary:Vertical sleeve gastrectomy (VSG) results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium; however, the mechanism remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the nuclear bile acid receptor farnesoid X receptor (FXR). FXR is a nuclear transcription factor that has been shown to regulate intestinal stem cell (ISC) function in cancer models. Therefore, we hypothesized that the VSG-induced increase in EECs is due to changes in intestinal differentiation driven by an increase in bile acid signaling through FXR. To test this, we performed VSG in mice that express EGFP in ISC/progenitor cells and performed RNA-Seq on GFP-positive cells sorted from the intestinal epithelia. We also assessed changes in EEC number (marked by glucagon-like peptide-1, GLP-1) in mouse intestinal organoids following treatment with bile acids, an FXR agonist, and an FXR antagonist. RNA-Seq of ISCs revealed that bile acid receptors are expressed in ISCs and that VSG explicitly alters expression of several genes that regulate EEC differentiation. Mouse intestinal organoids treated with bile acids and 2 different FXR agonists increased GLP-1-positive cell numbers, and administration of an FXR antagonist blocked these effects. Taken together, these data indicate that VSG drives ISC fate toward EEC differentiation through bile acid signaling.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.154302