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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2022-06-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.154302 |
| _version_ | 1828823740192915456 |
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| author | Ki-Suk Kim Bailey C.E. Peck Yu-Han Hung Kieran Koch-Laskowski Landon Wood Priya H. Dedhia Jason R. Spence Randy J. Seeley Praveen Sethupathy Darleen A. Sandoval |
| author_facet | Ki-Suk Kim Bailey C.E. Peck Yu-Han Hung Kieran Koch-Laskowski Landon Wood Priya H. Dedhia Jason R. Spence Randy J. Seeley Praveen Sethupathy Darleen A. Sandoval |
| author_sort | Ki-Suk Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T13:41:03Z |
| format | Article |
| id | doaj.art-3196098fe7dd4bbea918264023125186 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-12T13:41:03Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-3196098fe7dd4bbea9182640231251862022-12-22T00:22:48ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-06-01711Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signalingKi-Suk KimBailey C.E. PeckYu-Han HungKieran Koch-LaskowskiLandon WoodPriya H. DedhiaJason R. SpenceRandy J. SeeleyPraveen SethupathyDarleen A. SandovalVertical 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.https://doi.org/10.1172/jci.insight.154302Cell biologyMetabolism |
| spellingShingle | Ki-Suk Kim Bailey C.E. Peck Yu-Han Hung Kieran Koch-Laskowski Landon Wood Priya H. Dedhia Jason R. Spence Randy J. Seeley Praveen Sethupathy Darleen A. Sandoval Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling JCI Insight Cell biology Metabolism |
| title | Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling |
| title_full | Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling |
| title_fullStr | Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling |
| title_full_unstemmed | Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling |
| title_short | Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling |
| title_sort | vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling |
| topic | Cell biology Metabolism |
| url | https://doi.org/10.1172/jci.insight.154302 |
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