Enteroendocrine cell lineages that differentially control feeding and gut motility

  1. Marito Hayashi
  2. Judith A Kaye
  3. Ella R Douglas
  4. Narendra R Joshi
  5. Fiona M Gribble
  6. Frank Reimann
  7. Stephen D Liberles  Is a corresponding author
  1. Howard Hughes Medical Institute, Harvard Medical School, United States
  2. University of Cambridge, United Kingdom

Abstract

Enteroendocrine cells are specialized sensory cells of the gut-brain axis that are sparsely distributed along the intestinal epithelium. The functions of enteroendocrine cells have classically been inferred by the gut hormones they release. However, individual enteroendocrine cells typically produce multiple, sometimes apparently opposing, gut hormones in combination, and some gut hormones are also produced elsewhere in the body. Here, we developed approaches involving intersectional genetics to enable selective access to enteroendocrine cells in vivo in mice. We targeted FlpO expression to the endogenous Villin1 locus (in Vil1-p2a-FlpO knock-in mice) to restrict reporter expression to intestinal epithelium. Combined use of Cre and Flp alleles effectively targeted major transcriptome-defined enteroendocrine cell lineages that produce serotonin, glucagon-like peptide 1, cholecystokinin, somatostatin, or glucose-dependent insulinotropic polypeptide. Chemogenetic activation of different enteroendocrine cell types variably impacted feeding behavior and gut motility. Defining the physiological roles of different enteroendocrine cell types provides an essential framework for understanding sensory biology of the intestine.

Data availability

The source data excel file contains raw numerical data used for all bar graphs and statistical analyses. Single-cell transcriptome data are available at NCBI Gene Expression Omnibus with accession GSE224223

The following data sets were generated

Article and author information

Author details

  1. Marito Hayashi

    Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9367-6389
  2. Judith A Kaye

    Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  3. Ella R Douglas

    Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  4. Narendra R Joshi

    Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5030-389X
  5. Fiona M Gribble

    Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    Fiona M Gribble, Is a consultant for Kallyope, Inc..
  6. Frank Reimann

    Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9399-6377
  7. Stephen D Liberles

    Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    For correspondence
    Stephen_Liberles@hms.harvard.edu
    Competing interests
    Stephen D Liberles, Reviewing editor, eLifeSDL is a consultant for Kallyope, Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2177-9741

Funding

Food Allergy Science Initiative (n/A)

  • Stephen D Liberles

National Institutes of Health (DP1AT009497)

  • Stephen D Liberles

National Institutes of Health (R01DK103703)

  • Stephen D Liberles

Howard Hughes Medical Institute (n/a)

  • Stephen D Liberles

Japan Society for the Promotion of Science (n/a)

  • Marito Hayashi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Alexander Theodore Chesler, National Institutes of Health, United States

Ethics

Animal experimentation: All animal husbandry and procedures were performed in compliance with institutional animal care and use committee guidelines. All animal husbandry and procedures followed the ethical guidelines outlined in the NIH Guide for the Care and Use of Laboratory Animals (https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf), and all protocols were approved by the institutional animal care and use committee (IACUC) at Harvard Medical School.

Version history

  1. Received: March 9, 2022
  2. Preprint posted: March 20, 2022 (view preprint)
  3. Accepted: February 17, 2023
  4. Accepted Manuscript published: February 22, 2023 (version 1)
  5. Version of Record published: March 22, 2023 (version 2)

Copyright

© 2023, Hayashi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Marito Hayashi
  2. Judith A Kaye
  3. Ella R Douglas
  4. Narendra R Joshi
  5. Fiona M Gribble
  6. Frank Reimann
  7. Stephen D Liberles
(2023)
Enteroendocrine cell lineages that differentially control feeding and gut motility
eLife 12:e78512.
https://doi.org/10.7554/eLife.78512

Share this article

https://doi.org/10.7554/eLife.78512

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