Function and mechanisms of enteroendocrine cells and gut hormones in metabolism

Abstract

Gut hormones have many key roles in the control of metabolism, as they target diverse tissues involved in the control of intestinal function, insulin secretion, nutrient assimilation and food intake. Produced by scattered cells found along the length of the intestinal epithelium, gut hormones generate signals related to the rate of nutrient absorption, the composition of the luminal milieu and the integrity of the epithelial barrier. Gut hormones already form the basis for existing and developing therapeutics for type 2 diabetes mellitus and obesity, exemplified by the licensed glucagon-like peptide 1 (GLP1) mimetics and dipeptidyl peptidase inhibitors that enhance GLP1 receptor activation. Modulating the release of the endogenous stores of GLP1 and other gut hormones is thought to be a promising strategy to mimic bariatric surgery with its multifaceted beneficial effects on food intake, body weight and blood glucose levels. This Review focuses on the molecular mechanisms underlying the modulation of gut hormone release by food ingestion, obesity and the gut microbiota. Depending on the nature of the stimulus, release of gut hormones involves recruitment of a variety of signalling pathways, including G protein-coupled receptors, nutrient transporters and ion channels, which are targets for future therapeutics for diabetes mellitus and obesity.

Key points

  • Enteroendocrine cells produce a range of gut hormones that have key roles in the coordination of food digestion and absorption, insulin secretion and appetite.

  • Products of food digestion (for example, glucose, amino acids and fatty acids) and microbial fermentation (such as short chain fatty acids (SCFAs)) act as stimuli for local enteroendocrine cells.

  • Nutrient sensing by enteroendocrine cells involves a range of signalling pathways, including G protein-coupled receptors, nutrient transporters and ion channels.

  • Gut hormones, such as glucagon-like peptide 1, cholecystokinin and glucose-dependent insulinotropic polypeptide, are secreted rapidly following food ingestion and have key roles in human metabolism through their anorexigenic and/or insulinotropic actions.

  • The gut microbiota produces various metabolites (including SCFAs, secondary bile acids and lipopolysaccharides) that modulate enteroendocrine cells, generating hormonal signals that reflect dietary intake, microbial composition and epithelial integrity.

  • Bariatric surgery rearranges intestinal anatomy, resulting in markedly elevated postprandial concentrations of glucagon-like peptide 1 and peptide YY, which contribute to postsurgical weight loss and resolution of type 2 diabetes mellitus in humans.

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Fig. 1: Control of ghrelin secretion.
Fig. 2: The incretin effect.
Fig. 3: Coupling of gut hormone secretion in the upper small intestine to fat absorption.
Fig. 4: Microbiota interactions with EECs in the colon.
Fig. 5: Bariatric surgery for metabolic disease.

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Acknowledgements

The work of the authors is supported by the Wellcome Trust and the UK Medical Research Council.

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Nature Reviews Endocrinology thanks J. Campbell, D. Keating and other anonymous reviewers for their contribution to the peer review of this work.

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Gribble, F.M., Reimann, F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat Rev Endocrinol 15, 226–237 (2019). https://doi.org/10.1038/s41574-019-0168-8

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