Enteroendocrine cell lineages that differentially control feeding and gut motility

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.

Stimulating intestinal GIP release reduces food intake and body weight in mice

“…The robust suppression of food intake in GIP-Dq mice was surprising in the light of recently reported contradictory findings using the same GIP-Cre strain in a genetic intersectional model that restricted hM3Dq expression to the intestinal epithelium [ 20 ], and led us to consider possible explanations for the discrepancy. One idea we considered was whether there might be a cell population in the CNS that was directly activated by CNO in GIP-Dq mice but not in the intersectional model.…”

“…To enable chemogenetic stimulated secretion of GIP, GIP-Cre mice [ 21 ] were crossed with with Rosa26-fxSTOPfx-hM3Dq reporter mice [ 22 ] or with Vil1-p2a-FlpO & FL-hM3Dq positive mice, creating intestinally restricted (GIP-Dq INT ) hM3Dq expression [ 20 ].…”

“…Activation of GIP-Cre::hM3Dq cells in this model using CNO increased plasma GIP and improved glucose tolerance as expected, but also reduced food intake under a range of feeding paradigms. This suppression of feeding was surprising because we had earlier studied an intersectional model in which hM3Dq-DREADD expression was restricted to K-cells in the intestinal epithelium, and had not identified any feeding phenotype [ 20 ]. Further studies following up the finding of food intake suppression in the GIP-Dq model revealed that it was GIPR-dependent and was repeatable under a range of feeding paradigms, including in diet-induced obese (DIO) mice, and was also observed in the gut-restricted intersectional model.…”

Bisphenol A Analogues Induce Neuroendocrine Disruption via Gut–Brain Regulation in Zebrafish

“…Enteroendocrine cells are scattered along the digestive tract, where they function in sensing various environmental stimuli and secrete neurotransmitters (such as serotonin, histamine, and glutamate) to regulate diverse biological and physiological processes. , Other neurotransmitters, including acetylcholine, norepinephrine, and GABA, regulate secretion in intestinal endocrine cells . Chemogenetic activation of different EEC subtypes variably impacts behavior and gut motility . Exposure to BPA increases the number of 5-HT-positive cells in pig small intestinal mucosa due to inhibition of serotonin (5-HT) production by enterochromaffin cells .…”

Colitis-Induced Small Intestinal Hypomotility Is Dependent on Enteroendocrine Cell Loss in Mice

“… 26 , 27 There are at least 5 distinct EEC lineages defined by the expression of either ghrelin, glucose-dependent insulinotropic polypeptide, somatostatin, serotonin (enterochromaffin cells), or a combination of glucagon-like peptide 1, cholecystokinin, and/or neurotensin. 28 , 29 In human beings, genome-wide association studies have found EEC markers, including PHOX2B and UBE4A to be altered in specimens of terminal ileum from patients with Crohn's disease, 30 suggesting a role for EECs in colitis development. Alterations of enteroendocrine cell numbers and hormone secretion have been found in patients with inflammatory bowel disease and in animal models of colitis, 31 and previous investigators have explored the inflammatory and microbiologic triggers that induce EEC responses during intestinal inflammation.…”