Gut chemosensing mechanisms

Abstract

The enteroendocrine system is the primary sensor of ingested nutrients and is responsible for secreting an array of gut hormones, which modulate multiple physiological responses including gastrointestinal motility and secretion, glucose homeostasis, and appetite. This Review provides an up-to-date synopsis of the molecular mechanisms underlying enteroendocrine nutrient sensing and highlights our current understanding of the neuro-hormonal regulation of gut hormone secretion, including the interaction between the enteroendocrine system and the enteric nervous system. It is hoped that a deeper understanding of how these systems collectively regulate postprandial physiology will further facilitate the development of novel therapeutic strategies.

Figure 3. Neuroendocrine crosstalk in the gut.

The secretion of gut hormones from EECs is stimulated by the sensing of luminal factors (i), (e.g., nutrients, bile acids, microbial products) predominantly via apical GPRCs (G_q/G_s) and transporters. Gut hormones secreted into the subepithelial space mediate their local and systemic effects via a number of signaling pathways. These include absorption into the circulation to act in the classical (ii) endocrine manner; (iii) paracrine signaling involving activation of surface receptors (e.g. NPY1R on enterocytes; SSTR5 on L cells; immunoglobulin-like domain containing receptor 1 [ILDR1] on I cells) on the basolateral surface of neighboring enterocytes and/or other EECs (iv); and activation of GPCRs (e.g. GLP1R, NPY2R, CCK1R) on vagal afferents (v) to relay information centrally, or on enteric neurons to modulate intestinal function. Enteric neurons are also capable of sensing certain absorbed nutrients directly (vi). For example, subsets of enteric neurons express the SCFA receptor FFAR3. In turn, the ENS fine-tunes the function of EECs (vii), as evident from their expression of a number of neuropeptide receptors (e.g., galanin receptor [GALR1], bombesin receptors [BB2R], vasoactive intestinal peptide receptor 1 [VPAC1R]).

Figure 2. Glucose, fat, and amino acid sensing by EECs.

(A) Glucose sensing by EECs involves a number of mechanisms. A critical component of glucose sensing in the gut is Na⁺-coupled glucose uptake by SGLT1, which generates small currents that trigger depolarization and voltage-gated Ca²⁺ entry. Glucose metabolism, involving glucokinase and the closure of ATP-sensitive (K_ATP) channels, and basolateral/plasma glucose concentration may also play a role in glucose-stimulated gut hormone release. (B) There are several pathways by which fatty acids and amino acids are sensed by EECs. Fatty acids activate nutrient-sensing GPCRs, which include FFAR1 (GPR40) and FFAR4 (GPR120) for MCFAs and LCFAs and FFAR2 (GPR43) for SCFAs, leading to an increase in intracellular Ca²⁺. Activation of GPR119 by oleoylethanolamide and monoacylglycerols stimulates gut hormone secretion via an increase in intracellular cAMP. Similarly, amino acids and oligopeptides can also activate GPCRs such as the CaSR. In addition, electrogenic uptake of certain amino acids and dipeptides and tripeptides can also trigger membrane depolarization and gut hormone release.

Figure 1. Nutrient sensing by the enteroendocrine system.

Ingested food is digested into its nutrient components in the lumen of the small intestine. The small intestinal epithelium is arranged in villi containing, among other cell types, absorptive enterocytes and EECs. The presence of nutrients in the gut lumen stimulates EECs and triggers the secretion of gut hormones, which orchestrate the body’s postprandial response. Gut hormones modulate multiple physiological processes including gastrointestinal secretion and motility, insulin release, and satiety.