Enteroendocrine Cells: Sensing Gut Microbiota and Regulating Inflammatory Bowel Diseases

Abstract

Host sensing in the gut microbiota has been crucial in the regulation of intestinal homeostasis. Although inflammatory bowel diseases (IBDs), multifactorial chronic inflammatory conditions of the gastrointestinal tract, have been associated with intestinal dysbiosis, the detailed interactions between host and gut microbiota are still not completely understood. Enteroendocrine cells (EECs) represent 1% of the intestinal epithelium. Accumulating evidence indicates that EECs are key sensors of gut microbiota and/or microbial metabolites. They can secrete cytokines and peptide hormones in response to microbiota, either in traditional endocrine regulation or by paracrine impact on proximal tissues and/or cells or via afferent nerve fibers. Enteroendocrine cells also play crucial roles in mucosal immunity, gut barrier function, visceral hyperalgesia, and gastrointestinal (GI) motility, thereby regulating several GI diseases, including IBD. In this review, we will focus on EECs in sensing microbiota, correlating enteroendocrine perturbations with IBD, and the underlying mechanisms.

Keywords: enteroendocrine cells; gut dysfunction; gut microbiota; immune system; inflammatory bowel disease.

FIGURE 1.

Enteroendocrine cell influence on gut function in inflammatory bowel disease. Enteroendocrine cells possess multiple chemosensory receptors that can detect intestinal microbiota and microbial metabolites. In response, EECs can secrete peptide hormones and classical cytokines to the surrounding immune cells and modulate both the innate and adaptive immune systems. Besides that, EECs possess cytoplasmic processes in close proximity to enteric nerve terminals. The released hormones may regulate the visceral hyperalgesia and intestinal motility in a paracrine fashion, along with synaptic transmission. Furthermore, enteroendocrine hormones can modulate the intestinal epithelial barrier function through both transcellular and paracellular pathways. All this evidence predicts the crucial role of EECs in the pathophysiology of IBD.

FIGURE 2.

Interactions between the various receptors of enteroendocrine cells and the intestinal microbiota and/or microbial metabolites. G protein-coupled receptors, including GPR40, GPR41, GPR43, GPR119, and GPR120, have been recognized as sensing receptors for gut microbiota–derived SCFAs or LCFAs. Olfactory receptor 558, a microbial metabolite detector on EECs, can sense isovalerate, which is an SCFA. Toll-like receptors, such as TLR1, TLR2, and TLR4, can detect multiple intestinal bacterial TLR ligands (eg, bacterial LPS, flagellin, peptidoglycan). Taste receptors can respond to intestinal nutrients and bacterial quorum sensing molecules from Gram-negative bacteria.