Gut Microbiome Regulation of Gut Hormone Secretion

Abstract

The gut microbiome, comprising bacteria, viruses, fungi, and bacteriophages, is one of the largest microbial ecosystems in the human body and plays a crucial role in various physiological processes. This review explores the interaction between the gut microbiome and enteroendocrine cells (EECs), specialized hormone-secreting cells within the intestinal epithelium. EECs, which constitute less than 1% of intestinal epithelial cells, are key regulators of gut-brain communication, energy metabolism, gut motility, and satiety. Recent evidence shows that gut microbiota directly influence EEC function, maturation, and hormone secretion. For instance, commensal bacteria regulate the production of hormones like glucagon-like peptide 1 and peptide YY by modulating gene expression and vesicle cycling in EE cells. Additionally, metabolites such as short-chain fatty acids, derived from microbial fermentation, play a central role in regulating EEC signaling pathways that affect metabolism, gut motility, and immune responses. Furthermore, the interplay between gut microbiota, EECs, and metabolic diseases, such as obesity and diabetes, is examined, emphasizing the microbiome's dual role in promoting health and contributing to disease states. This intricate relationship between the gut microbiome and EECs offers new insights into potential therapeutic strategies for metabolic and gut disorders.

Keywords: enteroendocrine cells; gut hormone; gut microbiome; host physiology.

Figure 1.

Enteroendocrine (EE) hormone secretion along the gastrointestinal tract. Enteroendocrine cells (EECs) reside in the epithelium, making direct contact with dietary components and microbial products within the gut lumen. The luminal contents trigger the expression and secretion of different gut peptides, such as serotonin (5-HT); cholecystokinin (CCK); glucose-independent insulinotropic peptide (GIP); insulin-like peptide 5 (INSL-5); peptide YY (PYY); glucagon-like peptide 1 (GLP-1).

Figure 2.

Gut microbiota interactions with EECs. The gut microbiota generates a range of metabolites through the fermentation or enzymatic breakdown of proteins, carbohydrates, and primary bile acids. EECs sense microbial cues from the gut lumen through receptors, such as FFARs and Olfr588, which are mostly activated by fatty acids, including short-chain fatty acids (SCFAs) and branched-chain fatty acids. Secondary bile acids can signal through the Takeda G-protein receptor 5 (TGR5) on the basolateral membrane and through farnesoid X receptor (FXR), both of which are abundantly expressed in EECs in the distal gut. Indole, a catabolite derived from tryptophan, influences intestinal motility by activating transient receptor potential ankyrin A1 (Trpa1) on 5-HT expressing EC cells which can trigger calcium entry via voltage-gated calcium channels (VGCC). EECs directly sense bacteria via toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns (PAMPs) that are unique to each microorganism.

Figure 3.

Microbial regulation of host physiology through EEC hormones. EECs have the capacity to interact with microbiota from multiple regions along the gastrointestinal tract, including the stomach, upper gut (duodenum, jejunum, ileum) and distal gut (colon, rectum). Microbial metabolites, such as SCFAs, bile acids and indole, are ligands that act on their corresponding receptor. Activating these receptors trigger the release of gut hormones, which directly regulate key physiological processes such as appetite control, gut motility, insulin release, brown adipose tissue (BAT) thermogenesis, and lipid metabolism.