Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP-1 Secretion

Abstract

Glucagon-like peptide 1 (GLP-1) is a hormone released from enteroendocrine L cells. Although first described as a glucoregulatory incretin hormone, GLP-1 also suppresses inflammation and promotes mucosal integrity. Here, we demonstrate that plasma GLP-1 levels are rapidly increased by lipopolysaccharide (LPS) administration in mice via a Toll-like receptor 4 (TLR4)-dependent mechanism. Experimental manipulation of gut barrier integrity after dextran sodium sulfate treatment, or via ischemia/reperfusion experiments in mice, triggered a rapid rise in circulating GLP-1. This phenomenon was detected prior to measurable changes in inflammatory status and plasma cytokine and LPS levels. In human subjects, LPS administration also induced GLP-1 secretion. Furthermore, GLP-1 levels were rapidly increased following the induction of ischemia in the human intestine. These findings expand traditional concepts of enteroendocrine L cell biology to encompass the sensing of inflammatory stimuli and compromised mucosal integrity, linking glucagon-like peptide secretion to gut inflammation.

Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways

“…These data suggest that GFRAL neurons do not respond to meal-related signals and that GFRAL cells are distinct from CALCR neurons which respond to sCT and mealrelated cues (Cheng et al, 2020). Instead, GFRAL neurons respond to signals associated with pathophysiology, including GDF-15, GI distress, bacterial infection, and GLP-1 system stimulation (systemic inflammation, as during a variety of infections, activates the endogenous GLP-1 system (Lebrun et al, 2017)).…”

Establishing Boundaries: The Relationship That Exists between Intestinal Epithelial Cells and Gut-Dwelling Bacteria

“…Recent evidence has outlined how microbial-mediated release of these molecules may influence other types of EECs [35], depicting a complex rapport between the intestinal microbiota, gut hormone release, and host metabolism. EECs express TLRs and activation of such receptors by microbes trigger secretion of a selection of metabolically active hormones such as glucagon-like peptide 1 (GLP-1) [36], serotonin (5-HT) [37], and peptide tyrosine-tyrosine (PYY) [38]. Collectively, these hormones augment insulin [39], regulate mood, and induce satiety [40], respectively.…”

Loss of Glp2r signaling activates hepatic stellate cells and exacerbates diet-induced steatohepatitis in mice

“…Current concepts linking the gut to stellate cell activation highlight roles for microbial metabolites, including bile acids (40), as well as bacterial cell wall products, exemplified by lipopolysaccharide (41), which engage HSCs via distinct receptors and signaling pathways. Notably, bacterial metabolites (42) and cell membrane constituents such as LPS (43,44) as well as bile acids (45) are also potent stimulators of GLP-1 and GLP-2 secretion from enteroendocrine L cells (46). Our current findings demonstrate that loss of basal GLP-2R signaling is associated with HSC activation in mice with diet-induced hepatic injury.…”