Sugar Responses of Human Enterochromaffin Cells Depend on Gut Region, Sex, and Body Mass

Abstract

Gut-derived serotonin (5-HT) is released from enterochromaffin (EC) cells in response to nutrient cues, and acts to slow gastric emptying and modulate gastric motility. Rodent studies also evidence a role for gut-derived 5-HT in the control of hepatic glucose production, lipolysis and thermogenesis, and in mediating diet-induced obesity. EC cell number and 5-HT content is increased in the small intestine of obese rodents and human, however, it is unknown whether EC cells respond directly to glucose in humans, and whether their capacity to release 5-HT is perturbed in obesity. We therefore investigated 5-HT release from human duodenal and colonic EC cells in response to glucose, sucrose, fructose and α-glucoside (αMG) in relation to body mass index (BMI). EC cells released 5-HT only in response to 100 and 300 mM glucose (duodenum) and 300 mM glucose (colon), independently of osmolarity. Duodenal, but not colonic, EC cells also released 5-HT in response to sucrose and αMG, but did not respond to fructose. 5-HT content was similar in all EC cells in males, and colonic EC cells in females, but 3 to 4-fold higher in duodenal EC cells from overweight females (p < 0.05 compared to lean, obese). Glucose-evoked 5-HT release was 3-fold higher in the duodenum of overweight females (p < 0.05, compared to obese), but absent here in overweight males. Our data demonstrate that primary human EC cells respond directly to dietary glucose cues, with regional differences in selectivity for other sugars. Augmented glucose-evoked 5-HT release from duodenal EC is a feature of overweight females, and may be an early determinant of obesity.

Oral Supplementation of Sodium Butyrate Attenuates the Progression of Non-Alcoholic Steatohepatitis

“…These data suggest that the changes in melatonin in the small intestine found in our present study might have resulted from the modulation of HDAC activity and inactivation/degradation of AANAT. Furthermore, the results of others and our own group suggest that fructose may decrease serotonin bioavailability through a decrease in serotonin and SERT-mediated reuptake [53,54]. Indeed, here we showed that, after being exposed to fructose for only 1h, serotonin levels were significantly decreased in the small intestine.…”

Diet differentially regulates enterochromaffin cell serotonin content, density and nutrient sensitivity in the mouse small and large intestine

“…Mice were humanely killed by isoflurane overdose and cervical dislocation. Duodenum and colon were immediately removed and EC cells isolated and purified according to our previously published methods 14,16‐18,22 . In brief, the mucosal layer was removed in 4°C Krebs buffer (in mmol/L; NaCl 140, KCl 5, CaCl2 2, MgCl2 1, HEPES 10, D‐glucose 5, pH 7.4), minced, and digested in a combination of 1 part collagenase A (3 mg/mL, Roche Diagnostics GmbH) and 2 parts 0.05% trypsin‐EDTA (Sigma‐Aldrich) at 37°C for 30‐40 minutes with constant agitation.…”

“…Enterochromaffin (EC) cells act as important luminal sensors within the gut and have the capacity to acutely sense a number of nutrient stimuli 16 and secrete 5‐HT in response to luminal sugars 17 . In humans, the sensing of luminal glucose is disordered with obesity 18 ; however, the cellular changes underlying this are unknown. More recently, we demonstrated that effects of the gut microbial metabolites on gut‐derived 5‐HT 19 are a key driver of the microbiome effects on host glucose homeostasis 20 .…”

Obesity and Related Type 2 Diabetes: A Failure of the Autonomic Nervous System Controlling Gastrointestinal Function?

“…Serotonin (or 5-hydroxytryptamine, 5-HT), produced by the chromaffin cells of the proximal small intestine, plays an important role in the regulation of HGP through the activation of vagal afferent fibers to the brainstem (which express the related receptors) [104]. Obesity is characterized by an increased production of 5-HT in the small intestine, which is proportionate to BMI and level of hyperglycemia [104]. In rodents, the pharmacological block of the tryptophan-hydroxylase enzyme that catalyzes the formation of 5HT protects against obesity and hyperglycemia induced by HFD [104].…”

“…Obesity is characterized by an increased production of 5-HT in the small intestine, which is proportionate to BMI and level of hyperglycemia [104]. In rodents, the pharmacological block of the tryptophan-hydroxylase enzyme that catalyzes the formation of 5HT protects against obesity and hyperglycemia induced by HFD [104].…”