ReviewSignalling in the gut endocrine axis
Introduction
Enteroendocrine cells comprise 0.1 to 1% of the gut epithelium, and produce hormones that orchestrate the body's response to food ingestion. Although originally identified as regulators of gastrointestinal processes such as gall bladder contraction and pancreatic enzyme secretion, gut hormones also play important roles in the control of metabolism, being the first step in a gut-brain-pancreatic axis. As enteroendocrine cells directly face into the intestinal lumen, they are ideally placed to detect the composition of ingested food, the rate of nutrient absorption and the products of intestinal microbial metabolism. This review will discuss mechanisms by which enteroendocrine cells sense the luminal contents, and the importance of gut hormones for metabolic physiology and disease.
Section snippets
Enteroendocrine cells and their metabolic importance
Enteroendocrine cells are located along the length of the intestinal epithelium from the stomach to the rectum. They have classically been divided into sub-populations, each classified according to their production of one or a few distinct hormonal products. K-cells, for example, are predominantly located in the duodenum and produce glucose-dependent insulinotropic polypeptide (GIP), whereas L-cells are located in higher numbers in the distal small intestine and colon and primarily produce
Methods for studying signalling in EECs with focus on L-cells
Early studies investigating signalling pathways in EECs used the murine cell lines GLUTag and STC-1. GLUTag cells are a colonic tumour cell line producing the hormones GLP-1 and CCK, but not PYY [15], [16]. This pattern doesn't exactly match that of colonic L-cells which produce GLP-1 and PYY but only little CCK [3], but a large body of evidence suggests that they are a good model of mouse L-cells. STC-1 cells were derived from a small intestinal tumour, and produce a number of hormones,
Basic properties of enteroendocrine cells
Enteroendocrine cell lines and primary colonic L-cells are electrically active, firing action potentials carried by voltage gated sodium and calcium channels [24], [25], [26], [27]. A number of nutrients, including glucose and amino acids, trigger membrane depolarisation and increased action potential firing [28], [29]. This is associated with the influx of calcium through voltage gated Ca2 + currents, elevation of intracellular Ca2 + concentrations, and consequent stimulation of vesicle
Glucose sensing
In perfused intestine experiments, luminally-applied glucose or non-metabolisable glucose analogues were found to trigger GLP-1 secretion as long as the sugars were substrates of the brush border glucose uptake pathway and applied in the presence of Na+ ions [35], [36]. Both glucose uptake and GLP-1 secretion are blocked by phloridzin, an inhibitor of sodium-coupled glucose transporters, SGLT1, that are responsible for active glucose absorption across the apical epithelial surface. These
L-cell cross talk with the colonic microbiome
Under most circumstances, the digestion and absorption of ingested nutrients is completed within the proximal small intestine, and the colon should not receive much digestible food from the diet. Colonic microbiota will, however, metabolise a variety of substrates, including dietary fibre and bile acids, and even if ingested nutrients are efficiently absorbed higher up the intestinal tract, epithelial cell turnover results in persistent loss of dead cells into the gut lumen, which can act as an
Translational aspects – influence of diet, weight loss and surgery
An important unanswered question is whether the responsiveness of the gut endocrine axis is significantly altered by longer term dietary changes. Data from human studies suggest that people with obesity have raised fasting GLP-1 and lower fasting PYY plasma concentrations [64], [65], but whether these changes reflect the influence of different diets or body weight/adiposity is not clear. We evaluated whether L-cell function was altered by high fat diet feeding in mice, and observed higher
Conclusions
The gut endocrine axis provides an interface with the outside world, enabling the body to develop coordinated metabolic responses to nutrient intake. Enteroendocrine cells have developed a variety of sensory machineries capable of detecting multiple different components of ingested food. Interestingly, however, enteroendocrine cells seem particularly tuned to respond to nutrient absorption, rather than the mere presence of nutrients in the gut lumen. This solution enables the body to mount
Acknowledgements
FMG and FR are funded by grants from the Wellcome Trust and MRC.
References (71)
- et al.
Endocrine cells in human intestine: an immunocytochemical study
Gastroenterology
(1983) - et al.
Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects
Regul. Pept.
(2003) The cardiovascular biology of glucagon-like peptide-1
Cell Metab.
(2016)Cholecystokinin and gut-brain signalling
Regul. Pept.
(2009)- et al.
The role of gut hormones in the regulation of body weight and energy homeostasis
Mol. Cell. Endocrinol.
(2010) - et al.
Glucose sensing in L cells: a primary cell study
Cell Metab.
(2008) - et al.
Signalling pathways involved in the detection of peptones by murine small intestinal enteroendocrine L-cells
Peptides
(2016) - et al.
Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes
Regul. Pept.
(2004) - et al.
Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells
Mol. Metab.
(2013) - et al.
GPR40 (FFAR1) - combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo
Mol. Metab.
(2015)
The G protein-coupled receptor family C group 6 subtype A (GPRC6A) receptor is involved in amino acid-induced glucagon-like peptide-1 secretion from GLUTag cells
J. Biol. Chem.
Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells
Cell Rep.
High fat diet impairs the function of glucagon-like peptide-1 producing L-cells
Peptides
Enteroendocrine secretion of gut hormones in diabetes, obesity and after bariatric surgery
Curr. Opin. Pharmacol.
Enteroendocrine cells: chemosensors in the intestinal epithelium
Annu. Rev. Physiol.
Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry
Endocrinology
A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin
Endocrinology
Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses
J. Clin. Endocrinol. Metab.
Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus
J. Clin. Invest.
The physiology of glucagon-like peptide 1
Physiol. Rev.
Regulation of food intake: the gastric X/A-like endocrine cell in the spotlight
Curr. Gastroenterol. Rep.
PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation
Am. J. Phys. Regul. Integr. Comp. Phys.
Minireview: finding the sweet spot: peripheral versus central glucagon-like peptide 1 action in feeding and glucose homeostasis
Endocrinology
Activation of proglucagon gene-transcription by protein kinase-A in a novel mouse enteroendocrine cell-line
Mol. Endocrinol.
Peptide production and secretion in GLUTag, NCI-H716, and STC-1 cells: a comparison to native L-cells
J. Mol. Endocrinol.
Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells
Diabetologia
Distinct cellular origins for serotonin-expressing and enterochromaffin-like cells in the gastric corpus
Gastroenterology
Comprehensive profiling of GPCR expression in ghrelin-producing cells
Endocrinology
Gastrin-releasing peptide is a novel mediator of proximal nutrient-induced proglucagon-derived peptide secretion from the distal gut
Endocrinology
Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP
Am. J. Physiol. Endocrinol. Metab.
Characterization and functional role of voltage gated cation conductances in the glucagon-like peptide-1 secreting GLUTag cell line
J. Physiol. Lond.
Electrical activity-triggered glucagon-like peptide-1 secretion from primary murine L-cells
J. Physiol.
Expression of functional GABAA receptors in cholecystokinin-secreting gut neuroendocrine murine STC-1 cells
J. Physiol.
A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line
Diabetes
Glutamine potently stimulates glucagon-like peptide-1 secretion from GLUTag cells
Diabetologia
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