Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Interactions of Gut Endocrine Cells with Epithelium and Neurons

Rodger A. Liddle

10.1002/cphy.c170044

Source: Volume 8, Issue 3, July 2018

Published online: June 2018

Full Article on Wiley Online Library



ABSTRACT

Even the simplest animals possess sophisticated systems for sensing and securing nutrients. After all, ensuring adequate nutrition is essential for sustaining life. Once multicellular animals grew too large to be nourished by simple diffusion of nutrients from their environment, they required a digestive system for the absorption and digestion of food. The majority of cells in the digestive tract are enterocytes that are designed to absorb nutrients. However, the digestive tracts of animals ranging from worms to humans contain specialized cells that discriminate between nutrients and nondigestible ingestants. These cells “sense” both the environment within the gut lumen and nutrients as they cross the gut epithelium. This dual sensing is then translated into local signals that regulate the gut epithelium or distant signals through hormones or nerves. This review will discuss how sensors of the gut interact with cells of the epithelium and neurons to regulate epithelial integrity and initiate neural transmission from the gut lumen. © 2017 American Physiological Society. Compr Physiol 8:1019‐1030, 2018.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Anatomy of an EEC. EECs are single cells dispersed among enterocytes and other cells of the intestinal mucosa. The apical surface of most EECs is covered with microvilli and is open to the gut lumen. The basal region contains secretory vesicles and rests on the lamina propria. Secreted hormones are taken up into the blood. Some EECs (not pictured here) like ghrelin cells of the stomach are not exposed to the gut lumen.
Figure 2. Figure 2. Morphology of EECs throughout the GI tract. Many EECs in the proximal intestine have short and often multiple neuropods while EECs in the ileum and colon characteristically possess single neuropods that extend along the base of adjacent enterocytes. Modified, with permission, from (8).
Figure 3. Figure 3. 3D image of an EEC with a prominent neuropod and other neuron‐like features. (A) Serial block face scanning electron microscopy (SBEM) of an image with a tissue volume of 52327 µm3. (B) All nuclei from 145 epithelial cells, including 129 enterocytes, 11 goblet cells, 4 cells of various types, and 1 EEC. (C) The EEC was traced on each slice to reveal its entire ultrastructure. On the left, the cell has a tuft of microvilli exposed to the gut lumen, and on the right, there is a prominent neuropod that extends toward the basal lamina propria. (D) This neuropod is populated by mitochondria, in particular at the tip (blue), secretory vesicles (yellow), and filament‐like structures (orange). Top panels show the reconstructions of the cells, and bottom panels show a representative SBEM image of each feature. Structures of interest in the bottom panel have been pseudocolored to facilitate their visualization. Bars = 1 µm. From (9) with permission.
Figure 4. Figure 4. EEC‐neural connection. Schematic diagram illustrating the recently described connection between EECs and enteric nerves. It is believed that both enteric and vagal nerves innervate EECs.
Figure 5. Figure 5. EEC‐neural connection forms in vitro. (A) Coculture scheme of an enteroendocrine cell and a primary sensory neuron. EEC, enteroendocrine cell; TG, trigeminal neuron. (B) Time‐lapse sequence showing how a single Cck‐GFP EEC (green) connects to a sensory neuron (DiI‐labeled, red) in vitro. (C) The EEC–neuron connection is stable at 23 min, 14 s, and cells remained connected for 88 h until the end of the experiment. Time, hours:minutes. Scale bars: 10 μm. Modified, with permission, from (10).
Figure 6. Figure 6. Nutrients stimulate EECs through apical and basolateral receptors and transporters. Transporters for glucose (SGLT1), amino acids, and di‐ and tri‐peptides are expressed on the apical surface of EECs. Other transporters (e.g., GLUT2) and receptors for long (FFAR1 and FFAR4) and short (FFAR2 and FFAR3) chain fatty acids, fatty acids and lipoproteins (ILDR1), and amino acids (CaSR) are located on the basolateral surface of EECs and respond to absorbed nutrients.
Figure 7. Figure 7. Paracrine signaling in the intestine. Paracrine regulation of gastrin and gastric acid secretion by somatostatin‐producing cells in the stomach unveiled a route by which EECs may regulate neighboring cells. In the intestine, local release of PYY controls enterocyte fluid secretion and growth.
Figure 8. Figure 8. Fine tuning of EECs. It is likely that EECs respond to signals from neighboring cells such as enterocytes, glia, and efferent nerves. Absorbed fatty acids and locally released chylomicrons and lipoproteins stimulate receptors such as ILDR1 (red). Glia produce neurotrophins, which induce neuropod growth and some EECs, are also innervated by efferent nerves. An example illustrates nerve growth factor binding to the receptor TrkA (gray).


Figure 1. Anatomy of an EEC. EECs are single cells dispersed among enterocytes and other cells of the intestinal mucosa. The apical surface of most EECs is covered with microvilli and is open to the gut lumen. The basal region contains secretory vesicles and rests on the lamina propria. Secreted hormones are taken up into the blood. Some EECs (not pictured here) like ghrelin cells of the stomach are not exposed to the gut lumen.


Figure 2. Morphology of EECs throughout the GI tract. Many EECs in the proximal intestine have short and often multiple neuropods while EECs in the ileum and colon characteristically possess single neuropods that extend along the base of adjacent enterocytes. Modified, with permission, from (8).


Figure 3. 3D image of an EEC with a prominent neuropod and other neuron‐like features. (A) Serial block face scanning electron microscopy (SBEM) of an image with a tissue volume of 52327 µm3. (B) All nuclei from 145 epithelial cells, including 129 enterocytes, 11 goblet cells, 4 cells of various types, and 1 EEC. (C) The EEC was traced on each slice to reveal its entire ultrastructure. On the left, the cell has a tuft of microvilli exposed to the gut lumen, and on the right, there is a prominent neuropod that extends toward the basal lamina propria. (D) This neuropod is populated by mitochondria, in particular at the tip (blue), secretory vesicles (yellow), and filament‐like structures (orange). Top panels show the reconstructions of the cells, and bottom panels show a representative SBEM image of each feature. Structures of interest in the bottom panel have been pseudocolored to facilitate their visualization. Bars = 1 µm. From (9) with permission.


Figure 4. EEC‐neural connection. Schematic diagram illustrating the recently described connection between EECs and enteric nerves. It is believed that both enteric and vagal nerves innervate EECs.


Figure 5. EEC‐neural connection forms in vitro. (A) Coculture scheme of an enteroendocrine cell and a primary sensory neuron. EEC, enteroendocrine cell; TG, trigeminal neuron. (B) Time‐lapse sequence showing how a single Cck‐GFP EEC (green) connects to a sensory neuron (DiI‐labeled, red) in vitro. (C) The EEC–neuron connection is stable at 23 min, 14 s, and cells remained connected for 88 h until the end of the experiment. Time, hours:minutes. Scale bars: 10 μm. Modified, with permission, from (10).


Figure 6. Nutrients stimulate EECs through apical and basolateral receptors and transporters. Transporters for glucose (SGLT1), amino acids, and di‐ and tri‐peptides are expressed on the apical surface of EECs. Other transporters (e.g., GLUT2) and receptors for long (FFAR1 and FFAR4) and short (FFAR2 and FFAR3) chain fatty acids, fatty acids and lipoproteins (ILDR1), and amino acids (CaSR) are located on the basolateral surface of EECs and respond to absorbed nutrients.


Figure 7. Paracrine signaling in the intestine. Paracrine regulation of gastrin and gastric acid secretion by somatostatin‐producing cells in the stomach unveiled a route by which EECs may regulate neighboring cells. In the intestine, local release of PYY controls enterocyte fluid secretion and growth.


Figure 8. Fine tuning of EECs. It is likely that EECs respond to signals from neighboring cells such as enterocytes, glia, and efferent nerves. Absorbed fatty acids and locally released chylomicrons and lipoproteins stimulate receptors such as ILDR1 (red). Glia produce neurotrophins, which induce neuropod growth and some EECs, are also innervated by efferent nerves. An example illustrates nerve growth factor binding to the receptor TrkA (gray).
References
 1.Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJ, Zuker CS. A novel family of mammalian taste receptors. Cell 100: 693‐702, 2000.
 2.Angot E, Brundin P. Dissecting the potential molecular mechanisms underlying alpha‐synuclein cell‐to‐cell transfer in Parkinson's disease. Parkinsonism Relat Disord 15(Suppl 3): S143‐S147, 2009.
 3.Angot E, Steiner JA, Lema Tome CM, Ekstrom P, Mattsson B, Bjorklund A, Brundin P. Alpha‐synuclein cell‐to‐cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One 7: e39465, 2012.
 4.Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol 28: 325‐353, 1902.
 5.Bellono NW, Bayrer JR, Leitch DB, Castro J, Zhang C, O'Donnell TA, Brierley SM, Ingraham HA, Julius D. Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 170: 185‐198 e116, 2017.
 6.Bogunovic M, Dave SH, Tilstra JS, Chang DT, Harpaz N, Xiong H, Mayer LF, Plevy SE. Enteroendocrine cells express functional Toll‐like receptors. Am J Physiol Gastrointest Liver Physiol 292: G1770‐G1783, 2007.
 7.Bohorquez DV, Chandra R, Samsa LA, Vigna SR, Liddle RA. Characterization of basal pseudopod‐like processes in ileal and colonic PYY cells. J Mol Histol 42: 3‐13, 2011.
 8.Bohorquez DV, Liddle RA. Axon‐like basal processes in enteroendocrine cells: Characteristics and potential targets. Clin Transl Sci 4: 387‐391, 2011.
 9.Bohorquez DV, Samsa LA, Roholt A, Medicetty S, Chandra R, Liddle RA. An enteroendocrine cell‐enteric glia connection revealed by 3D electron microscopy. PLoS One 9: e89881, 2014.
 10.Bohorquez DV, Shahid RA, Erdmann A, Kreger AM, Wang Y, Calakos N, Wang F, Liddle RA. Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells. J Clin Invest 125: 782‐786, 2015.
 11.Braak H, Rub U, Gai WP, Del Tredici K. Idiopathic Parkinson's disease: Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110: 517‐536, 2003.
 12.Camilleri M. Physiological underpinnings of irritable bowel syndrome: Neurohormonal mechanisms. J Physiol 592: 2967‐2980, 2014.
 13.Cani PD, Holst JJ, Drucker DJ, Delzenne NM, Thorens B, Burcelin R, Knauf C. GLUT2 and the incretin receptors are involved in glucose‐induced incretin secretion. Mol Cell Endocrinol 276: 18‐23, 2007.
 14.Chandra R, Hiniker A, Kuo YM, Nussbaum RL, Liddle RA. α‐Synuclein in gut endocrine cells and its implications for Parkinson's disease. JCI Insight 2: e92295, 2017.
 15.Chandra R, Samsa LA, Vigna SR, Liddle RA. Pseudopod‐like basal cell processes in intestinal cholecystokinin cells. Cell Tissue Res 341: 289‐297, 2010.
 16.Chandra R, Wang Y, Shahid RA, Vigna SR, Freedman NJ, Liddle RA. Immunoglobulin‐like domain containing receptor 1 mediates fat‐stimulated cholecystokinin secretion. J Clin Invest 123: 3343‐3352, 2013.
 17.Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng L, Guo W, Zuker CS, Ryba NJ. T2Rs function as bitter taste receptors. Cell 100: 703‐711, 2000.
 18.Chimerel C, Emery E, Summers DK, Keyser U, Gribble FM, Reimann F. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep 9: 1202‐1208, 2014.
 19.Chorfa A, Betemps D, Morignat E, Lazizzera C, Hogeveen K, Andrieu T, Baron T. Specific pesticide‐dependent increases in alpha‐synuclein levels in human neuroblastoma (SH‐SY5Y) and melanoma (SK‐MEL‐2) cell lines. Toxicol Sci 133: 289‐297, 2013.
 20.Christensen LW, Kuhre RE, Janus C, Svendsen B, Holst JJ. Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP‐1 secretion from isolated perfused rat small intestine. Physiol Rep 3: e12551, 2015.
 21.Coates MD, Mahoney CR, Linden DR, Sampson JE, Chen J, Blaszyk H, Crowell MD, Sharkey KA, Gershon MD, Mawe GM, Moses PL. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology 126: 1657‐1664, 2004.
 22.Cohen LJ, Esterhazy D, Kim SH, Lemetre C, Aguilar RR, Gordon EA, Pickard AJ, Cross JR, Emiliano AB, Han SM, Chu J, Vila‐Farres X, Kaplitt J, Rogoz A, Calle PY, Hunter C, Bitok JK, Brady SF. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature 549: 48‐53, 2017.
 23.Cox HM. Neuropeptide Y receptors; antisecretory control of intestinal epithelial function. Auton Neurosci 133: 76‐85, 2007.
 24.Cox HM. Endogenous PYY and NPY mediate tonic Y1‐ and Y2‐mediated absorption in human and mouse colon. Nutrition 24: 900‐906, 2008.
 25.D'Alessio D. Is GLP‐1 a hormone: Whether and when? J Diabetes Investig 7(Suppl 1): 50‐55, 2016.
 26.Del Tredici K, Braak H. A not entirely benign procedure: Progression of Parkinson's disease. Acta Neuropathol 115: 379‐384, 2008.
 27.Depoortere I. Taste receptors of the gut: Emerging roles in health and disease. Gut 63: 179‐190, 2014.
 28.Drucker DJ. Glucagon‐like peptides: Regulators of cell proliferation, differentiation, and apoptosis. Mol Endocrinol 17: 161‐171, 2003.
 29.Drucker DJ, Yusta B. Physiology and pharmacology of the enteroendocrine hormone glucagon‐like peptide‐2. Annu Rev Physiol 76: 561‐583, 2014.
 30.Dyer J, Salmon KS, Zibrik L, Shirazi‐Beechey SP. Expression of sweet taste receptors of the T1R family in the intestinal tract and enteroendocrine cells. Biochem Soc Trans 33: 302‐305, 2005.
 31.Edfalk S, Steneberg P, Edlund H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57: 2280‐2287, 2008.
 32.El‐Salhy M, Gilja OH, Gundersen D, Hatlebakk JG, Hausken T. Endocrine cells in the ileum of patients with irritable bowel syndrome. World J Gastroenterol 20: 2383‐2391, 2014.
 33.El‐Salhy M, Seim I, Chopin L, Gundersen D, Hatlebakk JG, Hausken T. Irritable bowel syndrome: The role of gut neuroendocrine peptides. Front Biosci (Elite Ed) 4: 2783‐2800, 2012.
 34.Fetissov SO. Role of the gut microbiota in host appetite control: Bacterial growth to animal feeding behaviour. Nat Rev Endocrinol 13: 11‐25, 2017.
 35.Ghilardi JR, Allen CJ, Vigna SR, McVey DC, Mantyh PW. Cholecystokinin and neuropeptide Y receptors on single rabbit vagal afferent ganglion neurons: Site of prejunctional modulation of visceral sensory neurons. Brain Res 633: 33‐40, 1994.
 36.Gorboulev V, Schurmann A, Vallon V, Kipp H, Jaschke A, Klessen D, Friedrich A, Scherneck S, Rieg T, Cunard R, Veyhl‐Wichmann M, Srinivasan A, Balen D, Breljak D, Rexhepaj R, Parker HE, Gribble FM, Reimann F, Lang F, Wiese S, Sabolic I, Sendtner M, Koepsell H. Na(+)‐D‐glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose‐dependent incretin secretion. Diabetes 61: 187‐196, 2012.
 37.Gustafsson BI, Bakke I, Tommeras K, Waldum HL. A new method for visualization of gut mucosal cells, describing the enterochromaffin cell in the rat gastrointestinal tract. Scand J Gastroenterol 41: 390‐395, 2006.
 38.Hansen KB, Rosenkilde MM, Knop FK, Wellner N, Diep TA, Rehfeld JF, Andersen UB, Holst JJ, Hansen HS. 2‐Oleoyl glycerol is a GPR119 agonist and signals GLP‐1 release in humans. J Clin Endocrinol Metab 96: E1409‐E1417, 2011.
 39.Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G. Free fatty acids regulate gut incretin glucagon‐like peptide‐1 secretion through GPR120. Nat Med 11: 90‐94, 2005.
 40.Holzer P. Neuropeptides, microbiota, and behavior. Int Rev Neurobiol 131: 67‐89, 2016.
 41.Hyland NP, Sjoberg F, Tough IR, Herzog H, Cox HM. Functional consequences of neuropeptide Y Y 2 receptor knockout and Y2 antagonism in mouse and human colonic tissues. Br J Pharmacol 139: 863‐871, 2003.
 42.Koda S, Date Y, Murakami N, Shimbara T, Hanada T, Toshinai K, Niijima A, Furuya M, Inomata N, Osuye K, Nakazato M. The role of the vagal nerve in peripheral PYY3‐36‐induced feeding reduction in rats. Endocrinology 146: 2369‐2375, 2005.
 43.Larraufie P, Dore J, Lapaque N, Blottiere HM. TLR ligands and butyrate increase Pyy expression through two distinct but inter‐regulated pathways. Cell Microbiol 19: 2017.
 44.Larsson LI, Goltermann N, de Magistris L, Rehfeld JF, Schwartz TW. Somatostatin cell processes as pathways for paracrine secretion. Science 205: 1393‐1395, 1979.
 45.Latorre R, Huynh J, Mazzoni M, Gupta A, Bonora E, Clavenzani P, Chang L, Mayer EA, De Giorgio R, Sternini C. Expression of the bitter taste receptor, T2R38, in enteroendocrine cells of the colonic mucosa of overweight/obese vs. lean subjects. PLoS One 11: e0147468, 2016.
 46.Lauffer LM, Iakoubov R, Brubaker PL. GPR119 is essential for oleoylethanolamide‐induced glucagon‐like peptide‐1 secretion from the intestinal enteroendocrine L‐cell. Diabetes 58: 1058‐1066, 2009.
 47.Lee HJ, Shin SY, Choi C, Lee YH, Lee SJ. Formation and removal of alpha‐synuclein aggregates in cells exposed to mitochondrial inhibitors. J Biol Chem 277: 5411‐5417, 2002.
 48.Lehy T, Willems G. Population kinetics of antral gastrin cells in the mouse. Gastroenterology 71: 614‐619, 1976.
 49.Liou AP, Chavez DI, Espero E, Hao S, Wank SA, Raybould HE. Protein hydrolysate‐induced cholecystokinin secretion from enteroendocrine cells is indirectly mediated by the intestinal oligopeptide transporter Pept1. Am J Physiol Gastrointest Liver Physiol 300: G895‐G902, 2011.
 50.Liou AP, Sei Y, Zhao X, Feng J, Lu X, Thomas C, Pechhold S, Raybould HE, Wank SA. The extracellular calcium‐sensing receptor is required for cholecystokinin secretion in response to l‐phenylalanine in acutely isolated intestinal I cells. Am J Physiol Gastrointest Liver Physiol 300: G538‐G546, 2011.
 51.Liu B, Fang F, Pedersen NL, Tillander A, Ludvigsson JF, Ekbom A, Svenningsson P, Chen H, Wirdefeldt K. Vagotomy and Parkinson disease: A Swedish register‐based matched‐cohort study. Neurology 88: 1996‐2002, 2017.
 52.Lu WJ, Yang Q, Yang L, Lee D, D'Alessio D, Tso P. Chylomicron formation and secretion is required for lipid‐stimulated release of incretins GLP‐1 and GIP. Lipids 47: 571‐580, 2012.
 53.Ly CV, Verstreken P. Mitochondria at the synapse. Neuroscientist 12: 291‐299, 2006.
 54.Mace OJ, Affleck J, Patel N, Kellett GL. Sweet taste receptors in rat small intestine stimulate glucose absorption through apical GLUT2. J Physiol 582: 379‐392, 2007.
 55.Mace OJ, Schindler M, Patel S. The regulation of K‐ and L‐cell activity by GLUT2 and the calcium‐sensing receptor CasR in rat small intestine. J Physiol 590: 2917‐2936, 2012.
 56.Mannon PJ, Kanungo A, Mannon RB, Ludwig KA. Peptide YY/neuropeptide Y Y1 receptor expression in the epithelium and mucosal nerves of the human colon. Regul Pept 83: 11‐19, 1999.
 57.Matsumura K, Miki T, Jhomori T, Gonoi T, Seino S. Possible role of PEPT1 in gastrointestinal hormone secretion. Biochem Biophys Res Commun 336: 1028‐1032, 2005.
 58.Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS. Mammalian sweet taste receptors. Cell 106: 381‐390, 2001.
 59.Nohr MK, Pedersen MH, Gille A, Egerod KL, Engelstoft MS, Husted AS, Sichlau RM, Grunddal KV, Poulsen SS, Han S, Jones RM, Offermanns S, Schwartz TW. GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short‐chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 154: 3552‐3564, 2013.
 60.Okawa M, Fujii K, Ohbuchi K, Okumoto M, Aragane K, Sato H, Tamai Y, Seo T, Itoh Y, Yoshimoto R. Role of MGAT2 and DGAT1 in the release of gut peptides after triglyceride ingestion. Biochem Biophys Res Commun 390: 377‐381, 2009.
 61.Pan‐Montojo F, Schwarz M, Winkler C, Arnhold M, O'Sullivan GA, Pal A, Said J, Marsico G, Verbavatz JM, Rodrigo‐Angulo M, Gille G, Funk RH, Reichmann H. Environmental toxins trigger PD‐like progression via increased alpha‐synuclein release from enteric neurons in mice. Sci Rep 2: 898, 2012.
 62.Park JH, Rhee PL, Kim G, Lee JH, Kim YH, Kim JJ, Rhee JC, Song SY. Enteroendocrine cell counts correlate with visceral hypersensitivity in patients with diarrhoea‐predominant irritable bowel syndrome. Neurogastroenterol Motil 18: 539‐546, 2006.
 63.Patel S, Mace OJ, Tough IR, White J, Cock TA, Warpman Berglund U, Schindler M, Cox HM. Gastrointestinal hormonal responses on GPR119 activation in lean and diseased rodent models of type 2 diabetes. Int J Obes (Lond) 38: 1365‐1373, 2014.
 64.Pearse AG, Coulling I, Weavers B, Friesen S. The endocrine polypeptide cells of the human stomach, duodenum, and jejunum. Gut 11: 649‐658, 1970.
 65.Pearse AG, Polak JM. Neural crest origin of the endocrine polypeptide (APUD) cells of the gastrointestinal tract and pancreas. Gut 12: 783‐788, 1971.
 66.Psichas A, Reimann F, Gribble FM. Gut chemosensing mechanisms. J Clin Invest 125: 908‐917, 2015.
 67.Raybould HE. Does your gut taste? Sensory transduction in the gastrointestinal tract. News Physiol Sci 13: 275‐280, 1998.
 68.Raybould HE, Meyer JH, Tabrizi Y, Liddle RA, Tso P. Inhibition of gastric emptying in response to intestinal lipid is dependent on chylomicron formation. Am J Physiol 274: R1834‐R1838, 1998.
 69.Reimann F, Gribble FM. Mechanisms underlying glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 secretion. J Diabetes Investig 7(Suppl 1): 13‐19, 2016.
 70.Smith GP, Gibbs J. Satiating effect of cholecystokinin. Ann N Y Acad Sci 713: 236‐241, 1994.
 71.Svensson E, Horvath‐Puho E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sorensen HT. Vagotomy and subsequent risk of Parkinson's disease. Ann Neurol 78: 522‐529, 2015.
 72.Sykaras AG, Demenis C, Case RM, McLaughlin JT, Smith CP. Duodenal enteroendocrine I‐cells contain mRNA transcripts encoding key endocannabinoid and fatty acid receptors. PLoS One 7: e42373, 2012.
 73.Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, Marras C, Bhudhikanok GS, Kasten M, Chade AR, Comyns K, Richards MB, Meng C, Priestley B, Fernandez HH, Cambi F, Umbach DM, Blair A, Sandler DP, Langston JW. Rotenone, paraquat, and Parkinson's disease. Environ Health Perspect 119: 866‐872, 2011.
 74.Tolhurst G, Zheng Y, Parker HE, Habib AM, Reimann F, Gribble FM. Glutamine triggers and potentiates glucagon‐like peptide‐1 secretion by raising cytosolic Ca2+ and cAMP. Endocrinology 152: 405‐413, 2011.
 75.van de Wouw M, Schellekens H, Dinan TG, Cryan JF. Microbiota‐gut‐brain axis: Modulator of host metabolism and appetite. J Nutr 147: 727‐745, 2017.
 76.Verbaan D, Marinus J, Visser M, van Rooden SM, Stiggelbout AM, van Hilten JJ. Patient‐reported autonomic symptoms in Parkinson disease. Neurology 69: 333‐341, 2007.
 77.Wang Y, Chandra R, Samsa LA, Gooch B, Fee BE, Cook JM, Vigna SR, Grant AO, Liddle RA. Amino acids stimulate cholecystokinin release through the Ca2+‐sensing receptor. Am J Physiol Gastrointest Liver Physiol 300: G528‐G537, 2011.
 78.Weissmann C, Enari M, Klohn PC, Rossi D, Flechsig E. Transmission of prions. J Infect Dis 186(Suppl 2): S157‐S165, 2002.
 79.Wendelbo I, Mazzawi T, El‐Salhy M. Increased serotonin transporter immunoreactivity intensity in the ileum of patients with irritable bowel disease. Mol Med Rep 9: 180‐184, 2014.
 80.Worthington JJ, Reimann F, Gribble FM. Enteroendocrine cells‐sensory sentinels of the intestinal environment and orchestrators of mucosal immunity. Mucosal Immunol 11: 3‐20, 2017.
 81.Wu SV, Rozengurt N, Yang M, Young SH, Sinnett‐Smith J, Rozengurt E. Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC‐1 cells. Proc Natl Acad Sci U S A 99: 2392‐2397, 2002.

 

Teaching Material

R. A. Liddle. Interactions of Gut Endocrine Cells with Epithelium and Neurons. Compr Physiol 8: 2018, 1019-1030.

Didactic Synopsis

Major Teaching Points:

  • Enteroendocrine cells (EECs) are sensory cells of the gastrointestinal tract.
  • EECs synthesize and secrete gut hormones in response to ingested nutrients through nutrient transporters and receptors.
  • EECs connect to enteric neurons and sensory afferent nerves and have the tools to send and receive signals with the nervous system.
  • EECs act locally in a paracrine manner to influence intestinal secretion and mucosal integrity.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Anatomy of an enteroendocrine cell. This figure illustrates that EECs are single cells dispersed among enterocytes and other cells of the intestinal mucosa. The apical surface of most EECs is covered with microvilli and is open to the gut lumen. The basal region contains secretory vesicles and rests on the lamina propria. Secreted hormones are taken up into the blood.

Figure 2 Morphology of EECs throughout the GI tract. This figure illustrates that many EECs in the proximal intestine have short and often multiple neuropods while EECs in the colon characteristically possess single neuropods that extend along the base of adjacent enterocytes. Modified, with permission, from (8).

Figure 3 3D image of an EEC with a prominent neuropod and other neuron-like features. This figure illustrates a 3D image of an EEC. Note the tuft of microvilli on the left and the prominent neuropod of the right. The neuropod contains abundant mitochondria, in particular at the tip (blue), secretory vesicles (yellow), and filament-like structures (orange). Bars  =  1 µm. From (9) with permission.

Figure 4 EEC-neural connection. This figure illustrates the recently described connection between EECs and enteric nerves. It is believed that both enteric and vagal nerves innervate EECs.

Figure 5 EEC-neural connection forms in vitro. This figure captures images from a time-lapse sequence showing how a single EEC (green) connects to a sensory neuron (DiI-labeled, red) in vitro. Time, hours:minutes. Scale bars: 10 μm. Modified, with permission, from (10).

Figure 6 Nutrients stimulate EECs through apical and basolateral receptors and transporters. This figure illustrates the proposed locations of transporters for glucose (SGLT1), amino acids, and di- and tri-peptides on the apical surface of EECs. Other transporters (e.g., GLUT2) and receptors for long (FFAR1 and FFAR4) and short (FFAR2 and FFAR3) chain fatty acids, fatty acids and lipoproteins (ILDR1), and amino acids (CaSR) are located on the basolateral surface of EECs and respond to absorbed nutrients.

Figure 7 Paracrine signaling in the intestine. This figure illustrates the proposed local release of PYY that is believed to control enterocyte fluid secretion and growth.

Figure 8 Fine tuning of EECs. This figure illustrates the concept that EECs respond to signals from neighboring cells such as enterocytes, glia, and efferent nerves. Absorbed fatty acids and locally released chylomicrons and lipoproteins stimulate receptors such as ILDR1 (red). Glia produce neurotrophins (gray) which induce neuropod growth and some EECs are also innervated by efferent nerves.

 


Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Interactions of Gut Endocrine Cells with Epithelium and Neurons
 

How to Cite

Rodger A. Liddle. Interactions of Gut Endocrine Cells with Epithelium and Neurons. Compr Physiol 2018, 8: 1019-1030. doi: 10.1002/cphy.c170044