Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity

Mucosal Immunology

Volumn 11, Issue 1, 2018, Pages 3-20

  Worthington, J J ^a   Reimann, F ^b   Gribble, F M ^b  

^a LANCASTER UNIVERSITY   (United Kingdom)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKINE; ENTEROENDOCRINE PEPTIDE; UNCLASSIFIED DRUG; PATHOGEN ASSOCIATED MOLECULAR PATTERN; PEPTIDE HORMONE;

APPETITE; CELL FUNCTION; CORRELATION ANALYSIS; DISEASE MODEL; ENTERITIS; ENTEROENDOCRINE CELL; HUMAN; IMMUNOCOMPETENT CELL; IMMUNOMODULATION; INFLAMMATORY BOWEL DISEASE; INNATE IMMUNITY; INTESTINE EPITHELIUM; INTESTINE MUCOSA; INTESTINE TUMOR; MUCOSAL IMMUNITY; NONHUMAN; PERMEABILITY BARRIER; PRIORITY JOURNAL; PROTEIN SECRETION; REVIEW; VAGUS REFLEX; ANIMAL; DIGESTION; HOMEOSTASIS; IMMUNOLOGY; INFLAMMATION; METABOLISM; SENTINEL SURVEILLANCE;

ANIMALS; CYTOKINES; DIGESTION; ENTEROENDOCRINE CELLS; HOMEOSTASIS; HUMANS; IMMUNITY, MUCOSAL; INFLAMMATION; INTESTINAL MUCOSA; PATHOGEN-ASSOCIATED MOLECULAR PATTERN MOLECULES; PEPTIDE HORMONES; SENTINEL SURVEILLANCE;

EID: 85038846656     PISSN: 19330219     EISSN: 19353456     Source Type: Journal    
DOI: 10.1038/mi.2017.73     Document Type: Review

References (345)

1. Artis, D. and Grencis, R.K. The intestinal epithelium: sensors to effectors in nematode infection. Mucosal Immunol. 1, 252-264 (2008).
2. Peterson, L.W. and Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141-153 (2014).
3. Pastorelli, L., De Salvo, C., Mercado, J.R., Vecchi, M. and Pizarro, T.T. Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. Front. Immunol. 4, 280 (2013).
4. Begg, D.P. and Woods, S.C. The endocrinology of food intake. Nat. Rev. Endocrinol. 9, 584-597 (2013).
5. Gribble, F.M. and Reimann, F. Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu. Rev. Physiol. 78, 277-299 (2016).
6. Liou, A.P. et al. The G-protein-coupled receptor GPR40 directly mediates long-chain fatty acid-induced secretion of cholecystokinin. Gastroenterology 140, 903-912 (2011).
7. Bohorquez, D.V., Chandra, R., Samsa, L.A., Vigna, S.R. and Liddle, R.A. Characterization of basal pseudopod-like processes in ileal and colonic PYY cells. J. Mol. Histol. 42, 3-13 (2011).
8. Parker, H.E., Habib, A.M., Rogers, G.J., Gribble, F.M. and Reimann, F. Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells. Diabetologia 52, 289-298 (2009).
9. Reimann, F., Habib, A.M., Tolhurst, G., Parker, H.E., Rogers, G.J. and Gribble, F.M. Glucose sensing in L cells: a primary cell study. Cell Metab. 8, 532-539 (2008).
10. Engelstoft, M.S. et al. Research resource: a chromogranin a reporter for serotonin and histamine secreting enteroendocrine cells. Mol. Endocrinol. 29, 1658-1671 (2015).
11. Sakata, I. et al. Characterization of a novel ghrelin cell reporter mouse. Regul. Pept. 155, 91-98 (2009).
12. Adriaenssens, A. et al. A transcriptome-led exploration of molecular mechanisms regulating somatostatin-producing D-Cells in the gastric epithelium. Endocrinology 156, 3924-3936 (2015).
13. Nagatake, T., Fujita, H., Minato, N. and Hamazaki, Y. Enteroendocrine cells are specifically marked by cell surface expression of claudin-4 in mouse small intestine. PLoS ONE 9, e90638 (2014).
14. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003-1007 (2007).
15. Barker, N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat. Rev. Mol. Cell Biol. 15, 19-33 (2014).
16. Basak, O., Beumer, J., Wiebrands, K., Seno, H., van Oudenaarden, A. and Clevers, H. Induced quiescence of Lgr5+ stem cells in intestinal organoids enables differentiation of hormone-producing enteroendocrine cells. Cell Stem Cell 20, e174 (2017).
17. Shroyer, N.F., Helmrath, M.A., Wang, V.Y.C., Antalffy, B., Henning, S.J. and Zoghbi, H.Y. Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 132, 2478-2488 (2007).
18. Li, H.J., Ray, S.K., Singh, N.K., Johnston, B. and Leiter, A.B. Basic helix-loop-helix transcription factors and enteroendocrine cell differentiation. Diabetes Obes. Metab. 13 (Suppl 1), 5-12 (2011).
19. May, C.L. and Kaestner, K.H. Gut endocrine cell development. Mol. Cell Endocrinol. 323, 70-75 (2010).
20. Yang, Q., Bermingham, N.A., Finegold, M.J. and Zoghbi, H.Y. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294, 2155-2158 (2001).
21. Shroyer, N.F., Shultz, D.W., Venken, K.J., Bellen, H.J. and Zoghbi, H.Y. Gfi1 functions downstream of Math1 to control intestinal secretory cell differentiation. Gastroenterology 128, A127-A127 (2005).
22. Katz, J.P. et al. The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. Development 129, 2619-2628 (2002).
23. Bastide, P. et al. Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J. Cell Biol. 178, 635-648 (2007).
24. Mori-Akiyama, Y. et al. SOX9 is required for the differentiation of paneth cells in the intestinal epithelium. Gastroenterology 133, 539-546 (2007).
25. Gerbe, F. et al. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. J. Cell Biol. 192, 767-780 (2011).
26. Gerbe, F. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226-230 (2016).
27. Kanaya, T. et al. The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells. Nat. Immunol. 13, 729-736 (2012).
28. Knoop, K.A. et al. RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium. J. Immunol. 183, 5738-5747 (2009).
29. de Lau, W. et al. Peyer's patch M cells derived from Lgr5(+) stem cells require SpiB and are induced by RankL in cultured "miniguts". Mol. Cell Biol. 32, 3639-3647 (2012).
30. Mellitzer, G. et al. Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival. J. Clin. Invest. 120, 1708-1721 (2010).
31. Jenny,M. et al. Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J. 21, 6338-6347 (2002).
32. Knudsen, L.A., Petersen, N., Schwartz, T.W. and Egerod, K.L. The MicroRNA repertoire in enteroendocrine cells: identification of miR-375 as a potential regulator of the enteroendocrine lineage. Endocrinology 156, 3971-3983 (2015).
33. Mutoh, H., Fung, B.P.,Naya, F.J., Tsai, M.J., Nishitani, J. and Leiter, A.B. The basic helix-loop-helix transcription factor BETA2/NeuroD is expressed in mammalian enteroendocrine cells and activates secretin gene expression. Proc. Natl Acad. Sci. USA 94, 3560-3564 (1997).
34. Naya, F.J. et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev. 11, 2323-2334 (1997).
35. Rindi, G., Ratineau, C., Ronco, A., Candusso,M.E., Tsai,M. and Leiter, A.B. Targeted ablation of secretin-producing cells in transgenic mice reveals a common differentiation pathway with multiple enteroendocrine cell lineages in the small intestine. Development 126, 4149-4156 (1999).
36. Larsson, L.I., St-Onge, L., Hougaard, D.M., Sosa-Pineda, B. and Gruss, P. Pax 4 and 6 regulate gastrointestinal endocrine cell development. Mech. Dev. 79, 153-159 (1998).
37. Trinh, D.K., Zhang, K., Hossain, M., Brubaker, P.L. and Drucker, D.J. Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium. Diabetes 52, 425-433 (2003).
38. Hill, M.E., Asa, S.L. and Drucker, D.J. Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription. Mol. Endocrinol. 13, 1474-1486 (1999).
39. Terry, N.A., Walp, E.R., Lee, R.A., Kaestner, K.H. and May, C.L. Impaired enteroendocrine development in intestinal-specific Islet1 mouse mutants causes impaired glucose homeostasis. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G979-G991 (2014).
40. Larsson, L.I., Madsen, O.D., Serup, P., Jonsson, J. and Edlund, H. Pancreatic-duodenal homeobox 1-role in gastric endocrine patterning. Mech. Dev. 60, 175-184 (1996).
41. Miller, C.P., McGehee, R.E. Jr. and Habener, J.F. IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. EMBO J. 13, 1145-1156 (1994).
42. Offield, M.F. et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122, 983-995 (1996).
43. Lee, E., Ryu, G.R., Moon, S.D., Ko, S.H., Ahn, Y.B. and Song, K.H. Reprogramming of enteroendocrine K cells to pancreatic beta-cells through the combined expression of Nkx6.1 and Neurogenin3, and reaggregation in suspension culture. Biochem. Biophys. Res. Commun. 443, 1021-1027 (2014).
44. Desai, S. et al. Nkx2.2 regulates cell fate choice in the enteroendocrine cell lineages of the intestine. Dev. Biol. 313, 58-66 (2008).
45. Gross, S. et al. Nkx2.2 is expressed in a subset of enteroendocrine cells with expanded lineage potential. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G975-G987 (2015).
46. Middendorp, S. et al. Adult stem cells in the small intestine are intrinsically programmed with their location-specific function. Stem Cells 32, 1083-1091 (2014).
47. Fang, R., Olds, L.C. and Sibley, E. Spatio-temporal patterns of intestinespecific transcription factor expression during postnatal mouse gut development. Gene Exp. Patterns 6, 426-432 (2006).
48. Grainger, S., Savory, J.G. and Lohnes, D. Cdx2 regulates patterning of the intestinal epithelium. Dev. Biol. 339, 155-165 (2010).
49. Mutoh, H. et al. The intestine-specific homeobox gene Cdx2 induces expression of the basic helix-loop-helix transcription factor Math1. Differentiation 74, 313-321 (2006).
50. Beuling, E. et al. GATA factors regulate proliferation, differentiation, and gene expression in small intestine ofmature mice. Gastroenterology 140, e1211-e1212 (2011).
51. Bosse, T. et al. Gata4 is essential for the maintenance of Jejunal-Ileal identities in the adult mouse small intestine. Mol.Cell Biol. 26, 9060-9070 (2006).
52. Dimaline, R., Campbell, B.J., Watson, F., Sandvik, A.K., Struthers, J. and Noble, P.J. Regulated expression of GATA-6 transcription factor in gastric endocrine cells. Gastroenterology 112, 1559-1567 (1997).
53. Dusing, M.R. and Wiginton, D.A. Epithelial lineages of the small intestine have unique patterns of GATA expression. J. Mol. Histol. 36, 15-24 (2005).
54. Gao, X.P., Sedgwick, T., Shi, Y.B. and Evans, T. Distinct functions are implicated for theGATA-4,-5, and-6 transcription factors in the regulation of intestine epithelial cell differentiation. Mol. Cell Biol. 18, 2901-2911 (1998).
55. Lussier, C.R. et al. Loss of hepatocyte-nuclear-factor-1alpha impacts on adult mouse intestinal epithelial cell growth and cell lineages differentiation. PLoS ONE 5, e12378 (2010).
56. D'Angelo, A. et al. Hepatocyte nuclear factor 1alpha and beta control terminal differentiation and cell fate commitment in the gut epithelium. Development 137, 1573-1582 (2010).
57. Boudreau, F. et al. A novel colonic repressor element regulates intestinal gene expression by interacting with Cux/CDP. Mol. Cell Biol. 22, 5467-5478 (2002).
58. Amcheslavsky, A. et al. Enteroendocrine cells support intestinal stem-cell-mediated homeostasis in Drosophila. Cell Rep. 9, 32-39 (2014).
59. Radford, I.R. and Lobachevsky, P.N. An enteroendocrine cell-based model for a quiescent intestinal stem cell niche. Cell Prolif. 39, 403-414 (2006).
60. Jung, P. et al. Isolation of human colon stem cells using surface expression of PTK7. Stem Cell Rep. 5, 979-987 (2015).
61. Buczacki, S.J. et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495, 65-69 (2013).
62. Sykaras, A.G., Demenis, C., Case, R.M., McLaughlin, J.T. and Smith, C.P. Duodenal enteroendocrine I-cells contain mRNA transcripts encoding key endocannabinoid and fatty acid receptors. PLoS ONE 7, e42373 (2012).
63. Egerod, K.L. et al. A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin. Endocrinology 153, 5782-5795 (2012).
64. Habib, A.M. et al. Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology 153, 3054-3065 (2012).
65. Grunddal, K.V. et al. Neurotensin is coexpressed, coreleased, and acts together with GLP-1 and PYY in enteroendocrine control of metabolism. Endocrinology 157, 176-194 (2016).
66. Svendsen, B. et al. An analysis of cosecretion and coexpression of gut hormones from male rat proximal and distal small intestine. Endocrinology 156, 847-857 (2015).
67. Svendsen, B. et al. GLP1-and GIP-producing cells rarely overlap and differ by bombesin receptor-2 expression and responsiveness. J. Endocrinol. 228, 39-48 (2016).
68. Psichas, A., Reimann, F. & Gribble, F.M. Gut chemosensing mechanisms. J. Clin. Invest. 125, 908-917 (2015).
69. Diakogiannaki, E. et al. Oligopeptides stimulate glucagon-like peptide-1 secretion in mice through proton-coupled uptake and the calciumsensing receptor. Diabetologia 56, 2688-2696 (2013).
70. Gorboulev, V. et al. Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61, 187-196 (2012).
71. Gribble, F.M., Diakogiannaki, E. and Reimann, F. Gut hormone regulation and secretion via FFA1 and FFA4. Handb. Exp. Pharmacol. 236, 181-203 (2016).
72. Brighton, C.A. et al. Bile acids trigger GLP-1 release predominantly by accessing basolaterally located G protein-coupled bile acid receptors. Endocrinology 156, 3961-3970 (2015).
73. Christensen, L.W., Kuhre, R.E., Janus, C., Svendsen, B. and Holst, J.J. Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine. Physiol. Rep. 3, e12551 (2015).
74. Bogunovic, M. et al. Enteroendocrine cells express functional Toll-like receptors. Am. J. Physiol.-Gastrointest. Liver Physiol. 292, G1770-G1783 (2007).
75. Chimerel, C., Emery, E., Summers, D.K., Keyser, U., Gribble, F.M. and Reimann, F. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 9, 1202-1208 (2014).
76. Nguyen, A.T. et al. Lipopolysaccharides-mediated increase in glucosestimulated insulin secretion: involvement of the GLP-1 pathway. Diabetes 63, 471-482 (2014).
77. Samuel, B.S. et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl Acad. Sci. USA 105, 16767-16772 (2008).
78. Tolhurst, G. et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61, 364-371 (2012).
79. Psichas, A. et al. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. 39, 424-429 (2015).
80. Gabellec, M.M.,Griffais, R., Fillion, G. &Haour, F. Expression of interleukin 1 alpha, interleukin 1 beta and interleukin 1 receptor antagonist mRNA in mouse brain: regulation by bacterial lipopolysaccharide (LPS) treatment. Mol. Brain Res. 31, 122-130 (1995).
81. Saffouri, B., Weir, G., Bitar, K. and Makhlouf, G. Stimulation of gastrin secretion from the perfused rat stomach by somatostatin antiserum. Life Sci. 25, 1749-1753 (1979).
82. Engelstoft, M.S. et al. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol. Metab. 2, 376-392 (2013).
83. Houlden, A. et al. Chronic trichuris muris infection in C57BL/6 mice causes significant changes in host microbiota and metabolome: effects reversed by pathogen clearance. PLoS ONE 10, e0125945 (2015).
84. Karaki, S. et al. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res. 324, 353-360 (2006).
85. Zeng, M.Y., Inohara, N. and Nunez, G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol. 10, 18-26 (2017).
86. Wesemann, D.R. and Nagler, C.R. The microbiome, timing, and barrier function in the context of allergic disease. Immunity 44, 728-738 (2016).
87. Nohr, M.K. et al. 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).
88. Cani, P.D., Dewever, C. and Delzenne, N.M. Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats. Br. J. Nutr. 92, 521-526 (2004).
89. Delzenne, N.M., Cani, P.D., Daubioul, C. and Neyrinck, A.M. Impact of inulin and oligofructose on gastrointestinal peptides. Br. J. Nutr. 93 (Suppl 1), S157-S161 (2005).
90. Cani, P.D., Knauf, C., Iglesias, M.A., Drucker, D.J., Delzenne, N.M. and Burcelin, R. Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor. Diabetes 55, 1484-1490 (2006).
91. Ropert, A. et al. Colonic fermentation and proximal gastric tone in humans. Gastroenterology 111, 289-296 (1996).
92. Cani, P.D. et al. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am. J. Clin. Nutr. 90, 1236-1243 (2009).
93. Parnell, J.A. and Reimer, R.A. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am. J. Clin. Nutr. 89, 1751-1759 (2009).
94. Breton, J. et al. Gut commensal E. Coli proteins activate host satiety pathways following nutrient-induced bacterial growth. Cell Metab. 23, 324-334 (2016).
95. Cani, P.D., Everard, A. and Duparc, T. Gut microbiota, enteroendocrine functions and metabolism. Curr. Opin. Pharmacol. 13, 935-940 (2013).
96. Cani, P.D. and Knauf, C. How gut microbes talk to organs: the role of endocrine and nervous routes. Mol. Metab. 5, 743-752 (2016).
97. Cani, P.D. et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58, 1091-1103 (2009).
98. Everard, A. et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptinresistant mice. Diabetes 60, 2775-2786 (2011).
99. Plaisancie, P., Dumoulin, V., Chayvialle, J.A. and Cuber, J.C. Luminal glucagon-like peptide-1(7-36) amide-releasing factors in the isolated vascularly perfused rat colon. J. Endocrinol. 145, 521-526 (1995).
100. Lin, H.V. et al. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS ONE 7, e35240 (2012).
101. Cani, P.D. et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 50, 2374-2383 (2007).
102. Lee, S.J. et al. Disruption of the murine Glp2r impairs Paneth cell function and increases susceptibility to small bowel enteritis. Endocrinology 153, 1141-1151 (2012).
103. Harrison, E., Lal, S. and McLaughlin, J.T. Enteroendocrine cells in gastrointestinal pathophysiology. Curr. Opin. Pharmacol. 13, 941-945 (2013).
104. Rioux, J.D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596-604 (2007).
105. Sakiyama, T., Fujita, H. and Tsubouchi, H. Autoantibodies against ubiquitination factor E4A (UBE4A) are associated with severity of Crohn's disease. Inflamm. Bowel Dis. 14, 310-317 (2008).
106. Moran, G.W., Pennock, J. and McLaughlin, J.T. Enteroendocrine cells in terminal ileal Crohn's disease. J. Crohns Colitis 6, 871-880 (2012).
107. Rindi, G., Leiter, A.B., Kopin, A.S., Bordi, C. and Solcia, E. The "normal" endocrine cell of the gut: changing concepts and new evidences. Ann. N Y. Acad. Sci. 1014, 1-12 (2004).
108. Zissimopoulos, A. et al. Chromogranin A as a biomarker of disease activity and biologic therapy in inflammatory bowel disease: a prospective observational study. Scand. J. Gastroenterol. 49, 942-949 (2014).
109. Sciola, V. et al. Plasma chromogranin a in patients with inflammatory bowel disease. Inflamm. Bowel Dis. 15, 867-871 (2009).
110. Strid, H., Simren, M., Lasson, A., Isaksson, S., Stridsberg, M. and Ohman, L. Fecal chromogranins and secretogranins are increased in patients with ulcerative colitis but are not associated with disease activity. J. Crohns Colitis 7, e615-e622 (2013).
111. Wagner,M., Stridsberg,M., Peterson, C.G., Sangfelt, P., Lampinen, M. and Carlson, M. Increased fecal levels of chromogranin A, chromogranin B, and secretoneurin in collagenous colitis. Inflammation 36, 855-861 (2013).
112. Tari, A. et al. Peptide YY abnormalities in patients with ulcerative colitis. Jpn. J. Med. 27, 49-55 (1988).
113. Adrian, T.E., Savage, A.P., Bacarese-Hamilton, A.J., Wolfe, K., Besterman, H.S. and Bloom, S.R. Peptide YY abnormalities in gastrointestinal diseases. Gastroenterology 90, 379-384 (1986).
114. Koch, T.R., Roddy, D.R. and Go, V.L. Abnormalities of fasting serum concentrations of peptide YY in the idiopathic inflammatory bowel diseases. Am. J. Gastroenterol. 82, 321-326 (1987).
115. Moran, G.W., Leslie, F.C. & McLaughlin, J.T.Crohn's disease affecting the small bowel is associated with reduced appetite and elevated levels of circulating gut peptides. Clin. Nutr. 32, 404-411 (2013).
116. Payer, J. et al. Plasma somatostatin levels in ulcerative colitis. Hepatogastroenterology 41, 552-553 (1994).
117. Binimelis, J. et al. Circulating immunoreactive somatostatin in gastrointestinal diseases. Decrease after vagotomy and enhancement in active ulcerative colitis, irritable bowel syndrome, and duodenal ulcer. Scand. J. Gastroenterol. 22, 931-937 (1987).
118. Karmiris, K.,Koutroubakis, I.E., Xidakis, C., Polychronaki, M., Voudouri, T. and Kouroumalis, E.A. Circulating levels of leptin, adiponectin, resistin, and ghrelin in inflammatory bowel disease. Inflamm. Bowel Dis. 12, 100-105 (2006).
119. Peracchi, M. et al. Circulating ghrelin levels in patients with inflammatory bowel disease. Gut 55, 432-433 (2006).
120. Ates, Y., Degertekin, B., Erdil, A., Yaman, H. and Dagalp, K. Serum ghrelin levels in inflammatory bowel disease with relation to disease activity and nutritional status. Dig. Dis. Sci. 53, 2215-2221 (2008).
121. Cekic, C. et al. Evaluation of the relationship between serum ghrelin, C-reactive protein and interleukin-6 levels, and disease activity in inflammatory bowel diseases. Hepatogastroenterology 61, 1196-1200 (2014).
122. Nishi, Y. et al. Plasma leptin and ghrelin concentrations in patients with Crohn's disease. World J. Gastroenterol. 11, 7314-7317 (2005).
123. Triantafillidis, J.K. et al. Serum gastrin levels in patients with inflammatory bowel disease. Hepatogastroenterology 50 (Suppl 2), cccxv-cccxvii (2003).
124. Essop, A.R., Segal, I. & Ming, R.High serum gastrin in ulcerative colitis. N. Engl. J. Med. 307, 192 (1982).
125. Hopman, W.P., de Jong, D.J., Naber, A.H. and Jansen, J.B. Tumour necrosis factor alpha antibody affects gastrin release in Crohn disease. Scand. J. Gastroenterol. 38, 522-525 (2003).
126. Bendet, N. et al. Enhanced glucose-dependent glucagon-like peptide-1 and insulin secretion in Crohn patients with terminal ileum disease is unrelated to disease activity or ileal resection. Scand. J. Gastroenterol. 39, 650-656 (2004).
127. Vu, M.K., Gielkens, H.A., van Hogezand, R.A., van Oostayen, J.A., Lamers, C.B. and Masclee, A.A. Gallbladder motility in Crohn disease: influence of disease localization and bowel resection. Scand. J. Gastroenterol. 35, 1157-1162 (2000).
128. Keller, J., Beglinger, C., Holst, J.J., Andresen, V. and Layer, P. Mechanisms of gastric emptying disturbances in chronic and acute inflammation of the distal gastrointestinal tract. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G861-G868 (2009).
129. Keller, J. et al. Gastric emptying and disease activity in inflammatory bowel disease. Eur. J. Clin. Invest. 45, 1234-1242 (2015).
130. Dawson, J., Bryant, M.G., Bloom, S.R. and Peters, T.J. Gastrointestinal regulatory peptide storage granule abnormalities in jejunal mucosal diseases. Gut 25, 636-643 (1984).
131. Yokoyama, I., Kozuka, S. and Takagi, H. Gastrin producing cells in the regenerating mucosa of the small intestine. Jpn. J. Surg. 18, 54-60 (1988).
132. El-Salhy, M., Danielsson, A., Stenling, R. and Grimelius, L. Colonic endocrine cells in inflammatory bowel disease. J. Intern. Med. 242, 413-419 (1997).
133. Schmidt, P.T., Ljung, T., Hartmann, B., Hare, K.J., Holst, J.J. and Hellstrom, P.M. Tissue levels and post-prandial secretion of the intestinal growth factor, glucagon-like peptide-2, in controls and inflammatory bowel disease: comparison with peptide YY. Eur. J. Gastroenterol. Hepatol. 17, 207-212 (2005).
134. Magro, F. et al. Impaired synthesis or cellular storage of norepinephrine, dopamine, and 5-hydroxytryptamine in human inflammatory bowel disease. Dig. Dis. Sci. 47, 216-224 (2002).
135. El-Salhy,M., Gundersen,D., Hatlebakk, J.G.& Hausken, T. High densities of serotonin and peptide YY cells in the colon of patients with lymphocytic colitis. World J. Gastroenterol. 18, 6070-6075 (2012).
136. Watanabe, T., Kubota, Y., Sawada, T. and Muto, T. Distribution and quantification of somatostatin in inflammatory disease. Dis. Colon Rectum 35, 488-494 (1992).
137. Xiao, Q., Boushey, R.P., Cino, M., Drucker, D.J. and Brubaker, P.L. Circulating levels of glucagon-like peptide-2 in human subjects with inflammatory bowel disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278, R1057-R1063 (2000).
138. Tanaka, M. et al. Spatial distribution and histogenesis of colorectal Paneth cell metaplasia in idiopathic inflammatory bowel disease. J. Gastroenterol. Hepatol. 16, 1353-1359 (2001).
139. Ardesjo, B. et al. Immunoreactivity against Goblet cells in patients with inflammatory bowel disease. Inflamm. Bowel Dis. 14, 652-661 (2008).
140. Koehler, J.A. et al. GLP-1 R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. Cell Metab. 21, 379-391 (2015).
141. Dube, P.E., Forse, C.L., Bahrami, J. and Brubaker, P.L. The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice. Gastroenterology 131, 589-605 (2006).
142. Ivory, C.P.,Wallace, L.E., McCafferty, D.M. and Sigalet, D.L. Interleukin-10-independent anti-inflammatory actions of glucagon-like peptide 2. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G1202-G1210 (2008)
143. Kochar, B. et al. Safety and efficacy of teduglutide (Gattex) in patients with Crohn's Disease and need for parenteral support due to short bowel syndrome-associated intestinal failure. J. Clin. Gastroenterol. 51, 508-511 (2016).
144. Hirotani, Y., Mikajiri, K., Ikeda, K., Myotoku, M. and Kurokawa, N. Changes of the peptide YY levels in the intestinal tissue of rats with experimental colitis following oral administration of mesalazine and prednisolone. Yakugaku Zasshi 128, 1347-1353 (2008).
145. Zlatkina, A.R., Bezzubik, K.V., Peeters, T.L. and Kuznetsova, O.G. Plasma motilin and diarrhea in ulcerative colitis. Sov. Med. 53, 14-18 (1990).
146. Annese, V. et al. Polymorphism of motilin gene in patients with Crohn's disease. Dig. Dis. Sci. 43, 715-719 (1998).
147. McHugh, K., Castonguay, T.W., Collins, S.M. and Weingarten, H.P. Characterization of suppression of food intake following acute colon inflammation in the rat. Am. J. Physiol. 265 (5 Pt 2), R1001-R1005 (1993).
148. El-Salhy, M. and Hatlebakk, J.G. Changes in enteroendocrine and immune cells following colitis induction by TNBS in rats. Mol. Med. Rep. 14, 4967-4974 (2016).
149. O'Hara, J.R., Lomax, A.E., Mawe, G.M. and Sharkey, K.A. Ileitis alters neuronal and enteroendocrine signalling in guinea pig distal colon. Gut 56, 186-194 (2007).
150. Schmidt, P.T., Hartmann, B., Bregenholt, S., Hoist, J.J. and Claesson, M.H. Deficiency of the intestinal growth factor, glucagon-like peptide 2, in the colon of SCID mice with inflammatory bowel disease induced by transplantation of CD4+ T cells. Scand. J. Gastroenterol. 35, 522-527 (2000).
151. Bang-Berthelsen, C.H. et al. GLP-1 induces barrier protective expression in brunner's glands and regulates colonic inflammation. Inflamm. Bowel Dis. 22, 2078-2097 (2016).
152. Rubin, D.C., Zhang, H.Y., Qian, P.Q., Lorenz, R.G., Hutton, K. and Peters, M.G. Altered enteroendocrine cell expression in T cell receptor alpha chain knock-out mice. Microsc. Res. Tech. 51, 112-120 (2000).
153. Qian, B.F., El-Salhy, M.,Melgar, S., Hammarstrom, M.L. and Danielsson, A. Neuroendocrine changes in colon of mice with a disrupted IL-2 gene. Clin. Exp. Immunol. 120, 424-433 (2000).
154. Al Moutaery, A. Proglumide attenuates experimental colitis in rats. Exp. Toxicol. Pathol. 56, 327-332 (2005).
155. Barbier, M. et al. Proinflammatory role of leptin in experimental colitis in rats benefit of cholecystokinin-B antagonist and beta3-agonist. Life Sci. 69, 567-580 (2001).
156. Oehlers, S.H. et al. A whole animal chemical screen approach to identify modifiers of intestinal neutrophilic inflammation. FEBS J. 284, 402-441 (2016).
157. Palasz, A. et al. Nesfatin-1, a unique regulatory neuropeptide of the brain. Neuropeptides 46, 105-112 (2012).
158. Ozturk, C.C., Oktay, S., Yuksel, M., Akakin, D., Yarat, A. and Kasimay Cakir, O. Anti-inflammatory effects of nesfatin-1 in rats with acetic acid-induced colitis and underlying mechanisms. J. Physiol. Pharmacol. 66, 741-750 (2015).
159. Eliakim, R., Karmeli, F., Okon, E. and Rachmilewitz, D. Octreotide effectively decreases mucosal damage in experimental colitis. Gut 34, 264-269 (1993).
160. Li, X. et al. Somatostatin regulates tight junction proteins expression in colitis mice. Int. J. Clin. Exp. Pathol. 7, 2153-2162 (2014).
161. Li, X. et al. Somatostatin regulatesNHE8 protein expression via the ERK1/ 2 MAPK pathway in DSS-induced colitis mice. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G954-g963 (2016).
162. Brun, P. et al. Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G621-G629 (2005).
163. Drucker, D.J., Yusta, B., Boushey, R.P., DeForest, L. and Brubaker, P.L. Human [Gly2]GLP-2 reduces the severity of colonic injury in a murine model of experimental colitis. Am. J. Physiol. 276 (1 Pt 1), G79-G91 (1999).
164. Boushey, R.P., Yusta, B. and Drucker, D.J. Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis. Am. J. Physiol. 277 (5 Pt 1), E937-E947 (1999).
165. Alavi, K., Schwartz, M.Z., Palazzo, J.P. and Prasad, R. Treatment of inflammatory bowel disease in a rodent model with the intestinal growth factor glucagon-like peptide-2. J. Pediatr. Surg. 35, 847-851 (2000).
166. Halaclar,B., Agac, A.y.A.,Akcan, A.C.,Ay, A.,Oz, B.& Arslan, E. Effects of glucagon-like peptide-2 on bacterial translocation in rat models of colitis. Turk. J. Gastroenterol. 23, 691-698 (2012).
167. Anbazhagan, A.N. et al. GLP-1 nanomedicine alleviates gut inflammation. Nanomed.: Nanotechnol., Biol., Med. 13, 659-665 (2016).
168. Moran, G.W., Leslie, F.C., Levison, S.E. and McLaughlin, J.T. Enteroendocrine cells: neglected players in gastrointestinal disorders?. Ther. Adv. Gastroenterol. 1, 51-60 (2008).
169. Kiesler, P., Fuss, I.J. and Strober, W. Experimental models of inflammatory bowel diseases. Cell. Mol. Gastroenterol. Hepatol. 1, 154-170 (2015).
170. Matsumoto, S. et al. Inflammatory bowel disease-like enteritis and caecitis in a senescence accelerated mouse P1/Yit strain. Gut 43, 71-78 (1998).
171. el-Salhy, M. The nature and implication of intestinal endocrine cell changes in coeliac disease. Histol. Histopathol. 13, 1069-1075 (1998).
172. Domschke, S., Bloom, S.R., Adrian, T.E., Lux, G., Bryant, M.G. and Domschke, W. Coeliac sprue: abnormalities of the hormone profile of gastroduodenal mucosa. Scand. J. Gastroenterol. Suppl. 167, 86-89 (1989).
173. Papastamataki, M. et al. Incretins, amylin and other gut-brain axis hormones in children with coeliac disease. Eur. J. Clin. Invest. 44, 74-82 (2014).
174. Di Sabatino, A. et al. Increase in neuroendocrine cells in the duodenal mucosa of patients with refractory celiac disease. Am. J. Gastroenterol. 109, 258-269 (2014).
175. Jarocka-Cyrta, E., Kasacka, I. and Kaczmarski, M. The ghrelin-positive cells number is increased in duodenum in children with celiac disease. J. Endocrinol. Invest. 33, 165-170 (2010).
176. Rocco, A. et al. Tissue ghrelin level and gastric emptying rate in adult patients with celiac disease. Neurogastroenterol. Motility 20, 884-890 (2008).
177. Fraquelli, M., Bardella, M.T., Peracchi, M., Cesana, B.M., Bianchi, P.A. and Conte, D. Gallbladder emptying and somatostatin and cholecystokinin plasma levels in celiac disease. Am. J. Gastroenterol. 94, 1866-1870 (1999).
178. Caddy, G.R. et al. Plasma concentrations of glucagon-like peptide-2 in adult patients with treated and untreated coeliac disease. Eur. J. Gastroenterol. Hepatol. 18, 195-202 (2006).
179. Le Quellec, A., Kervran, A., Blache, P., Ciurana, A.J. and Bataille, D. [Oxyntomodulin, a new hormonal marker of intestinal malabsorption syndromes]. La Revue de Med. Interne 14, 982 (1993).
180. Bardella, M.T., Fraquelli, M., Peracchi, M., Cesana, B.M., Bianchi, P.A. and Conte, D. Gastric emptying and plasma neurotensin levels in untreated celiac patients. Scand. J. Gastroenterol. 35, 269-273 (2000).
181. Sjolund, K. and Ekman, R. Plasma motilin in untreated celiac disease. Peptides 24, 483-486 (2003).
182. Minderhoud, I.M., Oldenburg, B., Schipper, M.E., ter Linde, J.J. and Samsom, M. Serotonin synthesis and uptake in symptomatic patients with Crohn's disease in remission. Clin. Gastroenterol. Hepatol. 5, 714-720 (2007).
183. Keszthelyi, D. et al. Alterations in mucosal neuropeptides in patients with irritable bowel syndrome and ulcerative colitis in remission: a role in pain symptom generation?. Eur. J. Pain 17, 1299-1306 (2013).
184. Serna, H., Porras, M. and Vergara, P. Mast cell stabilizer ketotifen 4-(1-methyl-4-piperidylidene)-4H-benzo 4,5 cyclohepta 1,2-b thiophen-10(9H)-one fumarate prevents mucosal mast cell hyperplasia and intestinal dysmotility in experimental Trichinella spiralis inflammation in the rat. J. Pharmacol. Exp. Ther. 319, 1104-1111 (2006).
185. Torrents, D. and Vergara, P. In vivo changes in the intestinal reflexes and the response to CCK in the inflamed small intestine of the rat. Am. J. Physiol.-Gastrointest. Liver Physiol. 279, G543-G551 (2000).
186. Aerssens, J. et al. Alterations in the brain-gut axis underlying visceral chemosensitivity in Nippostrongylus brasiliensis-infected mice. Gastroenterology 132, 1375-1387 (2007).
187. Kalia, N. et al. Intestinal secretory and absorptive function in Trichinella spiralis mouse model of postinfective gut dysfunction: role of bile acids. Gut 57, 41-48 (2008).
188. Dlugosz, A. et al. Chlamydia trachomatis antigens in enteroendocrine cells and macrophages of the small bowel in patients with severe irritable bowel syndrome. BMC Gastroenterol. 10, 19 (2010).
189. Dynes, R.A., Poppi, D.P., Barrell, G.K. and Sykes, A.R. Elevation of feed intake in parasite-infected lambs by central administration of a cholecystokinin receptor antagonist. Br. J. Nutr. 79, 47-54 (1998).
190. Yang, S., Gaafar, S.M. and Bottoms, G.D. Effects of multiple dose infections with ascaris-suum on blood gastrointestinal hormone levels in pigs. Vet. Parasitol. 37, 31-44 (1990).
191. Forbes, A.B. et al. Associations between blood gastrin, ghrelin, leptin, pepsinogen and Ostertagia ostertagi antibody concentrations and voluntary feed intake in calves exposed to a trickle infection with O. ostertagi. Vet. Parasitol. 162, 295-305 (2009).
192. Scott, I. et al. Infection of sheep with adult and larval Ostertagia circumcincta: gastrin. Int. J. Parasitol. 28, 1393-1401 (1998).
193. Bosi, G., Shinn, A.P., Giari, L., Simoni, E., Pironi, F. and Dezfuli, B.S. Changes in the neuromodulators of the diffuse endocrine system of the alimentary canal of farmed rainbow trout, Oncorhynchus mykiss (Walbaum), naturally infected with Eubothrium crassum (Cestoda). J. Fish Dis. 28, 703-711 (2005).
194. Dezfuli, B.S., Pironi, F., Shinn, A.P.,Manera, M. and Giari, L. Histopathology and ultrastructure of Platichthys flesus naturally infected with Anisakis simplex s.l. larvae (Nematoda: anisakidae). J. Parasitol. 93, 1416-1423 (2007).
195. Worthington, J.J., Samuelson, L.C., Grencis, R.K. and McLaughlin, J.T. Adaptive immunity alters distinct host feeding pathways during nematode induced inflammation, a novel mechanism in parasite expulsion. PLoS Pathog. 9, e1003122 (2013).
196. McDermott, J.R., Leslie, F.C., D'Amato, M., Thompson, D.G., Grencis, R.K. and McLaughlin, J.T. Immune control of food intake: enteroendocrine cells are regulated by CD4(+) T lymphocytes during small intestinal inflammation. Gut 55, 492-497 (2006).
197. Ovington, K.S., Bacaresehamilton, A.J. and Bloom, S.R. Nippostrongylus-Brasiliensis-changes in plasma-levels of gastrointestinal hormones in the infected-rat. Exp. Parasitol. 60, 276-284 (1985).
198. Castro, G.A., Copeland, E.M., Dudrick, S.J. and Johnson, L.R. Serum and antral gastrin levels in rats infected with intestinal parasites. Am. J. Trop. Med. Hyg. 25, 848-853 (1976).
199. De Jonge, F. et al. Effects of Schistosoma mansoni infection on somatostatin and somatostatin receptor 2 A expression in mouse ileum. Neurogastroenterol. Motility 15, 149-159 (2003).
200. Leslie, F.C., Thompson, D.G., McLaughlin, J.T., Varro, A., Dockray,G.J. and Mandal, B.K. Plasma cholecystokinin concentrations are elevated in acute upper gastrointestinal infections. QJM 96, 870-871 (2003).
201. Roma, S.M. et al. Enteroendocrine cells modifications in Helicobacter pylori gastritis. Acta Gastroenterol. Latinoam. 31, 377-381 (2001).
202. Jeffery, P.L., McGuckin, M.A. and Linden, S.K. Endocrine impact of Helicobacter pylori: focus on ghrelin and ghrelin o-acyltransferase. World J. Gastroenterol. 17, 1249-1260 (2011).
203. Choi, Y.J. et al. Increase in plasma acyl ghrelin levels is associated with abatement of dyspepsia following Helicobacter pylori eradication. J. Gastroenterol. 51, 548-559 (2016).
204. Khosravi, Y. et al. Helicobacter pylori and gutmicrobiota modulate energy homeostasis prior to inducing histopathological changes in mice. Gut Microb. 7, 48-53 (2016).
205. van Marle, G., Sharkey, K.A., Gill, M.J. and Church, D.L. Gastrointestinal viral load and enteroendocrine cell number are associated with altered survival in HIV-1 infected individuals. PLoS ONE 8, e75967 (2013).
206. Dlugosz, A., Muschiol, S., Zakikhany, K., Assadi, G., D'Amato, M. and Lindberg, G. Human enteroendocrine cell responses to infection with Chlamydia trachomatis: a microarray study. Gut Pathog. 6, 24 (2014).
207. Gledhill, A., Hall, P.A., Cruse, J.P. and Pollock, D.J. Enteroendocrine cell hyperplasia, carcinoid tumours and adenocarcinoma in long-standing ulcerative colitis. Histopathology 10, 501-508 (1986).
208. Jezkova, J. et al. Brachyury identifies a class of enteroendocrine cells in normal human intestinal crypts and colorectal cancer. Oncotarget 7, 11478-11486 (2016).
209. Banck, M.S. et al. The genomic landscape of small intestine neuroendocrine tumors. J. Clin. Invest. 123, 2502-2508 (2013).
210. Leedham, S.J. MAP(K)ing the path to stem cell quiescence and the elusive enteroendocrine cell. Cell Stem Cell 20, 153-154 (2017).
211. Kunz, P.L. Carcinoid and neuroendocrine tumors: building on success. J. Clin. Oncol. 33, 1855-1863 (2015).
212. Gulubova, M. and Vlaykova, T. Chromogranin A-, serotonin-, synaptophysin-and vascular endothelial growth factor-positive endocrine cells and the prognosis of colorectal cancer: an immunohistochemical and ultrastructural study. J. Gastroenterol. Hepatol. 23, 1574-1585 (2008).
213. Swatek, J. and Chibowski, D. Endocrine cells in colorectal carcinomas. Immunohistochemical study. Polish J. Pathol. 51, 127-136 (2000).
214. Smith, D.M. Jr. and Haggitt, R.C. The prevalence and prognostic significance of argyrophil cells in colorectal carcinomas. Am. J. Surg. Pathol. 8, 123-128 (1984).
215. Cho, Y.B. et al. The clinical significance of neuroendocrine differentiation in T3-T4 node-negative colorectal cancer. Int. J. Surg. Pathol. 18, 201-206 (2010).
216. Kleist, B. and Poetsch, M. Neuroendocrine differentiation: the mysterious fellow of colorectal cancer. World J. Gastroenterol. 21, 11740-11747 (2015).
217. La Rosa, S., Chiaravalli, A.M., Capella, C., Uccella, S. and Sessa, F. Immunohistochemical localization of acidic fibroblast growth factor in normal human enterochromaffin cells and related gastrointestinal tumours. Virchows Archiv.: Int. J. Pathol. 430, 117-124 (1997).
218. Okines, A. and Cunningham, D. Current perspective: bevacizumab in colorectal cancer-A time for reappraisal?. Eur. J. Cancer 45, 2452-2461 (2009).
219. Kohne, C.H. and Lenz, H.J. Chemotherapy with targeted agents for the treatment of metastatic colorectal cancer. Oncologist 14, 478-488 (2009).
220. Ciunci, C.A. et al. Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer. Cancer 120, 77-85 (2014).
221. McRee, A.J. et al. A phase I trial of everolimus in combination with 5-FU/LV, mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors. Cancer Chemother. Pharmacol. 74, 117-123 (2014).
222. Drucker, D.J. Evolving concepts and translational relevance of enteroendocrine cell biology. J. Clin. Endocrinol. Metab. 101, 778-786 (2016).
223. El-Salhy, M. and Umezawa, K. Effects of AP1 and NFkappaB inhibitors on colonic endocrine cells in rats with TNBSinduced colitis. Mol. Med. Rep. 14, 1515-1522 (2016).
224. Zhang, W.J., Duan, J.Z., Lei, N., Xing, H., Shao, Y. and Yang, G.B. Cellular bases for interactions between immunocytes and enteroendocrine cells in the intestinal mucosal barrier of rhesus macaques. Cell Tissue Res. 350, 135-141 (2012).
225. O'Hara, J.R., Skinn, A.C., MacNaughton, W.K., Sherman, P.M. and Sharkey, K.A. Consequences of Citrobacter rodentium infection on enteroendocrine cells and the enteric nervous system in themouse colon. Cell Microbiol. 8, 646-660 (2006).
226. Motomura, Y., Verma-Gandhu, M., El-Sharkawy, R.T., McLaughlin, J., Grencis, R.K. and Khan, W.I. Colonic 5-HT and muscle responses to the same infectious agent differ in Th1 and Th2 dominant environments. Gastroenterology 126, A216-A216 (2004).
227. Wang, H.Q. et al. CD4(+) T cell-mediated immunological control of enterochromaffin cell hyperplasia and 5-hydroxytryptamine production in enteric infection. Gut 56, 949-957 (2007).
228. Motomura, Y. et al. Enterochromaffin cell and 5-hydroxytryptamine responses to the same infectious agent differ in Th1 and Th2 dominant environments. Gut 57, 475-481 (2008).
229. Hernandez-Trejo, J.A. et al. The pro-inflammatory cytokines IFNgamma/ TNFalpha increase chromogranin A-positive neuroendocrine cells in the colonic epithelium. Biochem. J. 473, 3805-3818 (2016).
230. O'Hara, J.R. and Sharkey, K.A. Proliferative capacity of enterochromaffin cells in guinea-pigs with experimental ileitis. Cell Tissue Res. 329, 433-441 (2007).
231. Mahapatro,M. et al. Programming of intestinal epithelial differentiation by IL-33 derived from pericryptal fibroblasts in response to systemic infection. Cell Rep. 15, 1743-1756 (2016).
232. Tsukahara, T. et al. Tumor necrosis factor alpha decreases glucagon-like peptide-2 expression by up-regulatingG-protein-coupled receptor 120 in Crohn disease. Am. J. Pathol. 185, 185-196 (2015).
233. Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481-1489 (2011).
234. Kidd, M., Gustafsson, B.I., Drozdov, I. and Modlin, I.M. IL1beta-and LPSinduced serotonin secretion is increased in EC cells derived from Crohn's disease. Neurogastroenterol. Motility 21, 439-450 (2009).
235. Wang, A. et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166, e1512 (2016).
236. Howitt, M.R. et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351, 1329-1333 (2016).
237. von Moltke, J., Ji, M., Liang, H.E. and Locksley, R.M. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221-225 (2016).
238. Grencis, R.K. & Worthington, J.J. Tuft cells: a new flavor in innate epithelial immunity. Trends Parasitol. 32, 583-585 (2016).
239. Selleri, S. et al. Induction of pro-inflammatory programs in enteroendocrine cells by the Toll-like receptor agonists flagellin and bacterial LPS. Int. Immunol. 20, 961-970 (2008).
240. Friedrich, M., Diegelmann, J., Schauber, J., Auernhammer, C.J. and Brand, S. Intestinal neuroendocrine cells and goblet cells are mediators of IL-17 A-amplified epithelial IL-17C production in human inflammatory bowel disease. Mucosal Immunol. 8, 943-958 (2014).
241. Hougaard, D.M. and Larsson, L.I. Carboxypeptidase E in rat antropyloric mucosa: distribution in progenitor and mature endocrine cell types. Histochem. Cell Biol. 121, 55-61 (2004).
242. Jeon, T.I., Seo, Y.K. and Osborne, T.F. Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK. Biochem. J. 438, 33-37 (2011).
243. Higgins, G.A., Kilpatrick, G.J., Bunce, K.T., Jones, B.J. and Tyers, M.B. 5-HT3 receptor antagonists injected into the area postrema inhibit cisplatininduced emesis in the ferret. Br. J. Pharmacol. 97, 247-255 (1989).
244. Hagbom, M. et al. Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting. PLoS Pathog. 7, e1002115 (2011).
245. Sukhdeo, M.V. and Sukhdeo, S.C. Gastrointestinal hormones: environmental cues for Fasciola hepatica?. Parasitology 98 (Pt 2), 239-243 (1989).
246. Delgado, M., Anderson, P., Garcia-Salcedo, J.A., Caro, M. and Gonzalez-Rey, E. Neuropeptides kill African trypanosomes by targeting intracellular compartments and inducing autophagic-like cell death. Cell Death Differ. 16, 406-416 (2009).
247. Chorny, A., Anderson, P., Gonzalez-Rey, E. and Delgado, M. Ghrelin protects against experimental sepsis by inhibiting high-mobility group box 1 release and by killing bacteria. J. Immunol. 180, 8369-8377 (2008).
248. Beebe, K., Park, D., Taghert, P.H. and Micchelli, C.A. The drosophila prosecretory transcription factor dimmed is dynamically regulated in adult enteroendocrine cells and protects against gram-negative infection. G3 5, 1517-1524 (2015).
249. Dong, C.X. et al. The intestinal epithelial insulin-like growth factor-1 receptor links glucagon-like peptide-2 action to gut barrier function. Endocrinology 155, 370-379 (2014).
250. Moran, G.W., O'Neill, C. and McLaughlin, J.T. GLP-2 enhances barrier formation and attenuates TNFalpha-induced changes in a Caco-2 cell model of the intestinal barrier. Regul. Pept. 178, 95-101 (2012).
251. Orskov, C., Hartmann, B., Poulsen, S.S., Thulesen, J., Hare, K.J. and Holst, J.J. GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors. Regul. Pept. 124, 105-112 (2005).
252. Yusta, B. et al. ErbB signaling is required for the proliferative actions of GLP-2 in the murine gut. Gastroenterology 137, 986-996 (2009).
253. Genton, L. and Kudsk, K.A. Interactions between the enteric nervous system and the immune system: role of neuropeptides and nutrition. Am. J. Surg. 186, 253-258 (2003).
254. Shajib, M.S. and Khan, W.I. The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiol. 213, 561-574 (2015).
255. Abella, V. et al. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat. Rev. Rheumatol. 13, 100-109 (2017).
256. O'Mahony, L., Akdis, M.& Akdis, C.A. Regulation of the immune response and inflammation by histamine and histamine receptors. J. Allergy Clin. Immunol. 128, 1153-1162 (2011).
257. Chung, Y., Kim, H., Im, E., Kim, P. and Yang, H. Th 17 cells and Nesfatin-1 are associated with spontaneous abortion in the CBA/j x DBA/2 mouse model. Dev. Reprod. 19, 243-252 (2015).
258. Dixit, V.D., Yang, H., Cooper-Jenkins, A., Giri, B.B., Patel, K. and Taub, D.D. Reduction of T cell-derived ghrelin enhances proinflammatory cytokine expression: implications for age-associated increases in inflammation. Blood 113, 5202-5205 (2009).
259. Xu, Y. et al. Ghrelin inhibits the differentiation of T helper 17 cells through mTOR/STAT3 signaling pathway. PLoS ONE 10, e0117081 (2015).
260. Souza-Moreira, L., Delgado-Maroto, V., Morell, M., O'Valle, F., Del Moral, R.G. and Gonzalez-Rey, E. Therapeutic effect of ghrelin in experimental autoimmune encephalomyelitis by inhibiting antigen-specific Th1/Th17 responses and inducing regulatory T cells. Brain Behav. Immun. 30, 54-60 (2013).
261. Dixit, V.D. et al. Ghrelin inhibits leptin-and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J. Clin. Invest. 114, 57-66 (2004).
262. Zhang, J.G., Liu, J.X., Jia, X.X., Geng, J., Yu, F. and Cong, B. Cholecystokinin octapeptide regulates the differentiation and effector cytokine production of CD4(+) Tcells in vitro. Int. Immunopharmacol. 20, 307-315 (2014).
263. Hadjiyanni, I., Siminovitch, K.A., Danska, J.S. and Drucker, D.J. Glucagonlike peptide-1 receptor signalling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T cells. Diabetologia 53, 730-740 (2010).
264. He, L. et al. Anti-inflammatory effects of exendin-4, a glucagon-like peptide-1 analog, on human peripheral lymphocytes in patients with type 2 diabetes. J. Diabetes Investig. 4, 382-392 (2013).
265. Lee, J.H. et al. Ghrelin augments murine T-cell proliferation by activation of the phosphatidylinositol-3-kinase, extracellular signal-regulated kinase and protein kinase C signaling pathways. FEBS Lett. 588, 4708-4719 (2014).
266. Pamukcu, O., Kumral, Z.N., Ercan, F., Yegen, B.C. and Ertem, D. Anti-inflammatory effect of obestatin and ghrelin in dextran sulfate sodium-induced colitis in rats. J. Pediatr. Gastroenterol. Nutr. 57, 211-218 (2013).
267. Hosomi, S. et al. Phenotypical and functional study of ghrelin and its receptor in the pathogenesis of Crohn's disease. Inflamm. Bowel Dis. 14, 1205-1213 (2008).
268. Tang, S.C., Braunsteiner, H. and Wiedermann, C.J. Regulation of human T lymphoblast growth by sensory neuropeptides: augmentation of cholecystokinin-induced inhibition ofMolt-4 proliferation by somatostatin and vasoactive intestinal peptide in vitro. Immunol. Lett. 34, 237-242 (1992).
269. Yoon, W.K. et al. Somatostatin down-regulates LFA-1 activation by modulating Rap1 expression in CD4+ and CD8+ T cells. Regul. Pept. 124, 151-156 (2005).
270. Petrovic-Djergovic, D.M., Rakin, A.K., Kustrimovic, N.Z., Ristovski, J.S., Dimitrijevic, L.A. and Mileva, M.V. Somatostatin modulates T cells development in adult rat thymus. Regul. Pept. 142, 101-110 (2007).
271. Yusta, B. et al. GLP-1 receptor (GLP-1 R) agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte (IEL) GLP-1 R. Diabetes 64, 2537-2549 (2015).
272. Lynch, L. et al. iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy. Cell Metab. 24, 510-519 (2016).
273. Hogan, A.E. et al. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia 54, 2745-2754 (2011).
274. Agro, A., Padol, I. and Stanisz, A.M. Immunomodulatory activities of the somatostatin analogue BIM 23014c: effects on murine lymphocyte proliferation and natural killer activity. Regul. Pept. 32, 129-139 (1991).
275. van Tol, E.A., Verspaget, H.W. and Lamers, C.B. Effects of CCK-8 andCCK-33 on human natural killer cell activity: studies on intestinal lamina propria and peripheral blood mononuclear cells. Immunopharmacology 25, 11-18 (1993).
276. Reardon, C. et al. Lymphocyte-derived ACh regulates local innate but not adaptive immunity. Proc. Natl Acad. Sci. USA 110, 1410-1415 (2013).
277. Zhang, J.G., Cong, B., Li, Q.X., Chen, H.Y., Qin, J. and Fu, L.H. Cholecystokinin octapeptide regulates lipopolysaccharide-activated B cells co-stimulatory molecule expression and cytokines production in vitro. Immunopharmacol. Immunotoxicol. 33, 157-163 (2011).
278. Liu, L. et al. Somatostatin improved B cells mature in macaques during intestinal ischemia-reperfusion. PLoS ONE 10, e0133692 (2015).
279. Sung, E.Z.,Da Silva, N.F., Goodyear, S.J., McTernan, P.G., Arasaradnam, R.P. and Nwokolo, C.U. Ghrelin promotes nuclear factor kappa-B activation in a human B-lymphocyte cell line. Mol. Biol. Rep. 38, 4833-4838 (2011).
280. Saada, S. et al. Differential expression of neurotensin and specific receptors, NTSR1 and NTSR2, in normal and malignant human B lymphocytes. J. Immunol. 189, 5293-5303 (2012).
281. Chen, J., Dong, J.T., Li, X.J., Gu, Y., Cheng, Z.J. & Cai, Y.K. Glucagon-like peptide-2 protects impaired intestinal mucosal barriers in obstructive jaundice rats. World J. Gastroenterol. 21, 484-490 (2015).
282. Hanna, M.K. et al. Individual neuropeptides regulate gut-associated lymphoid tissue integrity, intestinal immunoglobulin A levels, and respiratory antibacterial immunity. J. Parent. Enteral Nutr. 24, 261-268 (2000).
283. Jia, X. et al. CCK8 negatively regulates the TLR9-induced activation of human peripheral blood pDCs by targeting TRAF6 signaling. Eur. J. Immunol. 44, 489-499 (2014).
284. Kao, J.Y., Pierzchala, A., Rathinavelu, S., Zavros, Y., Tessier, A. and Merchant, J.L. Somatostatin inhibits dendritic cell responsiveness to Helicobacter pylori. Regul. Pept. 134, 23-29 (2006).
285. da Silva, L., Neves, B.M., Moura, L., Cruz, M.T. and Carvalho, E. Neurotensin downregulates the pro-inflammatory properties of skin dendritic cells and increases epidermal growth factor expression. Biochim. Biophys. Acta 1813, 1863-1871 (2011).
286. Li, Q. et al. Cholecystokinin octapeptide significantly suppresses collagen-induced arthritis in mice by inhibiting Th17 polarization primed by dendritic cells. Cell Immunol. 272, 53-60 (2011).
287. Dunzendorfer, S., Kaser, A., Meierhofer, C., Tilg, H. and Wiedermann, C.J. Cutting edge: peripheral neuropeptides attract immature and arrest mature blood-derived dendritic cells. J. Immunol. 166, 2167-2172 (2001).
288. Miyamoto, S. et al. Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage: antiinflammatory effect of cholecystokinin. Diabetes 61, 897-907 (2012).
289. Li, S. et al. CCK-8 inhibits LPS-induced IL-1beta production in pulmonary interstitial macrophages by modulating PKA, p38, and NF-kappaB pathway. Shock 27, 678-686 (2007).
290. De la Fuente, M., Campos, M., Del Rio, M. and Hernanz, A. Inhibition of murine peritoneal macrophage functions by sulfated cholecystokinin octapeptide. Regul. Pept. 55, 47-56 (1995).
291. Saia, R.S., Mestriner, F.L., Bertozi, G., Cunha, F.Q. and Carnio, E.C. Cholecystokinin inhibits inducible nitric oxide synthase expression by lipopolysaccharide-stimulated peritoneal macrophages. Mediators Inflamm. 2014, 896029 (2014).
292. Cunningham, M.E. et al. Cholecystokinin-stimulated monocytes produce inflammatory cytokinesandeicosanoids.Am. JGastroenterol.90,621-626(1995).
293. Liang, C.P., Han, S., Li, G., Tabas, I. and Tall, A.R. Impaired MEK signaling and SERCA expression promote ER stress and apoptosis in insulinresistant macrophages and are reversed by exenatide treatment. Diabetes 61, 2609-2620 (2012).
294. Hogan, A.E. et al. Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia 57, 781-784 (2014).
295. Xie, S. et al. GLP-2 suppresses LPS-induced inflammation in macrophages by inhibiting ERK phosphorylation and NF-kappaB activation. Cell Physiol. Biochem. 34, 590-602 (2014).
296. Komorowski, J. and Stepien, H. Somatostatin (SRIF) stimulates the release of interleukin-6 (IL-6) from human peripheral blood monocytes (PBM) in vitro. Neuropeptides 29, 77-81 (1995).
297. Peluso, G., Petillo, O., Melone, M.A.,Mazzarella, G., Ranieri, M. and Tajana, G.F. Modulation of cytokine production in activated human monocytes by somatostatin. Neuropeptides 30, 443-451 (1996).
298. Arakawa, M. et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 59, 1030-1037 (2010).
299. Dixit, V.D. et al. Ghrelin inhibits leptin-and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J. Clin. Invest. 114, 57-66 (2004).
300. Kellokoski, E., Kunnari, A., Jokela, M., Makela, S., Kesaniemi, Y.A. and Horkko, S. Ghrelin and obestatin modulate early atherogenic processes on cells: enhancement of monocyte adhesion and oxidized low-density lipoprotein binding. Metabolism 58, 1572-1580 (2009).
301. Tanaka, M. et al. Differential effects of GLP-1 receptor agonist on foam cell formation in monocytes between non-obese and obese subjects. Metabolism 65, 1-11 (2016).
302. Mitchell, P.D. et al. Glucagon-like peptide-1 receptor expression on human eosinophils and its regulation of eosinophil activation. Clin. Exp. Allergy. 47, 331-338 (2017).
303. De la Fuente, M., Carrasco, M. and Hernanz, A. Modulation of human neutrophil function in vitro by gastrin. J. Endocrinol. 153, 475-483 (1997).
304. Goldman, R., Bar-Shavit, Z. and Romeo, D. Neurotensin modulates human neutrophillocomotionandphagocytic capability.FEBSLett.159,63-67(1983).
305. Carrasco, M., Del Rio, M., Hernanz, A. and De la Fuente, M. Inhibition of human neutrophil functions by sulfated and nonsulfated cholecystokinin octapeptides. Peptides 18, 415-422 (1997).
306. Adeyemi, E.O., Savage, A.P., Bloom, S.R. and Hodgson, H.J. Somatostatin inhibits neutrophil elastase release in vitro. Peptides 11, 869-871 (1990).
307. Robbins, R.A., Nelson, K.J., Gossman, G.L. and Rubinstein, I. Neurotensin stimulates neutrophil adherence to bronchial epithelial cells in vitro. Life Sci. 56, 1353-1359 (1995).
308. Varol, C. et al. Long-acting glucose-dependent insulinotropic polypeptide ameliorates obesity-induced adipose tissue inflammation. J. Immunol. 193, 4002-4009 (2014).
309. Fukamachi, S. et al. Topical cholecystokinin depresses itch-associated scratching behavior in mice. J. Invest. Dermatol. 131, 956-961 (2011).
310. Vergara, P., Saavedra, Y. and Juanola, C. Neuroendocrine control of intestinal mucosal mast cells under physiological conditions. Neurogastroenterol. Motility 14, 35-42 (2002).
311. Saavedra, Y. and Vergara, P. Somatostatin inhibits intestinal mucosal mast cell degranulation in normal conditions and during mast cell hyperplasia. Regul. Pept. 111, 67-75 (2003).
312. Hirayama, T. et al. Ghrelin and obestatin promote the allergic action in rat peritoneal mast cells as basic secretagogues. Peptides 31, 2109-2113 (2010).
313. Grundemar, L. and Hakanson, R. Neuropeptide Y, peptide YY and C-terminal fragments release histamine from rat peritoneal mast cells. Br. J. Pharmacol. 104, 776-778 (1991).
314. Li, E., Zhao, A., Shea-Donohue, T. and Singer, S.M. Mast cell-mediated changes in smooth muscle contractility during mouse giardiasis. Infect. Immun. 75, 4514-4518 (2007).
315. Jenny, M. et al. Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J. 21, 6338-6347 (2002).
316. Li, H.J. et al. Distinct cellular origins for serotonin-expressing and enterochromaffin-like cells in the gastric corpus. Gastroenterology 1463, e753 (2014).
317. Lieb, K., Fiebich, B.L., Busse-Grawitz, M.,Hull, M., Berger,M. and Bauer, J. Effects of substance P and selected other neuropeptides on the synthesis of interleukin-1 beta and interleukin-6 in human monocytes: a re-examination. J. Neuroimmunol. 67, 77-81 (1996).
318. Goverse, G., Stakenborg, M. and Matteoli, G. The intestinal cholinergic anti-inflammatory pathway. J. Physiol. 594, 5771-5780 (2016).
319. Bohorquez, D.V., Samsa, L.A., Roholt, A., Medicetty, S., Chandra, R. and Liddle, R.A. An enteroendocrine cell-enteric glia connection revealed by 3D electron microscopy. PLoS ONE 9, e89881 (2014).
320. Bohorquez, D.V. et al. Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells. J. Clin. Invest. 125, 782-786 (2015).
321. Davies, G.A.,Bryant, A.R.,Reynolds, J.D., Jirik, F.R. & Sharkey,K.A.Prion diseases and the gastrointestinal tract. Canadian J. Gastroenterol. 20, 18-24 (2006).
322. Drummond, C.G., Bolock, A.M., Ma, C., Luke, C.J., Good, M. and Coyne, C.B. Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner. Proc. Natl Acad. Sci. USA 114, 1672-1677 (2017).
323. Luyer, M.D., Greve, J.W.M., Hadfoune, M., Jacobs, J.A., Dejong, C.H. and Buurman,W.A. Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve. J. Exp. Med. 202, 1023-1029 (2005).
324. Glatzle, J. et al. Chylomicron components activate duodenal vagal afferents via a cholecystokinin A receptor-mediated pathway to inhibit gastric motor function in the rat. J. Physiol. 550 (Pt 2), 657-664 (2003).
325. Lubbers, T. et al. Chylomicron formation and glucagon-like peptide 1 receptor are involved in activation of the nutritional anti-inflammatory pathway. J. Nutr. Biochem. 22, 1105-1111 (2011).
326. Wu, R. et al. Orexigenic hormone ghrelin attenuates local and remote organ injury after intestinal ischemia-reperfusion. PLoS ONE 3, e2026 (2008).
327. Sigalet, D.L. et al. Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G211-G221 (2007)
328. Lubbers, T., Luyer, M.D., de Haan, J.J., Hadfoune, M., Buurman, W.A. and Greve, J.W. Lipid-rich enteral nutrition reduces postoperative ileus in rats via activation of cholecystokinin-receptors. Ann. Surg. 249, 481-487 (2009).
329. Eisner, F., Martin, E.M., Kuper, M.A., Raybould, H.E. and Glatzle, J. CCK1-receptor stimulation protects against gut mediator-induced lung damage during endotoxemia. Cell. Phys. Biochem. 32, 1878-1890 (2013).
330. Ghia, J.E., Blennerhassett, P. and Collins, S.M. Vagus nerve integrity and experimental colitis. Am. J. Physiol.-Gastrointest. Liver Physiol. 293, G560-G567 (2007).
331. Matteoli, G. et al. A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut 63, 938-948 (2014).
332. de Haan, J.J. et al. Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G383-G391 (2013).
333. Dalli, J., Colas, R.A., Arnardottir, H. and Serhan, C.N. Vagal regulation of group 3 innate lymphoid cells and the immunoresolvent PCTR1 controls infection resolution. Immunity 46, 92-105 (2017).
334. Matteoli, G. and Boeckxstaens, G.E. The vagal innervation of the gut and immune homeostasis. Gut 62, 1214-1222 (2013).
335. Murray,M.J. & Murray, A.B. Anorexia of infection as a mechanism of host defense. Am. J. Clin. Nutr. 32, 593-596 (1979).
336. Wing, E.J. and Young, J.B. Acute starvation protects mice against Listeria monocytogenes. Infect. Immun. 28, 771-776 (1980).
337. Feingold, K.R. et al. FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob/ob mice from the toxicity of sepsis. Endocrinology 153, 2689-2700 (2012).
338. Ayres, J.S. and Schneider, D.S. The role of anorexia in resistance and tolerance to infections in Drosophila. PLoS Biol. 7, e1000150 (2009).
339. Castex, N., Fioramonti, J., Ducos de Lahitte, J., Luffau, G., More, J. and Bueno, L. Brain Fos expression and intestinal motor alterations during nematode-induced inflammation in the rat. Am. J. Physiol. 274 (1 Pt 1), G210-G216 (1998).
340. Gay, J., More, J., Bueno, L. and Fioramonti, J. CCK-induced Fos expression in brain stem is enhanced after intestinal nematode infection in rats. Brain Res. 942, 124-127 (2002).
341. Procaccini, C., Jirillo, E. and Matarese, G. Leptin as an immunomodulator. Mol. Aspects Med. 33, 35-45 (2012).
342. Lord, G.M., Matarese, G., Howard, L.K., Baker, R.J., Bloom, S.R. and Lechler, R.I. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897-901 (1998).
343. Batra, A. et al. Leptin: a critical regulator of CD4(+) T-cell polarization in vitro and in vivo. Endocrinology 151, 56-62 (2009).
344. Tu, T., Koski, K.G. and Scott, M.E. Mechanisms underlying reduced expulsion of a murine nematode infection during protein deficiency. Parasitology 135, 81-93 (2008).
345. McDermott, J.R., Bartram, R.E., Knight, P.A., Miller, H.R.P., Garrod, D.R. and Grencis, R.K. Mast cells disrupt epithelial barrier function during enteric nematode infection. Proc. Natl Acad. Sci. USA 100, 7761-7766 (2003).