Abstract
The intestinal mucosa is continuously exposed to a large number of commensal or pathogenic microbiota and foreign food antigens. The intestinal epithelium forms a dynamic physicochemical barrier to maintain immune homeostasis. To efficiently absorb nutrients from food, the epithelium in the small intestine has thin, permeable layers spread over a vast surface area. Epithelial cells are renewed from the crypt toward the villi, accompanying epithelial cell death and shedding, to control bacterial colonization. Tight junction and adherens junction proteins provide epithelial cell–cell integrity. Microbial signals are recognized by epithelial cells via toll-like receptors. Environmental signals from short-chain fatty acids derived from commensal microbiota metabolites, aryl hydrocarbon receptors, and hypoxia-induced factors fortify gut barrier function. Here we summarize recent findings regarding various environmental factors for gut barrier function. Further, we discuss the role of gut barriers in the pathogenesis of human intestinal disease and the challenges of therapeutic strategies targeting gut barrier restoration.
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References
Aihara E, Engevik KA, Montrose MH (2017) Trefoil factor peptides and gastrointestinal function. Annu Rev Physiol 79:357–380. https://doi.org/10.1146/annurev-physiol-021115-105447
Allaire JM, Crowley SM, Law HT, Chang SY, Ko HJ, Vallance BA (2019) The intestinal epithelium: central coordinator of mucosal immunity: (Trends in Immunology 39, 677–696, 2018). Trends Immunol 40(2):174. https://doi.org/10.1016/j.it.2018.12.0082018.12.008
Angus HCK, Butt AG, Schultz M, Kemp RA (2019) Intestinal organoids as a tool for inflammatory bowel disease research. Front Med (Lausanne) 6:334. https://doi.org/10.3389/fmed.2019.00334
Artis D, Wang ML, Keilbaugh SA, He W, Brenes M, Swain GP, Knight PA, Donaldson DD, Lazar MA, Miller HR, Schad GA, Scott P, Wu GD (2004) RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci USA 101(37):13596–13600. https://doi.org/10.1073/pnas.0404034101
Atreya R, Bloom S, Scaldaferri F, Gerardi V, Admyre C, Karlsson A, Knittel T, Kowalski J, Lukas M, Lofberg R, Nancey S, Petryka R, Rydzewska G, Schnabel R, Seidler U, Neurath MF, Hawkey C (2016) Clinical effects of a topically applied toll-like receptor 9 agonist in active moderate-to-severe ulcerative colitis. J Crohns Colitis 10(11):1294–1302. https://doi.org/10.1093/ecco-jcc/jjw103
Atuma C, Strugala V, Allen A, Holm L (2001) The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am J Physiol Gastrointest Liver Physiol 280(5):G922–G929. https://doi.org/10.1152/ajpgi.2001.280.5.G922
Barker N, Van Es JH, Kuipers J, Kujala P, Van Den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003–1007. https://doi.org/10.1038/nature06196
Beumer J, Clevers H (2016) Regulation and plasticity of intestinal stem cells during homeostasis and regeneration. Development 143(20):3639–3649. https://doi.org/10.1242/dev.133132
Bevins CL, Salzman NH (2011) Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol 9(5):356–368. https://doi.org/10.1038/nrmicro2546
Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, Tilg H, Watson A, Wells JM (2014) Intestinal permeability–a new target for disease prevention and therapy. BMC Gastroenterol 14:189. https://doi.org/10.1186/s12876-014-0189-7
Bolognini D, Tobin AB, Milligan G, Moss CE (2016) The pharmacology and function of receptors for short-chain fatty acids. Mol Pharmacol 89(3):388–398. https://doi.org/10.1124/mol.115.102301
Bosco MC, Pierobon D, Blengio F, Raggi F, Vanni C, Gattorno M, Eva A, Novelli F, Cappello P, Giovarelli M, Varesio L (2011) Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: identification of TREM-1 as a novel hypoxic marker in vitro and in vivo. Blood 117(9):2625–2639. https://doi.org/10.1182/blood-2010-06-292136
Campbell EL, Bruyninckx WJ, Kelly CJ, Glover LE, Mcnamee EN, Bowers BE, Bayless AJ, Scully M, Saeedi BJ, Golden-Mason L, Ehrentraut SF, Curtis VF, Burgess A, Garvey JF, Sorensen A, Nemenoff R, Jedlicka P, Taylor CT, Kominsky DJ, Colgan SP (2014) Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40(1):66–77. https://doi.org/10.1016/j.immuni.2013.11.020
Capaldo CT, Nusrat A (2015) Claudin switching: physiological plasticity of the Tight Junction. Semin Cell Dev Biol 42:22–29. https://doi.org/10.1016/j.semcdb.2015.04.003
Cario E (2008) Barrier-protective function of intestinal epithelial Toll-like receptor 2. Mucosal Immunol 1(Suppl 1):S62–S66. https://doi.org/10.1038/mi.2008.472008.47
Cash HL, Whitham CV, Behrendt CL, Hooper LV (2006) Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313(5790):1126–1130. https://doi.org/10.1126/science.1127119
Cavadas MA, Nguyen LK, Cheong A (2013) Hypoxia-inducible factor (HIF) network: insights from mathematical models. Cell Commun Signal 11(1):42. https://doi.org/10.1186/1478-811X-11-42
Chan WK, Yao G, Gu YZ, Bradfield CA (1999) Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. Demonstration of competition and compensation. J Biol Chem 274(17):12115–12123. https://doi.org/10.1074/jbc.274.17.12115
Chen J, Vitetta L (2020) The role of butyrate in attenuating pathobiont-induced hyperinflammation. Immune Netw 20(2):e15. https://doi.org/10.4110/in.2020.20.e15
Chen Y, Zhang HS, Fong GH, Xi QL, Wu GH, Bai CG, Ling ZQ, Fan L, Xu YM, Qin YQ, Yuan TL, Sun H, Fang J (2015) PHD3 stabilizes the tight junction protein occludin and protects intestinal epithelial barrier function. J Biol Chem 290(33):20580–20589. https://doi.org/10.1074/jbc.M115.653584
Clayburgh DR, Barrett TA, Tang Y, Meddings JB, Van Eldik LJ, Watterson DM, Clarke LL, Mrsny RJ, Turner JR (2005) Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. J Clin Invest 115(10):2702–2715. https://doi.org/10.1172/JCI24970
Cordero JB, Sansom OJ (2012) Wnt signalling and its role in stem cell-driven intestinal regeneration and hyperplasia. Acta Physiol (Oxf) 204(1):137–143. https://doi.org/10.1111/j.1748-1716.2011.02288.x
Cummins EP, Seeballuck F, Keely SJ, Mangan NE, Callanan JJ, Fallon PG, Taylor CT (2008) The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134(1):156–165. https://doi.org/10.1053/j.gastro.2007.10.012
Cunliffe RN, Mahida YR (2004) Expression and regulation of antimicrobial peptides in the gastrointestinal tract. J Leukoc Biol 75(1):49–58. https://doi.org/10.1189/jlb.0503249
Danese S, Grisham M, Hodge J, Telliez JB (2016) JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines. Am J Physiol Gastrointest Liver Physiol 310(3):G155–G162. https://doi.org/10.1152/ajpgi.00311.2015
Davis MA, Ireton RC, Reynolds AB (2003) A core function for p120-catenin in cadherin turnover. J Cell Biol 163(3):525–534. https://doi.org/10.1083/jcb.200307111
Demitrack ES, Samuelson LC (2016) Notch regulation of gastrointestinal stem cells. J Physiol 594(17):4791–4803. https://doi.org/10.1113/JP271667
Ehrlich AK, Pennington JM, Bisson WH, Kolluri SK, Kerkvliet NI (2018) TCDD, FICZ, and other high affinity AhR ligands dose-dependently determine the fate of CD4 + T cell differentiation. Toxicol Sci 161(2):310–320. https://doi.org/10.1093/toxsci/kfx215
Eisenhoffer GT, Loftus PD, Yoshigi M, Otsuna H, Chien CB, Morcos PA, Rosenblatt J (2012) Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature 484(7395):546–549. https://doi.org/10.1038/nature10999
Esposito G, Capoccia E, Turco F, Palumbo I, Lu J, Steardo A, Cuomo R, Sarnelli G, Steardo L (2014) Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-alpha activation. Gut 63(8):1300–1312. https://doi.org/10.1136/gutjnl-2013-305005
Fallon PG, Jolin HE, Smith P, Emson CL, Townsend MJ, Fallon R, Smith P, Mckenzie AN (2002) IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity 17(1):7–17. https://doi.org/10.1016/s1074-7613(02)00332-1
Fries W, Belvedere A, Vetrano S (2013) Sealing the broken barrier in IBD: intestinal permeability, epithelial cells and junctions. Curr Drug Targets 14(12):1460–1470. https://doi.org/10.2174/1389450111314120011
Fu J, Wei B, Wen T, Johansson ME, Liu X, Bradford E, Thomsson KA, Mcgee S, Mansour L, Tong M, Mcdaniel JM, Sferra TJ, Turner JR, Chen H, Hansson GC, Braun J, Xia L (2011) Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J Clin Invest 121(4):1657–1666. https://doi.org/10.1172/JCI45538
Galvez J, Rodriguez-Cabezas ME, Zarzuelo A (2005) Effects of dietary fiber on inflammatory bowel disease. Mol Nutr Food Res 49(6):601–608. https://doi.org/10.1002/mnfr.200500013
Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V, Cesses P, Garnier L, Pouzolles M, Brulin B, Bruschi M, Harcus Y, Zimmermann VS, Taylor N, Maizels RM, Jay P (2016) Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529(7585):226–230. https://doi.org/10.1038/nature16527
Glover LE, Colgan SP (2011) Hypoxia and metabolic factors that influence inflammatory bowel disease pathogenesis. Gastroenterology 140(6):1748–1755. https://doi.org/10.1053/j.gastro.2011.01.056
Graham WV, He W, Marchiando AM, Zha J, Singh G, Li HS, Biswas A, Ong M, Jiang ZH, Choi W, Zuccola H, Wang Y, Griffith J, Wu J, Rosenberg HJ, Wang Y, Snapper SB, Ostrov D, Meredith SC, Miller LW, Turner JR (2019) Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis. Nat Med 25(4):690–700. https://doi.org/10.1038/s41591-019-0393-7
Gribble FM, Reimann F (2016) Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu Rev Physiol 78:277–299. https://doi.org/10.1146/annurev-physiol-021115-105439
Gu Y, Forostyan T, Sabbadini R, Rosenblatt J (2011) Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway. J Cell Biol 193(4):667–676. https://doi.org/10.1083/jcb.201010075
Gui X, Meng Z, Mcconnell YJ, Liu S, Falck VG, Mack LA, Temple WJ (2017) Differing expression profiles of Notch/enterocyte and Wnt/secretory lineage signallings are associated with morphological diversity of appendiceal tumours. J Clin Pathol 70(1):40–50. https://doi.org/10.1136/jclinpath-2016-203645
Guo H, German P, Bai S, Barnes S, Guo W, Qi X, Lou H, Liang J, Jonasch E, Mills GB, Ding Z (2015) The PI3K/AKT pathway and renal cell carcinoma. J Genet Genom 42(7):343–353. https://doi.org/10.1016/j.jgg.2015.03.003
Guo R, Sakamoto H, Sugiura S, Ogawa M (2007) Endothelial cell motility is compatible with junctional integrity. J Cell Physiol 211(2):327–335. https://doi.org/10.1002/jcp.20937
Gupta R, Chaudhary AR, Shah BN, Jadhav AV, Zambad SP, Gupta RC, Deshpande S, Chauthaiwale V, Dutt C (2014) Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates murine colitis. Clin Exp Gastroenterol 7:13–23. https://doi.org/10.2147/CEG.S51923
Han S, Xu W, Wang Z, Qi X, Wang Y, Ni Y, Shen H, Hu Q, Han W (2016) Crosstalk between the HIF-1 and Toll-like receptor/nuclear factor-kappaB pathways in the oral squamous cell carcinoma microenvironment. Oncotarget 7(25):37773–37789. https://doi.org/10.18632/oncotarget.9329
Hao N, Whitelaw ML (2013) The emerging roles of AhR in physiology and immunity. Biochem Pharmacol 86(5):561–570. https://doi.org/10.1016/j.bcp.2013.07.004
Hase K, Eckmann L, Leopard JD, Varki N, Kagnoff MF (2002) Cell differentiation is a key determinant of cathelicidin LL-37/human cationic antimicrobial protein 18 expression by human colon epithelium. Infect Immun 70(2):953–963. https://doi.org/10.1128/iai.70.2.953-963.2002
Heazlewood CK, Cook MC, Eri R, Price GR, Tauro SB, Taupin D, Thornton DJ, Png CW, Crockford TL, Cornall RJ, Adams R, Kato M, Nelms KA, Hong NA, Florin TH, Goodnow CC, Mcguckin MA (2008) Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med 5(3):e54. https://doi.org/10.1371/journal.pmed.0050054
Helander HF, Fandriks L (2012) The enteroendocrine “letter cells”—time for a new nomenclature? Scand J Gastroenterol 47(1):3–12. https://doi.org/10.3109/00365521.2011.638391
Honda T, Shimizu K, Kawakatsu T, Yasumi M, Shingai T, Fukuhara A, Ozaki-Kuroda K, Irie K, Nakanishi H, Takai Y (2003) Antagonistic and agonistic effects of an extracellular fragment of nectin on formation of E-cadherin-based cell-cell adhesion. Genes Cells 8(1):51–63. https://doi.org/10.1046/j.1365-2443.2003.00616.x
Howitt MR, Lavoie S, Michaud M, Blum AM, Tran SV, Weinstock JV, Gallini CA, Redding K, Margolskee RF, Osborne LC, Artis D, Garrett WS (2016) Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351(6279):1329–1333. https://doi.org/10.1126/science.aaf1648
Hsu SY, Liang SG, Hsueh AJ (1998) Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol Endocrinol 12(12):1830–1845. https://doi.org/10.1210/mend.12.12.0211
Hsu YC, Li L, Fuchs E (2014) Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157(4):935–949. https://doi.org/10.1016/j.cell.2014.02.057
Ikuta T, Eguchi H, Tachibana T, Yoneda Y, Kawajiri K (1998) Nuclear localization and export signals of the human aryl hydrocarbon receptor. J Biol Chem 273(5):2895–2904. https://doi.org/10.1074/jbc.273.5.2895
Iyer SS, Gensollen T, Gandhi A, Oh SF, Neves JF, Collin F, Lavin R, Serra C, Glickman J, De Silva PSA, Sartor RB, Besra G, Hauser R, Maxwell A, Llebaria A, Blumberg RS (2018) Dietary and microbial oxazoles induce intestinal inflammation by modulating aryl hydrocarbon receptor responses. Cell 173(5):1123-1134 e11. https://doi.org/10.1016/j.cell.2018.04.037
Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC (2008) The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci USA 105(39):15064–15069. https://doi.org/10.1073/pnas.0803124105
Kaiko GE, Ryu SH, Koues OI, Collins PL, Solnica-Krezel L, Pearce EJ, Pearce EL, Oltz EM, Stappenbeck TS (2016) The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165(7):1708–1720. https://doi.org/10.1016/j.cell.2016.05.018
Kamdar K, Johnson AMF, Chac D, Myers K, Kulur V, Truevillian K, Depaolo RW (2018) Innate recognition of the microbiota by TLR1 promotes epithelial homeostasis and prevents chronic inflammation. J Immunol 201(1):230–242. https://doi.org/10.4049/jimmunol.1701216
Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH (2004) Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 114(8):1098–1106. https://doi.org/10.1172/JCI21086
Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5:461. https://doi.org/10.3389/fimmu.2014.00461
Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, Wilson KE, Glover LE, Kominsky DJ, Magnuson A, Weir TL, Ehrentraut SF, Pickel C, Kuhn KA, Lanis JM, Nguyen V, Taylor CT, Colgan SP (2015) Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17(5):662–671. https://doi.org/10.1016/j.chom.2015.03.005
Kim S-H, Jang Y-S (2020) Recent insights into cellular crosstalk in respiratory and gastrointestinal mucosal immune systems. Immune Netw 20(6):e44. https://doi.org/10.4110/in.2020.20.e44
Knudsen KA, Soler AP, Johnson KR, Wheelock MJ (1995) Interaction of alpha-actinin with the cadherin/catenin cell-cell adhesion complex via alpha-catenin. J Cell Biol 130(1):67–77. https://doi.org/10.1083/jcb.130.1.67
Kong S, Zhang YH, Zhang W (2018) Regulation of intestinal epithelial cells properties and functions by amino acids. Biomed Res Int 2018:2819154. https://doi.org/10.1155/2018/2819154
Kordjazy N, Haj-Mirzaian A, Haj-Mirzaian A, Rohani MM, Gelfand EW, Rezaei N, Abdolghaffari AH (2018) Role of toll-like receptors in inflammatory bowel disease. Pharmacol Res 129:204–215. https://doi.org/10.1016/j.phrs.2017.11.017
Lai Y, Gallo RL (2009) AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol 30(3):131–141. https://doi.org/10.1016/j.it.2008.12.003
Lanis JM, Alexeev EE, Curtis VF, Kitzenberg DA, Kao DJ, Battista KD, Gerich ME, Glover LE, Kominsky DJ, Colgan SP (2017) Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia. Mucosal Immunol 10(5):1133–1144. https://doi.org/10.1038/mi.2016.133
Laroui H, Ingersoll SA, Liu HC, Baker MT, Ayyadurai S, Charania MA, Laroui F, Yan Y, Sitaraman SV, Merlin D (2012) Dextran sodium sulfate (DSS) induces colitis in mice by forming nano-lipocomplexes with medium-chain-length fatty acids in the colon. PLoS One 7(3):e32084. https://doi.org/10.1371/journal.pone.0032084
Le Duc Q, Shi Q, Blonk I, Sonnenberg A, Wang N, Leckband D, De Rooij J (2010) Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II-dependent manner. J Cell Biol 189(7):1107–1115. https://doi.org/10.1083/jcb.201001149
Lee B, Moon KM, Kim CY (2018) Tight junction in the intestinal epithelium: its association with diseases and regulation by phytochemicals. J Immunol Res 2018:2645465. https://doi.org/10.1155/2018/26454652018/2645465
Lee WJ, Hase K (2014) Gut microbiota-generated metabolites in animal health and disease. Nat Chem Biol 10(6):416–424. https://doi.org/10.1038/nchembio.1535
Lee YS, Kim TY, Kim Y, Lee SH, Kim S, Kang SW, Yang JY, Baek IJ, Sung YH, Park YY, Hwang SW, Kim OE, Liu KS, Kamada S, Gao N, Kweon N (2018) Microbiota-derived lactate accelerates intestinal stem-cell-mediated epithelial development. Cell Host Microbe 24(6):833-846 e6. https://doi.org/10.1016/j.chom.2018.11.002
Linden SK, Sutton P, Karlsson NG, Korolik V, Mcguckin MA (2008) Mucins in the mucosal barrier to infection. Mucosal Immunol 1(3):183–197. https://doi.org/10.1038/mi.2008.5
Lopez J, Grinspan A (2016) Fecal microbiota transplantation for inflammatory bowel disease. Gastroenterol Hepatol (N Y) 12(6):374–379
Lu Z, Ding L, Lu Q, Chen YH (2013) Claudins in intestines: distribution and functional significance in health and diseases. Tissue Barriers 1(3):e24978. https://doi.org/10.4161/tisb.24978
Lueschow SR, Mcelroy SJ (2020) The paneth cell: the curator and defender of the immature small intestine. Front Immunol 11:587. https://doi.org/10.3389/fimmu.2020.00587
Ma J, Rubin BK, Voynow JA (2018) Mucins, mucus, and goblet cells. Chest 154(1):169–176. https://doi.org/10.1016/j.chest.2017.11.008
Mabbott NA, Donaldson DS, Ohno H, Williams IR, Mahajan A (2013) Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol 6(4):666–677. https://doi.org/10.1038/mi.2013.30
Macdonald TT (1992) Epithelial proliferation in response to gastrointestinal inflammation. Ann NY Acad Sci 664:202–209. https://doi.org/10.1111/j.1749-6632.1992.tb39761.x
Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, Ballet V, Claes K, Van Immerseel F, Verbeke K, Ferrante M, Verhaegen J, Rutgeerts P, Vermeire S (2014) A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63(8):1275–1283. https://doi.org/10.1136/gutjnl-2013-304833
Madara JL (1982) Cup cells: structure and distribution of a unique class of epithelial cells in guinea pig, rabbit, and monkey small intestine. Gastroenterology 83(5):981–994. https://doi.org/10.1016/S0016-5085(82)80064-4
Marinelli L, Martin-Gallausiaux C, Bourhis JM, Beguet-Crespel F, Blottiere HM, Lapaque N (2019) Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells. Sci Rep 9(1):643. https://doi.org/10.1038/s41598-018-37019-2
Marks E, Goggins BJ, Cardona J, Cole S, Minahan K, Mateer S, Walker MM, Shalwitz R, Keely S (2015) Oral delivery of prolyl hydroxylase inhibitor: AKB-4924 promotes localized mucosal healing in a mouse model of colitis. Inflamm Bowel Dis 21(2):267–275. https://doi.org/10.1097/MIB.0000000000000277
Martin-Gallausiaux C, Beguet-Crespel F, Marinelli L, Jamet A, Ledue F, Blottiere HM, Lapaque N (2018) Butyrate produced by gut commensal bacteria activates TGF-beta1 expression through the transcription factor SP1 in human intestinal epithelial cells. Sci Rep 8(1):9742. https://doi.org/10.1038/s41598-018-28048-y
Mascanfroni ID, Takenaka MC, Yeste A, Patel B, Wu Y, Kenison JE, Siddiqui S, Basso AS, Otterbein LE, Pardoll DM, Pan F, Priel A, Clish CB, Robson SC, Quintana FJ (2015) Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-alpha. Nat Med 21(6):638–646. https://doi.org/10.1038/nm.3868
Medema JP, Vermeulen L (2011) Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature 474(7351):318–326. https://doi.org/10.1038/nature10212
Metidji A, Omenetti S, Crotta S, Li Y, Nye E, Ross E, Li V, Maradana MR, Schiering C, Stockinger B (2018) The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 49(2):353-362 e5. https://doi.org/10.1016/j.immuni.2018.07.010
Michielan A, D’inca R, (2015) Intestinal permeability in inflammatory bowel disease: pathogenesis, clinical evaluation, and therapy of leaky gut. Mediators Inflamm 2015:628157. https://doi.org/10.1155/2015/6281572015/628157
Middelhoff M, Westphalen CB, Hayakawa Y, Yan KS, Gershon MD, Wang TC, Quante M (2017) Dclk1-expressing tuft cells: critical modulators of the intestinal niche? Am J Physiol Gastrointest Liver Physiol 313(4):G285–G299. https://doi.org/10.1152/ajpgi.00073.2017
Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P, Biancone L, Macdonald TT, Pallone F, Monteleone G (2011) Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141(1):237–248. https://doi.org/10.1053/j.gastro.2011.04.0072011.04.007
Mukherjee S, Karmakar S, Babu SP (2016) TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review. Braz J Infect Dis 20(2):193–204. https://doi.org/10.1016/j.bjid.2015.10.011
Mukherjee S, Zheng H, Derebe MG, Callenberg KM, Partch CL, Rollins D, Propheter DC, Rizo J, Grabe M, Jiang QX, Hooper LV (2014) Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505(7481):103–107. https://doi.org/10.1038/nature12729
Naganuma M, Sugimoto S, Mitsuyama K, Kobayashi T, Yoshimura N, Ohi H, Tanaka S, Andoh A, Ohmiya N, Saigusa K, Yamamoto T, Morohoshi Y, Ichikawa H, Matsuoka K, Hisamatsu T, Watanabe K, Mizuno S, Suda W, Hattori M, Fukuda S, Hirayama A, Abe T, Watanabe M, Hibi T, Suzuki Y, Kanai T, Group IS (2018) Efficacy of Indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis. Gastroenterology 154(4):935–947. https://doi.org/10.1053/j.gastro.2017.11.024
Neurath MF (2017) Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol 14(5):269–278. https://doi.org/10.1038/nrgastro.2016.208
Nighot M, Al-Sadi R, Guo S, Rawat M, Nighot P, Watterson MD, Ma TY (2017) Lipopolysaccharide-induced increase in intestinal epithelial tight permeability is mediated by toll-like receptor 4/myeloid differentiation primary response 88 (MyD88) activation of myosin light chain kinase expression. Am J Pathol 187(12):2698–2710. https://doi.org/10.1016/j.ajpath.2017.08.005
Parada Venegas D, De La Fuente MK, Landskron G, Gonzalez MJ, Quera R, Dijkstra G, Harmsen HJM, Faber KN, Hermoso MA (2019) Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol 10:277. https://doi.org/10.3389/fimmu.2019.00277
Peterson CY, Costantini TW, Loomis WH, Putnam JG, Wolf P, Bansal V, Eliceiri BP, Baird A, Coimbra R (2010) Toll-like receptor-4 mediates intestinal barrier breakdown after thermal injury. Surg Infect (Larchmt) 11(2):137–144. https://doi.org/10.1089/sur.2009.053
Porter EM, Bevins CL, Ghosh D, Ganz T (2002) The multifaceted Paneth cell. Cell Mol Life Sci 59(1):156–170. https://doi.org/10.1007/s00018-002-8412-z
Priyadarshini M, Kotlo KU, Dudeja PK, Layden BT (2018) Role of short chain fatty acid receptors in intestinal physiology and pathophysiology. Compr Physiol 8(3):1091–1115. https://doi.org/10.1002/cphy.c170050
Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118(2):229–241. https://doi.org/10.1016/j.cell.2004.07.002
Ramanan D, Cadwell K (2016) Intrinsic defense mechanisms of the intestinal epithelium. Cell Host Microbe 19(4):434–441. https://doi.org/10.1016/j.chom.2016.03.0032016.03.003
Rankin EB, Giaccia AJ (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 15(4):678–685. https://doi.org/10.1038/cdd.2008.21
Robinson A, Keely S, Karhausen J, Gerich ME, Furuta GT, Colgan SP (2008) Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134(1):145–155. https://doi.org/10.1053/j.gastro.2007.09.033
Rothhammer V, Quintana FJ (2019) The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol 19(3):184–197. https://doi.org/10.1038/s41577-019-0125-8
Santos AJM, Lo YH, Mah AT, Kuo CJ (2018) The intestinal stem cell niche: homeostasis and adaptations. Trends Cell Biol 28(12):1062–1078. https://doi.org/10.1016/j.tcb.2018.08.001
Sasaki N, Sachs N, Wiebrands K, Ellenbroek SI, Fumagalli A, Lyubimova A, Begthel H, Van Den Born M, Van Es JH, Karthaus WR, Li VS, Lopez-Iglesias C, Peters PJ, Van Rheenen J, Van Oudenaarden A, Clevers H (2016) Reg4 + deep crypt secretory cells function as epithelial niche for Lgr5 + stem cells in colon. Proc Natl Acad Sci USA 113(37):E5399–E5407. https://doi.org/10.1073/pnas.1607327113
Sato T, Van Es JH, Snippert HJ, Stange DE, Vries RG, Van Den Born M, Barker N, Shroyer NF, Van De Wetering M, Clevers H (2011) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469(7330):415–418. https://doi.org/10.1038/nature09637
Sato T, Vries RG, Snippert HJ, Van De Wetering M, Barker N, Stange DE, Van Es JH, Abo A, Kujala P, Peters PJ, Clevers H (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459(7244):262–265. https://doi.org/10.1038/nature07935
Schiering C, Wincent E, Metidji A, Iseppon A, Li Y, Potocnik AJ, Omenetti S, Henderson CJ, Wolf CR, Nebert DW, Stockinger B (2017) Feedback control of AHR signalling regulates intestinal immunity. Nature 542(7640):242–245. https://doi.org/10.1038/nature21080
Serra D, Mayr U, Boni A, Lukonin I, Rempfler M, Challet Meylan L, Stadler MB, Strnad P, Papasaikas P, Vischi D, Waldt A, Roma G, Liberali P (2019) Self-organization and symmetry breaking in intestinal organoid development. Nature 569(7754):66–72. https://doi.org/10.1038/s41586-019-1146-y
Shah YM, Ito S, Morimura K, Chen C, Yim SH, Haase VH, Gonzalez FJ (2008) Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology 134(7):2036–2048. https://doi.org/10.1053/j.gastro.2008.03.0092008.03.009
Shan M, Gentile M, Yeiser JR, Walland AC, Bornstein VU, Chen K, He B, Cassis L, Bigas A, Cols M, Comerma L, Huang B, Blander JM, Xiong H, Mayer L, Berin C, Augenlicht LH, Velcich A, Cerutti A (2013) Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342(6157):447–453. https://doi.org/10.1126/science.1237910
Shimotoyodome A, Meguro S, Hase T, Tokimitsu I, Sakata T (2000) Short chain fatty acids but not lactate or succinate stimulate mucus release in the rat colon. Comp Biochem Physiol A Mol Integr Physiol 125(4):525–531. https://doi.org/10.1016/s1095-6433(00)00183-5
Siegert I, Schodel J, Nairz M, Schatz V, Dettmer K, Dick C, Kalucka J, Franke K, Ehrenschwender M, Schley G, Beneke A, Sutter J, Moll M, Hellerbrand C, Wielockx B, Katschinski DM, Lang R, Galy B, Hentze MW, Koivunen P, Oefner PJ, Bogdan C, Weiss G, Willam C, Jantsch J (2015) Ferritin-mediated iron sequestration stabilizes hypoxia-inducible factor-1alpha upon LPS activation in the presence of ample oxygen. Cell Rep 13(10):2048–2055. https://doi.org/10.1016/j.celrep.2015.11.005
Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG, Hiwale AA, Saiyed T, Patel P, Vijay-Kumar M, Langille MGI, Douglas GM, Cheng X, Rouchka EC, Waigel SJ, Dryden GW, Alatassi H, Zhang HG, Haribabu B, Vemula PK, Jala VR (2019) Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun 10(1):89. https://doi.org/10.1038/s41467-018-07859-7
Sivaprakasam S, Bhutia YD, Yang S, Ganapathy V (2017) Short-chain fatty acid transporters: role in colonic homeostasis. Compr Physiol 8(1):299–314. https://doi.org/10.1002/cphy.c170014
Spit M, Koo BK, Maurice MM (2018) Tales from the crypt: intestinal niche signals in tissue renewal, plasticity and cancer. Open Biol. https://doi.org/10.1098/rsob.180120
Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Van Assche G, Geboes K, Ceuppens JL, Rutgeerts P (2002) Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroenterol 97(8):2000–2004. https://doi.org/10.1111/j.1572-0241.2002.05914.x
Tachibana K, Nakanishi H, Mandai K, Ozaki K, Ikeda W, Yamamoto Y, Nagafuchi A, Tsukita S, Takai Y (2000) Two cell adhesion molecules, nectin and cadherin, interact through their cytoplasmic domain-associated proteins. J Cell Biol 150(5):1161–1176. https://doi.org/10.1083/jcb.150.5.1161
Takahashi T, Shiraishi A (2020) Stem cell signaling pathways in the small intestine. Int J Mol Sci. https://doi.org/10.3390/ijms21062032
Takai Y, Nakanishi H (2003) Nectin and afadin: novel organizers of intercellular junctions. J Cell Sci 116(Pt 1):17–27. https://doi.org/10.1242/jcs.00167
Takeichi M (2014) Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat Rev Mol Cell Biol 15(6):397–410. https://doi.org/10.1038/nrm3802
Tambuwala MM, Cummins EP, Lenihan CR, Kiss J, Stauch M, Scholz CC, Fraisl P, Lasitschka F, Mollenhauer M, Saunders SP, Maxwell PH, Carmeliet P, Fallon PG, Schneider M, Taylor CT (2010) Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology 139(6):2093–2101. https://doi.org/10.1053/j.gastro.2010.06.068
Taylor CT, Dzus AL, Colgan SP (1998) Autocrine regulation of epithelial permeability by hypoxia: role for polarized release of tumor necrosis factor alpha. Gastroenterology 114(4):657–668. https://doi.org/10.1016/s0016-5085(98)70579-7
Tomic G, Morrissey E, Kozar S, Ben-Moshe S, Hoyle A, Azzarelli R, Kemp R, Chilamakuri CSR, Itzkovitz S, Philpott A, Winton DJ (2018) Phospho-regulation of ATOH1 is required for plasticity of secretory progenitors and tissue regeneration. Cell Stem Cell 23(3):436-443 e7. https://doi.org/10.1016/j.stem.2018.07.002
Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV (2008) Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA 105(52):20858–20863. https://doi.org/10.1073/pnas.0808723105
Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X, Koren O, Ley R, Wakeland EK, Hooper LV (2011) The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334(6053):255–258. https://doi.org/10.1126/science.1209791
Van Es JH, Sato T, Van De Wetering M, Lyubimova A, Yee Nee AN, Gregorieff A, Sasaki N, Zeinstra L, Van Den Born M, Korving J, Martens ACM, Barker N, Van Oudenaarden A, Clevers H (2012) Dll1 + secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14(10):1099–1104. https://doi.org/10.1038/ncb2581
Van Itallie CM, Anderson JM (2006) Claudins and epithelial paracellular transport. Annu Rev Physiol 68:403–429. https://doi.org/10.1146/annurev.physiol.68.040104.131404
Van Itallie CM, Anderson JM (2014) Architecture of tight junctions and principles of molecular composition. Semin Cell Dev Biol 36:157–165. https://doi.org/10.1016/j.semcdb.2014.08.011
Vancamelbeke M, Vermeire S (2017) The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol 11(9):821–834. https://doi.org/10.1080/17474124.2017.1343143
Vinolo MA, Rodrigues HG, Hatanaka E, Hebeda CB, Farsky SH, Curi R (2009) Short-chain fatty acids stimulate the migration of neutrophils to inflammatory sites. Clin Sci (Lond) 117(9):331–338. https://doi.org/10.1042/CS20080642
Volk N, Lacy B (2017) Anatomy and physiology of the small bowel. Gastrointest Endosc Clin N Am 27(1):1–13. https://doi.org/10.1016/j.giec.2016.08.001
Xiao T, Wu S, Yan C, Zhao C, Jin H, Yan N, Xu J, Wu Y, Li C, Shao Q, Xia S (2018) Butyrate upregulates the TLR4 expression and the phosphorylation of MAPKs and NK-kappaB in colon cancer cell in vitro. Oncol Lett 16(4):4439–4447. https://doi.org/10.3892/ol.2018.9201
Xue X, Ramakrishnan S, Anderson E, Taylor M, Zimmermann EM, Spence JR, Huang S, Greenson JK, Shah YM (2013) Endothelial PAS domain protein 1 activates the inflammatory response in the intestinal epithelium to promote colitis in mice. Gastroenterology 145(4):831–841. https://doi.org/10.1053/j.gastro.2013.07.010
Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY (2001) Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294(5549):2155–2158. https://doi.org/10.1126/science.1065718
Yu M, Wang Q, Ma Y, Li L, Yu K, Zhang Z, Chen G, Li X, Xiao W, Xu P, Yang H (2018) Aryl hydrocarbon receptor activation modulates intestinal epithelial barrier function by maintaining tight junction integrity. Int J Biol Sci 14(1):69–77. https://doi.org/10.7150/ijbs.22259
Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D’angelo C, Massi-Benedetti C, Fallarino F, Carvalho A, Puccetti P, Romani L (2013) Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39(2):372–385. https://doi.org/10.1016/j.immuni.2013.08.003
Zhang YZ, Li YY (2014) Inflammatory bowel disease: pathogenesis. World J Gastroenterol 20(1):91–99. https://doi.org/10.3748/wjg.v20.i1.91
Zhao Y, Chen F, Wu W, Sun M, Bilotta AJ, Yao S, Xiao Y, Huang X, Eaves-Pyles TD, Golovko G, Fofanov Y, D’souza W, Zhao Q, Liu Z, Cong Y (2018) GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal Immunol 11(3):752–762. https://doi.org/10.1038/mi.2017.118
Zhao Y, Ma T, Chen W, Chen Y, Li M, Ren L, Chen J, Cao R, Feng Y, Zhang H, Shi R (2016) MicroRNA-124 promotes intestinal inflammation by targeting aryl hydrocarbon receptor in Crohn’s disease. J Crohns Colitis 10(6):703–712. https://doi.org/10.1093/ecco-jcc/jjw010
Zhu K, Meng Q, Zhang Z, Yi T, He Y, Zheng J, Lei W (2019) Aryl hydrocarbon receptor pathway: role, regulation and intervention in atherosclerosis therapy (Review). Mol Med Rep 20(6):4763–4773. https://doi.org/10.3892/mmr.2019.10748
Zihni C, Mills C, Matter K, Balda MS (2016) Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol 17(9):564–580. https://doi.org/10.1038/nrm.2016.80
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This work was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning (Grant Nos. NRF-2019R1I1A1A01057559, NRF-2020R1A2B5B01001690).
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Seo, K., Seo, J., Yeun, J. et al. The role of mucosal barriers in human gut health. Arch. Pharm. Res. 44, 325–341 (2021). https://doi.org/10.1007/s12272-021-01327-5
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DOI: https://doi.org/10.1007/s12272-021-01327-5