The Pivotal Role of Microbiota in Modulating the Neuronal–Glial–Epithelial Unit

References

• Martini E, Krug SM, Siegmund B, et al. Mend your fences: the epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cell Mol Gastroenterol Hepatol. 2017;4(1):33–46. doi:10.1016/j.jcmgh.2017.03.00728560287
   PubMed Web of Science ®Google Scholar
• Cardoso-Silva D, Deborah D, Itzlinger A, et al. Intestinal barrier function in gluten-related disorders. Nutrients. 2019;11(10):2325. doi:10.3390/nu11102325
   PubMed Web of Science ®Google Scholar
• Heiss CN, Olofsson LE. The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system. J Neuroendocrinol. 2019;31(5):e12684. doi:10.1111/jne.1268430614568
   PubMed Web of Science ®Google Scholar
• Million M, Larauch M. Stress, sex, and the enteric nervous system. Neurogastroenterol Motil. 2016;28(9):1283–1289. doi:10.1111/nmo.1293727561694
   PubMed Web of Science ®Google Scholar
• Ma Q, Xing C, Long W, et al. Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis. J Neuroinflammation. 2019;16(1):53. doi:10.1186/s12974-019-1434-330823925
   PubMed Web of Science ®Google Scholar
• Hollister EB, Riehle K, Luna RA, et al. Structure and function of the healthy pre-adolescent pediatric gut microbiome. Microbiome. 2015;3(1):36. doi:10.1186/s40168-015-0101-x26306392
   PubMed Web of Science ®Google Scholar
• Allen A, Flemström G, Garne A, et al. Gastroduodenal mucosal protection. Physiol Rev. 1993;73(4):823–857. doi:10.1152/physrev.1993.73.4.8238415927
   PubMed Web of Science ®Google Scholar
• Bansil R, Turner BS. The biology of mucus: composition, synthesis and organization. Adv Drug Deliv Rev. 2017;124:S0169409X17302041.
   Web of Science ®Google Scholar
• Johansson MEV, Mia P, Joel P, et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Gut Microbes. 2008;105(39):51–54.
   Google Scholar
• Johansson MEV, Gustafsson JK, Holménlarsson J, et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut. 2014;63(2):281–291. doi:10.1136/gutjnl-2012-30320723426893
   PubMed Web of Science ®Google Scholar
• Ayabe T, Satchell DP, Wilson CL, et al. Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol. 2000;1(2):113–118. doi:10.1038/7778311248802
   PubMed Web of Science ®Google Scholar
• Vaishnava S, Yamamoto M, Severson KM, et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science. 2011;334(6053):255–258. doi:10.1126/science.120979121998396
   PubMed Web of Science ®Google Scholar
• Johansson MEV. Fast renewal of the distal colonic mucus layers by the surface goblet cells as measured by in vivo labeling of mucin glycoproteins. PLoS One. 2012;7(7):e41009. doi:10.1371/journal.pone.004100922815896
   PubMed Web of Science ®Google Scholar
• Specian RD, Neutra MR. Mechanism of rapid mucus secretion in goblet cells stimulated by acetylcholine. J Cell Biol. 1980;85(3):626–640. doi:10.1083/jcb.85.3.6267391135
   PubMed Web of Science ®Google Scholar
• Farquhar MG, Palade GE. Junctional complexes in various epithelia. J Cell Biol. 1963;17(2):375–412. doi:10.1083/jcb.17.2.37513944428
   PubMed Web of Science ®Google Scholar
• Stevenson BR, Siliciano JD, Mooseker MS, et al. Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol. 1986;103(3):755–766. doi:10.1083/jcb.103.3.7553528172
   PubMed Web of Science ®Google Scholar
• Furuse M, Hirase T, Itoh M, et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123(6):1777–1788. doi:10.1083/jcb.123.6.17778276896
   PubMed Web of Science ®Google Scholar
• Mikio F, Kohji F, Takashi H, et al. Claudin-1 and −2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 1998;141(7):1539–1550. doi:10.1083/jcb.141.7.15399647647
   PubMed Web of Science ®Google Scholar
• Furuse M. Knockout animals and natural mutations as experimental and diagnostic tool for studying tight junction functions in vivo. Biochim Biophys Acta. 2009;1788(4):813–819. doi:10.1016/j.bbamem.2008.07.01718706387
   PubMed Web of Science ®Google Scholar
• Pearce SC, Al-Jawadi A, Kishida K, et al. Marked differences in tight junction composition and macromolecular permeability among different intestinal cell types. BMC Biol. 2018;16(1):19. doi:10.1186/s12915-018-0481-z29391007
   PubMed Web of Science ®Google Scholar
• Rosenthal R, Günzel D, Krug SM, et al. Claudin-2-mediated cation and water transport share a common pore. Acta Physiol. 2016;219(2):521–536. doi:10.1111/apha.12742
   Web of Science ®Google Scholar
• Weber CR, Liang GH, Wang Y, et al. Claudin-2-dependent paracellular channels are dynamically gated. Elife. 2015;4:e09906. doi:10.7554/eLife.0990626568313
   PubMed Web of Science ®Google Scholar
• Umeda K, Ikenouchi J, Katahira-Tayama S, et al. ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation. Cell. 2006;126(4):741–754. doi:10.1016/j.cell.2006.06.04316923393
   PubMed Web of Science ®Google Scholar
• Rodgers LS, Tanner Beam M, Anderson JM, et al. Epithelial barrier assembly requires coordinated activity of multiple domains of the tight junction protein ZO-1. J Cell Sci. 2013;126(7):1565–1575. doi:10.1242/jcs.11339923418357
   PubMed Web of Science ®Google Scholar
• Van Itallie CM, Fanning AS, Bridges A, et al. ZO-1 stabilizes the tight junction solute barrier through coupling to the perijunctional cytoskeleton. Mol Biol Cell. 2009;20(17):3930. doi:10.1091/mbc.e09-04-032019605556
   PubMed Web of Science ®Google Scholar
• Antoni L, Nuding S, Weller D, et al. Human colonic mucus is a reservoir for antimicrobial peptides. J Crohn's Colitis. 2013;7(12):e652–e664. doi:10.1016/j.crohns.2013.05.00623787054
   PubMedGoogle Scholar
• Sohini M, Hooper LV. Antimicrobial defense of the intestine. Immunity. 2015;42(1):28–39. doi:10.1016/j.immuni.2014.12.02825607457
   PubMed Web of Science ®Google Scholar
• Nochi T, Denton P, Wahl A, et al. Cryptopatches are essential for the development of human GALT. Cell Rep. 2013;3(6):1874–1884. doi:10.1016/j.celrep.2013.05.03723791525
   PubMed Web of Science ®Google Scholar
• Haber AL, Biton M, Rogel N, et al. A single-cell survey of the small intestinal epithelium. Nature. 2017;551(7680):333–339. doi:10.1038/nature2448929144463
   PubMed Web of Science ®Google Scholar
• Rouch JD, Scott A, Lei NY, et al. Development of functional microfold (M) cells from intestinal stem cells in primary human enteroids. PLoS One. 2016;11(1):e0148216. doi:10.1371/journal.pone.014821626820624
   PubMed Web of Science ®Google Scholar
• Koji H, Kazuya K, Tomonori N, et al. Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature. 2010;462(6):226–230.
   Google Scholar
• Rios D, Wood MB, Li J, et al. Antigen sampling by intestinal M cells is the principal pathway initiating mucosal IgA production to commensal enteric bacteria. Mucosal Immunol. 2016;9(4):907–916. doi:10.1038/mi.2015.12126601902
   PubMed Web of Science ®Google Scholar
• Mabbott NA, Donaldson DS, Ohno H, et al. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 2013;6(4):666–677. doi:10.1038/mi.2013.3023695511
   PubMed Web of Science ®Google Scholar
• Schmidt TH, Oliver B, Gray EE, et al. CXCR4 promotes B cell egress from Peyer’s patches. J Exp Med. 2013;210(6):1099–1107. doi:10.1084/jem.2012257423669394
   PubMed Web of Science ®Google Scholar
• Kim SH, Kim YN, Jang YS. Cutting edge: LL-37-mediated formyl peptide receptor-2 signaling in follicular dendritic cells contributes to B cell activation in Peyer’s patch germinal centers. J Immunol. 2017;198(2):629–633. doi:10.4049/jimmunol.160088627974458
   PubMed Web of Science ®Google Scholar
• Carlsen HS, Baekkevold ES, F-e J, et al. B cell attracting chemokine 1 (CXCL13) and its receptor CXCR5 are expressed in normal and aberrant gut associated lymphoid tissue. Gut. 2002;51(3):364–371. doi:10.1136/gut.51.3.36412171958
   PubMed Web of Science ®Google Scholar
• Wang J, Ford HR, Grishin AV. NF-|[kappa]|B-mediated expression of MAPK phosphatase-1 is an early step in desensitization to TLR ligands in enterocytes. Mucosal Immunol. 2010;3(5):523–534. doi:10.1038/mi.2010.3520555314
   PubMed Web of Science ®Google Scholar
• Lim ES, Rodriguez C, Holtz LR. Amniotic fluid from healthy term pregnancies does not harbor a detectable microbial community. Microbiome. 2018;6(1):87. doi:10.1186/s40168-018-0475-729751830
   PubMed Web of Science ®Google Scholar
• Collado MC, Rautava S, Aakko J, et al. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep. 2016;6(1):23129. doi:10.1038/srep2312927001291
   PubMed Web of Science ®Google Scholar
• Jiménez E, Fernández L, Marín ML, et al. Isolation of commensal bacteria from umbilical cord blood of healthy neonates born by cesarean section. Curr Microbiol. 2005;51(4):270–274. doi:10.1007/s00284-005-0020-316187156
   PubMed Web of Science ®Google Scholar
• Moran Y, Tommi V, Heli S, et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med. 2016;8(343):343ra381.
   Web of Science ®Google Scholar
• Ho TTB, Groer MW, Kane B, et al. Dichotomous development of the gut microbiome in preterm infants. Microbiome. 2018;6(1):157. doi:10.1186/s40168-018-0547-830208950
   PubMed Web of Science ®Google Scholar
• Lundgren SN, Madan JC, Emond JA, et al. Maternal diet during pregnancy is related with the infant stool microbiome in a delivery mode-dependent manner. Microbiome. 2018;6(1):109. doi:10.1186/s40168-018-0490-829973274
   PubMed Web of Science ®Google Scholar
• Grier A, Qiu X, Bandyopadhyay S, et al. Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth. Microbiome. 2017;5(1):158. doi:10.1186/s40168-017-0377-029228972
   PubMed Web of Science ®Google Scholar
• Jha AR, Davenport ER, Gautam Y, et al. Gut microbiome transition across a lifestyle gradient in himalaya. PLoS Biol. 2018;16(11):e2005396. doi:10.1371/journal.pbio.200539630439937
   PubMed Web of Science ®Google Scholar
• Liang Y, Liang S, Zhang Y, et al. Oral administration of compound probiotics ameliorates HFD-induced gut microbe dysbiosis and chronic metabolic inflammation via the G protein-coupled receptor 43 in non-alcoholic fatty liver disease rats. Probiotics Antimicrob Proteins. 2019;11(1):175–185. doi:10.1007/s12602-017-9378-329353414
   PubMed Web of Science ®Google Scholar
• Abildgaard A, Kern T, Pedersen O, et al. The antidepressant-like effect of probiotics and their faecal abundance may be modulated by the cohabiting gut microbiota in rats. Eur Neuropsychopharmacol. 2019;29(1):98–110. doi:10.1016/j.euroneuro.2018.10.01130396698
   PubMed Web of Science ®Google Scholar
• Kim CJ, Walmsley SL, Raboud JM, et al. Can probiotics reduce inflammation and enhance gut immune health in people living with HIV: study Designs for the Probiotic Visbiome for Inflammation and Translocation (PROOV IT) pilot trials. HIV Clin Trials. 2016;17(4):147–157. doi:10.1080/15284336.2016.118482727267710
   PubMed Web of Science ®Google Scholar
• Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017;389(10075):1218. doi:10.1016/S0140-6736(17)30182-428214091
   PubMed Web of Science ®Google Scholar
• Ali K, Green SJ, Engen PA, et al. Colonic bacterial composition in Parkinson’s disease. Mov Disorders. 2015;30(10):1351–1360. doi:10.1002/mds.26307
   Web of Science ®Google Scholar
• Kallol Ray C, Pablo MM, Schapira AHV, et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disorders. 2010;21(7):916–923.
   Google Scholar
• Kelly LP, Carvey PM, Ali K, et al. Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson’s disease. Mov Disord. 2014;29(8):999–1009. doi:10.1002/mds.2573624898698
   PubMed Web of Science ®Google Scholar
• Barichella M, Severgnini M, Cilia R, et al. Unraveling gut microbiota in Parkinson’s disease and atypical parkinsonism. Mov Disorders. 2019;34(3):396–405. doi:10.1002/mds.27581
   PubMed Web of Science ®Google Scholar
• Qian Y, Yang X, Xu S, et al. Alteration of the fecal microbiota in Chinese patients with Parkinson’s disease. Brain Behav Immun. 2018;70:S088915911830028X. doi:10.1016/j.bbi.2018.02.016
   Web of Science ®Google Scholar
• Minato T, Maeda T, Fujisawa Y, et al. Progression of Parkinson’s disease is associated with gut dysbiosis: two-year follow-up study. PLoS One. 2017;12(11):e0187307. doi:10.1371/journal.pone.018730729091972
   PubMed Web of Science ®Google Scholar
• Sampson T, Debelius J, Thron T, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167(6):1469. doi:10.1016/j.cell.2016.11.01827912057
   PubMed Web of Science ®Google Scholar
• Schwiertz A, Spiegel J, Dillmann U, et al. Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson’s disease. Parkinsonism Relat Disord. 2018;50:104–107. doi:10.1016/j.parkreldis.2018.02.02229454662
   PubMed Web of Science ®Google Scholar
• Perez-Pardo P, Dodiya HB, Engen PA, et al. Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice. Gut. 2019;68(5):829–843. doi:10.1136/gutjnl-2018-31684430554160
   PubMed Web of Science ®Google Scholar
• Clairembault T, Leclair-Visonneau L, Coron E, et al. Structural alterations of the intestinal epithelial barrier in Parkinson’s disease. Acta Neuropathol Commun. 2015;3(1):12. doi:10.1186/s40478-015-0196-025775153
   PubMed Web of Science ®Google Scholar
• Unger MM, Spiegel J, Dillmann KU, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord. 2016;32:66–72. doi:10.1016/j.parkreldis.2016.08.01927591074
   PubMed Web of Science ®Google Scholar
• Thomas C, Willem K, Laurène LV, et al. Enteric GFAP expression and phosphorylation in Parkinson’s disease. J Neurochem. 2014;130(6):805–815. doi:10.1111/jnc.1274224749759
   PubMed Web of Science ®Google Scholar
• Sangjune K, Seung-Hwan K, Tae-In K, et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron. 2019;103(4):627–641.e7. doi:10.1016/j.neuron.2019.05.03531255487
   PubMed Web of Science ®Google Scholar
• Souza HSP, De Claudio F. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol. 2016;13(1):13–27.26627550
   PubMed Web of Science ®Google Scholar
• Crigottier-Gois M. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Digest World Core Med J. 2006;55(2):205–211.
   Google Scholar
• Hai-Qin M, Ting-Ting Y, Xiao-Jing Z, et al. Fecal microbial dysbiosis in Chinese patients with inflammatory bowel disease. World J Gastroenterol. 2018;24(13):1464–1477. doi:10.3748/wjg.v24.i13.146429632427
   PubMed Web of Science ®Google Scholar
• Maukonen J, Kolho KL, Paasela M, et al. Altered fecal microbiota in paediatric inflammatory bowel disease. J Crohn's Colitis. 2015;9(12):1088. doi:10.1093/ecco-jcc/jjv14726351391
   PubMedGoogle Scholar
• Harry S, Bénédicte P, Laurie W, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA. 2008;105(43):16731–16736. doi:10.1073/pnas.080481210518936492
   PubMed Web of Science ®Google Scholar
• Seksik P, Rigottier-Gois L, Gramet G, et al. Alterations of the dominant faecal bacterial groups in patients with Crohn’s disease of the colon. Gut. 2003;52(2):237. doi:10.1136/gut.52.2.23712524406
   PubMed Web of Science ®Google Scholar
• Darfeuille-Michaud A, Neut C, Barnich N, et al. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease. Gastroenterology. 1998;115(6):1405–1413. doi:10.1016/S0016-5085(98)70019-89834268
   PubMed Web of Science ®Google Scholar
• Ridler C. IBD: dysbiosis underlies CARD9 risk alleles in colitis. Nat Rev Gastroenterol Hepatol. 2016;13(6):316. doi:10.1038/nrgastro.2016.82
   Google Scholar
• Margarita MM, Jérémy D, Nicolas D, et al. Western diet induces dysbiosis with increased E coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation. Gut. 2014;63(1):116. doi:10.1136/gutjnl-2012-30411923598352
   PubMed Web of Science ®Google Scholar
• Miyoshi J, Bobe AM, Miyoshi S, et al. Peripartum antibiotics promote gut dysbiosis, loss of immune tolerance, and inflammatory bowel disease in genetically prone offspring. Cell Rep. 2017;20(2):491. doi:10.1016/j.celrep.2017.06.06028700948
   PubMed Web of Science ®Google Scholar
• Örtqvist AK, Lundholm C, Halfvarson J. Fetal and early life antibiotics exposure and very early onset inflammatory bowel disease: a population-based study. Gut. 2019;68(2):218–225. doi:10.1136/gutjnl-2017-31435229321166
   PubMed Web of Science ®Google Scholar
• Tytgat KM, Vand der Wal JW, Einerhand AW, et al. Quantitative analysis of MUC2 synthesis in ulcerative colitis. Biochem Biophys Res Commun. 1996;224(2):397. doi:10.1006/bbrc.1996.10398702401
   PubMed Web of Science ®Google Scholar
• Sluis MVD, Koning BAED, Bruijn ACJMD, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 2006;131(1):117–129. doi:10.1053/j.gastro.2006.04.02016831596
   PubMed Web of Science ®Google Scholar
• Pullan RD, Thomas GA, Rhodes M, et al. Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut. 1994;35(3):353–359. doi:10.1136/gut.35.3.3538150346
   PubMed Web of Science ®Google Scholar
• Raouf AH, Tsai HH, Parker N, et al. Sulphation of colonic and rectal mucin in inflammatory bowel disease: reduced sulphation of rectal mucus in ulcerative colitis. Clin Sci. 1992;83(5):623. doi:10.1042/cs0830623
   PubMed Web of Science ®Google Scholar
• Lennon G, Balfe Á, Bambury N, et al. Correlations between colonic crypt mucin chemotype, inflammatory grade and Desulfovibrio species in ulcerative colitis. Colorectal Dis. 2014;16(5):O161–O169. doi:10.1111/codi.1250324345279
   PubMed Web of Science ®Google Scholar
• Shaw KA, Bertha M, Hofmekler T, et al. Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease. Genome Med. 2016;8(1):1–13. doi:10.1186/s13073-016-0331-y26750923
   PubMed Web of Science ®Google Scholar
• Forbes JD, Van DG, Bernstein CN. Microbiome survey of the inflamed and noninflamed gut at different compartments within the gastrointestinal tract of inflammatory bowel disease patients. Inflamm Bowel Dis. 2016;22(4):817.26937623
   PubMed Web of Science ®Google Scholar
• Furness JB, Jones C, Nurgali K, et al. Intrinsic primary afferent neurons and nerve circuits within the intestine. Prog Neurobiol. 2004;72(2):143–164. doi:10.1016/j.pneurobio.2003.12.00415063530
   PubMed Web of Science ®Google Scholar
• Kapur RP, Yost C, Palmiter RD. A transgenic model for studying development of the enteric nervous system in normal and aganglionic mice. Development. 1992;116(1):167–175. doi:10.1242/dev.116.1.1671483385
   PubMed Web of Science ®Google Scholar
• Young HM, Hearn CJ, Ciampoli D, et al. A single rostrocaudal colonization of the rodent intestine by enteric neuron precursors is revealed by the expression of Phox2b, Ret, and p75 and by explants grown under the kidney capsule or in organ culture. Dev Biol. 1998;202(1):67–84. doi:10.1006/dbio.1998.89879758704
   PubMed Web of Science ®Google Scholar
• Chihiro N, Toshihiro U, Takayuki M, et al. Trans-mesenteric neural crest cells are the principal source of the colonic enteric nervous system. Nat Neurosci. 2012;15(9):1211–1218. doi:10.1038/nn.318422902718
   PubMed Web of Science ®Google Scholar
• Rodrigues DM, Li AY, Nair DG, et al. Glial cell line-derived neurotrophic factor is a key neurotrophin in the postnatal enteric nervous system. Neurogastroenterol Motil. 2011;23(2):e44–e56. doi:10.1111/j.1365-2982.2010.01626.x21087354
   PubMed Web of Science ®Google Scholar
• Toshihiro U, Sanjay J, Shigenobu Y, et al. Conditional ablation of GFRalpha1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung’s disease phenotype. Development. 2007;134(11):2171–2181. doi:10.1242/dev.00138817507417
   PubMed Web of Science ®Google Scholar
• Hongtao W, Inna H, William P, et al. The timing and location of glial cell line-derived neurotrophic factor expression determine enteric nervous system structure and function. J Neurosci. 2010;30(4):1523–1538. doi:10.1523/JNEUROSCI.3861-09.201020107080
   PubMed Web of Science ®Google Scholar
• Joseph NM, Shenghui H, Elsa Q, et al. Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J Clin Invest. 2011;121(9):3398. doi:10.1172/JCI5818621865643
   PubMed Web of Science ®Google Scholar
• Kulkarni S, Micci MA, Leser J, et al. Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis. Proc Natl Acad Sci USA. 2017;114(18):E3709. doi:10.1073/pnas.161940611428420791
   PubMed Web of Science ®Google Scholar
• Collins J, Borojevic R, Verdu EF, et al. Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterol Motil. 2013;26(1):98–107. doi:10.1111/nmo.1223624329946
   PubMed Web of Science ®Google Scholar
• Kabouridis P, Lasrado R, Mccallum S, et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron. 2015;85(2):289–295. doi:10.1016/j.neuron.2014.12.03725578362
   PubMed Web of Science ®Google Scholar
• Angrist M, Bolk S, Halushka M, et al. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet. 1996;14(3):341–344. doi:10.1038/ng1196-3418896568
   PubMed Web of Science ®Google Scholar
• Brun P, Giron MC, Qesari M, et al. Toll-like receptor 2 regulates intestinal inflammation by controlling integrity of the enteric nervous system. Gastroenterology. 2013;145(6):1323–1333. doi:10.1053/j.gastro.2013.08.04723994200
   PubMed Web of Science ®Google Scholar
• Bruna P, Gobbo S, Caputi V, et al. Toll like receptor-2 regulates production of glial-derived neurotrophic factors in murine intestinal smooth muscle cells. Mol Cell Neurosci. 2015;68:24–35. doi:10.1016/j.mcn.2015.03.01825823690
   PubMed Web of Science ®Google Scholar
• Valentina C, Ilaria M, Viviana F, et al. Antibiotic-induced dysbiosis of the microbiota impairs gut neuromuscular function in juvenile mice. Br J Pharmacol. 2017;174(20):3623–3639. doi:10.1111/bph.1396528755521
   PubMed Web of Science ®Google Scholar
• Rao M, Gershon MD. Neurogastroenterology: the dynamic cycle of life in the enteric nervous system. Nat Rev Gastroenterol Hepatol. 2017;14(8):453–454. doi:10.1038/nrgastro.2017.8528655880
   PubMed Web of Science ®Google Scholar
• Mcvey Neufeld KA, Perez-Burgos A, Mao YK, et al. The gut microbiome restores intrinsic and extrinsic nerve function in germ-free mice accompanied by changes in calbindin. Neurogastroenterol Motil. 2015;27(5):627–636. doi:10.1111/nmo.1253425727007
   PubMed Web of Science ®Google Scholar
• Filipe DV, Estelle G, Louise MSH, et al. Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc Nat Acad Sci. 2018;115(25):6458–6463. doi:10.1073/pnas.172001711529866843
   PubMed Web of Science ®Google Scholar
• Liu MT, Kuan Y-H, Wang J, et al. 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J Neurosci. 2009;29(31):9683–9699. doi:10.1523/JNEUROSCI.1145-09.200919657021
   PubMed Web of Science ®Google Scholar
• Yano J, Yu K, Donaldson G, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2):264–276. doi:10.1016/j.cell.2015.02.04725860609
   PubMed Web of Science ®Google Scholar
• Neunlist M, Landeghem LV, Mahé MM, et al. The digestive neuronal-glial-epithelial unit: a new actor in gut health and disease. Nat Rev Gastroenterol Hepatol. 2013;10(2):90–100. doi:10.1038/nrgastro.2012.22123165236
   PubMed Web of Science ®Google Scholar
• Pellegrini C, Antonioli L, Colucci R, et al. Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases? Acta Neuropathol. 2018;136(3):345–361. doi:10.1007/s00401-018-1856-529797112
   PubMed Web of Science ®Google Scholar
• Savage DC, Siegel JE, Snellen JE, et al. Transit time of epithelial cells in the small intestines of germfree mice and ex-germfree mice associated with indigenous microorganisms. Appl Environ Microbiol. 1981;42(6):996–1001. doi:10.1128/aem.42.6.996-1001.19817198427
   PubMed Web of Science ®Google Scholar
• Banasaz M, Norin E, Midtvedt T. The role of gender, age and microbial status on cell kinetics in the gastrointestinal tract of mice. Microb Ecol Health Dis. 2001;13(3):135–142. doi:10.3402/mehd.v13i3.8015
   Google Scholar
• Banasaz M, Norin E, Holma R, et al. Increased enterocyte production in gnotobiotic rats mono-associated with Lactobacillus rhamnosus GG. Appl Environ Microbiol. 2002;68(6):3031–3034. doi:10.1128/AEM.68.6.3031-3034.200212039764
   PubMed Web of Science ®Google Scholar
• Yu Y, Lu L, Sun J, et al. Preterm infant gut microbiota affects intestinal epithelial development in a humanized microbiome gnotobiotic mouse model. AJP Gastrointest Liver Physiol. 2016;311(3):G521–G532. doi:10.1152/ajpgi.00022.2016
   Web of Science ®Google Scholar
• Barker N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol. 2014;15(1):19. doi:10.1038/nrm372124326621
   PubMed Web of Science ®Google Scholar
• Duman-Scheel M, Weng L, Xin S, et al. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature. 2002;417(6886):299–304. doi:10.1038/417299a12015606
   PubMed Web of Science ®Google Scholar
• Gladden AB, Diehl JA. Cell cycle progression without cyclin E/CDK2: breaking down the walls of dogma. Cancer Cell. 2003;4(3):160–162. doi:10.1016/S1535-6108(03)00217-414522248
   PubMed Web of Science ®Google Scholar
• Takahiro M, Thierry P, Béatrice R, et al. Epithelial cell proliferation arrest induced by Lactate and Acetate from Lactobacillus casei and Bifidobacterium breve. PLoS One. 2013;8(4):e63053. doi:10.1371/journal.pone.006305323646174
   PubMed Web of Science ®Google Scholar
• Lee Y-S, Kim T-Y, Kim Y, et al. Microbiota-derived lactate accelerates intestinal stem-cell-mediated epithelial development. Cell Host Microbe. 2018;24(6):833–846.e6. doi:10.1016/j.chom.2018.11.00230543778
   PubMed Web of Science ®Google Scholar
• Song X, Dai D, He X, et al. Growth factor FGF2 cooperates with interleukin-17 to repair intestinal epithelial damage. Immunity. 2015;43(3):488–501. doi:10.1016/j.immuni.2015.06.02426320657
   PubMed Web of Science ®Google Scholar
• Naito T, Mulet C, De Castro C, et al. Lipopolysaccharide from crypt-specific core microbiota modulates the colonic epithelial proliferation-to-differentiation balance. Mbio. 2017;8(5):e01680–01617. doi:10.1128/mBio.01680-1729042502
   PubMed Web of Science ®Google Scholar
• Ren X, Zhu Y, Gamallat Y, et al. E. coli O124 K72 alters the intestinal barrier and the tight junctions proteins of Guinea pig intestine. Biomed Pharmacother. 2017;94:468–473. doi:10.1016/j.biopha.2017.07.12328779708
   PubMed Web of Science ®Google Scholar
• Moyano-Porcile V, Olavarría-Ramírez L, González-Arancibia C, et al. Short-term effects of Poly(I:C) on gut permeability. Pharmacol Res. 2015;101:130–136. doi:10.1016/j.phrs.2015.06.01626145280
   PubMed Web of Science ®Google Scholar
• Ewaschuk JB, Diaz H, Meddings L, et al. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):G1025–1034. doi:10.1152/ajpgi.90227.200818787064
   PubMed Web of Science ®Google Scholar
• Lindemans CA, Calafiore M, Mertelsmann AM, et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature. 2015;528(7583):560–564. doi:10.1038/nature1646026649819
   PubMed Web of Science ®Google Scholar
• Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol. 2011;12(5):383–390. doi:10.1038/ni.202521502992
   PubMed Web of Science ®Google Scholar
• Burgueño JF, Barba A, Eyre E, et al. TLR2 and TLR9 modulate enteric nervous system inflammatory responses to lipopolysaccharide. J Neuroinflammation. 2016;13(1):187. doi:10.1186/s12974-016-0653-027538577
   PubMed Web of Science ®Google Scholar
• Prigent A, Gonzales J, Durand T, et al. Acute inflammation down-regulates alpha-synuclein expression in enteric neurons. Journal of Neurochemistry. 2019;148(6):746–760. doi:10.1111/jnc.1465630589944
   PubMed Web of Science ®Google Scholar
• Murakami M, Ohta T, Ito S. Lipopolysaccharides enhance the action of bradykinin in enteric neurons via secretion of interleukin-1beta from enteric glial cells. J Neurosci Res. 2009;87(9):2095–2104. doi:10.1002/jnr.2203619235895
   PubMed Web of Science ®Google Scholar
• Soret R, Chevalier J, Coppet PD, et al. Short-chain fatty acids regulate the enteric neurons and control gastrointestinal motility in rats. Gastroenterology. 2010;138(5):1772–1782. doi:10.1053/j.gastro.2010.01.05320152836
   PubMed Web of Science ®Google Scholar
• Nøhr MK, Pedersen MH, Gille A, 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. 2013;154(10):3552–3564. doi:10.1210/en.2013-114223885020
   PubMed Web of Science ®Google Scholar
• Shands JW. Evidence for a bilayer structure in gram-negative Lipopolysaccharide: relationship to toxicity. Infect Immun. 1971;4(2):167–172. doi:10.1128/iai.4.2.167-172.19714949485
   PubMed Web of Science ®Google Scholar
• Harlan JM, Harker LA, Reidy MA, et al. Lipopolysaccharide-mediated bovine endothelial cell injury in vitro. Lab Investig. 1983;48(3):269–274.6827807
   PubMed Web of Science ®Google Scholar
• Ge Y, Ezzell RM, Warren HS. Localization of endotoxin in the rat intestinal epithelium. J Infect Dis. 2000;182(3):873–881. doi:10.1086/31578410950783
   PubMed Web of Science ®Google Scholar
• Hagar JA, Powell DA, Aachoui Y, et al. Cytoplasmic LPS activates Caspase-11: implications in TLR4-independent endotoxic shock. Science. 2013;341(6151):1250–1253. doi:10.1126/science.124098824031018
   PubMed Web of Science ®Google Scholar
• Sumbria RK, Grigoryan MM, Vasilevko V, et al. A murine model of inflammation-induced cerebral microbleeds. J Neuroinflammation. 2016;13(1):218. doi:10.1186/s12974-016-0693-527577728
   PubMed Web of Science ®Google Scholar
• de Souza Xavier Costa N, Ribeiro Júnior G, Dos Santos Alemany AA, et al. Early and late pulmonary effects of nebulized LPS in mice: an acute lung injury model. PLoS One. 2017;12(9):e0185474. doi:10.1371/journal.pone.018547428953963
   PubMed Web of Science ®Google Scholar
• Tulkens J, Vergauwen G, Van Deun J, et al. Increased levels of systemic LPS-positive bacterial extracellular vesicles in patients with intestinal barrier dysfunction. Gut. 2020;69(1):191–193. doi:10.1136/gutjnl-2018-31772630518529
   PubMed Web of Science ®Google Scholar
• Plaen IGD, Tan X-D, Chang H, et al. Lipopolysaccharide activates nuclear factor kappaB in rat intestine: role of endogenous platelet-activating factor and tumour necrosis factor. Br J Pharmacol. 2000;129(2):307–314. doi:10.1038/sj.bjp.070305510694237
   PubMed Web of Science ®Google Scholar
• Guo S, Al-Sadi R, Said HM, et al. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am J Pathol. 2013;182(2):375–387. doi:10.1016/j.ajpath.2012.10.01423201091
   PubMed Web of Science ®Google Scholar
• Nighot M, Al-Sadi R, Guo S, et al. 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. 2017;187(12):2698–2710. doi:10.1016/j.ajpath.2017.08.00529157665
   PubMed Web of Science ®Google Scholar
• Yanhai F, Yu W, Pei W, et al. Short-chain fatty acids manifest stimulative and protective effects on intestinal barrier function through the inhibition of NLRP3 inflammasome and autophagy. Cell Physiol Biochem. 2018;49(1):190–205. doi:10.1159/00049285330138914
   PubMedGoogle Scholar
• Priyadarshini M, Kotlo KU, Dudeja PK, et al. Role of short chain fatty acid receptors in intestinal physiology and pathophysiology. Compr Physiol. 2018;8(3):1091–1115.29978895
   PubMed Web of Science ®Google Scholar
• Wu W, Sun M, Chen F, et al. Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal Immunol. 2016;10(4):946–956. doi:10.1038/mi.2016.11427966553
   PubMed Web of Science ®Google Scholar
• Kim MH, Kang SG, Park JH, et al. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. 2013;145(2):396–406.e1–10. doi:10.1053/j.gastro.2013.04.056
   Web of Science ®Google Scholar
• Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132(1):397–414. doi:10.1053/j.gastro.2006.11.00217241888
   PubMed Web of Science ®Google Scholar
• Ghia JE, Li N, Wang H, et al. Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology. 2009;137(5):1649–1660. doi:10.1053/j.gastro.2009.08.04119706294
   PubMed Web of Science ®Google Scholar
• Stavely R, Fraser S, Sharma S, et al. The onset and progression of chronic colitis parallels increased mucosal serotonin release via enterochromaffin cell hyperplasia and downregulation of the serotonin reuptake transporter. Inflamm Bowel Dis. 2018;24(5):1021–1034. doi:10.1093/ibd/izy01629668991
   PubMed Web of Science ®Google Scholar
• Li N, Ghia J-E, Wang H, et al. Serotonin activates dendritic cell function in the context of gut inflammation. Am J Clin Pathol. 2011;178(2):662–671. doi:10.1016/j.ajpath.2010.10.028
   Web of Science ®Google Scholar
• Guseva D, Holst K, Kaune B, et al. Serotonin 5-HT7 receptor is critically involved in acute and chronic inflammation of the gastrointestinal tract. Inflamm Bowel Dis. 2014;20(9):1516–1529. doi:10.1097/MIB.000000000000015025072499
   PubMed Web of Science ®Google Scholar
• Kim JJ, Bridle BW, Ghia J-E, et al. Targeted inhibition of serotonin type 7 (5-HT7) receptor function modulates immune responses and reduces the severity of intestinal inflammation. J Immunol. 2013;190(9):4795–4804. doi:10.4049/jimmunol.120188723554310
   PubMed Web of Science ®Google Scholar
• Grishin A, Bowling J, Bell B, et al. Roles of nitric oxide and intestinal microbiota in the pathogenesis of necrotizing enterocolitis. J Pediatr Surg. 2015;51(1):13–17. doi:10.1016/j.jpedsurg.2015.10.00626577908
   PubMed Web of Science ®Google Scholar
• Hyde ER, Andrade F, Vaksman Z, et al. Metagenomic analysis of nitrate-reducing bacteria in the oral cavity: implications for nitric oxide homeostasis. PLoS One. 2014;9(3):e88645. doi:10.1371/journal.pone.008864524670812
   PubMed Web of Science ®Google Scholar
• Farlik M, Reutterer B, Schindler C, et al. Nonconventional initiation complex assembly by STAT and NF-κB transcription factors regulates nitric oxide synthase expression. Immunity. 2010;33(1):25–34. doi:10.1016/j.immuni.2010.07.00120637660
   PubMed Web of Science ®Google Scholar
• Venkataramana S, Lourenssen S, Miller KG, et al. Early inflammatory damage to intestinal neurons occurs via inducible nitric oxide synthase. Neurobiol Dis. 2015;75:40–52. doi:10.1016/j.nbd.2014.12.01425562655
   PubMed Web of Science ®Google Scholar
• Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–1439. doi:10.1152/physrev.00034.200617928588
   PubMed Web of Science ®Google Scholar
• Cho YM, Fujita Y, Kieffer TJ. Glucagon-like peptide-1: glucose homeostasis and beyond. Annu Rev Physiol. 2014;76(1):535–559. doi:10.1146/annurev-physiol-021113-17031524245943
   PubMed Web of Science ®Google Scholar
• Backhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Nat Acad Sci. 2004;101(44):15718–15723. doi:10.1073/pnas.040707610115505215
   PubMed Web of Science ®Google Scholar
• Grasset E, Puel A, Charpentier J, et al. A specific gut microbiota dysbiosis of Type 2 diabetic mice induces GLP-1 resistance through an enteric NO-dependent and gut-brain axis mechanism. Cell Metab. 2017;25(5):1075–1090.e5. doi:10.1016/j.cmet.2017.04.01328467926
   PubMed Web of Science ®Google Scholar
• Lebrun LJ, Lenaerts K, Kiers D, et al. Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion. Cell Rep. 2017;21(5):1160–1168. doi:10.1016/j.celrep.2017.10.00829091756
   PubMed Web of Science ®Google Scholar
• Yang M, Fukui H, Eda H, et al. Involvement of gut microbiota in the association between GLP-1/GLP-1 receptor expression and gastrointestinal motility. Am J Physiol Gastrointest Liver Physiol. 2017;312(4):G367–G373. doi:10.1152/ajpgi.00232.201628154011
   PubMed Web of Science ®Google Scholar
• Song X, Gao H, Lin Y, et al. Alterations in the microbiota drive interleukin-17C production from intestinal epithelial cells to promote tumorigenesis. Immunity. 2014;40(1):140–152. doi:10.1016/j.immuni.2013.11.01824412611
   PubMed Web of Science ®Google Scholar
• Lee JS, Tato CM, Joyce-Shaikh B, et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity. 2015;43(4):727–738. doi:10.1016/j.immuni.2015.09.00326431948
   PubMed Web of Science ®Google Scholar
• Ogawa A, Andoh A, Araki Y, et al. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol. 2004;110(1):55–62. doi:10.1016/j.clim.2003.09.01314962796
   PubMed Web of Science ®Google Scholar
• Gaffen SL, Jain R, Garg AV, et al. The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. 2014;14(9):585–600. doi:10.1038/nri370725145755
   PubMed Web of Science ®Google Scholar
• Zheng Y, Valdez PA, Danilenko DM, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008;14(3):282–289. doi:10.1038/nm172018264109
   PubMed Web of Science ®Google Scholar