The intestinal barrier in multiple sclerosis: Implications for pathophysiology and therapeutics

Brain

Volumn 141, Issue 7, 2018, Pages 1900-1916

  Camara Lemarroy, Carlos R ^a,b   Metz, Luanne ^a,b   Meddings, Jonathan B ^a   Sharkey, Keith A ^a,b   Wee Yong, V ^a,b  

^a UNIVERSITY OF CALGARY   (Canada)

^b UNIVERSITY OF CALGARY   (Canada)

Author keywords

disease modifying therapies; inflammatory bowel disease; intestinal barrier; microbiota; multiple sclerosis

Indexed keywords

ALEMTUZUMAB; ALPHA INTERFERON; BETA INTERFERON; FINGOLIMOD; FUMARIC ACID DIMETHYL ESTER; GLATIRAMER; LARAZOTIDE; MINOCYCLINE; NATALIZUMAB; PHOSPHATIDYLCHOLINE; PROBIOTIC AGENT; TERIFLUNOMIDE; VITAMIN D;

DEMYELINATION; DIET THERAPY; DIGESTIVE SYSTEM INFLAMMATION; DRUG TARGETING; FECAL MICROBIOTA TRANSPLANTATION; GASTROINTESTINAL DISEASE; HOMEOSTASIS; HUMAN; INFLAMMATORY BOWEL DISEASE; INTESTINE FLORA; MICROGLIA; MUCOSAL IMMUNITY; MULTIPLE SCLEROSIS; NONHUMAN; PATHOPHYSIOLOGY; PERMEABILITY BARRIER; PRIORITY JOURNAL; REVIEW; TIGHT JUNCTION; TREATMENT OUTCOME; BRAIN; INTESTINE; INTESTINE MUCOSA; METABOLISM; PATHOLOGY; PHYSIOLOGY;

BRAIN; GASTROINTESTINAL MICROBIOME; HOMEOSTASIS; HUMANS; INTESTINAL MUCOSA; INTESTINES; MULTIPLE SCLEROSIS; PROBIOTICS; TIGHT JUNCTIONS;

EID: 85049632164     PISSN: 00068950     EISSN: 14602156     Source Type: Journal    
DOI: 10.1093/brain/awy131     Document Type: Review

References (205)

1. Abreu MT. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 2010; 10: 131-44.
2. Acharya M, Mukhopadhyay S, Païdassi H, Jamil T, Chow C, Kissler S, et al. v Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice. J Clin Invest 2010; 120: 4445-52.
3. Aharoni R, Kayhan B, Arnon R. Therapeutic effect of the immunomodulator glatiramer acetate on trinitrobenzene sulfonic acidinduced experimental colitis. Inflamm Bowel Dis 2005; 11: 106-15.
4. Aharoni R, Sonego H, Brenner O, Eilam R, Arnon R. Therapeutic effect of glatiramer acetate in a murine model of inflammatory bowel disease is mediated by anti-inflammatory T-cells. Immunol Lett 2007; 112: 110-19.
5. Al-Sadi R, Guo S, Ye D, Rawat M, Ma TY. TNF-α modulation of intestinal tight junction permeability is mediated by NIK/IKK-axis activation of the canonical NF-κB pathway. Am J Pathol 2016; 186: 1151-65.
6. Altowaijri G, Fryman A, Yadav V. Dietary interventions and multiple sclerosis. Curr Neurol Neurosci Rep 2017; 17: 28.
7. Antoni L, Nuding S, Wehkamp J, Stange EF. Intestinal barrier in inflammatory bowel disease. World J Gastroenterol 2014; 20: 1165-79.
8. Bamias G, Clark DJ, Rivera-Nieves J. Leukocyte traffic blockade as a therapeutic strategy in inflammatory bowel disease. Curr Drug Targets 2013; 14: 1490-500.
9. Barcellos LF, Kamdar BB, Ramsay PP, DeLoa C, Lincoln RR, Caillier S, et al. Clustering of autoimmune diseases in families with a highrisk for multiple sclerosis: a descriptive study. Lancet Neurol 2006; 5: 924-31.
10. Batur-Caglayan HZ, Irkec C, Yildirim-Capraz I, Atalay-Akyurek N, Dumlu S. A case of multiple sclerosis and celiac disease. Case Rep Neurol Med 2013; 2013: 576921.
11. Berer K, Boziki M, Krishnamoorthy G. Selective accumulation of proinflammatory T cells in the intestinecontributes to the resistance to autoimmune demyelinating disease. PLoS One 2014; 9: e87876.
12. Berer K, Gerdes LA, Cekanaviciute E, Jia X, Xiao L, Xia Z, et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci USA 2017; 114: 10719-24.
13. Berer K, Krishnamoorthy G. Microbial view of central nervous system autoimmunity. FEBS Lett 2014; 588: 4207-13.
14. Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 2011; 479: 538-41.
15. Bilgic B, Aygun D, Arslan AB, Bayram A, Akyuz F, Sencer S, et al. Silent neurological involvement in biopsy-defined coeliac patients. Neurol Sci 2013; 34: 2199-204
16. Bonitz JA, Son JY, Chandler B, Tomaio JN, Qin Y, Prescott LM, et al. A sphingosine-1 phosphate agonist (FTY720) limits trauma/hemorrhagic shock-induced multiple organ dysfunction syndrome. Shock 2014; 42: 448-55.
17. Bostick JW, Zhou L. Innate lymphoid cells in intestinal immunity and inflammation. Cell Mol Life Sci 2016; 73: 237-52.
18. Bradley LM, Malo ME, Fong S, Tonkonogy SL, Watson SR. Blockade of both L-selectin and alpha4 integrins abrogates naive CD4 cell trafficking and responses in gut-associated lymphoid organs. Int Immunol 1998; 10: 961-8.
19. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 2014; 6: 263ra158.
20. Bron PA, Kleerebezem M, Brummer RJ, Cani PD, Mercenier A, MacDonald TT, et al. Can probiotics modulate human disease by impacting intestinal barrier function? Br J Nutr 2017; 117: 93-107.
21. Buscarinu MC, Cerasoli B, Annibali V, Policano C, Lionetto L, Capi M, et al. Altered intestinal permeability in patients with relapsingremitting multiple sclerosis: a pilot study. Mult Scler 2017; 23: 442-6.
22. Buscarinu MC, Romano S, Mechelli R, Pizzolato Umeton R, Ferraldeschi M, Fornasiero A, et al. Intestinal permeabiliy in relapsing-remitting multiple sclerosis. Neurotherapeutics 2018; 15: 68-74.
23. Cantarel BL, Waubant E, Chehoud C, Kuczynski J, DeSantis TZ, Warrington J, et al. Gut microbiota in multiple sclerosis: possible influence of immunomodulators. J Investig Med 2015; 63: 729-34.
24. Capaldo CT, Powell DN, Kalman D. Layered defense: how mucus and tight junctions seal the intestinal barrier. J Mol Med 2017; 95: 927-34.
25. Casella G, Bordo BM, Schalling R, Villanacci V, Salemme M, Di Bella C, et al. Neurological disorders and celiac disease. Minerva Gastroenterol Dietol 2016; 62: 197-206.
26. Casella G, Tontini GE, Bassotti G, Pastorelli L, Villanacci V, Spina L, et al. Neurological disorders and inflammatory bowel diseases. World J Gastroenterol 2014; 20: 8764-82.
27. Casili G, Cordaro M, Impellizzeri D, Bruschetta G, Paterniti I, Cuzzocrea S, et al. Dimethyl fumarate reduces inflammatory responses in experimental colitis. J Crohns Colitis 2016; 10: 472-83.
28. Cekanaviciute E, Yoo BB, Runia TF, Debelius JW, Singh S, Nelson CA, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci USA 2017; 114: 10713-18.
29. Chen J, Chia N, Kalari KR, Yao JZ, Novotna M, Soldan MM, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep 2016; 6: 28484.
30. Chen M, Lee G, Kwong LN, Lamont S, Chaves C. Cerebral white matter lesions in patients with Crohn's disease. J Neuroimaging 2012; 22: 38-41.
31. Cheroutre H, Lambolez F, Mucida D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol 2011; 11: 445-56.
32. Chiba K, Yanagawa Y, Masubuchi Y, Kataoka H, Kawaguchi T, Ohtsuki M, et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol 1998; 160: 5037-44.
33. Chitrala KN, Guan H, Singh NP, Busbee B, Gandy A, Mehrpouya-Bahrami P, et al. CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice. Eur J Immunol 2017; 47: 1188-99.
34. Choi W, Yeruva S, Turner JR. Contributions of intestinal epithelial barriers to health and disease. Exp Cell Res 2017; 358: 71-7.
35. Colpitts SL, Kasper LH. Influence of the gut microbiome on autoimmunity in the central nervous system. J Immunol 2017; 198: 596-604.
36. Cosorich I, Dalla-Costa G, Sorini C, Ferrarese R, Messina MJ, Dolpady J, et al. High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv 2017; 3: e1700492.
37. Danese S, Semeraro S, Marini M, Roberto I, Armuzzi A, Papa A, et al. Adhesion molecules in inflammatory bowel disease: therapeutic implications for gut inflammation. Dig Liver Dis 2005; 37: 811-18.
38. Daniel C, Sartory N, Zahn N, Geisslinger G, Radeke HH, Stein JM. FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+ CD25 + regulatory T cells. J Immunol 2007; 178: 2458-68.
39. De Felice KM, Novotna M, Enders FT, Faubion WA, Tremaine WJ, Kantarci OH, et al. Idiopathic inflammatory demyelinating disease of the central nervous system in patients with inflammatory bowel disease: retrospective analysis of 9095 patients. Aliment Pharmacol Ther 2015; 41: 99-107.
40. de Lau LM, de Vries JM, van der Woude CJ, Kuipers EJ, Siepman DA, Sillevis Smitt PA, et al. Acute CNS white matter lesions in patients with inflammatory bowel disease. Inflamm Bowel Dis 2009; 15: 576-80.
41. de Souza HSP, Fiocchi C, Iliopoulos D. The IBD interactome: an integrated view of aetiology, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol 2017; 14: 739-49.
42. Delgado ME, Grabinger T, Brunner T. Cell death at the intestinal epithelial front line. FEBS J 2016; 283: 2701-19.
43. Dimitrov V, White JH. Vitamin D signaling in intestinal innate immunity and homeostasis. Mol Cell Endocrinol 2017; 453: 68-78.
44. Dong J, Wang H, Zhao J, Sun J, Zhang T, Zuo L, et al. SEW2871 protects from experimental colitis through reduced epithelial cell apoptosis and improved barrier function in interleukin-10 gene-deficient mice. Immunol Res 2015; 61: 303-11.
45. D'Souza WN, Douangpanya J, Mu S, Jaeckel P, Zhang M, Maxwell JR, et al. Differing roles for short chain fatty acids and GPR43 agonism in the regulation of intestinal barrier function and immune responses. PLoS One 2017; 12: e0180190.
46. Du J, Chen Y, Shi Y, Liu T, Cao Y, Tang Y, et al. 1,25-Dihydroxyvitamin D protects intestinal epithelial barrier by regulating the myosin light chain kinase signaling pathway. Inflamm Bowel Dis 2015; 21: 2495-506.
47. Dupont A, Heinbockel L, Brandenburg K, Hornef MW. Antimicrobial peptides and the enteric mucus layer act in concert to protect the intestinal mucosa. Gut Microbes 2014; 5: 761-5.
48. Erny D, Hraběde Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 2015; 18: 965-77.
49. Erny D, Hraběde Angelis AL, Prinz M. Communicating systems in the body: how microbiota and microglia cooperate. Immunology 2017; 150: 7-15.
50. Escribano BM, Medina-Fernández FJ, Aguilar-Luque M, Agüera E, Feijoo M, Garcia-Maceira FI, et al. Lipopolysaccharide binding protein and oxidative stress in a multiple sclerosis model. Neurotherapeutics 2017; 14: 199-211.
51. Esplugues E, Huber S, Gagliani N, Hauser AE, Town T, Wan YY, et al. Control of TH17 cells occurs in the small intestine. Nature 2011; 475: 514-18.
52. Esposito S, Bonavita S, Sparaco M, Gallo A, Tedeschi G. The role of diet in multiple sclerosis: a review. Nutr Neurosci 2017, in press. doi: 10.1080/1028415X.2017.1303016.
53. Ezendam J, de Klerk A, Gremmer ER, van Loveren H. Effects of Bifidobacterium animalis administered during lactation on allergic and autoimmune responses in rodents. Clin Exp Immunol 2008; 154: 424-31.
54. Farstad IN, Halstensen TS, Kvale D, Fausa O, Brandtzaeg P. Topographic distribution of homing receptors on B and T cells in human gut-associated lymphoid tissue: relation of L-selectin and integrin alpha 4 beta 7 to naive and memory phenotypes. Am J Pathol 1997; 150: 187-99.
55. Ferro JM, Oliveira SN, Correia L. Neurologic manifestations of inflammatory bowel diseases. Handb Clin Neurol 2014; 120: 595-605.
56. Finsterer J, Leutmezer F. Celiac disease with cerebral and peripheral nerve involvement mimicking multiple sclerosis. J Med Life 2014; 7: 440-4.
57. Fiorino G, Correale C, Fries W, Repici A, Malesci A, Danese S. Leukocyte traffic control: a novel therapeutic strategy for inflammatory bowel disease. Expert Rev Clin Immunol 2010; 6: 567-72.
58. Fleming JO, Isaak A, Lee JE, Luzzio CC, Carrithers MD, Cook TD, et al. Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study. Mult Scler 2011; 17: 743-54.
59. France MM, Turner JR. The mucosal barrier at a glance. J Cell Sci 2017; 130: 307-14.
60. Frister A, Schmidt C, Schneble N, Brodhun M, Gonnert FA, Bauer M, et al. Phosphoinositide 3-kinase-affects LPS-induced disturbance of blood-brain barrier via lipid kinase-independent control of cAMP in microglial cells. Neuromolecular Med 2014; 16: 704-13.
61. Fujimori H, Miura S, Koseki S, Hokari R, Komoto S, Hara Y, et al. Intravital observation of adhesion of lamina propria lymphocytes to microvessels of small intestine in mice. Gastroenterology 2002; 122: 734-44.
62. Gangwar R, Meena AS, Shukla PK, Nagaraja AS, Dorniak PL, Pallikuth S, et al. Calcium-mediated oxidative stress: a common mechanism in tight junctiondisruption by different types of cellular stress. Biochem J 2017; 474: 731-49.
63. Garrido-Mesa N, Camuesco D, Arribas B, Comalada M, Bailón E, Cueto-Sola M, et al. The intestinal anti-inflammatory effect of minocycline in experimental colitis involves both its immunomodulatory and antimicrobial properties. Pharmacol Res 2011a; 63: 308-19.
64. Garrido-Mesa N, Utrilla P, Comalada M, Zorrilla P, Garrido-Mesa J, Zarzuelo A, et al. The association of minocycline and the probiotic Escherichia coli Nissle 1917 results in an additive beneficial effect in a DSS model of reactivated colitis in mice. Biochem Pharmacol 2011b; 82: 1891-900.
65. Gasbarrini G, Montalto M. Structure and function of tight junctions. Role in intestinal barrier. Ital J Gastroenterol Hepatol 1999; 31: 481-8.
66. Gebregiworgis T, Nielsen HH, Massilamany C, Gangaplara A, Reddy J, Illes Z, et al. A urinary metabolic signature for multiple sclerosis and neuromyelitis optica. J Proteome Res 2016; 15: 659-66.
67. Geissler A, Andus T, Roth M, Kullmann F, Caesar I, Held P, et al. Focal white-matter lesions in brain of patients with inflammatory bowel disease. Lancet 1995; 345: 897-8.
68. Giles EM, Stagg AJ. Type 1 interferon in the human intestine-A coordinator of the immune response to the microbiota. Inflamm Bowel Dis 2017; 23: 524-33.
69. Giuliani F, Hader W, Yong VW. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. J Leukoc Biol 2005; 78: 135-43.
70. Goll R, van Beelen Granlund A. Intestinal barrier homeostasis in inflammatory bowel disease. Scand J Gastroenterol 2015; 50: 3-12.
71. Gopalakrishnan S, Tripathi A, Tamiz AP. Larazotide acetate promotes tight junction assembly in epithelial cells. Peptides 2012; 35: 95-101.
72. Goteri G, Rupoli S, Tassetti A, Pulini S, Morichetti D, Filosa A, et al. Severe diarrhoea during Campath-1H treatment for refractory cutaneous T-cell lymphoma. Ann Hematol 2006; 85: 617-19.
73. Greenspon J, Li R, Xiao L, Rao JN, Sun R, Strauch ED, et al. Sphingosine-1-phosphate regulates the expression of adherens junction protein E-cadherin and enhances intestinal epithelial cell barrier function. Dig Dis Sci 2011; 56: 1342-53.
74. Gronke K, Kofoed-Nielsen M, Diefenbach A. Isolation and flow cytometry analysis of innate lymphoid cells from the intestinal lamina propria. Methods Mol Biol 2017; 1559: 255-65.
75. Gupta JK, Ingegno AP, Cook AW, Pertschuk LP. Multiple sclerosis and malabsorption. Am J Gastroenterol 1977; 68: 560-5.
76. Haak BW, Wiersinga WJ. The role of the gut microbiota in sepsis. Lancet Gastroenterol Hepatol 2017; 2: 135-43.
77. Haghikia A, Jörg S, Duscha A, Berg J, Manzel A, Waschbisch A, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 2015; 43: 817-29.
78. Halin C, Scimone ML, Bonasio R, Gauguet JM, Mempel TR, Quackenbush E, et al. The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches. Blood 2005; 106: 1314-22.
79. Hamann A, Andrew DP, Jablonski-Westrich D, Holzmann B, Butcher EC. Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol 1994; 152: 3282-93.
80. Hartung HP, Aktas O, Boyko AN. Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis. Mult Scler 2015; 21: 22-34.
81. Hashiguchi M, Kashiwakura Y, Kojima H, Kobayashi A, Kanno Y, Kobata T. Peyer's patch innate lymphoid cells regulate commensal bacteria expansion. Immunol Lett 2015; 165: 1-9.
82. Henning G, Ohl L, Junt T, Reiterer P, Brinkmann V, Nakano H, et al. CC chemokine receptor 7-dependent and-independent pathways for lymphocyte homing: modulation by FTY720. J Exp Med 2001; 194: 1875-81.
83. Holmberg FEO, Pedersen J, Jorgensen P, Soendergaard C, Jensen KB, Nielsen OH. Intestinal barrier integrity and inflammatory bowel disease: stem cell-based approaches to regenerate the barrier. J Tissue Eng Regen Med 2018; 12: 923-35. 10.1002/term.2506.
84. Huang TY, Chu HC, Lin YL, Lin CK, Hsieh TY, Chang WK, et al. Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases. Toxicol Appl Pharmacol 2009; 237: 69-82.
85. Jäger S, Stange EF, Wehkamp J. Inflammatory bowel disease: an impaired barrier disease. Langenbecks Arch Surg 2013; 398: 1-12.
86. Jangi S, Gandhi R, Cox LM, Li N, von Glehn F, Yan R, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun 2016; 7: 12015.
87. Kadowaki A, Miyake S, Saga R, Chiba A, Mochizuki H, Yamamura T. Gut environment-induced intraepithelial autoreactive CD4( + ) T cells suppress central nervous system autoimmunity via LAG-3. Nat Commun 2016; 7: 11639.
88. Kamphuis WW, Derada Troletti C, Reijerkerk A, Romero IA, de Vries HE. The blood-brain barrier in multiple sclerosis: microRNAs as key regulators. CNS Neurol Disord Drug Targets 2015; 14: 157-67.
89. Katlinskaya YV, Katlinski KV, Lasri A, Li N, Beiting DP, Durham AC, et al. Type I interferons control proliferation and function of the intestinalepithelium. Mol Cell Biol 2016; 36: 1124-35.
90. Katsanos AH, Katsanos KH. Inflammatory bowel disease and demyelination: more than just a coincidence? Expert Rev Clin Immunol 2014; 10: 363-73.
91. Kelly CP, Green PH, Murray JA. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebocontrolled study. Aliment Pharmacol Ther 2013; 37: 252-62.
92. Khaleghi S, Ju JM, Lamba A, Murray JA. The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate. Therap Adv Gastroenterol 2016; 9: 37-49.
93. Kiela PR, Ghishan FK. Physiology of intestinal absorption and secretion. Best Pract Res Clin Gastroenterol 2016; 30: 145-59.
94. Kim HH, Jeong IH, Hyun JS, Kong BS, Kim HJ, Park SJ. Metabolomic profiling of CSF in multiple sclerosis and neuromyelitis optica spectrum disorder by nuclear magnetic resonance. PLoS One 2017; 12: e0181758.
95. Kimura K, Nakamura M, Sato W, Okamoto T, Araki M, Lin Y, et al. Disrupted balance of T cells under natalizumab treatment in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2016; 3: e210.
96. Kirchner M, Mafura M, Hunt T, Abu-Oun M, Nunez-Garcia J, Hu Y, et al. Antimicrobial resistance characteristics and fitness of Gramnegative fecal bacteria from volunteers treated with minocycline or amoxicillin. Front Microbiol 2014; 5: 722.
97. König J, Wells J, Cani PD, García-Ródenas CL, MacDonald T, Mercenier A, Whyte J, et al. Human intestinal barrier function in health and disease. Clin Transl Gastroenterol 2016; 7: e196.
98. Kosmidou M, Katsanos AH, Katsanos KH, Kyritsis AP, Tsivgoulis G, Christodoulou D, et al. Multiple sclerosis and inflammatory bowel diseases: a systematic review and meta-analysis. J Neurol 2017; 264: 254-9.
99. Kouchaki E, Tamtaji OR, Salami M, Bahmani F, Daneshvar Kakhaki R, Akbari E, et al. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Clin Nutr 2017; 36: 1245-8.
100. Kraus J, Ling AK, Hamm S, Voigt K, Oschmann P, Engelhardt B. Interferon-beta stabilizes barrier characteristics of brain endothelial cells in vitro. Ann Neurol 2004; 56: 192-205.
101. Krom H, Sprangers F, van den Berg R, Benninga MA, Kindermann A. Transverse myelitis as manifestation of celiac disease in a toddler. Pediatrics 2017; 139: e20161381.
102. Kwon HK, Kim GC, Kim Y, Hwang W, Jash A, Sahoo A, et al. Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response. Clin Immunol 2013; 146: 217-27.
103. Lange LS, Shiner M. Small-bowel abnormalities in multiple sclerosis. Lancet 1976; 2: 1319-22.
104. Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2011; 108 (Suppl 1): 4615-22.
105. Leffler DA, Kelly CP, Abdallah HZ. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol 2012; 107: 1554-62.
106. Leffler DA, Kelly CP, Green PH. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology 2015; 148: 1311-19.
107. LeMessurier KS, Häcker H, Chi L, Tuomanen E, Redecke V. Type I interferon protects against pneumococcal invasive disease by inhibiting bacterial transmigration across the lung. PLoS Pathog 2013; 9: e1003727.
108. Li H, Sun J, Wang F, Ding G, Chen W, Fang R, et al. Sodium butyrate exerts neuroprotective effects by restoring the blood-brain barrier in traumatic brain injury mice. Brain Res 2016; 1642: 70-8.
109. Li Q, Wang C, Tang C, He Q, Li J. Lymphocyte depletion after alemtuzumab induction disrupts intestinal fungal microbiota in cynomolgus monkeys. Transplantation 2014; 98: 951-9.
110. Li Q, Zhang Q, Wang C, Jiang S, Li N, Li J. The response of intestinal stem cells and epithelium after alemtuzumab administration. Cell Mol Immunol 2011; 8: 325-32.
111. Li Q, Zhang Q, Wang C, Tang C, Zhang Y, Jiang S, et al. Influence of alemtuzumab on the intestinal Paneth cells and microflora in macaques. Clin Immunol 2010; 136: 375-86.
112. Li QR, Wang CY, Tang C, He Q, Li N, Li JS. Reciprocal interaction between intestinal microbiota and mucosal lymphocyte in cynomolgus monkeys after alemtuzumab treatment. Am J Transplant 2013; 13: 899-910.
113. Li YC, Chen Y, Du J. Critical roles of intestinal epithelial vitamin D receptor signaling in controlling gut mucosal inflammation. J Steroid Biochem Mol Biol 2015; 148: 179-83.
114. Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol 2017; 18: 2.
115. Liu W, Chen Y, Golan MA, Annunziata ML, Du J, Dougherty U, et al. Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis. J Clin Invest 2013; 123: 3983-96.
116. Long TM, Nisa S, Donnenberg MS, Hassel BA. Enteropathogenic Escherichia coli inhibits type I interferon-and RNase L-mediated host defense to disrupt intestinalepithelial cell barrier function. Infect Immun 2014; 82: 2802-14.
117. Lundblad C, Axelberg H, Graönde PO. Treatment with the sphingosine-1-phosphate analogue FTY 720 reduces loss of plasma volume during experimental sepsis in the rat. Acta Anaesthesiol Scand 2013; 57: 713-18.
118. Ma N, Wu Y, Xie F, Du K, Wang Y, Shi L, et al. Dimethyl fumarate reduces the risk of mycotoxins via improving intestinal barrier and microbiota. Oncotarget 2017; 8: 44625-38.
119. Mangalam A, Shahi SK, Luckey D, Karau M, Marietta E, Luo N, et al. Human gut-derived commensal bacteria suppress CNS inflammatory and demyelinating disease. Cell Rep 2017; 20: 1269-77.
120. Martini E, Krug SM, Siegmund B, Neurath MF, Becker C. Mend your fences: the epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cell Mol Gastroenterol Hepatol 2017; 4: 33-46.
121. Melton AC, Bailey-Bucktrout SL, Travis MA, Fife BT, Bluestone JA, Sheppard D. Expression of vb8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice. J Clin Invest 2010; 120: 4436-44.
122. Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G, et al. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med 2017; 376: 2122-33.
123. Miller AE. Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis. Clin Ther 2015; 37: 2366-80.
124. Mirabella M, Cianfoni A, Bucci M, Nociti V, Sancricca C, Patanella AK, et al. Coeliac disease presenting with acute disseminated encephalomyelitis. Eur J Neurol 2006; 13: 202-3.
125. Miranda-Hernandez S, Baxter AG. Role of toll-like receptors in multiple sclerosis. Am J Clin Exp Immunol 2013; 2: 75-93.
126. Miura S, Tsuzuki Y, Kurose I, Suematsu M, Shigematsu T, Kimura H, et al. Endotoxin stimulates lymphocyte-endothelial interactions in rat intestinal Peyer's patches and villus mucosa. Am J Physiol 1996; 271: G282-92.
127. Miyake S, Kim S, Suda W, Oshima K, Nakamura M, Matsuoka T, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to clostridia XIVa and IV clusters. PLoS One 2015; 10: e0137429.
128. Mizuno M, Noto D, Kaga N, Chiba A, Miyake S. The dual role of short fatty acid chains in the pathogenesis of autoimmune disease models. PLoS One 2017; 12: e0173032.
129. Morís G. Inflammatory bowel disease: an increased risk factor for neurologic complications. World J Gastroenterol 2014; 20: 1228-37.
130. Moubareck C, Gavini F, Vaugien L, Butel MJ, Doucet-Populaire F. Antimicrobial susceptibility of bifidobacteria. J Antimicrob Chemother 2005; 55: 38-44.
131. Mu Q, Kirby J, Reilly CM, Luo XM. Leaky gut as a danger signal for autoimmune diseases. Front Immunol 2017; 8: 598.
132. Nakahashi-Oda C, Udayanga KG, Nakamura Y, Nakazawa Y, Totsuka N, Miki H, et al. Apoptotic epithelial cells control the abundance of Treg cells at barrier surfaces. Nat Immunol 2016; 17: 441-50.
133. Nalle SC, Turner JR. Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease. Mucosal Immunol 2015; 8: 720-30.
134. Nouri M, Bredberg A, Westroöm B, Lavasani S. Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells. PLoS One 2014; 9: e106335.
135. Ochoa-Repá raz J, Colpitts SL, Kircher C, Kasper EJ, Telesford KM, Begum-Haque S, et al. Induction of gut regulatory CD39 + T cells by teriflunomide protects against EAE. Neurol Neuroimmunol Neuroinflamm 2016; 3: e291.
136. Ochoa-Repá raz J, Magori K, Kasper LH. The chicken or the egg dilemma: intestinal dysbiosis in multiple sclerosis. Ann Transl Med 2017; 5: 145.
137. Ochoa-Repá raz J, Mielcarz DW, Ditrio LE, Burroughs AR, Begum-Haque S, Dasgupta S, et al. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol 2010a; 185: 4101-8.
138. Ochoa-Repá raz J, Mielcarz DW, Wang Y, Begum-Haque S, Dasgupta S, Kasper DL, et al. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol 2010b; 3: 487-95.
139. Odenwald MA, Turner JR. The intestinal epithelial barrier: a therapeutic target? Nat Rev Gastroenterol Hepatol 2017; 14: 9-21.
140. Olivares-Villagómez D, Van Kaer L. Intestinal intraepithelial lymphocytes: sentinels of the mucosal barrier. Trends Immunol 2018; 39: 264-75.
141. Ortiz GG, Pacheco-Moisés FP, Macías-Islas MÁ, Flores-Alvarado LJ, Mireles-Ramírez MA, González-Renovato ED, et al. Role of the blood-brain barrier in multiple sclerosis. Arch Med Res 2014; 45: 687-97.
142. Pá szti-Gere E, Jerzsele A , Balla P, Ujhelyi G, Széká cs A. Reinforced epithelial barrier integrity via matriptase induction with sphingosine-1-phosphate did not result in disturbances in physiological redox status. Oxid Med Cell Longev 2016; 2016: 9674272.
143. Paterson BM, Lammers KM, Arrieta MC. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther 2007; 26: 757-66.
144. Patten DA, Collett A. Exploring the immunomodulatory potential of microbial-associated molecular patterns derived from the enteric bacterial microbiota. Microbiology 2013; 159: 1535-44.
145. Peng L, Li ZR, Green RS, Holzman IR, Lin J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr 2009; 139: 1619-25.
146. Persson EK, Scott CL, Mowat AM, Agace WW. Dendritic cell subsets in the intestinal lamina propria: ontogeny and function. Eur J Immunol 2013; 43: 3098-107.
147. Pröbstel AK, Baranzini SE. The role of the gut microbiome in multiple sclerosis risk and progression: towards characterization of the "MS Microbiome". Neurotherapeutics 2018; 15: 126-34.
148. Qu L, Li Q, Jiang H, Gu L, Zhang Q, Wang C, et al. Effect of antimouse CD52 monoclonal antibody on mouse intestinal intraepithelial lymphocytes. Transplantation 2009; 88: 766-72.
149. Qu LL, Lyu YQ, Jiang HT, Shan T, Zhang JB, Li QR, et al. Effect of alemtuzumab on intestinal intraepithelial lymphocytes and intestinal barrier function in cynomolgus model. Chin Med J 2015; 128: 680-6.
150. Raftery T, Martineau AR, Greiller CL, Ghosh S, McNamara D, Bennett K, et al. Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn's disease: results from a randomised double-blind placebo-controlled study. United European Gastroenterol J 2015; 3: 294-302.
151. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004; 118: 229-41.
152. Reinhold AK, Rittner HL. Barrier function in the peripheral and central nervous system-A review. Pflugers Arch 2017; 469: 123-34.
153. Reynolds JM, Martinez GJ, Nallaparaju KC, Chang SH, Wang YH, Dong C. Cutting edge: regulation of intestinal inflammation and barrier function by IL-17C. J Immunol 2012; 189: 4226-30.
154. Rochereau N, Verrier B, Pin JJ, Genin C, Paul S. Phenotypic localization of distinct DC subsets in mouse Peyer Patch. Vaccine 2011; 29: 3655-61.
155. Rodrigo L, Hernández-Lahoz C, Fuentes D, Alvarez N, López-Vá zquez A, Gonzá lez S. Prevalence of celiac disease in multiple sclerosis. BMC Neurol 2011; 11: 31.
156. Ronchetti AM, Henry B, Ambert-Balay K, Pothier P, Decroocq J, Leblond V, et al. Norovirus-related chronic diarrhea in a patient treated with alemtuzumab for chronic lymphocytic leukemia. BMC Infect Dis 2014; 14: 239.
157. Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 2016; 22: 586-97.
158. Rumah KR, Linden J, Fischetti VA, Vartanian T. Isolation of Clostridium perfringens type B in an individual at first clinical presentation of multiplesclerosis provides clues for environmental triggers of the disease. PLoS One 2013; 8: e76359.
159. Rumah KR, Vartanian TK, Fischetti VA. Oral multiple sclerosis drugs inhibit the in vitro growth of epsilon toxin producing gut bacterium, clostridium perfringens. Front Cell Infect Microbiol 2017; 7: 11.
160. Salvatore S, Finazzi S, Ghezzi A, Tosi A, Barassi A, Luini C, et al. Multiple sclerosis and celiac disease: is there an increased risk? Mult Scler 2004; 10: 711-12.
161. Sánchez-Navarro M, Garcia J, Giralt E, TeixidóM. Using peptides to increase transport across the intestinal barrier. Adv Drug Deliv Rev 2016; 106: 355-66.
162. Schumann M, Siegmund B, Schulzke JD, Fromm M. Celiac disease: role of the epithelial barrier. Cell Mol Gastroenterol Hepatol 2017; 3: 150-62.
163. Secher T, Kassem S, Benamar M, Bernard I, Boury M, Barreau F, et al. Oral Administration of the probiotic strain escherichia coli nissle 1917 reduces susceptibility to neuroinflammation and repairs experimental autoimmune encephalomyelitis-induced intestinal barrier dysfunction. Front Immunol 2017; 8: 1096.
164. Shen B, Yu H, Hao X, Qu L, Cai X, Li N. Impact of antimouse CD52 monoclonal antibody on graft's intraepithelial lymphocytes after orthotopic small bowel transplantation in mice. Transplantation 2013; 95: 663-70.
165. Shen B, Yu H, Yu T, Shen J, Meng N, Cai X. A CD52 antibody impairs mouse-transplanted intestinal tight junctions. J Surg Res 2015; 196: 278-84.
166. Shi N, Li N, Duan X, Niu H. Interaction between the gut microbiome and mucosal immune system. Mil Med Res 2017; 4: 14.
167. Simone IL, Federico F, Trojano M, Tortorella C, Liguori M, Giannini P, et al. High resolution proton MR spectroscopy of cerebrospinal fluid in MS patients. Comparison with biochemical changes in demyelinating plaques. J Neurol Sci 1996; 144: 182-90.
168. Smith RJ, Rao-Bhatia A, Kim TH. Signaling and epigenetic mechanisms of intestinal stem cells and progenitors: insight into crypt homeostasis, plasticity, and niches. Wiley Interdiscip Rev Dev Biol 2017; 6: e281.
169. Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation. Gastroenterology 2013; 145: 946-53.
170. Spirin NN, Rumiantseva TA, Kiselev DV, Spirina1 NN. Cellular composition of Peyer's patches and peripheral lymph nodes in experimental allergic encephalomyelitis during fingolimod therapy. Zh Nevrol Psikhiatr Im S S Korsakova 2014; 114: 71-6.
171. Stange EF. Improvement of a 'Leaky' intestinal barrier. Dig Dis 2017; 35: 21-4.
172. Stio M, Retico L, Annese V, Bonanomi AG. Vitamin D regulates the tight-junction protein expression in active ulcerative colitis. Scand J Gastroenterol 2016; 51: 1193-9.
173. Stremmel W, Gauss A. Lecithin as a therapeutic agent in ulcerative colitis. Dig Dis 2013; 31: 388-90.
174. Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers 2016; 4: e1251384.
175. Sugito K, Koshinaga T, Inoue M, Ikeda T, Hagiwara N, Fukuzawa M. Effect of FTY720 in rat small bowel transplantation: expression of mucosal addressin cell adhesion molecule-1. Transplant Proc 2005; 37: 4472-4.
176. Swidsinski A, Dörffel Y, Loening-Baucke V, Gille C, Göktas Ö, Reishauer A, et al. Reduced mass and diversity of the colonic microbiome in patients with multiple sclerosis and their improvement with ketogenic diet. Front Microbiol 2017; 8: 1141.
177. Takata K, Kinoshita M, Okuno T, Moriya M, Kohda T, Honorat JA, et al. The lactic acid bacterium Pediococcus acidilactici suppresses autoimmune encephalomyelitis by inducing IL-10-producing regulatory T cells. PLoS One 2011; 6: e27644.
178. Tamtaji OR, Kouchaki E, Salami M, Aghadavod E, Akbari E, Tajabadi-Ebrahimi M, et al. The effects of probiotic supplementation on gene expression related to inflammation, insulin, and lipids in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. J Am Coll Nutr 2017; 36: 660-5.
179. Tanaka T, Ohtsuka Y, Yagita H, Shiratori Y, Omata M, Okumura K. Involvement of alpha 1 and alpha 4 integrins in gut mucosal injury of graft-versus-host disease. Int Immunol 1995; 7: 1183-9.
180. Tang X, Maricic I, Kumar V. Anti-TCR antibody treatment activates a novel population of nonintestinal CD8 alpha alpha + TCR alpha beta + regulatory T cells and prevents experimental autoimmune encephalomyelitis. J Immunol 2007; 178: 6043-50.
181. Teixeira B, Bittencourt VC, Ferreira TB, Kasahara TM, Barros PO, Alvarenga R, et al. Low sensitivity to glucocorticoid inhibition of in vitro Th17-related cytokine production in multiple sclerosis patients is related to elevated plasma lipopolysaccharide levels. Clin Immunol 2013; 148: 209-18.
182. Tremlett H, Fadrosh DW, Faruqi AA, Hart J, Roalstad S, Graves J, et al. Gut microbiota composition and relapse risk in pediatric MS: a pilot study. J Neurol Sci 2016b; 363: 153-7.
183. Tremlett H, Fadrosh DW, Faruqi AA, Zhu F, Hart J, Roalstad S, et al. Gut microbiota in early pediatric multiple sclerosis: a case-control study. Eur J Neurol 2016a; 23: 1308-21.
184. Tschurtschenthaler M, Wang J, Fricke C, Fritz TM, Niederreiter L, Adolph TE, et al. Type I interferon signalling in the intestinal epithelium affects Paneth cells, microbial ecology and epithelialregeneration. Gut 2014; 63: 1921-31.
185. Venkatesan A. Multiple sclerosis and infections. Neurodegener Dis Manag 2015; 5 (Suppl 6): 11-14.
186. Vijiaratnam N, Rath L, Xu SS, Skibina O. Pancolitis a novel early complication of Alemtuzumab for MS treatment. Mult Scler Relat Disord 2016; 7: 83-4.
187. Volynets V, Rings A, Bárdos G, Ostaff MJ, Wehkamp J, Bischoff SC. Intestinal barrier analysis by assessment of mucins, tight junctions, and-defensins in healthy C57BL/6J and BALB/cJ mice. Tissue Barriers 2016; 4: e1208468.
188. Wan Saudi WS, Sjoöblom M. Short-chain fatty acids augment rat duodenal mucosal barrier function. Exp Physiol 2017; 102: 791-803.
189. Wang Y, Begum-Haque S, Telesford KM, Ochoa-Repá raz J, Christy M, Kasper EJ, et al. A commensal bacterial product elicits and modulates migratory capacity of CD39( + ) CD4 T regulatory subsets in the suppression of neuroinflammation. Gut Microbes 2014; 5: 552-61.
190. Wekerle H. Brain autoimmunity and intestinal microbiota: 100 trillion game changers. Trends Immunol 2017; 38: 483-97.
191. Wells JM, Brummer RJ, Derrien M, MacDonald TT, Troost F, Cani PD, et al. Homeostasis of the gut barrier and potential biomarkers. Am J Physiol Gastrointest Liver Physiol 2017; 312: G171-93.
192. Wells JM, Rossi O, Meijerink M, van Baarlen P. Epithelial crosstalk at the microbiota-mucosal interface. Proc Natl Acad Sci USA 2011; 108 (Suppl 1): 4607-14.
193. Westall FC. Molecular mimicry revisited: gut bacteria and multiple sclerosis. J Clin Microbiol 2006; 44: 2099-104.
194. Willemsen LE, Koetsier MA, van Deventer SJ, van Tol EA. Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by intestinal myofibroblasts. Gut 2003; 52: 1442-7.
195. Yablecovitch D, Shabat-Simon M, Aharoni R, Eilam R, Brenner O, Arnon R. Beneficial effect of glatiramer acetate treatment on syndecan-1 expression in dextran sodium sulfate colitis. J Pharmacol Exp Ther 2011; 337: 391-9.
196. Yacyshyn B, Meddings J, Sadowski D, Bowen-Yacyshyn MB. Multiple sclerosis patients have peripheral blood CD45RO+ B cells and increased intestinal permeability. Dig Dis Sci 1996; 41: 2493-8.
197. Yanagawa Y, Masubuchi Y, Chiba K. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats, III. Increase in frequency of CD62L-positive T cells in Peyer's patches by FTY720-induced lymphocyte homing. Immunology 1998; 95: 591-4.
198. Yang S, Yu M, Sun L, Xiao W, Yang X, Sun L, et al. Interferon-induced intestinal epithelial barrier dysfunction by NF-B/HIF-1 pathway. J Interferon Cytokine Res 2014; 34: 195-203.
199. Yi H, Jiang D, Zhang L, Xiong H, Han F, Wang Y. Developmental expression of STATs, nuclear factor-B and inflammatory genes in the jejunum of piglets during weaning. Int Immunopharmacol 2016; 36: 199-204.
200. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol 2004; 3: 744-51.
201. Yoseph BP, Klingensmith NJ, Liang Z, Breed ER, Burd EM, Mittal R, et al. Mechanisms of intestinal barrier dysfunction in sepsis. Shock 2016; 46: 52-9.
202. Yu T, Yang HS, Lu XJ, Xia ZS, Ouyang H, Shan TD, et al. Association of bactericidal dysfunction of paneth cells in streptozocin-induced diabetic mice with insulin deficiency. Med Sci Monit 2016; 22: 3062-72.
203. Zaura E, Brandt BW, Teixeira de Mattos MJ, Buijs MJ, Caspers MP, Rashid MU, et al. Same exposure but two radically different responses to antibiotics: resilience of the salivary microbiome versus long-term microbial shifts in feces. MBio 2015; 6: e01693-15.
204. Zikou AK, Kosmidou M, Astrakas LG, Tzarouchi LC, Tsianos E, Argyropoulou MI. Brain involvement in patients with inflammatory bowel disease: a voxel-based morphometry and diffusion tensor imaging study. Eur Radiol 2014; 24: 2499-506.
205. Zundler S, Becker E, Weidinger C, Siegmund B. Anti-adhesion therapies in inflammatory bowel disease-molecular and clinical aspects. Front Immunol 2017; 8: 891.