Non-infectious uveitis is considered an autoimmune disease responsible for a significant burden of blindness in developed countries and recent studies have linked its pathogenesis to dysregulation of the gut microbiota. We tested the immunomodulatory properties of two probiotics, Escherichia coli Nissle 1917 (EcN) and E. coli O83:K24:H31 (EcO), in a model of experimental autoimmune uveitis (EAU). To determine the importance of bacterial viability and treatment timing, mice were orally treated with live or autoclaved bacteria in both preventive and therapeutic schedules. Disease severity was assessed by ophthalmoscopy and histology, immune phenotypes in mesenteric and cervical lymph nodes were analyzed by flow cytometry and the gut immune environment was analyzed by RT-PCR and/or gut tissue culture. EcN, but not EcO, protected against EAU but only as a live organism and only when administered before or at the time of disease induction. Successful prevention of EAU was accompanied by a decrease in IRBP-specific T cell response in the lymph nodes draining the site of immunization as early as 7 days after the immunization and eye-draining cervical lymph nodes when the eye inflammation became apparent. Furthermore, EcN promoted an anti-inflammatory response in Peyer's patches, increased gut antimicrobial peptide expression and decreased production of inducible nitric oxide synthase in macrophages. In summary, we show here that EcN controls inflammation in EAU and suggest that probiotics may have a role in regulating the gut-eye axis.

Centre for Experimental Immunology Lions Eye Institute Nedlands Western Australia 6009 Australia

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague 128 08 Prague Czech Republic

Immunology and Virology Program Centre for Ophthalmology and Visual Science The University of Western Australia Crawley Western Australia 6009 Australia

Institute of Microbiology of the Czech Academy of Sciences v v i 142 20 Prague Czech Republic

Institute of Microbiology of the Czech Academy of Sciences v v i 549 22 Novy Hradek Czech Republic

Section of Immunology and Infection Institute of Medical Sciences University of Aberdeen Aberdeen AB24 3FX UK

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Miserocchi E., Fogliato G., Modorati G., Bandello F. Review on the worldwide epidemiology of uveitis. Eur. J. Ophthalmol. 2013;23:705–717. doi: 10.5301/ejo.5000278. PubMed DOI

Forrester J.V., Klaska I.P., Yu T., Kuffova L. Uveitis in Mouse and Man. Int. Rev. Immunol. 2013;32:76–96. doi: 10.3109/08830185.2012.747524. PubMed DOI

Durrani K., Zakka F.R., Ahmed M., Memon M., Siddique S.S., Foster C.S. Systemic therapy with conventional and novel immunomodulatory agents for ocular inflammatory disease. Surv. Ophthalmol. 2011;56:474–510. doi: 10.1016/j.survophthal.2011.05.003. PubMed DOI

Durrani O.M., Meads C.A., Murray P.I. Uveitis: A potentially blinding disease. Ophthalmologica. 2004;218:223–236. doi: 10.1159/000078612. PubMed DOI

Rosenbaum J.T., Asquith M. The microbiome and HLA-B27-associated acute anterior uveitis. Nat. Rev. Rheumatol. 2018;14:704–713. doi: 10.1038/s41584-018-0097-2. PubMed DOI PMC

Horai R., Caspi R.R. Microbiome and Autoimmune Uveitis. Front. Immunol. 2019;10:232. doi: 10.3389/fimmu.2019.00232. PubMed DOI PMC

Kverka M., Tlaskalova-Hogenova H. Intestinal Microbiota: Facts and Fiction. Dig. Dis. 2017;35:139–147. doi: 10.1159/000449095. PubMed DOI

Tlaskalova-Hogenova H., Stepankova R., Kozakova H., Hudcovic T., Vannucci L., Tuckova L., Rossmann P., Hrncir T., Kverka M., Zakostelska Z., et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: Contribution of germ-free and gnotobiotic animal models of human diseases. Cell. Mol. Immunol. 2011;8:110–120. doi: 10.1038/cmi.2010.67. PubMed DOI PMC

Kalyana Chakravarthy S., Jayasudha R., Sai Prashanthi G., Ali M.H., Sharma S., Tyagi M., Shivaji S. Dysbiosis in the Gut Bacterial Microbiome of Patients with Uveitis, an Inflammatory Disease of the Eye. Indian J. Microbiol. 2018;58:457–469. doi: 10.1007/s12088-018-0746-9. PubMed DOI PMC

Oezguen N., Yalcinkaya N., Kucukali C.I., Dahdouli M., Hollister E.B., Luna R.A., Turkoglu R., Kurtuncu M., Eraksoy M., Savidge T.C., et al. Microbiota stratification identifies disease-specific alterations in neuro-Behcet’s disease and multiple sclerosis. Clin. Exp. Rheumatol. 2019;37(Suppl. 121):58–66. PubMed

Ye Z., Wu C., Zhang N., Du L., Cao Q., Huang X., Tang J., Wang Q., Li F., Zhou C., et al. Altered gut microbiome composition in patients with Vogt-Koyanagi-Harada disease. Gut Microbes. 2020;11:539–555. doi: 10.1080/19490976.2019.1700754. PubMed DOI PMC

Ye Z., Zhang N., Wu C., Zhang X., Wang Q., Huang X., Du L., Cao Q., Tang J., Zhou C., et al. A metagenomic study of the gut microbiome in Behcet’s disease. Microbiome. 2018;6:135. doi: 10.1186/s40168-018-0520-6. PubMed DOI PMC

Bejaoui M., Sokol H., Marteau P. Targeting the Microbiome in Inflammatory Bowel Disease: Critical Evaluation of Current Concepts and Moving to New Horizons. Dig. Dis. 2015;33:105–112. doi: 10.1159/000437104. PubMed DOI

Lin P. Importance of the intestinal microbiota in ocular inflammatory diseases: A review. Clin. Exp. Ophthalmol. 2019;47:418–422. doi: 10.1111/ceo.13493. PubMed DOI

Jernberg C., Lofmark S., Edlund C., Jansson J.K. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J. 2007;1:56–66. doi: 10.1038/ismej.2007.3. PubMed DOI

Nobel Y.R., Cox L.M., Kirigin F.F., Bokulich N.A., Yamanishi S., Teitler I., Chung J., Sohn J., Barber C.M., Goldfarb D.S., et al. Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment. Nat. Commun. 2015;6:7486. doi: 10.1038/ncomms8486. PubMed DOI PMC

Cox L.M., Yamanishi S., Sohn J., Alekseyenko A.V., Leung J.M., Cho I., Kim S.G., Li H., Gao Z., Mahana D., et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158:705–721. doi: 10.1016/j.cell.2014.05.052. PubMed DOI PMC

Kugadas A., Wright Q., Geddes-McAlister J., Gadjeva M. Role of Microbiota in Strengthening Ocular Mucosal Barrier Function through Secretory IgA. Investig. Ophthalmol. Vis. Sci. 2017;58:4593–4600. doi: 10.1167/iovs.17-22119. PubMed DOI PMC

Horai R., Zárate-Bladés C.R., Dillenburg-Pilla P., Chen J., Kielczewski J.L., Silver P.B., Jittayasothorn Y., Chan C.C., Yamane H., Honda K., et al. Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site. Immunity. 2015;43:343–353. doi: 10.1016/j.immuni.2015.07.014. PubMed DOI PMC

Heissigerova J., Seidler Stangova P., Klimova A., Svozilkova P., Hrncir T., Stepankova R., Kverka M., Tlaskalova-Hogenova H., Forrester J.V. The Microbiota Determines Susceptibility to Experimental Autoimmune Uveoretinitis. J. Immunol. Res. 2016;2016:5065703. doi: 10.1155/2016/5065703. PubMed DOI PMC

Kim J., Choi S.H., Kim Y.J., Jeong H.J., Ryu J.S., Lee H.J., Kim T.W., Im S.H., Oh J.Y., Kim M.K. Clinical Effect of IRT-5 Probiotics on Immune Modulation of Autoimmunity or Alloimmunity in the Eye. Nutrients. 2017;9:1166. doi: 10.3390/nu9111166. PubMed DOI PMC

Nakamura Y.K., Janowitz C., Metea C., Asquith M., Karstens L., Rosenbaum J.T., Lin P. Short chain fatty acids ameliorate immune-mediated uveitis partially by altering migration of lymphocytes from the intestine. Sci. Rep. 2017;7:11745. doi: 10.1038/s41598-017-12163-3. PubMed DOI PMC

Chen X., Su W., Wan T., Yu J., Zhu W., Tang F., Liu G., Olsen N., Liang D., Zheng S.G. Sodium butyrate regulates Th17/Treg cell balance to ameliorate uveitis via the Nrf2/HO-1 pathway. Biochem. Pharmacol. 2017;142:111–119. doi: 10.1016/j.bcp.2017.06.136. PubMed DOI

Food and Agriculture Organization. World Health Organization . Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria. Volume 85 FAO; Cordoba, Spain: 2001. Probiotics in food. Health and nutritional properties and guidelines for evaluation.

Metchnikoff E. The Prolongation of Life: Optimistic Studies. G. P. Putnam’s Sons; New York, NY, USA: London, UK: 1908. p. 181. Mitchell, P.C., Ed. and Translator.

Islam S.U. Clinical Uses of Probiotics. Medicine. 2016;95:e2658. doi: 10.1097/MD.0000000000002658. PubMed DOI PMC

Scaldaferri F., Gerardi V., Mangiola F., Lopetuso L.R., Pizzoferrato M., Petito V., Papa A., Stojanovic J., Poscia A., Cammarota G., et al. Role and mechanisms of action of Escherichia coli Nissle 1917 in the maintenance of remission in ulcerative colitis patients: An update. World J. Gastroenterol. 2016;22:5505–5511. doi: 10.3748/wjg.v22.i24.5505. PubMed DOI PMC

Kruis W., Chrubasik S., Boehm S., Stange C., Schulze J. A double-blind placebo-controlled trial to study therapeutic effects of probiotic Escherichia coli Nissle 1917 in subgroups of patients with irritable bowel syndrome. Int. J. Colorectal. Dis. 2012;27:467–474. doi: 10.1007/s00384-011-1363-9. PubMed DOI PMC

Henker J., Laass M., Blokhin B.M., Bolbot Y.K., Maydannik V.G., Elze M., Wolff C., Schulze J. The probiotic Escherichia coli strain Nissle 1917 (EcN) stops acute diarrhoea in infants and toddlers. Eur. J. Pediatr. 2007;166:311–318. doi: 10.1007/s00431-007-0419-x. PubMed DOI PMC

Secher T., Kassem S., Benamar M., Bernard I., Boury M., Barreau F., Oswald E., Saoudi A. 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. doi: 10.3389/fimmu.2017.01096. PubMed DOI PMC

Secher T., Maillet I., Mackowiak C., Le Berichel J., Philippeau A., Panek C., Boury M., Oswald E., Saoudi A., Erard F., et al. The probiotic strain Escherichia coli Nissle 1917 prevents papain-induced respiratory barrier injury and severe allergic inflammation in mice. Sci. Rep. 2018;8:11245. doi: 10.1038/s41598-018-29689-9. PubMed DOI PMC

Hrdy J., Vlasakova K., Cerny V., Sukenikova L., Novotna O., Petraskova P., Borakova K., Lodinova-Zadnikova R., Kolarova L., Prokesova L. Decreased allergy incidence in children supplemented with E. coli O83:K24:H31 and its possible modes of action. Eur. J. Immunol. 2018;48:2015–2030. doi: 10.1002/eji.201847636. PubMed DOI

Lodinova-Zadnikova R., Cukrowska B., Tlaskalova-Hogenova H. Oral administration of probiotic Escherichia coli after birth reduces frequency of allergies and repeated infections later in life (after 10 and 20 years) Int. Arch. Allergy Immunol. 2003;131:209–211. doi: 10.1159/000071488. PubMed DOI

Zwicker C., Sarate P., Drinic M., Ambroz K., Korb E., Smole U., Kohler C., Wilson M.S., Kozakova H., Sebo P., et al. Prophylactic and therapeutic inhibition of allergic airway inflammation by probiotic Escherichia coli O83. J. Allergy Clin. Immunol. 2018;142:1987–1990 e1987. doi: 10.1016/j.jaci.2018.07.029. PubMed DOI

Markowiak P., Slizewska K. Effects of Probiotics, Prebiotics, and Synbiotics on Human Health. Nutrients. 2017;9:1021. doi: 10.3390/nu9091021. PubMed DOI PMC

Klimova A., Seidler Stangova P., Svozilkova P., Forrester J.V., Klaska I., Heissigerova J. The critical points in induction of experimental autoimmune uveitis. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc. Czech Repub. 2016;160:140–142. doi: 10.5507/bp.2015.056. PubMed DOI

Paques M., Guyomard J.L., Simonutti M., Roux M.J., Picaud S., Legargasson J.F., Sahel J.A. Panretinal, high-resolution color photography of the mouse fundus. Investig. Ophthalmol. Vis. Sci. 2007;48:2769–2774. doi: 10.1167/iovs.06-1099. PubMed DOI

Seidler Stangova P., Dusek O., Klimova A., Heissigerova J., Kucera T., Svozilkova P. Metronidazole Attenuates the Intensity of Inflammation in Experimental Autoimmune Uveitis. Folia Biol. 2019;65:265–274. PubMed

Xu H., Koch P., Chen M., Lau A., Reid D.M., Forrester J.V. A clinical grading system for retinal inflammation in the chronic model of experimental autoimmune uveoretinitis using digital fundus images. Exp. Eye Res. 2008;87:319–326. doi: 10.1016/j.exer.2008.06.012. PubMed DOI

Kostovcikova K., Coufal S., Galanova N., Fajstova A., Hudcovic T., Kostovcik M., Prochazkova P., Jiraskova Zakostelska Z., Cermakova M., Sediva B., et al. Diet Rich in Animal Protein Promotes Pro-inflammatory Macrophage Response and Exacerbates Colitis in Mice. Front. Immunol. 2019;10:919. doi: 10.3389/fimmu.2019.00919. PubMed DOI PMC

Cossarizza A., Chang H.D., Radbruch A., Acs A., Adam D., Adam-Klages S., Agace W.W., Aghaeepour N., Akdis M., Allez M., et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition) Eur. J. Immunol. 2019;49:1457–1973. doi: 10.1002/eji.201970107. PubMed DOI PMC

Qiu Z., Sheridan B.S. Isolating Lymphocytes from the Mouse Small Intestinal Immune System. J. Vis. Exp. 2018 doi: 10.3791/57281. PubMed DOI PMC

Kverka M., Zakostelska Z., Klimesova K., Sokol D., Hudcovic T., Hrncir T., Rossmann P., Mrazek J., Kopecny J., Verdu E.F., et al. Oral administration of Parabacteroides distasonis antigens attenuates experimental murine colitis through modulation of immunity and microbiota composition. Clin. Exp. Immunol. 2011;163:250–259. doi: 10.1111/j.1365-2249.2010.04286.x. PubMed DOI PMC

Roche H.M. Dietary modulation of energy homoeostasis and metabolic-inflammation. Proc. Nutr. Soc. 2019;78:313–318. doi: 10.1017/S0029665118002872. PubMed DOI

Zhang X., Goncalves R., Mosser D.M. The isolation and characterization of murine macrophages. Curr. Protoc. Immunol. 2008;83:14.1.1–14.1.14. doi: 10.1002/0471142735.im1401s83. PubMed DOI PMC

Grewal I.S., Flavell R.A. CD40 and CD154 in cell-mediated immunity. Annu. Rev. Immunol. 1998;16:111–135. doi: 10.1146/annurev.immunol.16.1.111. PubMed DOI

Rose S., Misharin A., Perlman H. A novel Ly6C/Ly6G-based strategy to analyze the mouse splenic myeloid compartment. Cytometry A. 2012;81:343–350. doi: 10.1002/cyto.a.22012. PubMed DOI PMC

Nakamura Y.K., Metea C., Karstens L., Asquith M., Gruner H., Moscibrocki C., Lee I., Brislawn C.J., Jansson J.K., Rosenbaum J.T., et al. Gut Microbial Alterations Associated with Protection from Autoimmune Uveitis. Investig. Ophthalmol. Vis. Sci. 2016;57:3747–3758. doi: 10.1167/iovs.16-19733. PubMed DOI PMC

Zakostelska Z., Malkova J., Klimesova K., Rossmann P., Hornova M., Novosadova I., Stehlikova Z., Kostovcik M., Hudcovic T., Stepankova R., et al. Intestinal Microbiota Promotes Psoriasis-Like Skin Inflammation by Enhancing Th17 Response. PLoS ONE. 2016;11:e0159539. doi: 10.1371/journal.pone.0159539. PubMed DOI PMC

Kokesova A., Frolova L., Kverka M., Sokol D., Rossmann P., Bartova J., Tlaskalova-Hogenova H. Oral administration of probiotic bacteria (E. coli Nissle, E. coli O83, Lactobacillus casei) influences the severity of dextran sodium sulfate-induced colitis in BALB/c mice. Folia Microbiol. 2006;51:478–484. doi: 10.1007/BF02931595. PubMed DOI

Lodinova-Zadnikova R., Tlaskalova H., Bartakova Z. The antibody response in infants after colonization of the intestine with E. coli O83. Artificial colonization used as a prevention against nosocomial infections. Adv. Exp. Med. Biol. 1991;310:329–335. doi: 10.1007/978-1-4615-3838-7_42. PubMed DOI

Hejnova J., Dobrindt U., Nemcova R., Rusniok C., Bomba A., Frangeul L., Hacker J., Glaser P., Sebo P., Buchrieser C. Characterization of the flexible genome complement of the commensal Escherichia coli strain A0 34/86 (O83: K24: H31) Microbiology. 2005;151:385–398. doi: 10.1099/mic.0.27469-0. PubMed DOI

Mahnic A., Auchtung J.M., Poklar Ulrih N., Britton R.A., Rupnik M. Microbiota in vitro modulated with polyphenols shows decreased colonization resistance against Clostridioides difficile but can neutralize cytotoxicity. Sci. Rep. 2020;10:8358. doi: 10.1038/s41598-020-65253-0. PubMed DOI PMC

Wang X., Yang S., Li S., Zhao L., Hao Y., Qin J., Zhang L., Zhang C., Bian W., Zuo L., et al. Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents. Gut. 2020 doi: 10.1136/gutjnl-2019-319766. PubMed DOI PMC

Kumar B., Cashman S.M., Kumar-Singh R. Complement-Mediated Activation of the NLRP3 Inflammasome and Its Inhibition by AAV-Mediated Delivery of CD59 in a Model of Uveitis. Mol. Ther. 2018;26:1568–1580. doi: 10.1016/j.ymthe.2018.03.012. PubMed DOI PMC

Azad M.A.K., Sarker M., Wan D. Immunomodulatory Effects of Probiotics on Cytokine Profiles. Biomed. Res. Int. 2018;2018:8063647. doi: 10.1155/2018/8063647. PubMed DOI PMC

Libbey J.E., Sanchez J.M.S., Fleming B.A., Doty D.J., DePaula-Silva A.B., Mulvey M.A., Fujinami R.S. Modulation of experimental autoimmune encephalomyelitis through colonisation of the gut with Escherichia coli. Benef. Microbes. 2020;11:669–684. doi: 10.3920/BM2020.0012. PubMed DOI

Zakostelska Z., Kverka M., Klimesova K., Rossmann P., Mrazek J., Kopecny J., Hornova M., Srutkova D., Hudcovic T., Ridl J., et al. Lysate of probiotic Lactobacillus casei DN-114 001 ameliorates colitis by strengthening the gut barrier function and changing the gut microenvironment. PLoS ONE. 2011;6:e27961. doi: 10.1371/journal.pone.0027961. PubMed DOI PMC

Petnicki-Ocwieja T., Hrncir T., Liu Y.J., Biswas A., Hudcovic T., Tlaskalova-Hogenova H., Kobayashi K.S. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc. Natl. Acad. Sci. USA. 2009;106:15813–15818. doi: 10.1073/pnas.0907722106. PubMed DOI PMC

Ivanov I.I., Frutos Rde L., Manel N., Yoshinaga K., Rifkin D.B., Sartor R.B., Finlay B.B., Littman D.R. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe. 2008;4:337–349. doi: 10.1016/j.chom.2008.09.009. PubMed DOI PMC

Mu Q., Kirby J., Reilly C.M., Luo X.M. Leaky Gut as a Danger Signal for Autoimmune Diseases. Front. Immunol. 2017;8:598. doi: 10.3389/fimmu.2017.00598. PubMed DOI PMC

Ukena S.N., Singh A., Dringenberg U., Engelhardt R., Seidler U., Hansen W., Bleich A., Bruder D., Franzke A., Rogler G., et al. Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PLoS ONE. 2007;2:e1308. doi: 10.1371/journal.pone.0001308. PubMed DOI PMC

Mondel M., Schroeder B.O., Zimmermann K., Huber H., Nuding S., Beisner J., Fellermann K., Stange E.F., Wehkamp J. Probiotic E. coli treatment mediates antimicrobial human beta-defensin synthesis and fecal excretion in humans. Mucosal Immunol. 2009;2:166–172. doi: 10.1038/mi.2008.77. PubMed DOI PMC

Pradhan S., Weiss A.A. Probiotic Properties of Escherichia coli Nissle in Human Intestinal Organoids. mBio. 2020;11 doi: 10.1128/mBio.01470-20. PubMed DOI PMC

Smith P.M., Howitt M.R., Panikov N., Michaud M., Gallini C.A., Bohlooly Y.M., Glickman J.N., Garrett W.S. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569–573. doi: 10.1126/science.1241165. PubMed DOI PMC

Furusawa Y., Obata Y., Fukuda S., Endo T.A., Nakato G., Takahashi D., Nakanishi Y., Uetake C., Kato K., Kato T., et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446–450. doi: 10.1038/nature12721. PubMed DOI

Tanabe S., Kinuta Y., Saito Y. Bifidobacterium infantis suppresses proinflammatory interleukin-17 production in murine splenocytes and dextran sodium sulfate-induced intestinal inflammation. Int. J. Mol. Med. 2008;22:181–185. doi: 10.3892/ijmm_00000006. PubMed DOI

Round J.L., Mazmanian S.K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl. Acad. Sci. USA. 2010;107:12204–12209. doi: 10.1073/pnas.0909122107. PubMed DOI PMC

Martin R., Chain F., Miquel S., Lu J., Gratadoux J.J., Sokol H., Verdu E.F., Bercik P., Bermudez-Humaran L.G., Langella P. The commensal bacterium Faecalibacterium prausnitzii is protective in DNBS-induced chronic moderate and severe colitis models. Inflamm. Bowel Dis. 2014;20:417–430. doi: 10.1097/01.MIB.0000440815.76627.64. PubMed DOI

Bai Y., Mansell T.J. Production and Sensing of Butyrate in a Probiotic Escherichia coli Strain. Int. J. Mol. Sci. 2020;21:3615. doi: 10.3390/ijms21103615. PubMed DOI PMC

Mowat A.M. Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 2003;3:331–341. doi: 10.1038/nri1057. PubMed DOI

Zhao R., Zhou H., Zhang J., Liu X., Su S.B. Interleukin-1beta promotes the induction of retinal autoimmune disease. Int. Immunopharmacol. 2014;22:285–292. doi: 10.1016/j.intimp.2014.06.041. PubMed DOI

Wang S., Song R., Wang Z., Jing Z., Wang S., Ma J. S100A8/A9 in Inflammation. Front. Immunol. 2018;9:1298. doi: 10.3389/fimmu.2018.01298. PubMed DOI PMC

Wang Y.Q., Dai X.D., Ran Y., Cao Y., Lan C.L., Guan J.T., Liu C., Yang F.M., Gan Y.J., Liu B.J., et al. Circulating S100A8/A9 Levels Reflect Intraocular Inflammation in Uveitis Patients. Ocul. Immunol. Inflamm. 2020;28:133–141. doi: 10.1080/09273948.2018.1538461. PubMed DOI

Kim H.A., Han J.H., Kim W.J., Noh H.J., An J.M., Yim H., Jung J.Y., Kim Y.S., Suh C.H. TLR4 Endogenous Ligand S100A8/A9 Levels in Adult-Onset Still’s Disease and Their Association with Disease Activity and Clinical Manifestations. Int. J. Mol. Sci. 2016;17:1342. doi: 10.3390/ijms17081342. PubMed DOI PMC

Ehrchen J.M., Sunderkotter C., Foell D., Vogl T., Roth J. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J. Leukoc. Biol. 2009;86:557–566. doi: 10.1189/jlb.1008647. PubMed DOI

Janowitz C., Nakamura Y.K., Metea C., Gligor A., Yu W., Karstens L., Rosenbaum J.T., Asquith M., Lin P. Disruption of Intestinal Homeostasis and Intestinal Microbiota during Experimental Autoimmune Uveitis. Investig. Ophthalmol. Vis. Sci. 2019;60:420–429. doi: 10.1167/iovs.18-24813. PubMed DOI PMC

Schlee M., Wehkamp J., Altenhoefer A., Oelschlaeger T.A., Stange E.F., Fellermann K. Induction of human beta-defensin 2 by the probiotic Escherichia coli Nissle 1917 is mediated through flagellin. Infect. Immun. 2007;75:2399–2407. doi: 10.1128/IAI.01563-06. PubMed DOI PMC

Wehkamp J., Harder J., Wehkamp K., Wehkamp-von Meissner B., Schlee M., Enders C., Sonnenborn U., Nuding S., Bengmark S., Fellermann K., et al. NF-kappaB- and AP-1-mediated induction of human beta defensin-2 in intestinal epithelial cells by Escherichia coli Nissle 1917: A novel effect of a probiotic bacterium. Infect. Immun. 2004;72:5750–5758. doi: 10.1128/IAI.72.10.5750-5758.2004. PubMed DOI PMC

Oshima N., Ishihara S., Rumi M.A., Aziz M.M., Mishima Y., Kadota C., Moriyama I., Ishimura N., Amano Y., Kinoshita Y. A20 is an early responding negative regulator of Toll-like receptor 5 signalling in intestinal epithelial cells during inflammation. Clin. Exp. Immunol. 2010;159:185–198. doi: 10.1111/j.1365-2249.2009.04048.x. PubMed DOI PMC

Ahmadi S., Wang S., Nagpal R., Wang B., Jain S., Razazan A., Mishra S.P., Zhu X., Wang Z., Kavanagh K., et al. A human-origin probiotic cocktail ameliorates aging-related leaky gut and inflammation via modulating the microbiota/taurine/tight. JCI Insight. 2020;5:e132055. doi: 10.1172/jci.insight.132055. PubMed DOI PMC

Sakai Y., Arie H., Ni Y., Zhuge F., Xu L., Chen G., Nagata N., Suzuki T., Kaneko S., Ota T., et al. Lactobacillus pentosus strain S-PT84 improves steatohepatitis by maintaining gut permeability. J. Endocrinol. 2020;247:169–181. doi: 10.1530/JOE-20-0105. PubMed DOI

Cuffaro B., Assohoun A.L.W., Boutillier D., Sukenikova L., Desramaut J., Boudebbouze S., Salome-Desnoulez S., Hrdy J., Waligora-Dupriet A.J., Maguin E., et al. In Vitro Characterization of Gut Microbiota-Derived Commensal Strains: Selection of Parabacteroides distasonis Strains Alleviating TNBS-Induced Colitis in Mice. Cells. 2020;9:2104. doi: 10.3390/cells9092104. PubMed DOI PMC

Jia H.P., Wowk S.A., Schutte B.C., Lee S.K., Vivado A., Tack B.F., Bevins C.L., McCray P.B., Jr. A novel murine beta -defensin expressed in tongue, esophagus, and trachea. J. Biol. Chem. 2000;275:33314–33320. doi: 10.1074/jbc.M006603200. PubMed DOI

Wang Y., Sun L., Chen S., Guo S., Yue T., Hou Q., Feng M., Xu H., Liu Y., Wang P., et al. The administration of Escherichia coli Nissle 1917 ameliorates irinotecan-induced intestinal barrier dysfunction and gut microbial dysbiosis in mice. Life Sci. 2019;231:116529. doi: 10.1016/j.lfs.2019.06.004. PubMed DOI

Bhattarai Y. Microbiota-gut-brain axis: Interaction of gut microbes and their metabolites with host epithelial barriers. Neurogastroenterol. Motil. 2018;30:e13366. doi: 10.1111/nmo.13366. PubMed DOI

Alvarez C.S., Badia J., Bosch M., Gimenez R., Baldoma L. Outer Membrane Vesicles and Soluble Factors Released by Probiotic Escherichia coli Nissle 1917 and Commensal ECOR63 Enhance Barrier Function by Regulating Expression of Tight Junction Proteins in Intestinal Epithelial Cells. Front. Microbiol. 2016;7:1981. doi: 10.3389/fmicb.2016.01981. PubMed DOI PMC

Okunuki Y., Mukai R., Nakao T., Tabor S.J., Butovsky O., Dana R., Ksander B.R., Connor K.M. Retinal microglia initiate neuroinflammation in ocular autoimmunity. Proc. Natl. Acad. Sci. USA. 2019;116:9989–9998. doi: 10.1073/pnas.1820387116. PubMed DOI PMC

Mantovani A., Sica A., Sozzani S., Allavena P., Vecchi A., Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–686. doi: 10.1016/j.it.2004.09.015. PubMed DOI

Oral, not gut microbiota diversity, reflects the inflammation and neoplasia in patients with uveitis and vitreoretinal lymphoma

Experimental model of primary intraocular lymphoma based on BALB/CaNn strain and A20 cells is optimal for investigational research

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