Psoriasis is a chronic inflammatory skin disease in which Th17 cells play a crucial role. Since indigenous gut microbiota influences the development and reactivity of immune cells, we analyzed the link among microbiota, T cells and the formation of psoriatic lesions in the imiquimod-induced murine model of psoriasis. To explore the role of microbiota, we induced skin inflammation in germ-free (GF), broad-spectrum antibiotic (ATB)-treated or conventional (CV) BALB/c and C57BL/6 mice. We found that both mice reared in GF conditions for several generations and CV mice treated with ATB were more resistant to imiquimod-induced skin inflammation than CV mice. The ATB treatment dramatically changed the diversity of gut bacteria, which remained stable after subsequent imiquimod application; ATB treatment resulted in a substantial increase in the order Lactobacillales and a significant decrease in Coriobacteriales and Clostridiales. Moreover, as compared to CV mice, imiquimod induced a lower degree of local and systemic Th17 activation in both GF and ATB-treated mice. These findings suggest that gut microbiota control imiquimod-induced skin inflammation by altering the T cell response.

Department of Dermatology 2nd Medical Faculty Charles University Prague and Bulovka Hospital Prague Czech Republic

Institute of Experimental Medicine of the Czech Academy of Sciences v v i Prague Czech Republic

Institute of Microbiology of the Czech Academy of Sciences v v i Nový Hrádek Czech Republic

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

Institute of Molecular Genetics of the Czech Academy of Sciences v v i Prague Czech Republic

Zobrazit více v PubMed

Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133(2):377–85. Epub 2012/09/28. jid2012339 [pii] 10.1038/jid.2012.339 . PubMed DOI

Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol. 2009;129(6):1339–50. Epub 2009/03/27. jid200959 [pii] 10.1038/jid.2009.59 . PubMed DOI

Bhatia BK, Millsop JW, Debbaneh M, Koo J, Linos E, Liao W. Diet and psoriasis, part II: celiac disease and role of a gluten-free diet. J Am Acad Dermatol. 2014;71(2):350–8. Epub 2014/05/02. S0190-9622(14)01244-4 [pii] 10.1016/j.jaad.2014.03.017 PubMed DOI PMC

Debbaneh M, Millsop JW, Bhatia BK, Koo J, Liao W. Diet and psoriasis, part I: Impact of weight loss interventions. J Am Acad Dermatol. 2014;71(1):133–40. Epub 2014/04/09. S0190-9622(14)01126-8 [pii] 10.1016/j.jaad.2014.02.012 PubMed DOI PMC

Di Meglio P, Duarte JH, Ahlfors H, Owens ND, Li Y, Villanova F, et al. Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity. 2014;40(6):989–1001. Epub 2014/06/10. S1074-7613(14)00183-6 [pii] 10.1016/j.immuni.2014.04.019 PubMed DOI PMC

Fry L, Baker BS, Powles AV, Fahlen A, Engstrand L. Is chronic plaque psoriasis triggered by microbiota in the skin? Br J Dermatol. 2013;169(1):47–52. Epub 2013/03/26. 10.1111/bjd.12322 . PubMed DOI

Noah PW. The role of microorganisms in psoriasis. Semin Dermatol. 1990;9(4):269–76. Epub 1990/12/01. . PubMed

McFadden JP, Baker BS, Powles AV, Fry L. Psoriasis and streptococci: the natural selection of psoriasis revisited. Br J Dermatol. 2009;160(5):929–37. Epub 2009/03/25. BJD9102 [pii] 10.1111/j.1365-2133.2009.09102.x . PubMed DOI

Naldi L, Peli L, Parazzini F, Carrel CF. Family history of psoriasis, stressful life events, and recent infectious disease are risk factors for a first episode of acute guttate psoriasis: results of a case-control study. J Am Acad Dermatol. 2001;44(3):433–8. Epub 2001/02/24. S0190-9622(01)37292-4 [pii] 10.1067/mjd.2001.110876 . PubMed DOI

Alekseyenko AV, Perez-Perez GI, De Souza A, Strober B, Gao Z, Bihan M, et al. Community differentiation of the cutaneous microbiota in psoriasis. Microbiome. 2013;1(1):31 Epub 2014/01/24. 2049-2618-1-31 [pii] 10.1186/2049-2618-1-31 PubMed DOI PMC

Gao Z, Tseng CH, Strober BE, Pei Z, Blaser MJ. Substantial alterations of the cutaneous bacterial biota in psoriatic lesions. PLoS One. 2008;3(7):e2719 Epub 2008/07/24. 10.1371/journal.pone.0002719 PubMed DOI PMC

Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–98. 10.1016/j.cell.2009.09.033 PubMed DOI PMC

Stepankova R, Powrie F, Kofronova O, Kozakova H, Hudcovic T, Hrncir T, et al. Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells. Inflamm Bowel Dis. 2007;13(10):1202–11. Epub 2007/07/04. 10.1002/ibd.20221 . PubMed DOI

Hansen CH, Nielsen DS, Kverka M, Zakostelska Z, Klimesova K, Hudcovic T, et al. Patterns of early gut colonization shape future immune responses of the host. PLoS One. 2012;7(3):e34043 10.1371/journal.pone.0034043 PubMed DOI PMC

Zanvit P, Konkel JE, Jiao X, Kasagi S, Zhang D, Wu R, et al. Antibiotics in neonatal life increase murine susceptibility to experimental psoriasis. Nat Commun. 2015;6:8424 Epub 2015/09/30. ncomms9424 [pii] 10.1038/ncomms9424 ; PubMed Central PMCID: PMC4598725. PubMed DOI PMC

Klimesova K, Kverka M, Zakostelska Z, Hudcovic T, Hrncir T, Stepankova R, et al. Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice. Inflamm Bowel Dis. 2013;19(6):1266–77. 10.1097/MIB.0b013e318281330a PubMed DOI PMC

Hrncir T, Stepankova R, Kozakova H, Hudcovic T, Tlaskalova-Hogenova H. Gut microbiota and lipopolysaccharide content of the diet influence development of regulatory T cells: studies in germ-free mice. BMC Immunol. 2008;9:65 Epub 2008/11/08. 1471-2172-9-65 [pii] 10.1186/1471-2172-9-65 PubMed DOI PMC

van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. 2009;182(9):5836–45. Epub 2009/04/22. 182/9/5836 [pii] 10.4049/jimmunol.0802999 . PubMed DOI

Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ, et al. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 2010;3(2):148–58. Epub 2009/11/27. mi2009132 [pii] 10.1038/mi.2009.132 PubMed DOI PMC

Reikvam DH, Erofeev A, Sandvik A, Grcic V, Jahnsen FL, Gaustad P, et al. Depletion of murine intestinal microbiota: effects on gut mucosa and epithelial gene expression. PLoS One. 2011;6(3):e17996 Epub 2011/03/30. 10.1371/journal.pone.0017996 PubMed DOI PMC

Zakostelska Z, Kverka M, Klimesova K, Rossmann P, Mrazek J, Kopecny 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(11):e27961 10.1371/journal.pone.0027961 PubMed DOI PMC

Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335–6. Epub 2010/04/13. nmeth.f.303 [pii] 10.1038/nmeth.f.303 PubMed DOI PMC

Bacchetti De Gregoris T, Aldred N, Clare AS, Burgess JG. Improvement of phylum- and class-specific primers for real-time PCR quantification of bacterial taxa. J Microbiol Methods. 2011;86(3):351–6. 10.1016/j.mimet.2011.06.010 . PubMed DOI

Pantelyushin S, Haak S, Ingold B, Kulig P, Heppner FL, Navarini AA, et al. Rorgammat+ innate lymphocytes and gammadelta T cells initiate psoriasiform plaque formation in mice. J Clin Invest. 2012;122(6):2252–6. Epub 2012/05/02. 61862 [pii] 10.1172/JCI61862 PubMed DOI PMC

Yoshiki R, Kabashima K, Honda T, Nakamizo S, Sawada Y, Sugita K, et al. IL-23 from Langerhans cells is required for the development of imiquimod-induced psoriasis-like dermatitis by induction of IL-17A-producing gammadelta T cells. J Invest Dermatol. 2014;134(7):1912–21. Epub 2014/02/27. jid201498 [pii] 10.1038/jid.2014.98 . PubMed DOI

Tlaskalova-Hogenova H, Stepankova R, Kozakova H, Hudcovic T, Vannucci L, Tuckova L, 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(2):110–20. Epub 2011/02/01. cmi201067 [pii] 10.1038/cmi.2010.67 . PubMed DOI PMC

Gomez de Aguero M, Ganal-Vonarburg SC, Fuhrer T, Rupp S, Uchimura Y, Li H, et al. The maternal microbiota drives early postnatal innate immune development. Science. 2016;351(6279):1296–302. 10.1126/science.aad2571 . PubMed DOI

Flutter B, Nestle FO. TLRs to cytokines: mechanistic insights from the imiquimod mouse model of psoriasis. Eur J Immunol. 2013;43(12):3138–46. Epub 2013/11/21. 10.1002/eji.201343801 . PubMed DOI

Arck P, Handjiski B, Hagen E, Pincus M, Bruenahl C, Bienenstock J, et al. Is there a 'gut-brain-skin axis'? Exp Dermatol. 2010;19(5):401–5. Epub 2010/02/02. EXD1060 [pii] 10.1111/j.1600-0625.2009.01060.x . PubMed DOI

Bowe W, Patel NB, Logan AC. Acne vulgaris, probiotics and the gut-brain-skin axis: from anecdote to translational medicine. Benef Microbes. 2014;5(2):185–99. Epub 2013/07/28. 0U3X16807123W358 [pii] 10.3920/BM2012.0060 . PubMed DOI

Majamaa H, Isolauri E. Evaluation of the gut mucosal barrier: evidence for increased antigen transfer in children with atopic eczema. J Allergy Clin Immunol. 1996;97(4):985–90. Epub 1996/04/01. S0091674996000899 [pii]. . PubMed

Parodi A, Paolino S, Greco A, Drago F, Mansi C, Rebora A, et al. Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol. 2008;6(7):759–64. Epub 2008/05/06. S1542-3565(08)00155-9 [pii] 10.1016/j.cgh.2008.02.054 . PubMed DOI

Huang BL, Chandra S, Shih DQ. Skin manifestations of inflammatory bowel disease. Front Physiol. 2012;3:13 Epub 2012/02/22. 10.3389/fphys.2012.00013 PubMed DOI PMC

Leffler DA, Green PH, Fasano A. Extraintestinal manifestations of coeliac disease. Nat Rev Gastroenterol Hepatol. 2015;12(10):561–71. Epub 2015/08/12. nrgastro.2015.131 [pii] 10.1038/nrgastro.2015.131 . PubMed DOI

Scher JU, Ubeda C, Artacho A, Attur M, Isaac S, Reddy SM, et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol. 2015;67(1):128–39. Epub 2014/10/17. 10.1002/art.38892 PubMed DOI PMC

Weinstock LB, Steinhoff M. Rosacea and small intestinal bacterial overgrowth: prevalence and response to rifaximin. J Am Acad Dermatol. 2013;68(5):875–6. Epub 2013/04/23. S0190-9622(12)02330-4 [pii] 10.1016/j.jaad.2012.11.038 . PubMed DOI

Bjorksten B, Naaber P, Sepp E, Mikelsaar M. The intestinal microflora in allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy. 1999;29(3):342–6. Epub 1999/04/15. . PubMed

Majamaa H, Isolauri E. Probiotics: a novel approach in the management of food allergy. J Allergy Clin Immunol. 1997;99(2):179–85. Epub 1997/02/01. S0091674997000304 [pii]. . PubMed

Viljanen M, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy. 2005;60(4):494–500. Epub 2005/02/25. ALL514 [pii] 10.1111/j.1398-9995.2004.00514.x PubMed DOI

Chen L, Zou Y, Peng J, Lu F, Yin Y, Li F, et al. Lactobacillus acidophilus suppresses colitis-associated activation of the IL-23/Th17 axis. J Immunol Res. 2015;2015:909514 Epub 2015/05/15. 10.1155/2015/909514 PubMed DOI PMC

Cardone M, Dzutsev AK, Li H, Riteau N, Gerosa F, Shenderov K, et al. Interleukin-1 and interferon-gamma orchestrate beta-glucan-activated human dendritic cell programming via IkappaB-zeta modulation. PLoS One. 2014;9(12):e114516 Epub 2014/12/05. 10.1371/journal.pone.0114516 PONE-D-14-36425 [pii]. PubMed DOI PMC

Johansen C, Mose M, Ommen P, Bertelsen T, Vinter H, Hailfinger S, et al. IkappaBzeta is a key driver in the development of psoriasis. Proc Natl Acad Sci U S A. 2015;112(43):E5825–33. Epub 2015/10/16. 1509971112 [pii] 10.1073/pnas.1509971112 PubMed DOI PMC

Lysate of Parabacteroides distasonis prevents severe forms of experimental autoimmune encephalomyelitis by modulating the priming of T cell response

Paradoxical Reactions to Anti-TNFα and Anti-IL-17 Treatment in Psoriasis Patients: Are Skin and/or Gut Microbiota Involved?

Contribution of Infectious Agents to the Development of Celiac Disease

Severity of Experimental Autoimmune Uveitis Is Reduced by Pretreatment with Live Probiotic Escherichia coli Nissle 1917

Dysbiosis of Skin Microbiota in Psoriatic Patients: Co-occurrence of Fungal and Bacterial Communities

Crucial Role of Microbiota in Experimental Psoriasis Revealed by a Gnotobiotic Mouse Model