Psoriatic patients have altered microbiota, both in the intestine and on the skin. It is not clear, however, whether this is a cause or consequence of the disease. In this study, using an experimental mouse model of psoriasis induced by imiquimod (IMQ), we show that oral treatment with a broad spectrum of antibiotics (MIX) or metronidazole (MET) alone mitigates the severity of skin inflammation through downregulation of Th17 immune response in conventional mice. Since some antibiotics, including MET, can influence immune system reactivity, we also evaluated the effect of MIX in the same model under germ-free (GF) conditions. GF mice treated with MET did not show milder signs of imiquimod-induced skin inflammation (IISI) which supports the conclusion that the therapeutic effect is mediated by changes in microbiota composition. Moreover, compared to controls, mice treated with MIX had a significantly higher abundance of the genus Lactobacillus in the intestine and on the skin. Mice treated with MET had a significantly higher abundance of the genera Bifidobacterium and Enterococcus both on the skin and in the intestine and of Parabacteroides distasonis in the intestine. Additionally, GF mice and mice monocolonized with either Lactobacillus plantarum or segmented filamentous bacteria (SFB) were more resistant to IISI than conventional mice. Interestingly, compared to GF mice, IMQ induced a higher degree of systemic Th17 activation in mice monocolonized with SFB but not with L. plantarum. The present findings provide evidence that intestinal and skin microbiota directly regulates IISI and emphasizes the importance of microbiota in the pathogenesis of psoriasis.

1st Faculty of Medicine Charles University Prague Czechia

BIOCEV Institute of Microbiology Czech Academy of Sciences Vestec Czechia

Department of Dermatology and Bulovka Hospital 2nd Faculty of Medicine Charles University Prague Czechia

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

Institute of Microbiology of the Czech Academy of Sciences v v i Novy Hradek Czechia

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

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

Zobrazit více v PubMed

Al-Banna N. A., Pavlovic D., Grundling M., Zhou J., Kelly M., Whynot S., et al. . (2013). Impact of antibiotics on the microcirculation in local and systemic inflammation. Clin. Hemorheol. Microcirc. 53, 155–169. 10.3233/CH-2012-1583, PMID: PubMed DOI

Alekseyenko A. V., Perez-Perez G. I., De Souza A., Strober B., Gao Z., Bihan M., et al. (2013). Community differentiation of the cutaneous microbiota in psoriasis. Microbiome 1:31. 10.1186/2049-2618-1-31 PubMed DOI PMC

Armstrong A. W., Harskamp C. T., Armstrong E. J. (2013). Psoriasis and metabolic syndrome: a systematic review and meta-analysis of observational studies. J. Am. Acad. Dermatol. 68, 654–662. 10.1016/j.jaad.2012.08.015 PubMed DOI

Becker E., Bengs S., Aluri S., Opitz L., Atrott K., Stanzel C., et al. (2016). Doxycycline, metronidazole and isotretinoin: do they modify microRNA/mRNA expression profiles and function in murine T-cells? Sci. Rep. 6:37082. 10.1038/srep37082 PubMed DOI PMC

Boehncke W. H. (2018). Systemic inflammation and cardiovascular comorbidity in psoriasis patients: causes and consequences. Front. Immunol. 9:579. 10.3389/fimmu.2018.00579 PubMed DOI PMC

Buyuk A. Y., Kavala M. (2000). Oral metronidazole treatment of lichen planus. J. Am. Acad. Dermatol. 43, 260–262. 10.1067/mjd.2000.104683 PubMed DOI

Caporaso J. G., Kuczynski J., Stombaugh J., Bittinger K., Bushman F. D., Costello E. K., et al. (2010). QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335–336. 10.1038/nmeth.f.303 PubMed DOI PMC

Castiglione F., Rispo A., Di Girolamo E., Cozzolino A., Manguso F., Grassia R., et al. (2003). Antibiotic treatment of small bowel bacterial overgrowth in patients with Crohn’s disease. Aliment. Pharmacol. Ther. 18, 1107–1112. 10.1046/j.1365-2036.2003.01800.x PubMed DOI

Dejaco C., Harrer M., Waldhoer T., Miehsler W., Vogelsang H., Reinisch W. (2003). Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn’s disease. Aliment. Pharmacol. Ther. 18, 1113–1120. 10.1046/j.1365-2036.2003.01793.x, PMID: PubMed DOI

Drago F., Ciccarese G., Indemini E., Savarino V., Parodi A. (2018). Psoriasis and small intestine bacterial overgrowth. Int. J. Dermatol. 57, 112–113. 10.1111/ijd.13797, PMID: PubMed DOI

Erdman S. E., Poutahidis T. (2014). Probiotic ‘glow of health’: it’s more than skin deep. Benef. Microbes 5, 109–119. 10.3920/BM2013.0042 PubMed DOI PMC

Fry L., Baker B. S., Powles A. V., Fahlen A., Engstrand L. (2013). Is chronic plaque psoriasis triggered by microbiota in the skin? Br. J. Dermatol. 169, 47–52. 10.1111/bjd.12322, PMID: PubMed DOI

Furusawa Y., Obata Y., Fukuda S., Endo T. A., Nakato G., Takahashi D., et al. (2013). Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450. 10.1038/nature12721 PubMed DOI

Gao Z., Tseng C. H., Strober B. E., Pei Z., Blaser M. J. (2008). Substantial alterations of the cutaneous bacterial biota in psoriatic lesions. PLoS One 3:e2719. 10.1371/journal.pone.0002719, PMID: PubMed DOI PMC

Gorska S., Schwarzer M., Jachymek W., Srutkova D., Brzozowska E., Kozakova H., et al. (2014). Distinct immunomodulation of bone marrow-derived dendritic cell responses to Lactobacillus plantarum WCFS1 by two different polysaccharides isolated from Lactobacillus rhamnosus LOCK 0900. Appl. Environ. Microbiol. 80, 6506–6516. 10.1128/AEM.02104-14 PubMed DOI PMC

Grove D. I., Mahmound A. A., Warren K. S. (1977). Suppression of cell-mediated immunity by metronidazole. Int. Arch. Allergy Appl. Immunol. 54, 422–427. PubMed

Heissigerova J., Seidler Stangova P., Klimova A., Svozilkova P., Hrncir T., Stepankova R., et al. . (2016). The microbiota determines susceptibility to experimental autoimmune uveoretinitis. J. Immunol. Res. 2016:5065703. 10.1155/2016/5065703, PMID: PubMed DOI PMC

Horton D. B., Scott F. I., Haynes K., Putt M. E., Rose C. D., Lewis J. D., et al. . (2016). Antibiotic exposure, infection, and the development of pediatric psoriasis: a nested case-control study. JAMA Dermatol. 152, 191–199. 10.1001/jamadermatol.2015.3650, PMID: PubMed DOI PMC

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

Ivanov I. I., Atarashi K., Manel N., Brodie E. L., Shima T., Karaoz U., et al. (2009). Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498. 10.1016/j.cell.2009.09.033 PubMed DOI PMC

Jang S. E., Han M. J., Kim S. Y., Kim D. H. (2014). Lactobacillus plantarum CLP-0611 ameliorates colitis in mice by polarizing M1 to M2-like macrophages. Int. Immunopharmacol. 21, 186–192. 10.1016/j.intimp.2014.04.021, PMID: PubMed DOI

Kim H., Kim H. R., Kim N. R., Jeong B. J., Lee J. S., Jang S., et al. . (2015). Oral administration of Lactobacillus plantarum lysates attenuates the development of atopic dermatitis lesions in mouse models. J. Microbiol. 53, 47–52. 10.1007/s12275-015-4483-z, PMID: PubMed DOI

Kong H. H., Oh J., Deming C., Conlan S., Grice E. A., Beatson M. A., et al. . (2012). Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 22, 850–859. 10.1101/gr.131029.111, PMID: PubMed DOI PMC

Kozakova H., Schwarzer M., Tuckova L., Srutkova D., Czarnowska E., Rosiak I., et al. . (2016). Colonization of germ-free mice with a mixture of three lactobacillus strains enhances the integrity of gut mucosa and ameliorates allergic sensitization. Cell. Mol. Immunol. 13, 251–262. 10.1038/cmi.2015.09, PMID: PubMed DOI PMC

Levkovich T., Poutahidis T., Smillie C., Varian B. J., Ibrahim Y. M., Lakritz J. R., et al. . (2013). Probiotic bacteria induce a ‘glow of health’. PLoS One 8, e53867. 10.1371/journal.pone.0053867, PMID: PubMed DOI PMC

Mak R. K., Hundhausen C., Nestle F. O. (2009). Progress in understanding the immunopathogenesis of psoriasis. Actas Dermosifiliogr. 100(Suppl. 2), 2–13. 10.1016/S0001-7310(09)73372-1 PubMed DOI PMC

Mariman R., Reefman E., Tielen F., Persoon-Deen C., van de Mark K., Worms N., et al. . (2016). Lactobacillus plantarum NCIMB8826 ameliorates inflammation of colon and skin in human APOC1 transgenic mice. Benef. Microbes 7, 215–225. 10.3920/BM2015.0074, PMID: PubMed DOI

McFadden J. P., Baker B. S., Powles A. V., Fry L. (2009). Psoriasis and streptococci: the natural selection of psoriasis revisited. Br. J. Dermatol. 160, 929–937. 10.1111/j.1365-2133.2009.09102.x PubMed DOI

Naldi L., Peli L., Parazzini F., Carrel C. F. (2001). 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. 44, 433–438. 10.1067/mjd.2001.110876 PubMed DOI

Noah P. W. (1990). The role of microorganisms in psoriasis. Semin. Dermatol. 9, 269–276. PMID: PubMed

O’Neill C. A., Monteleone G., McLaughlin J. T., Paus R. (2016). The gut-skin axis in health and disease: a paradigm with therapeutic implications. Bioessays 38, 1167–1176. 10.1002/bies.201600008, PMID: PubMed DOI

Ramírez-Boscá A., Navarro-López V., Martínez-Andrés A., Such J., Francés R., Horga de la Parte J., et al. (2015). Identification of bacterial dna in the peripheral blood of patients with active psoriasis. JAMA Dermatol. 151, E1–E2. 10.1001/jamadermatol.2014.5585 PubMed DOI

Rasi A., Behzadi A. H., Davoudi S., Rafizadeh P., Honarbakhsh Y., Mehran M., et al. . (2010). Efficacy of oral metronidazole in treatment of cutaneous and mucosal lichen planus. J. Drugs Dermatol. 9, 1186–1190. PMID: PubMed

Reikvam D. H., Erofeev A., Sandvik A., Grcic V., Jahnsen F. L., Gaustad P., et al. . (2011). Depletion of murine intestinal microbiota: effects on gut mucosa and epithelial gene expression. PLoS One 6:e17996. 10.1371/journal.pone.0017996, PMID: PubMed DOI PMC

Rutgeerts P., Hiele M., Geboes K., Peeters M., Penninckx F., Aerts R., et al. . (1995). Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 108, 1617–1621. 10.1016/0016-5085(95)90121-3, PMID: PubMed DOI

Salem I., Ramser A., Isham N., Ghannoum M. A. (2018). The gut microbiome as a major regulator of the gut-skin axis. Front. Microbiol. 9:1459. 10.3389/fmicb.2018.01459 PubMed DOI PMC

Schwarzer M., Hermanova P., Srutkova D., Golias J., Hudcovic T., Zwicker C., et al. (2019). Germ-free mice exhibit mast cells with impaired functionality and gut homing and do not develop food allergy. Front. Immunol. 10:205. 10.3389/fimmu.2019.00205 PubMed DOI PMC

Scott N. A., Andrusaite A., Andersen P., Lawson M., Alcon-Giner C., Leclaire C., et al. . (2018). Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis. Sci. Transl. Med. 10. 10.1126/scitranslmed.aao4755, PMID: PubMed DOI PMC

Smith P. M., Howitt M. R., Panikov N., Michaud M., Gallini C. A., Bohlooly Y. M., et al. . (2013). The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573. 10.1126/science.1241165, PMID: PubMed DOI PMC

Snel J., Heinen P. P., Blok H. J., Carman R. J., Duncan A. J., Allen P. C., et al. . (1995). Comparison of 16S rRNA sequences of segmented filamentous bacteria isolated from mice, rats, and chickens and proposal of “Candidatus Arthromitus”. Int. J. Syst. Bacteriol. 45, 780–782. 10.1099/00207713-45-4-780, PMID: PubMed DOI

Steinhart A. H., Feagan B. G., Wong C. J., Vandervoort M., Mikolainis S., Croitoru K., et al. . (2002). Combined budesonide and antibiotic therapy for active Crohn’s disease: a randomized controlled trial. Gastroenterology 123, 33–40. 10.1053/gast.2002.34225, PMID: PubMed DOI

Stepankova R., Powrie F., Kofronova O., Kozakova H., Hudcovic T., Hrncir T., et al. . (2007). Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells. Inflamm. Bowel Dis. 13, 1202–1211. 10.1002/ibd.20221, PMID: PubMed DOI

Tan L., Zhao S., Zhu W., Wu L., Li J., Shen M., et al. . (2018). The Akkermansia muciniphila is a gut microbiota signature in psoriasis. Exp. Dermatol. 27, 144–149. 10.1111/exd.13463, PMID: PubMed DOI

Tett A., Pasolli E., Farina S., Truong D. T., Asnicar F., Zolfo M., et al. (2017). Unexplored diversity and strain-level structure of the skin microbiome associated with psoriasis. NPJ Biofilms Microbiomes 3:14. 10.1038/s41522-017-0022-522 PubMed DOI PMC

Tlaskalova-Hogenova H., Stepankova R., Kozakova H., Hudcovic T., Vannucci L., Tuckova L., et al. . (2011). 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. 8, 110–120. 10.1038/cmi.2010.67, PMID: PubMed DOI PMC

Tsankov N., Botev-Zlatkov N., Lazarova A. Z., Kostova M., Popova L., Tonev S. (1988). Psoriasis and drugs: influence of tetracyclines on the course of psoriasis. J. Am. Acad. Dermatol. 19, 629–632. PubMed

van der Fits L., Mourits S., Voerman J. S., Kant M., Boon L., Laman J. D., et al. (2009). Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182, 5836–5845. 10.4049/jimmunol.0802999 PubMed DOI

Viaud S., Saccheri F., Mignot G., Yamazaki T., Daillere R., Hannani D., et al. . (2013). The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976. 10.1126/science.1240537, PMID: PubMed DOI PMC

Vlachos C., Gaitanis G., Katsanos K. H., Christodoulou D. K., Tsianos E., Bassukas I. D. (2016). Psoriasis and inflammatory bowel disease: links and risks. Psoriasis 6, 73–92. 10.2147/PTT.S85194ptt-6-073 PubMed DOI PMC

Wahba-Yahav A. V. (1995). Idiopathic lichen planus: treatment with metronidazole. J. Am. Acad. Dermatol. 33, 301–302. PubMed

Waldman A., Gilhar A., Duek L., Berdicevsky I. (2001). Incidence of Candida in psoriasis - a study on the fungal flora of psoriatic patients. Mycoses 44, 77–81. 10.1046/j.1439-0507.2001.00608.x, PMID: PubMed DOI

Weisenseel P., Laumbacher B., Besgen P., Ludolph-Hauser D., Herzinger T., Roecken M., et al. . (2002). Streptococcal infection distinguishes different types of psoriasis. J. Med. Genet. 39, 767–768. 10.1136/jmg.39.10.767, PMID: PubMed DOI PMC

Yan D., Issa N., Afifi L., Jeon C., Chang H. W., Liao W. (2017). The role of the skin and gut microbiome in psoriatic disease. Curr. Dermatol. Rep. 6, 94–103. 10.1007/s13671-017-0178-5, PMID: PubMed DOI PMC

Zakostelska Z., Kverka M., Klimesova K., Rossmann P., Mrazek J., Kopecny J., et al. . (2011). Lysate of probiotic Lactobacillus casei DN-114 001 ameliorates colitis by strengthening the gut barrier function and changing the gut microenvironment. PLoS One 6:e27961. 10.1371/journal.pone.0027961, PMID: PubMed DOI PMC

Zakostelska Z., Malkova J., Klimesova K., Rossmann P., Hornova M., Novosadova I., et al. . (2016). Intestinal microbiota promotes psoriasis-like skin inflammation by enhancing Th17 response. PLoS One 11:e0159539. 10.1371/journal.pone.0159539, PMID: PubMed DOI PMC

Zanvit P., Konkel J. E., Jiao X., Kasagi S., Zhang D., Wu R., et al. (2015). Antibiotics in neonatal life increase murine susceptibility to experimental psoriasis. Nat. Commun. 6:8424. 10.1038/ncomms9424 PubMed DOI PMC

Zeng J., Luo S., Huang Y., Lu Q. (2017). Critical role of environmental factors in the pathogenesis of psoriasis. J. Dermatol. 44, 863–872. 10.1111/1346-8138.13806, PMID: PubMed DOI

Bifidobacteria in disease: from head to toe

Genetic background and microbiome drive susceptibility to epicutaneous sensitization and food allergy in adjuvant-free mouse model

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

Skin microbiota signature distinguishes IBD patients and reflects skin adverse events during anti-TNF therapy

Contribution of Infectious Agents to the Development of Celiac Disease