Toll-Like Receptor 7 Agonist-Induced Dermatitis Causes Severe Dextran Sulfate Sodium Colitis by Altering the Gut Microbiome and Immune Cells

doi:10.1016/j.jcmgh.2018.09.010

. 2018 Sep 25;7(1):135-156.

doi: 10.1016/j.jcmgh.2018.09.010. eCollection 2019.

Toll-Like Receptor 7 Agonist-Induced Dermatitis Causes Severe Dextran Sulfate Sodium Colitis by Altering the Gut Microbiome and Immune Cells

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
² Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Japan Agency for Medical Research and Development, AMED, Tokyo, Japan. Electronic address: tsujino1224@keio.jp.
³ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Miyarisan Pharmaceutical Co, Ltd, Tokyo, Japan.
⁴ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Institute of Health Sciences, Ezaki Glico Co, Ltd, Nishiyodogawa, Osaka, Japan.
⁵ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Tanabe Mitsubishi Pharmaceutical Co, Ltd, Tokyo, Japan.
⁶ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Japan Agency for Medical Research and Development, AMED, Tokyo, Japan. Electronic address: takagast@keio.jp.

PMID: 30510995
PMCID: PMC6260383
DOI: 10.1016/j.jcmgh.2018.09.010

Toll-Like Receptor 7 Agonist-Induced Dermatitis Causes Severe Dextran Sulfate Sodium Colitis by Altering the Gut Microbiome and Immune Cells

Hiroki Kiyohara et al. Cell Mol Gastroenterol Hepatol. 2018.

. 2018 Sep 25;7(1):135-156.

doi: 10.1016/j.jcmgh.2018.09.010. eCollection 2019.

Authors

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
² Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Japan Agency for Medical Research and Development, AMED, Tokyo, Japan. Electronic address: tsujino1224@keio.jp.
³ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Miyarisan Pharmaceutical Co, Ltd, Tokyo, Japan.
⁴ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Institute of Health Sciences, Ezaki Glico Co, Ltd, Nishiyodogawa, Osaka, Japan.
⁵ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Tanabe Mitsubishi Pharmaceutical Co, Ltd, Tokyo, Japan.
⁶ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Japan Agency for Medical Research and Development, AMED, Tokyo, Japan. Electronic address: takagast@keio.jp.

PMID: 30510995
PMCID: PMC6260383
DOI: 10.1016/j.jcmgh.2018.09.010

Abstract

Background & aims: Psoriasis and inflammatory bowel disease (IBD) are both chronic inflammatory diseases occurring in the skin and gut, respectively. It is well established that psoriasis and IBD have high concordance rates, and similar changes in immune cells and microbiome composition have been reported in both conditions. To study this connection, we used a combination murine model of psoriatic dermatitis and colitis in which mice were treated topically with the Toll-like receptor 7 agonist imiquimod (IMQ) and fed dextran sulfate sodium (DSS).

Methods: We applied IMQ topically to B6 mice (IMQ mice) and subsequently fed them 2% DSS in their drinking water. Disease activity and immune cell phenotypes were analyzed, and the microbial composition of fecal samples was investigated using 16S ribosomal RNA sequencing. We transplanted feces from IMQ mice to germ-free IQI/Jic (IQI) mice and fed them DSS to assess the effect of the gut microbiome on disease.

Results: We first confirmed that IMQ mice showed accelerated DSS colitis. IMQ mice had decreased numbers of IgD⁺ and IgM⁺ B cells and increased numbers of non-cytokine-producing macrophages in the gut. Moreover, the gut microbiomes of IMQ mice were perturbed, with significant reductions of Lactobacillus johnsonii and Lactobacillus reuteri populations. Germ-free mice transplanted with feces from IMQ mice, but not with feces from untreated mice, also developed exacerbated DSS colitis.

Conclusions: These results suggest that skin inflammation may contribute to pathogenic conditions in the gut via immunologic and microbiological changes. Our finding of a novel potential skin-gut interaction provides new insights into the coincidence of psoriasis and IBD.

Keywords: Abx, antibiotics; BM, bone marrow; BSA, bovine serum albumin; DAI, disease activity index; DSS, dextran sulfate sodium; Dermatitis; FITC, fluorescein isothiocyanate; GF, germ-free; Gut Microbiome; HBSS, Hank’s balanced salt solution; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; IMQ, imiquimod; IP, intraperitoneally; IQI, IQI/Jic; Inflammatory Bowel Disease; LP, lamina propria; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; OTU, operational taxonomic unit; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PE, phycoerythrin; PMA, phorbol 12-myristate-13-acetate; SPF, specific pathogen-free; TLR, Toll-like receptor; TNF, tumor necrosis factor; Th, T helper; Treg, regulatory T cells; WT, wild-type; ZO-1, zonula occludens-1; dLN, draining lymph node; gnoto, gnotobiote; pDC, plasmacytoid dendritic cell; rRNA, ribosomal RNA.

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Figures

**Figure 1**
**Psoriasis-like dermatitis exacerbates DSS colitis.** (A) Experimental protocol for induction of psoriasis-like dermatitis by IMQ. (B) Skin appearance of psoriasis-like dermatitis on day 14 of IMQ or vehicle treatment. (C) Clinical score for psoriasis-like dermatitis (psoriasis area severity index [PASI] score) at the end of IMQ treatment (on day 17). (D) Representative H&E staining of colon sections at the end of IMQ treatment (on day 17). *Scale bar*: 100 μm. (E) Experimental protocol. Mice treated topically with IMQ or vehicle as shown in panel A, were subsequently induced with acute colitis by 2% (wt/vol) DSS for 7 days (n = 8 in each group). (F) Body weight changes during administration of DSS. (G) Representative photograph of colon on day 7 of DSS colitis. (H) Colon length on day 7 of DSS colitis. (I) DAI score on day 7 of DSS colitis. (J) Representative H&E staining of distal colon section on day 7 of DSS colitis. *Scale bar*: 100 μm. (K) Histologic score for colitis on day 7 of DSS colitis. (L) Representative plots of flow cytometry analysis for colonic lamina propria macrophages (CD45⁺ lineage^-CD11b⁺CD64⁺ cells). The plots are gated on CD45⁺CD3^-CD19^-B220^-NK1.1^- cells. (M) Percentage (*left*) and absolute number (*right*) of colonic lamina propria macrophages. (N and O) Representative plots of flow cytometry analysis for CD80⁺ macrophages in colonic lamina propria. Percentage of CD80⁺ cells in macrophages. (P) Representative plots of flow cytometry analysis for CD45⁺ colonic lamina propria lymphocytes. (Q and R) Percentage and absolute number of B cells (*left*) and T cells (*right*) in CD45⁺ cells. (S) Absolute number of IgA⁺ B cells (*left*), IgD⁺ B cells (*middle*), and IgM⁺ B cells (*right*). (T) Representative plots of flow cytometry analysis for IgA⁺ plasma cells in colonic lamina propria (*left*) and absolute number (*right*). The plots are gated on CD45⁺CD3^-CD4^-CD8^-NK1.1^- cells. (U) Percentage of IgA-coated fecal bacteria analyzed by flow cytometry. Each symbol represents an individual mouse (n = 3–8). Statistical analyses were performed with the Student t test. *P < .05, **P < .01, ***P < .001, NS; not significant. *Error bars* represent the SEM of samples within a group.

**Figure 2**
**IMQ dermatitis mice did not increase intestinal permeability but altered immune cell composition in the intestine.** (A) Analysis for intestinal permeability of mice induced psoriasis-like dermatitis (on day 17 of IMQ or vehicle treatment), by using 4 kilodaltons (*left*) or 70 kilodaltons (*right*) FITC-dextran. Plasma FITC-dextran concentrations were determined by fluorescence intensity, after 1, 2 and 4 hours from oral administration of FITC-dextran (n = 4, in each group). Seventy kilodaltons FITC-dextran was administered intravenously as a positive control. (B) Quantitative PCR analysis for *ZO-1* and *occludin* in colonic epithelial cells after topical IMQ treatment (on day 17) analyzed by real-time PCR. (C) Western blot analysis for occludin expression in colonic epithelial cells after topical IMQ treatment (on day 17). Western blot (*left*) and relative protein levels (*right*) of occludin. (D) Immunofluorescence staining was performed in control and IMQ mice. ZO-1 (*top*, green), occludin (*middle*, red), claudin (*bottom*, green) stained with 4′,6-diamidino-2-phenylindole (DAPI; blue) in colon tissue. Four to 5 sections from each mice were obtained and the average positive area of each protein was compared with the DAPI-positive area measured (n = 4–5, each *dot* represents each mouse). (F) Quantitative PCR analysis for *Reg IIIγ* in colonic epithelial cells after topical IMQ treatment (on day 17) analyzed by real-time PCR. (G) Representative plots of flow cytometry analysis for macrophages (CD11b⁺CD64⁺ cells) in CD45⁺CD3^-CD19^- B220^-NK1.1^- colonic lamina propria after IMQ treatment (on day 17) (n = 6 in each group). Percentage (*left*) and absolute number (*right*) of macrophages in colonic lamina propria. (H and I) Percentage and absolute number of CD206⁺ (*left*) or CD80⁺ (*right*) macrophages. (I) Quantitative PCR analysis of *IL10*, *Tnf-α*, *Il6*, *IL12b*, *Arg-1*, and *Nos2* in LP CD11b⁺s (n = 3–4 in each group). (J) CD11b⁺ cells were sorted by magnetic activated cell sorting from colonic lamina propria mononuclear cells on day 17 of IMQ treatment (LP CD11b⁺s). LP CD11b⁺s were cultured with lipopolysaccharide (LPS) or peptidoglycan (PGN) for 24 hours in vitro, and concentrations of cytokines in the supernatant were measured by cytometric bead array. Unstimulated control was cultured with medium (Med). (K) Western blot analysis for NLRP3 in peritoneal cavity cells, which are composed mainly of macrophages. Western blot (*left*) and relative protein levels (*right*) of NLRP3 (n = 7–8, pooled from 2 independent experiments, in each group). (L) Percentage of ILC3 in CD45⁺CD3^-CD19^- cells and (M) pDCs in CD45⁺CD11b^-CD11c⁺ cells in colonic lamina propria (ILC3, CD45⁺CD3^-CD19^-Rorγt⁺ cells; pDC, CD45⁺CD11b^-CD11c⁺B220⁺PDCA-1⁺ cells. Each symbol represents an individual mouse (n = 4–8). Statistical analyses were performed with the Student t test. *P < .05, **P < .01, ***P < .001. *Error bars* represent the SEM of samples within a group.

**Figure 3**
**The reduction of IgD**⁺**and IgM**⁺**B cells of colon in IMQ mice was not caused by migration to skin or skin draining lymph nodes, or by systemic B-cell depletion.** (A) Representative plots of flow cytometry analysis for lymphocytes in CD45⁺ colonic lamina propria. (B and C) Percentage (*left*) and absolute number (*right*) of (B) T cells and (C) B cells in CD45⁺ colonic lamina propria as shown in panel A. (D) Representative plots of flow cytometry analysis for IFN-γ and IL17A in CD3⁺CD4⁺ cells from colonic lamina propria, skin dLN. and mesenteric lymph node (MLN), stimulated with PMA, ionomycin, and IL23 for 4 hours. (E) Percentage of IFN-γ⁺ (*top*) and IL17A⁺ (*bottom*) cells in CD3⁺CD4⁺ lymphocytes from each organ. (F and G) Intracellular staining and the ratio of Foxp3 in CD3⁺CD4⁺ lymphocytes from each organ. (H) Absolute number of IgA⁺ B cells (*left*), IgD⁺ B cells (*middle*), and IgM⁺ B cells (*right*). (I) Percentage in CD45⁺ cells of IgA⁺B220^- plasma cells. (J) Concentration of IgA in feces measured by enzyme-linked immunosorbent assay. (K) Percentage of IgA-coated bacteria in feces. (L) Representative plots of flow cytometry analysis for B cells in epidermis, dermis, skin dLNs, spleen, and MLN after topical IMQ treatment. The numbers within plots indicate the percentages of gated cells. The plots are gated on CD45⁺ cells. (M) Percentages of B cells in CD45⁺ cells in epidermis, dermis, skin dLN, spleen, and MLN as shown in panel L. (N) Absolute number of B cells (*top*), IgD⁺ B cells (*middle*), and IgM⁺ B cells (*bottom*) in skin dLN and MLN. Each symbol represents an individual mouse (n = 4–8). Statistical analyses were performed with the Student t test. *P < .05, **P < .01, ***P < .001. *Error bars* represent the SEM of samples within a group.

**Figure 4**
**Psoriasis-like dermatitis was required to induce immunologic changes in the gut and to exacerbate DSS colitis.** (*A–C*) Psoriasis-like dermatitis was induced by topical IMQ treatment in TLR7^-/- mice (IMQ-ΔTLR7 mice) and WT mice (WT-IMQ mice). As control, vehicle was applied to TLR7^-/- mice (cont-ΔTLR7 mice) instead of IMQ, and the severity of dermatitis and B cell change in colonic lamina propria were assessed. Skin appearance after induction of psoriasis-like dermatitis by (A) IMQ, (B) Psoriasis Area and Severity Index (PASI) score, and (C) the percentage of B cells in colonic lamina propria analyzed by flow cytometry. (*D–I*) IMQ was injected IP to mice daily for a week and lymphocytes in colonic lamina propria were analyzed. PBS was injected instead of IMQ as control. (D) Experimental protocol, (E) absolute number of lamina propria mononuclear cells (LPMCs), (F) percentage in CD45⁺lineage^- cells (*left*) and absolute number (*right*) of macrophages in colonic lamina propria, (G) percentage in CD45⁺ cells (*left*) and absolute number (*right*) of T cells, and (H) B cells. (I) Percentages in the total B cells of IgA⁺ B cells, IgD⁺ B cells, and IgM⁺ B cells. (J) Experimental protocol. Mice injected IP with IMQ or PBS were further administered 2% (wt/vol) DSS for 7 days to induce colitis, and the severity of colitis was assessed. (K) Representative photograph of colon on day 7 of DSS colitis. (L) Body weight change during DSS administration. (M) Colon length on day 7 of DSS colitis. (N) DAI score on day 7 of DSS colitis. Each symbol represents an individual mouse (n = 3–5). Statistical analyses were performed with the Student t test. *P < .05, **P < .01, ***P < .005. *Error bars* represent the SEM of samples within a group. Lineage, CD3, CD19, B220, and NK1.1.

**Figure 5**
**IMQ-induced psoriasis-like dermatitis alters gut microbial compositions.** 16S rRNA metagenomic analysis for fecal samples derived from mice after IMQ or vehicle treatment (n = 4 in each group). Feces were collected on day 17 of IMQ or vehicle treatment, as shown in Figure 1A. (A) Number of OTUs. (B) Principal coordinate analysis based on unweighted UniFrac distances (*left*) and weighted UniFrac distances (*right*). The 2 principal components (PC1 and PC2) explained 45.1% and 89.9% in the principal coordinate analysis based on unweighted and weighted UniFrac distances, respectively. (C) Phylum and (D) family level bacterial compositions of IMQ or vehicle-treated mice. (E and F) Relative abundance of each (E) family and (F) genera. (G) Proportion of each *Lactobacillus* species in control mice. (H) Relative abundance of 3 dominant *Lactobacillus* species in control and IMQ mice. Statistical analyses were performed with (A, E, and F) the Mann–Whitney U test, or (B) the Permanova test. *P < .05. *Error bars* represent the SEM of samples within a group.

**Figure 6**
**A gut microbiome in IMQ mice is essential to induce severe DSS colitis.** (A) Mice were administered a mixture of ampicillin, neomycin, vancomycin, and metronidazole by oral gavage 3 times a week until the end of the experiment. IMQ treatment was started 1 week after starting Abx treatment. Colonic lamina propria mononuclear cells after IMQ treatment (on day 17) were analyzed by flow cytometry. (B and C) Flow cytometry analysis, the ratio and cell number of CD11b⁺CD64⁺ cells in CD45⁺CD3^-CD19^- B220^-NK1.1^- cells from colon lamina propria mononuclear cells. (D and E) Flow cytometry analysis, the ratio and cell number of CD19⁺ cells in CD45⁺ cells from colon lamina propria mononuclear cells. (*F–H*) Percentage in the total B cells (*left*) and absolute number (*right*) of (F) IgA⁺ B cells, (G) IgD⁺ B cells, and (H) IgM⁺ B cells in CD45⁺ cells from colon lamina propria mononuclear cells. (I) Mice were administered Abx (a mixture of ampicillin, neomycin, vancomycin, and metronidazole) or distilled water by oral gavage 3 times a week until the end of the experiment. Topical IMQ treatment was started 1 week after starting Abx or distilled water. A total of 2% (wt/vol) DSS subsequently was administered to all mice for 7 days after topical treatment of IMQ or vehicle. (J) Psoriasis Area and Severity Index (PASI) score on day 16 of IMQ or vehicle treatment. (K) Body weight changes during administration of DSS. (L) Body weight percentages on day 7 of DSS colitis. (M) Representative photograph of colon on day 7 of DSS colitis. (N) Colon length on day 7 of DSS colitis. (O) DAI score on day 7 of DSS colitis. (P) Representative H&E staining of distal colon section on day 7 of DSS colitis. *Scale bar*: 100 μm. (Q) Histologic score for colitis on day 7 of DSS colitis (water-cont-DSS and water-IMQ-DSS, n = 11; Abx-cont-DSS, n = 9; Abx-IMQ-DSS, n = 7). Each symbol represents an individual mouse. Statistical analyses were performed with the Student t test or 1-way analysis of variance followed by the Tukey multiple comparison test. *P < .05, **P < .01, ***P < .001. *Error bars* represent the SEM of samples within a group. Data are pooled from 2 independent experiments.

**Figure 7**
**Fecal microbiome transplantation of IMQ mice exacerbated DSS colitis.** (A) GF mice were transplanted with a fecal microbiome derived from control mice (cont gnoto mice) or IMQ-treated mice (IMQ gnoto mice). Three weeks after transplantation, immune cells were analyzed by flow cytometry. (B) Percentage (*left*) and absolute number (*right*) of CD11b⁺CD64⁺ cells in CD45⁺CD3^-CD19^-B220^- NK1.1^- cells from colonic lamina propria. (C) Percentage (*left*) and absolute number (*right*) of B cells in CD45⁺ colonic lamina propria. (D) Percentage of IgA⁺ (*left*), IgD⁺ (*middle*), and IgM⁺ (*right*) B cells in the total B cells from colonic lamina propria (n = 6–7 in each group). (E) Experimental protocol. Cont gnoto mice and IMQ gnoto mice (shown in panel A) were further induced with acute colitis by 3% (wt/vol) DSS. After administration of DSS for 7 days, the severity of colitis was assessed. (F) Representative photograph of colon on day 7 of DSS colitis. (G) Body weight on day 7 of DSS colitis. (H) Colon length on day 7 of DSS colitis. (I) Partial DAI score on day 7 of DSS colitis. Partial DAI score was calculated as the sum of scores for perianal bleeding (0–4) and diarrhea (0–4) (part of the DAI score except for the body weight loss component). (J) Representative H&E staining of distal colon section on day 7 of DSS colitis. *Scale bar*: 100 μm. (K) Histologic score of colitis on day 7 of DSS (n = 3–5 in each group). (L) Experimental protocol. Mice treated with IMQ or vehicle subsequently were induced with colitis by 2% (wt/vol) DSS for 7 days. Feces derived from control mice, or saline, was administered daily by oral gavage, from the day before starting DSS to the end of the experiment. (M) Body weight changes during administration of DSS and (N) the percentage of the initial value (day 0 of DSS) of body weight on day 7 of DSS colitis. (O) DAI score on day 7 of DSS colitis (n = 6 in each group). (P) Experimental protocol. Mice treated with IMQ or vehicle were subsequently induced with colitis by 2% (wt/vol) DSS for 7 days. A mixture of *L johnsonii* and *L reuteri*, or saline, was administered daily by oral gavage, from the day before starting DSS to the end of the experiment. (Q) Body weight changes during administration of DSS and (R) the percentage of the initial value (day 0 of DSS) of body weight on day 7 of DSS colitis. (S) DAI score on day 7 of DSS colitis (n = 8 in each group). Each symbol represents an individual mouse. Statistical analyses were performed with the Student t test. *P < .05, **P < .01, ***P < .001. *Error bars* represent the SEM of samples within a group.

**Figure 8**
**Both hematopoietic and nonhematopoietic TLR7-positive cells enhance IMQ-DSS colitis.** (A) Experimental protocol. (B) Body weight changes during administration of DSS. (C) Body weight on day 7 of DSS colitis. (D) DAI score on day 7 of DSS colitis. (E) Representative photograph of colon on day 7 of DSS colitis. (F) Colon length on day 7 of DSS colitis. (G) Representative H&E staining of distal colon section on day 7 of DSS colitis. *Scale bar*: 100 μm. (H) Histologic score for colitis on day 7 of DSS colitis. Each symbol represents an individual mouse (n = 5–6). Statistical analyses were performed with 1-way analysis of variance followed by the Tukey multiple comparison test. *P < .05, **P < .01, ***P < .001. *Error bars* represent the SEM of samples within a group.

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References

1. Parisi R., Symmons D.P., Griffiths C.E., Ashcroft D.M. Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) Project Team. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133:377–385. - PubMed
1. Drago L., De Grandi R., Altomare G., Pigatto P., Rossi O., Toscano M. Skin microbiota of first cousins affected by psoriasis and atopic dermatitis. Clin Mol Allergy. 2016;14:2. - PMC - PubMed
1. Zakostelska Z., Malkova J., Klimesova K., Rossmann P., Hornova M., Novosadova I., Stehlikova Z., Kostovcik M., Hudcovic T., Stepankova R., Juzlova K., Hercogova J., Tlaskalova-Hogenova H., Kverka M. Intestinal microbiota promotes psoriasis-like skin inflammation by enhancing Th17 response. PLoS One. 2016;11:e0159539. - PMC - PubMed
1. Protic M., Schoepfer A., Yawalkar N., Vavricka S., Seibold F. Development of psoriasis in IBD patients under TNF-antagonist therapy is associated neither with anti-TNF-antagonist antibodies nor trough levels. Scand J Gastroenterol. 2016;51:1482–1488. - PubMed
1. Cargill M., Schrodi S.J., Chang M., Garcia V.E., Brandon R., Callis K.P., Matsunami N., Ardlie K.G., Civello D., Catanese J.J., Leong D.U., Panko J.M., McAllister L.B., Hansen C.B., Papenfuss J., Prescott S.M., White T.J., Leppert M.F., Krueger G.G., Begovich A.B. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80:273–290. - PMC - PubMed

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[1] Parisi R., Symmons D.P., Griffiths C.E., Ashcroft D.M. Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) Project Team. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133:377–385. - PubMed

[2] Parisi R., Symmons D.P., Griffiths C.E., Ashcroft D.M. Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) Project Team. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133:377–385. - PubMed

[3] Drago L., De Grandi R., Altomare G., Pigatto P., Rossi O., Toscano M. Skin microbiota of first cousins affected by psoriasis and atopic dermatitis. Clin Mol Allergy. 2016;14:2. - PMC - PubMed

[4] Drago L., De Grandi R., Altomare G., Pigatto P., Rossi O., Toscano M. Skin microbiota of first cousins affected by psoriasis and atopic dermatitis. Clin Mol Allergy. 2016;14:2. - PMC - PubMed

[5] Zakostelska Z., Malkova J., Klimesova K., Rossmann P., Hornova M., Novosadova I., Stehlikova Z., Kostovcik M., Hudcovic T., Stepankova R., Juzlova K., Hercogova J., Tlaskalova-Hogenova H., Kverka M. Intestinal microbiota promotes psoriasis-like skin inflammation by enhancing Th17 response. PLoS One. 2016;11:e0159539. - PMC - PubMed

[6] Zakostelska Z., Malkova J., Klimesova K., Rossmann P., Hornova M., Novosadova I., Stehlikova Z., Kostovcik M., Hudcovic T., Stepankova R., Juzlova K., Hercogova J., Tlaskalova-Hogenova H., Kverka M. Intestinal microbiota promotes psoriasis-like skin inflammation by enhancing Th17 response. PLoS One. 2016;11:e0159539. - PMC - PubMed

[7] Protic M., Schoepfer A., Yawalkar N., Vavricka S., Seibold F. Development of psoriasis in IBD patients under TNF-antagonist therapy is associated neither with anti-TNF-antagonist antibodies nor trough levels. Scand J Gastroenterol. 2016;51:1482–1488. - PubMed

[8] Protic M., Schoepfer A., Yawalkar N., Vavricka S., Seibold F. Development of psoriasis in IBD patients under TNF-antagonist therapy is associated neither with anti-TNF-antagonist antibodies nor trough levels. Scand J Gastroenterol. 2016;51:1482–1488. - PubMed

[9] Cargill M., Schrodi S.J., Chang M., Garcia V.E., Brandon R., Callis K.P., Matsunami N., Ardlie K.G., Civello D., Catanese J.J., Leong D.U., Panko J.M., McAllister L.B., Hansen C.B., Papenfuss J., Prescott S.M., White T.J., Leppert M.F., Krueger G.G., Begovich A.B. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80:273–290. - PMC - PubMed

[10] Cargill M., Schrodi S.J., Chang M., Garcia V.E., Brandon R., Callis K.P., Matsunami N., Ardlie K.G., Civello D., Catanese J.J., Leong D.U., Panko J.M., McAllister L.B., Hansen C.B., Papenfuss J., Prescott S.M., White T.J., Leppert M.F., Krueger G.G., Begovich A.B. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80:273–290. - PMC - PubMed

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Toll-Like Receptor 7 Agonist-Induced Dermatitis Causes Severe Dextran Sulfate Sodium Colitis by Altering the Gut Microbiome and Immune Cells

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Toll-Like Receptor 7 Agonist-Induced Dermatitis Causes Severe Dextran Sulfate Sodium Colitis by Altering the Gut Microbiome and Immune Cells

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