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. 2015 Sep 29:6:8424.
doi: 10.1038/ncomms9424.

Antibiotics in neonatal life increase murine susceptibility to experimental psoriasis

Peter Zanvit  1 , Joanne E Konkel  1   2 , Xue Jiao  1   3 , Shimpei Kasagi  1 , Dunfang Zhang  1   4 , Ruiqing Wu  1   4 , Cheryl Chia  1 , Nadim J Ajami  5 , Daniel P Smith  5 , Joseph F Petrosino  5 , Brittany Abbatiello  1 , Hiroko Nakatsukasa  1 , Qianming Chen  4 , Yasmine Belkaid  6 , Zi-Jiang Chen  3 , WanJun Chen  1
Affiliations

Antibiotics in neonatal life increase murine susceptibility to experimental psoriasis

Peter Zanvit et al. Nat Commun. .

Abstract

Psoriasis is an inflammatory skin disease affecting ∼2% of the world's population, but the aetiology remains incompletely understood. Recently, microbiota have been shown to differentially regulate the development of autoimmune diseases, but their influence on psoriasis is incompletely understood. We show here that adult mice treated with antibiotics that target Gram-negative and Gram-positive bacteria develop ameliorated psoriasiform dermatitis induced by imiquimod, with decreased pro-inflammatory IL-17- and IL-22-producing T cells. Surprisingly, mice treated neonatally with these antibiotics develop exacerbated psoriasis induced by imiquimod or recombinant IL-23 injection when challenged as adults, with increased IL-22-producing γδ(+) T cells. 16S rRNA gene compositional analysis reveals that neonatal antibiotic-treatment dysregulates gut and skin microbiota in adults, which is associated with increased susceptibility to experimental psoriasis. This link between neonatal antibiotic-mediated imbalance in microbiota and development of experimental psoriasis provides precedence for further investigation of its specific aetiology as it relates to human psoriasis VSports手机版. .

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Figures

Figure 1
Figure 1. Imiquimod increases IL-17 and IL-22 in both γδ and αβ T cells in skin.
Skin and ear of wild type C57BL/6 mice were treated by topical application of imiquimod cream (Fougera, n=4) or control cream (Vaseline, n=3) for 6 consecutive days. (a) Weight loss of imiquimod and control cream treated mice monitored daily. (b) Photographs of imiquimod and control cream treated skin and ear; photos were taken at day 6. H&E stained ear and back skin sections of imiquimod treated and control mice. Scale bar, 200 μm. (c) Thickness of skin measured by Digimatic Caliper at day 6 in control and imiquimod treated mice. Data showed represents average of at least two measurements. (d) Ear thickness of imiquimod and control cream treated mice monitored daily. Ear thickness was measured using Digimatic Caliper. (e) Quantitative PCR analysis of Th17 associated cytokines and Foxp3 in skin after 6 days of imiquimod and control cream treatment. (f) Representative flow cytometric analysis of TCRγδ+Vγ4+IL-17+ (upper raw) and TCRγδ+Vγ4+IL-22+ cells (lower row) in the skin of control (n=3) and imiquimod treated mice (n=4). (g) Representative flow cytometric analysis of single-positive TCRβ+IL-17+ (upper raw) or TCRβ+IL-22+ (lower raw) cells in the skin of control (n=3) and imiquimod treated mice (n=4). Data representative of more than three experiments, results are shown as mean±s.e.m., significance determined by unpaired two-tailed Student's t-test (*P<0.05; **P<0.01; ***P<0.001).
Figure 2
Figure 2. Antibiotics in adult mice ameliorate psoriasis by reduction of IL-17 and IL-22 in T cells.
Young adult mice (4-weeks-old) were exposed to antibiotics in drinking water (adultATB) for four weeks, and last six consecutive days followed by imiquimod treatment. (a) Representative photographs of back skin of control and adultATB mice followed by imiquimod treatment. Photos were taken at day 6. (b) H&E stained skin sections of control and adultATB mice after imiquimod treatment. Scale bar, 200 μm. (c) Thickness of skin measured by digimatic caliper at day 6 in control and imiquimod treated mice. Data showed represents average of at least two measurements. Increased skin infiltration in control compared adultATB mice based on staining of skin CD45+ cells. (d) Flow cytometric analysis of single-positive CD3+TCRγδlow+IL-17+ cells or CD3+TCRγδ−IL-17+ cells in control (n=6–7) and adultATB (n=6–7) mice after imiquimod treatment. (e) Flow cytometric analysis of single-positive CD3+TCRγδlow+IL-22+ cells or CD3+TCRγδ−IL-22+ cells in control (n=6) and adultATB (n=6) mice after imiquimod treatment. (f) Frequency of skin CD3+TCRβ+Foxp3+ cells in the skin of control (n=5) and adultATB (n=7) mice after imiquimod treatment. (g) Diversity of the microbiota (Observed OTUs, Shannon Index) in adultATB and control mice. Primary samples were collected per cage (Pooled samples from 3 independent experiments) and analysed using 16S rRNA sequencing of region V4. (h) Relative abundance at phylum level between control and adultATB mice. Each column represents pooled samples from individual experiments. (i) Summarized phylum level analysis from three individual experiments showing difference between control and adultATB mice. (j) Relative abundance at family level between control and adultATB mice. Each column represents pooled samples from individual experiments. (k) Summarized family level analysis from three individual experiments showing difference between control and adultATB mice. Results are shown as mean±s.e.m., significance in (c–f) was determined by unpaired two-tailed Student's t-test (*P<0.05; **P<0.01; ***P<0.001), significance in (i,k) was determined using the non-parametric Kruskal–Wallis test (*P<0.05).
Figure 3
Figure 3. Neonatal antibiotic treatment of mice increases severity of psoriasis.
Breeding pairs were given antibiotics vancomycin+polymyxin B in drinking water immediately after pups delivery for 3 weeks of rearing (neoATB). After weaning, mice were housed or cohoused (mice without antibiotics treatment together with mice treated with antibiotics) in normal specific pathogen-free conditions for next 8 weeks. The mice were then treated with imiquimod cream for 4 consecutive days. (a) Representative photographs of back skin in controls (mice without antibiotic treatment); neonatally antibiotics treated mice (neoATB) or cohoused mice (control–neoATB resp. NeoATB–control) after imiquimod treatment. Photos were taken at day 5. (b) H&E stained skin sections of control, neoATB and cohoused mice after imiquimod treatment. Scale bar, 200 μm. (c) Weight loss of control, neoATB and cohoused mice during imiquimod treatment monitored daily. (d) Skin thickness of control, neoATB and cohoused mice measured at day 5. Skin thickness was measured by digimatic caliper by at least two investigators and data showed represents average of at least two measurements. (e) Flow cytometric analysis of single-positive TCRγδ+Vγ4+IL-17+ cells or CD3+TCRβ+ IL-17+ cells in control (n=8), neoATB (n=7) and cohoused mice (n=5) after imiquimod treatment. (f) Flow cytometric analysis of single-positive TCRγδ+Vγ4+IL-22+ cells or CD3+TCRβ+ IL-22+ cells in control (n=6), neoATB (n=7) and cohoused mice (n=5) after imiquimod treatment. (g) Frequency of skin TCRβ+CD3+Foxp3+ cells in control (n=5), neoATB (n=4) and cohoused mice (n=4) after imiquimod treatment. (h) Quantitative PCR analysis of IL-17, IL-22, IL-1β, IL-23p19 and Foxp3 in the skin of control (n=7–10), neoATB (n=7–10) and Cohoused mice (n=7) after imiquimod treatment. Data representative of five experiments (control versus neoATB) or two experiments (Cohoused), results are shown as mean±s.e.m., significance in (c) was determined by one-way analysis of variance followed by Dunnett posttest or in (d–h) by Tukey's posttest (*P<0.05; **P<0.01; ***P<0.001).
Figure 4
Figure 4. Neonatal antibiotic treatment alters bacterial communities in adult age.
Faecal samples were collected per mouse and analysed by 16S rRNA sequencing of region V4. (a) Diversity of the microbiota (Observed OTUs, Shannon Index) in control (n=6), neoATB (n=7), control–neoATB (n=8) and neoATB–control (n=8) mice. (b) Beta diversity (PCoA) was used to compare distance measure (Unweighted and Weighted Unifrac), diversity (Jaccard) or dissimilarity (Bray–Curtis) between control, neoATB, control–neoATB and neoATB–control treatments. Relative abundance at Phylum (c,d) or Family (e,f) levels between control, neoATB, control–neoATB and neoATB–control mice. Each column in (c,e) represents individual mouse. (d–f) represents summary data from two individual experiments at phylum (d) or family (f) level between control, neoATB, control–neoATB and neoATB–control mice. Significance was determined using the non-parametric Kruskal–Wallis test (*P<0.05; **P<0.01; ***P<0.001).
Figure 5
Figure 5. Changes in gut microflora composition after antibiotic treatment in adult versus neonatal antibiotic treated adult mice.
(a) PCoA bi-plot illustrating the clustering of samples based on unweighted and weighted Unifrac distances between adultATB and neoATB treated mice and their controls. (b) Phylum level comparison of gut commensal microflora between adultATB and adult neoATB mice. (c) Family level comparison of gut commensal microflora between adultATB and adult neoATB mice. (d) Increased abundance of family Lachnospiraceae on the skin of neoATB compared with adultATB mice. Data are representative of two independent neoATB and three independent adultATB experiments. Significance in (b,c) was determined using the non-parametric Kruskal–Wallis test (*P<0.05).
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