Mehta Heena, Goulet Philippe-Olivier, Mashiko Shunya, Desjardins Jade, Pérez Gemma, Koenig Martial, Senécal Jean-Luc, Constante Marco, Santos Manuela M, Sarfati Marika
Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
Laboratory for Research in Autoimmunity, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
J Invest Dermatol. 2017 Nov;137(11):2316-2325. doi: 10.1016/j.jid.2017.06.019. Epub 2017 Jul 27.
Patients with systemic sclerosis (SSc) display altered intestinal microbiota. However, the influence of intestinal dysbiosis on the development of experimental SSc remains unknown. Topoisomerase I peptide-loaded dendritic cell immunization induces SSc-like disease, with progressive skin and lung fibrosis. Breeders were given streptomycin and pups continued to receive antibiotic (ATB) until endpoint (lifelongATB). Alternately, ATB was withdrawn (earlyATB) or initiated (adultATB) during adulthood. Topoisomerase I peptide-loaded dendritic cell (no ATB) immunization induced pronounced skin fibrosis, with increased matrix (Col1a1), profibrotic (Il13, Tweakr), and vascular function (Serpine1) gene expression. Remarkably, earlyATB exposure was sufficient to augment skin Col5a1 and Il13 expression, and inflammatory cell infiltration, which included IL-13 cells, mononuclear phagocytes, and mast cells. Moreover, skin pathology exacerbation was also observed in lifelongATB and adultATB groups. Oral streptomycin administration induced intestinal dysbiosis, with exposure limited to early life (earlyATB) being sufficient to cause long-term modification of the microbiota and a shift toward increased Bacteroidetes/Firmicutes ratio. Finally, aggravated lung fibrosis and dysregulated pulmonary T-cell responses were observed in earlyATB and lifelongATB but not adultATB-exposed mice. Collectively, intestinal microbiota manipulation with streptomycin exacerbated pathology in two distinct sites, skin and lungs, with early life being a critical window to affect the course of SSc-like disease.
系统性硬化症（SSc）患者的肠道微生物群会发生改变。然而，肠道菌群失调对实验性SSc发展的影响尚不清楚。负载拓扑异构酶I肽的树突状细胞免疫可诱发类似SSc的疾病，并伴有进行性皮肤和肺纤维化。给繁殖鼠注射链霉素，幼崽持续接受抗生素（ATB）直至实验终点（终身ATB）。或者，在成年期停用ATB（早期停用ATB）或开始使用ATB（成年期使用ATB）。负载拓扑异构酶I肽的树突状细胞（未使用ATB）免疫诱导了明显的皮肤纤维化，基质（Col1a1）、促纤维化（Il13、Tweakr）和血管功能（Serpine1）基因表达增加。值得注意的是，早期暴露于ATB足以增加皮肤Col5a1和Il13的表达以及炎症细胞浸润，其中包括IL-13细胞、单核吞噬细胞和肥大细胞。此外，在终身ATB组和成年期使用ATB组中也观察到皮肤病理学加重。口服链霉素会导致肠道菌群失调，仅早期暴露于链霉素（早期停用ATB）就足以引起微生物群的长期改变，并导致拟杆菌门/厚壁菌门比例增加。最后，在早期停用ATB组和终身ATB组的小鼠中观察到肺纤维化加重和肺T细胞反应失调，但成年期使用ATB组未观察到。总的来说，用链霉素操纵肠道微生物群会加剧皮肤和肺这两个不同部位的病理变化，早期生命是影响类似SSc疾病进程的关键窗口期。
