Fadlallah Sukayna, Bitar Elio R, Hussein Hadi, Jallad Mary-Ann, Matar Ghassan M, Rahal Elias A
Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut , Beirut, Lebanon.
Center for Infectious Diseases Research, American University of Beirut , Beirut, Lebanon.
Microbiol Spectr. 2023 Aug 24;11(5):e0204223. doi: 10.1128/spectrum.02042-23.
Epstein-Barr virus (EBV) DNA may influence the development of autoimmune diseases by increasing the production of proinflammatory cytokines. Such cytokines have been associated with inducing the dysbiosis of colonic microbiota, which, in turn, is a risk factor for autoimmune diseases such as rheumatoid arthritis (RA). Therefore, we investigated the role that EBV DNA may play in modulating the intestinal microbiota and consequent exacerbation of arthritis in a mouse model. Mice were treated with collagen (arthritis-inducing agent), EBV DNA and collagen, EBV DNA, or water. Fecal samples were collected from arthritic and control mice, and 16S rRNA sequencing was performed to determine the effect of EBV DNA on the composition of colonic microbiota. EBV DNA causes a change in the alpha diversity of the microbiota resulting in an increased Chao1 microbial richness and decreased Shannon diversity index in the RA mouse model. In addition, the abundance of particular genera/genus clusters was significantly altered among the various groups, with the EBV DNA-exacerbated arthritic group having the highest number of altered genera/genus cluster abundances. This group also had the highest number of cells co-expressing IL-17A, FOXP3, and IFNγ in the colons. Antimicrobial-cleared mice transplanted with fecal samples from EBV DNA-exacerbated arthritic mice showed a higher incidence and enhanced severity of RA compared to those transplanted with fecal samples from water or collagen-treated mice. IMPORTANCE Epstein-Barr virus (EBV) DNA alters the composition and diversity of the gut microbiota in a rheumatoid arthritis (RA) mouse model. These induced changes are associated with enhanced severity of symptoms. This better understanding of the various factors involved in the development of RA will possibly help in creating individualized treatments for RA patients including target mediators triggered by viral DNA. Given that a large swathe of the population harbors EBV, a significant proportion of subjects with arthritis may benefit from possible approaches that target EBV or mediators triggered by this virus.
爱泼斯坦-巴尔病毒（EBV）DNA可能通过增加促炎细胞因子的产生来影响自身免疫性疾病的发展。此类细胞因子与诱导结肠微生物群失调有关，而结肠微生物群失调反过来又是类风湿性关节炎（RA）等自身免疫性疾病的一个风险因素。因此，我们在小鼠模型中研究了EBV DNA在调节肠道微生物群以及随后加重关节炎方面可能发挥的作用。小鼠分别接受胶原蛋白（关节炎诱导剂）、EBV DNA与胶原蛋白、EBV DNA或水的处理。从患关节炎的小鼠和对照小鼠中收集粪便样本，并进行16S rRNA测序，以确定EBV DNA对结肠微生物群组成的影响。在RA小鼠模型中，EBV DNA导致微生物群的α多样性发生变化，导致Chao1微生物丰富度增加，香农多样性指数降低。此外，不同组之间特定属/属簇的丰度有显著改变，EBV DNA加重的关节炎组中改变的属/属簇丰度数量最多。该组结肠中同时表达IL-17A、FOXP3和IFNγ的细胞数量也最多。与移植水或胶原蛋白处理小鼠粪便样本的小鼠相比，移植EBV DNA加重的关节炎小鼠粪便样本的抗菌清除小鼠显示出更高的RA发病率和更严重的病情。重要性：在类风湿性关节炎（RA）小鼠模型中，爱泼斯坦-巴尔病毒（EBV）DNA改变了肠道微生物群的组成和多样性。这些诱导的变化与症状严重程度的增加有关。对RA发病过程中涉及的各种因素的更好理解可能有助于为RA患者制定个性化治疗方案，包括针对病毒DNA触发目标介质的治疗方案。鉴于大量人群携带EBV，很大一部分关节炎患者可能会从针对EBV或由该病毒触发的介质的可能方法中受益。
