Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
Invest Ophthalmol Vis Sci. 2023 Nov 1;64(14):43. doi: 10.1167/iovs.64.14.43.
Using the model of experimental autoimmune uveitis (EAU) induced by immunization with a retinal antigen, two studies have reported contradictory results on disease development following oral antibiotic treatment (ABX). We showed that long-term ABX did not affect EAU, but another study showed that short-term ABX was protective. We therefore studied the effects of ABX on EAU, gut microbiota, and host immune responses as a function of treatment duration.
EAU-susceptible mice were treated orally with broad-spectrum antibiotics starting at least 10 weeks (long-term) or 1 week (short-term) before immunization until termination of the experiment. Gut microbiota were characterized by 16S amplicon sequencing, and host gut immune elements were studied phenotypically and functionally.
Long-term ABX had no effect, whereas short-term ABX delayed EAU, as previously reported by us and others, respectively. Microbial sequencing revealed progressive reduction of gut microbiota that showed some differences in the two ABX groups. Interestingly, duration of ABX was associated with a gradual disappearance of the CD4+ and CD4+CD8+ subset of gut intraepithelial lymphocytes (IELs). This IEL subset is microbiota dependent and is absent in germ-free mice. Relative abundance of Lactobacillus reuteri correlated with the frequencies of CD4+CD8+ IELs. IELs suppressed antigen-specific activation of autoreactive T cells in culture.
Gut microbiota may play dual roles in uveitis development: They promote EAU development but also help maintain IEL populations that have regulatory function against autoreactive T cells. We propose that the progressive loss of this population during long-term ABX reverses the EAU-ameliorating effects of microbiota depletion.
通过用视网膜抗原免疫诱导实验性自身免疫性葡萄膜炎（EAU）模型，两项研究报告了口服抗生素治疗（ABX）后疾病发展的结果相互矛盾。我们表明，长期 ABX 治疗不会影响 EAU，但另一项研究表明短期 ABX 是保护性的。因此，我们研究了 ABX 对 EAU、肠道微生物群和宿主免疫反应的影响，其作用取决于治疗持续时间。
在免疫前至少 10 周（长期）或 1 周（短期）开始，用广谱抗生素对 EAU 易感小鼠进行口服治疗，直至实验结束。通过 16S 扩增子测序对肠道微生物群进行特征分析，并对宿主肠道免疫成分进行表型和功能研究。
正如我们和其他人之前报道的那样，长期 ABX 没有效果，而短期 ABX 则延迟了 EAU。微生物测序显示肠道微生物群逐渐减少，两组 ABX 之间存在一些差异。有趣的是，ABX 的持续时间与肠道上皮内淋巴细胞（IEL）中 CD4+和 CD4+CD8+亚群的逐渐消失相关。这个 IEL 亚群依赖于微生物群，在无菌小鼠中不存在。乳杆菌属 reuteri 的相对丰度与 CD4+CD8+IEL 的频率相关。IEL 抑制了培养中抗原特异性激活的自身反应性 T 细胞。
肠道微生物群可能在葡萄膜炎发展中起双重作用：它们促进 EAU 的发展，但也有助于维持具有调节作用的 IEL 群体，对抗自身反应性 T 细胞。我们提出，在长期 ABX 期间这种群体的逐渐丧失，逆转了微生物群耗竭对 EAU 的改善作用。
