Department of Medicine, Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Department of Medicine, Gastroenterology & Hepatology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
mSphere. 2021 Oct 27;6(5):e0066921. doi: 10.1128/mSphere.00669-21.
Clostridioides difficile infection (CDI) is the most common hospital-acquired infection in the United States. Antibiotic-induced dysbiosis is the primary cause of susceptibility, and fecal microbiota transplantation (FMT) has emerged as an effective therapy for recurrence. We previously demonstrated in the mouse model of CDI that antibiotic-induced dysbiosis reduced colonic expression of interleukin 25 (IL-25) and that FMT protected in part by restoring IL-25 signaling. Here, we conducted a prospective study in humans to test if FMT induced IL-25 expression in the colons of patients with recurrent CDI (rCDI). Colonic biopsy specimens and blood were collected at the time of FMT and 60 days later. Colon biopsy specimens were analyzed for IL-25 protein levels, total tissue transcriptome, and epithelium-associated microbiota before and after FMT, and peripheral immune cells were immunophenotyped. FMT increased alpha diversity of the colonic microbiota and levels of IL-25 in colonic tissue. In addition, FMT increased expression of homeostatic genes and repressed inflammatory genes. Finally, circulating Th17 cells were decreased post-FMT. The increase in levels of the cytokine IL-25 accompanied by decreased inflammation is consistent with FMT acting in part to protect from recurrent CDI via restoration of commensal activation of type 2 immunity. Fecal microbiota transplantation (FMT) is an effective treatment for C. difficile infection for most patients; however, introducing a complex mixture of microbes also has had unintended consequences for some patients. Attempts to create a standardized probiotic therapeutic that recapitulates the efficacy of FMT have been unsuccessful to date. We sought to understand what immune markers are changed in patients undergoing FMT to treat recurrent C. difficile infection and identified an immune signaling molecule, IL-25, that was restored by FMT. This finding indicates that adjunctive therapy with IL-25 could be useful in treating C. difficile infection.
艰难梭菌感染（CDI）是美国最常见的医院获得性感染。抗生素诱导的微生态失调是易感性的主要原因，粪便微生物群移植（FMT）已成为复发性疾病的有效治疗方法。我们之前在 CDI 的小鼠模型中证明，抗生素诱导的微生态失调降低了结肠中白细胞介素 25（IL-25）的表达，而 FMT 通过部分恢复 IL-25 信号起到保护作用。在这里，我们在人类中进行了一项前瞻性研究，以测试 FMT 是否会在复发性 CDI（rCDI）患者的结肠中诱导 IL-25 的表达。在 FMT 时和 60 天后收集结肠活检标本和血液。在 FMT 前后分析结肠活检标本的 IL-25 蛋白水平、总组织转录组和上皮相关微生物群，并对周围免疫细胞进行免疫表型分析。FMT 增加了结肠微生物群的α多样性和结肠组织中 IL-25 的水平。此外，FMT 增加了稳态基因的表达并抑制了炎症基因的表达。最后，FMT 后循环 Th17 细胞减少。细胞因子 IL-25 水平的增加伴随着炎症的减少，这与 FMT 通过恢复 2 型免疫的共生激活来部分保护免受复发性 CDI 一致。粪便微生物群移植（FMT）是大多数患者治疗艰难梭菌感染的有效方法；然而，引入复杂的微生物混合物也给一些患者带来了意想不到的后果。迄今为止，试图创建一种可重现 FMT 疗效的标准化益生菌治疗方法都没有成功。我们试图了解接受 FMT 治疗复发性艰难梭菌感染的患者有哪些免疫标志物发生了变化，并确定了一种免疫信号分子 IL-25，它可通过 FMT 恢复。这一发现表明，IL-25 的辅助治疗可能对治疗艰难梭菌感染有用。
