Microbial metabolites are an emerging class of mediators influencing CD4+ T-cell function. To advance the understanding of direct causal microbial factors contributing to Crohn's disease, we screened 139 predicted Crohn's disease-associated microbial metabolites for their bioactivity on human CD4+ T-cell functions induced by disease-associated T helper 17 (Th17) polarizing conditions. We observed 15 metabolites with CD4+ T-cell bioactivity, 3 previously reported, and 12 unprecedented. A deeper investigation of the microbe-derived metabolite, ascorbate, revealed its selective inhibition on activated human CD4+ effector T cells, including IL-17A-, IL-4-, and IFNγ-producing cells. Mechanistic assessment suggested the apoptosis of activated human CD4+ T cells associated with selective inhibition of energy metabolism. These findings suggest a substantial rate of relevant T-cell bioactivity among Crohn's disease-associated microbial metabolites, and evidence for novel modes of bioactivity, including targeting of T-cell energy metabolism.

中文翻译：

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克罗恩病相关微生物代谢物的筛选将抗坏血酸鉴定为活化的人类 T 细胞的新型代谢抑制剂。

微生物代谢物是一类影响 CD4+ T 细胞功能的新兴介质。为了促进对导致克罗恩病的直接致病微生物因素的理解，我们筛选了 139 种预测的克罗恩病相关微生物代谢物，以了解它们对疾病相关 T 辅助细胞 17 (Th17) 极化条件诱导的人类 CD4+ T 细胞功能的生物活性。我们观察到 15 种具有 CD4+ T 细胞生物活性的代谢物，其中 3 种以前报道过，12 种前所未有。对微生物衍生代谢物抗坏血酸的更深入研究揭示了它对活化的人 CD4+ 效应 T 细胞的选择性抑制，包括产生 IL-17A、IL-4 和 IFNγ 的细胞。机制评估表明，活化的人 CD4+ T 细胞凋亡与能量代谢的选择性抑制有关。