Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade.
Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade.
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DOI：
10.1073/pnas.1921223117
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发表时间：
2020-11-03
影响因子：
11.1
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Sun S;Luo L;Liang W;Yin Q;Guo J;Rush AM;Lv Z;Liang Q;Fischbach MA;Sonnenburg JL;Dodd D;Davis MM;Wang F
数百万人在柜台上服用益生菌，但很少有人知道它们的作用以及它们是否真的有效。在这里，我们表明，在小鼠中，引入双歧杆菌，最常用的益生菌之一，不仅殖民肠道，而且还改变了整个微生物景观。我们以前发现，这种治疗可以拯救小鼠免受由抗CTLA-4抗体引起的致命炎症综合征，抗CTLA-4抗体是一种检查点抑制剂，通常会引起接受癌症治疗的人类的自身免疫。在这里，我们表明，这种效果至少部分是由于这种益生菌治疗对调节性CD 4+细胞的影响，其代谢和免疫抑制功能被改变。已知这些CD 4+调节性T细胞是控制小鼠和人类免疫系统中自身反应性的关键机制。因此，我们发现了益生菌治疗与控制过度免疫反应的已知主要机制之一之间的直接联系。减弱免疫耐受的免疫检查点阻断抗体已被用于有效治疗癌症，但它们也可能引发严重的免疫相关不良事件。之前，我们发现双歧杆菌可以在CTLA-4阻断的情况下减轻小鼠的肠道免疫病理学。在这里，我们研究了这一过程的机制。我们发现双歧杆菌以调节性T细胞（Treg）依赖的方式系统地改变了肠道微生物群的组成。此外，这种改变的肠道菌群增强了线粒体适应性和IL-10介导的肠道THBG抑制功能，有助于在免疫检查点阻断期间改善结肠炎。
Many millions of people take probiotics over the counter, but very little is known about what they do and whether they really work. Here we show that in mice, introducing Bifidobacterium, one of the most commonly used probiotics, not only colonizes the gut, but also alters the entire microbiotic landscape. We previously found that this treatment rescues mice from an otherwise fatal inflammatory syndrome brought on by anti–CTLA-4 antibody, a checkpoint inhibitor that often causes autoimmunity in humans undergoing cancer treatment. Here we show that this is effect is due, at least in part, to the effect of this probiotic treatment on regulatory CD4+ cells, whose metabolic and immune suppressive functions are altered. These CD4+ regulatory T cells are known to be a key mechanism in the control of autoreactivity in the immune system in both mice and humans. Thus, we found a direct connection between probiotic treatment and one of the known principal mechanisms for controlling excess immune responses. Immune checkpoint-blocking antibodies that attenuate immune tolerance have been used to effectively treat cancer, but they can also trigger severe immune-related adverse events. Previously, we found that Bifidobacterium could mitigate intestinal immunopathology in the context of CTLA-4 blockade in mice. Here we examined the mechanism underlying this process. We found that Bifidobacterium altered the composition of the gut microbiota systematically in a regulatory T cell (Treg)-dependent manner. Moreover, this altered commensal community enhanced both the mitochondrial fitness and the IL-10–mediated suppressive functions of intestinal Tregs, contributing to the amelioration of colitis during immune checkpoint blockade.
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DOI：
10.1073/pnas.1712901115
发表时间：
2018-01-02
影响因子：
11.1
作者：
Wang, Feng;Yin, Qian;Davis, Mark M.
通讯作者：
Davis, Mark M.
影响因子：
82.9
作者：
Wang, Yinghong;Wiesnoski, Diana H.;Jenq, Robert R.
通讯作者：
Jenq, Robert R.
DOI：
10.1126/science.aac4255
发表时间：
2015-11-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Sivan A;Corrales L;Hubert N;Williams JB;Aquino-Michaels K;Earley ZM;Benyamin FW;Lei YM;Jabri B;Alegre ML;Chang EB;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
29.4
作者：
Nieuwdorp, Max;Gilijamse, Pim W.;Kaplan, Lee M.
通讯作者：
Kaplan, Lee M.
影响因子：
16.6
作者：
Dubin K;Callahan MK;Ren B;Khanin R;Viale A;Ling L;No D;Gobourne A;Littmann E;Huttenhower C;Pamer EG;Wolchok JD
通讯作者：
Wolchok JD