Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
Cell Host Microbe. 2021 Jun 9;29(6):959-974.e7. doi: 10.1016/j.chom.2021.03.016. Epub 2021 Apr 23.
Microbiota play critical roles in regulating colitis and colorectal cancer (CRC). However, it is unclear how the microbiota generate protective immunity against these disease states. Here, we find that loss of the innate and adaptive immune signaling molecule, TAK1, in myeloid cells (Tak1) yields complete resistance to chemical-induced colitis and CRC through microbiome alterations that drive protective immunity. Tak1 mice exhibit altered microbiota that are critical for resistance, with antibiotic-mediated disruption ablating protection and Tak1 microbiota transfer conferring protection against colitis or CRC. The altered microbiota of Tak1 mice promote IL-1β and IL-6 signaling pathways, which are required for induction of protective intestinal Th17 cells and resistance. Specifically, Odoribacter splanchnicus is abundant in Tak1 mice and sufficient to induce intestinal Th17 cell development and confer resistance against colitis and CRC in wild-type mice. These findings identify specific microbiota strains and immune mechanisms that protect against colitis and CRC.
微生物组在调节结肠炎和结直肠癌（CRC）方面发挥着关键作用。然而，目前尚不清楚微生物组如何产生针对这些疾病状态的保护性免疫。在这里，我们发现髓样细胞中先天和适应性免疫信号分子 TAK1 的缺失（Tak1）通过改变微生物组产生对化学诱导的结肠炎和 CRC 的完全抗性，从而驱动保护性免疫。Tak1 小鼠表现出改变的微生物组，这对于抵抗是至关重要的，抗生素介导的破坏会消除保护作用，而 Tak1 微生物组转移则赋予对结肠炎或 CRC 的保护作用。Tak1 小鼠的改变的微生物组促进了 IL-1β 和 IL-6 信号通路，这是诱导保护性肠道 Th17 细胞和抵抗所必需的。具体而言，Odo ribacter splanchnicus 在 Tak1 小鼠中丰富，足以诱导肠道 Th17 细胞的发育，并赋予野生型小鼠对结肠炎和 CRC 的抵抗能力。这些发现确定了特定的微生物菌株和免疫机制，可预防结肠炎和 CRC。
