Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

胆汁酸的微生物转化影响肠道免疫稳态，但其对炎症病理的影响仍然很大程度上未知。使用移植物抗宿主病 (GVHD) 小鼠模型，我们发现 T 细胞驱动的炎症降低了微生物组编码的胆汁盐水解酶 (BSH) 基因的丰度，并降低了非结合胆汁酸和微生物衍生的胆汁酸的水平。几种微生物衍生的胆汁酸减弱了法尼醇 X 受体 (FXR) 的激活，表明炎症期间这些代谢物的损失可能会增加 FXR 活性并加剧病程。事实上，在小鼠 GVHD 期间，死亡率随着 FXR 的药理学激活而增加，并随着其在供体 T 细胞中的基因消除而降低。此外，同种异体造血细胞移植后患有 GVHD 的患者表现出类似的 BSH 损失以及相关的非结合胆汁酸和微生物衍生胆汁酸的减少。此外，FXR 拮抗剂熊去氧胆酸可减少人类 T 细胞的增殖，并降低患者 GVHD 相关死亡率的风险。我们认为，炎症过程中微生物来源的胆汁酸的失调和损失可能是放大 T 细胞介导的疾病的重要机制。