Although the association between the microbiome and IBD and liver diseases is known, the cause and effect remain elusive. By connecting human microphysiological systems of the gut, liver, and circulating Treg and Th17 cells, we created a multi-organ model of ulcerative colitis (UC) ex vivo. The approach shows microbiome-derived short-chain fatty acids (SCFAs) to either improve or worsen UC severity, depending on the involvement of effector CD4 T cells. Using multiomics, we found SCFAs increased production of ketone bodies, glycolysis, and lipogenesis, while markedly reducing innate immune activation of the UC gut. However, during acute T cell-mediated inflammation, SCFAs exacerbated CD4⁺ T cell-effector function, partially through metabolic reprograming, leading to gut barrier disruption and hepatic injury. These paradoxical findings underscore the emerging utility of human physiomimetic technology in combination with systems immunology to study causality and the fundamental entanglement of immunity, metabolism, and tissue homeostasis.

尽管微生物组和IBD与肝病之间的关联是已知的，但其因果关系仍然难以捉摸。通过连接肠道，肝脏和循环的Treg和Th17细胞的人类微生理系统，我们体外建立了溃疡性结肠炎（UC）的多器官模型。该方法显示微生物组衍生的短链脂肪酸（SCFA）可以改善或恶化UC严重程度，具体取决于效应CD4 T细胞的参与。使用多组学方法，我们发现SCFA可增加酮体的产量，糖酵解和脂肪生成，同时显着降低UC肠道的先天免疫活化。然而，在急性T细胞介导的炎症过程中，SCFA加剧了CD4 ⁺T细胞效应子的功能部分通过代谢重编程，导致肠道屏障破坏和肝损伤。这些矛盾的发现突显了人体仿生技术与系统免疫学结合起来用于研究因果关系以及免疫，代谢和组织稳态的基本纠缠的新兴效用。