Physiomimetic model of the human Gut-Liver axis for studies of inflammatory diseases. Physiomimetic model of the human Gut-Liver axis for studies of inflammatory diseases

Association between the microbiome, IBD and liver diseases are known, yet cause and effect remain elusive. By connecting human microphysiological systems of the gut, liver and circulating Treg/Th17 cells, we modeled progression of ulcerative colitis (UC) ex vivo. We show that microbiome-derived short-chain fatty acids (SCFA) may either improve or worsen disease severity, depending on the activation state of CD4 T cells. Employing a multiomic approach, we found SCFA reduced innate activation of the UC gut and increased hepatic metabolism. However, during acute T cell-mediated inflammation, SCFA exacerbate CD4 T cell effector function leading to gut barrier disruption and liver damage. These paradoxical findings underscore the emerging utility of human physiomimetic technology in combination with systems immunology to study causality and temporal facets of gut-liver axis related diseases where animal models might leave ambiguity. Overall design: RNA-Seq analyses of tissues from a physiomimetic model of the human gut-liver axis; samples collected and analyzed in triplicates collected under different connectivity patterns.

微生物组、炎症性肠病（IBD）与肝脏疾病之间的关联已被学界证实，但二者间的因果关系仍难以明确。本研究通过整合人体肠道、肝脏及循环调节性T细胞（Treg）/辅助性T细胞17（Th17）的微生理系统，在体外构建了溃疡性结肠炎（UC）的疾病进展模型。研究发现，微生物组衍生的短链脂肪酸（SCFA）可根据CD4 T细胞的活化状态，对疾病严重程度起到改善或加重的双向调控作用。通过多组学分析手段，我们观察到SCFA可抑制溃疡性结肠炎病灶肠道的先天活化，并增强肝脏代谢功能。但在T细胞介导的急性炎症状态下，SCFA会增强CD4 T细胞的效应功能，进而引发肠道屏障破坏与肝脏损伤。这些看似矛盾的研究结果，凸显了将人体生理模拟技术与系统免疫学相结合的新兴应用价值——该组合策略可用于探究肠-肝轴相关疾病的因果关系与时间维度特征，而传统动物模型往往难以明确此类问题。研究整体设计：对人体肠-肝轴生理模拟模型的组织样本进行RNA测序（RNA-Seq）分析；在不同连接模式下收集样本，并设置三次生物学重复进行检测分析。