Gut-Liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids
Gut-Liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids
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DOI：
10.1101/706812
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发表时间：
2019-07
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影响因子：
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通讯作者：
M. Trapecar;C. Communal;J. Velazquez;C. Maass;Yu-Ja Huang;Kirsten Schneider;Charles W. Wright;G. Eng;Omer H. Yilmaz;D. Trumper;L. Griffith
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作者：
M. Trapecar;C. Communal;J. Velazquez;C. Maass;Yu-Ja Huang;Kirsten Schneider;Charles W. Wright;G. Eng;Omer H. Yilmaz;D. Trumper;L. Griffith
微生物组、IBD 和肝脏疾病之间的关联已为人所知，但其因果关系仍然难以捉摸。通过连接肠道、肝脏和循环 Treg/Th17 细胞的人体微生理系统，我们模拟了溃疡性结肠炎 (UC) 的离体进展。我们发现，微生物组衍生的短链脂肪酸 (SCFA) 可能会改善或恶化疾病的严重程度，具体取决于 CD4 T 细胞的激活状态。采用多组学，我们发现 SCFA 增加了酮体、糖酵解和脂肪生成的产生，同时显着减少了 UC 肠道的先天免疫激活。然而，在急性 T 细胞介导的炎症过程中，SCFA 部分通过代谢重编程加剧了 CD4+ T 细胞效应功能，导致肠道屏障破坏和肝损伤。这些矛盾的发现强调了人体拟态技术与系统免疫学相结合的新兴实用性，以研究免疫、新陈代谢和组织稳态的因果关系和基本纠缠。
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 multiomics, we found SCFA 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, SCFA 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.