Gut-Liver Physiomimetics Reveal Paradoxical Modulation of IBD-Related Inflammation by Short-Chain Fatty Acids
Author(s)Trapecar, Martin; Communal, Catherine; Velazquez, Jason G; Maass, Christian Alexander; Huang, Yu-Ja; Schneider, Kirsten; Wright, Charles; Butty, Vincent L G; Eng, George M.; Yilmaz, Omer; Trumper, David L; Griffith, Linda G; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Mechanical Engineering; Massachusetts Institute of Technology. Research Laboratory of Electronics; Massachusetts Institute of Technology. Department of Biology
Trapecar, Martin et al. "Gut-Liver Physiomimetics Reveal Paradoxical Modulation of IBD-Related Inflammation by Short-Chain Fatty Acids." Cell Systems 10, 3 (March 2020): P223-239.E9 © 2020 Elsevier Inc