Gut-Liver Physiomimetics Reveal Paradoxical Modulation of IBD-Related Inflammation by Short-Chain Fatty Acids

Overview

Journal Cell Syst

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2020 Mar 20

PMID 32191873

Citations 77

Authors

Martin Trapecar

Catherine Communal

Jason Velazquez

Christian Alexander Maass

Yu-Ja Huang

Kirsten Schneider

Charles W Wright

Vincent Butty

George Eng

Omer Yilmaz

David Trumper

Linda G Griffith

Affiliations

Soon will be listed here.

Abstract

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.

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