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.