Integrated gut/liver microphysiological systems elucidates inflammatory inter‐tissue crosstalk

Abstract

A capability for analyzing complex cellular communication among tissues is important in drug discovery and development, and in vitro technologies for doing so are required for human applications. A prominent instance is communication between the gut and the liver, whereby perturbations of one tissue can influence behavior of the other. Here, we present a study on human gut-liver tissue interactions under normal and inflammatory contexts, via an integrative multi-organ platform comprising human liver (hepatocytes and Kupffer cells) and intestinal (enterocyte, goblet cells, and dendritic cells) models. Our results demonstrated long-term (>2 weeks) maintenance of intestinal (e.g., barrier integrity) and hepatic (e.g., albumin) functions in baseline interaction. Gene expression data comparing liver in interaction with gut, versus isolation, revealed modulation of bile acid metabolism. Intestinal FGF19 secretion and associated inhibition of hepatic CYP7A1 expression provided evidence of physiologically relevant gut-liver crosstalk. Moreover, significant non-linear modulation of cytokine responses was observed under inflammatory gut-liver interaction; for example, production of CXCR3 ligands (CXCL9,10,11) was synergistically enhanced. RNA-seq analysis revealed significant upregulation of IFNα/β/γ signaling during inflammatory gut-liver crosstalk, with these pathways implicated in the synergistic CXCR3 chemokine production. Exacerbated inflammatory response in gut-liver interaction also negatively affected tissue-specific functions (e.g., liver metabolism). These findings illustrate how an integrated multi-tissue platform can generate insights useful for understanding complex pathophysiological processes such as inflammatory organ crosstalk.

Gut-Liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids

“…We focused initial experiments on behaviors of the gut-liver axis in the absence and presence of SCFA without adaptive immune cells, using the gut and liver MPSs connected at recirculating flow rates of 30 ml/day. Integration of gut and liver MPSs significantly affects their individual phenotypes and gene expression ( Fig.S4A,B) in accordance with our previous observations during interaction of a CaCo-2 cell based MPS with the liver MPS (30,31). The most notable effects were decreased glycolysis and increased CYP450 and steroid hormone synthesis of the gut MPS ( Fig.S4A) and increased CYP450 activity with downregulation of inflammatory pathways in the liver MPSs (Fig.S4B).…”

“…MPSs are in vitro models that are both complex -comprising multiple cell types, specialized microenvironments, and perfusion -and yet reductionist, as they capture only the most salient features of in vivo organ behavior required to model the physiological process in question. We previously developed a physiomimetic platform technology that supports long-term (weeks) integrated co-culture of up to 10 fluidically-communicating MPSs, featuring individuallyaddressable on-board microfluidic pumps compatible with highly lipophilic compounds such as steroid hormones (29)(30)(31). Here, we use a new iteration of the platform designed to model the gut-liver-immune axis by connecting a gut MPS of UC (primary human UC epithelium, dendritic cells and macrophages) with a liver MPS (healthy human hepatocytes and Kupffer cells) and circulating Treg/Th17 cells.…”

Gut–liver on a chip toward an in vitro model of hepatic steatosis

“…Another major advantage of an organ‐on‐a‐chip system is that it is capable of realizing the interaction between different organs (Sung et al, ; Sung, Kam, & Shuler, ). In particular, interactions between the gut and the liver have been the focus of intense research (Chen et al, ; Choe, Ha, Choi, Choi, & Sung, ; D. W. Lee, Ha, Choi, & Sung, ). For example, Leclerc et al, developed a microfluidic gut–liver chip to study the first‐pass metabolism of drugs (Bricks et al, ; Prot et al, ).…”

“…In particular, interactions between the gut and the liver have been the focus of intense research (Chen et al, 2017;Choe, Ha, Choi, Choi, & Sung, 2017;D. W. Lee, Ha, Choi, & Sung, 2017).…”

Mucus models to evaluate the diffusion of drugs and particles

“…In another system, human liver (i.e. human primary hepatocytes and Kupffer cells) and intestinal (C2BBe1 Caco-2 clone, HT29-MTX, and human primary dendritic cells) modules were used to study gut-liver interaction for 2 weeks[115, 116]. Endotoxemia, a condition characterized by the presence of circulating lipopolysaccharide (LPS), was simulated by the addition of 2 ng/mL LPS into the circulating media.…”