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Integrated gut–liver-on-a-chip platform as an in vitro human model of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) afflicts a large percentage of the population, but no effective treatments have been established so far because of the unsuitability of in vitro assays and experimental models using animals. By co-culturing human gut and liver cell lines interconnected via microfluidics for a closed circulation loop, we created a gut–liver-on-a-chip (iGLC) platform as an in vitro human model of the gut–liver axis (GLA) for the initiation and progression of NAFLD. Microscopic high-content analysis followed by mRNA sequencing showed that co-culturing the gut and liver cells significantly affected each cell type compared to culturing them separately. NAFLD-inducing free fatty acids (FFAs) accumulated in the gut cells and elevated gene expressions associated with retinol metabolism and glucuronidation. The FFA-treated liver cells accumulated intracellular lipid droplets and showed an increase in gene expressions associated with a cellular response to copper ions and endoplasmic reticulum stress. As an in vitro human GLA model, the iGLC platform may serve as an alternative to animal experiments for investigating NAFLD mechanisms.