New gut-liver-on-a-chip device can lead to a cure for fatty liver disease

Here is how a unique integrated gut-liver-on-a-chip platform can help scientists understand non-alcoholic fatty liver disease better than ever.
Rupendra Brahambhatt
An illustration of the integrated gut-liver-on-a-chip.
An illustration of the integrated gut-liver-on-a-chip.

Mindy Takamiya/Kyoto University iCeMS

A team of researchers at Kyoto University in Japan has created an integrated gut-liver-on-a-chip platform (iGLC) that promises to reveal valuable information on non-alcoholic fatty liver disease (NAFLD), an incurable chronic condition that currently affects the lives of nearly 25 percent of the adult population in the U.S. 

NAFLD occurs due to the deposition of excessive fat in the liver. Many patients who face severe liver damage due to this disease are also at high risk of developing diabetes, heart ailments, cancer, and various liver-related health issues. 

“NAFLD is expected to afflict 33.5% of the United States population over 15 years of age by 2030. Currently, liver transplantation is the only method to cure patients with severe liver diseases, and finding donors that match patients is extremely difficult,” the researchers note.

Other medication-based NAFLD treatment methods only provide temporary relief against its various symptoms. Currently, many scientists across the globe are investigating the disease in order to devise an effective NAFLD treatment strategy, and this is where the iGLC platform could really play an important role, according to the researchers.

Decoding NAFLD using the integrated gut-liver-on-a-chip platform 

New gut-liver-on-a-chip device can lead to a cure for fatty liver disease
Diagram depicting the function of the chip platform.

The researchers suggest that the biological interactions taking place at the gut-liver axis (GLA) in animals and humans are very different from each other. So, unlike many other diseases, one cannot study NAFLD simply using animal models such as mice. This is why they developed iGLC, which actually mimics the circulations that occur between the human gut and liver. 

GLA is the communication channel between the liver, intestine, and gut microorganisms. The researcher kept their focus on the gut-liver axis while testing their platform because this particular spot in the human body is considered one of the most crucial points from where NAFLD and many other liver disorders originate and advance further. 

During the study, the Japanese researchers created two separate chambers connected via a fluidic channel comprising opening and closing valves. The first and second chambers contained co-cultured human gut and liver cell lines, respectively. 

The iGLC platform they made is designed using a type of silicone called polydimethylsiloxane (PDMS). They further coated iGLC with additional substances to keep fat molecules away from the chip and prevent undesirable cell growth. Moreover, the platform also comes with an integrated micro pump and some microvalves that regulate the flow of fluids.

They employed the iGLC platform to pump a fluid medium between the two chambers while keeping the fluids and cell lines separate—this is similar to the various interactions that take place at GLA. The researchers further tested the interaction between the two chip organs by adding substances like free fatty acids (FFAs) to the platform.

“We also induced a NAFLD-like cellular state by administering FFAs into the platform for two durations (1 and 7 days) to represent the initial and progressive NAFLD. Finally, we investigated the unique cellular phenotypic changes and associated gene networks for the GLA in the NAFLD-like cellular state by microscopic single-cell profiling in combination with mRNA sequencing,” said the authors.

They noticed that after seven days of FFA circulation in the iGLC, the cells died — a trend also observed in many real-life cases of NAFLD. 

It must be noted that similar to living human liver and gut cells, the platform is not affected by factors like gut microbiome. However, it can mimic NAFLD-like conditions better than any other existing device, according to the researchers.

Corresponding study author Yoshikazu Hirai believes that iGLC could play an important role in increasing our understanding of NAFLD. He further added, “We next plan to use liver and gut organoids derived from human stem cells so we can investigate NAFLD under precisely controlled conditions that more closely mimic patients’ physiological contexts.” 

The study is published in the journal Communications Biology.

Study Abstract:

Non-alcoholic fatty liver disease (NAFLD) afflicts a significant percentage of the population; however, no effective treatments have yet been established because of the unsuitability of in vitro assays and animal experimental models. Here, we present an integrated-gut-liver-on-a-chip (iGLC) platform as an in vitro human model of the gut-liver axis (GLA) by co-culturing human gut and liver cell lines interconnected via microfluidics in a closed circulation loop, for the initiation and progression of NAFLD by treatment with free fatty acids (FFAs) for 1 and 7 days, respectively. Co-cultured Caco-2 gut-mimicking cells and HepG2 hepatocyte-like cells demonstrate the protective effects from apoptosis against FFAs treatment, whereas mono-cultured cells exhibit induced apoptosis. Phenotype and gene expression analyses reveal that the FFAs-treated gut and liver cells accumulated intracellular lipid droplets and show an increase in gene expression 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 the mechanisms of NAFLD.

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