Integrated gut/liver microphysiological systems elucidates inflammatory inter-tissue crosstalk.

Area of Science:

• Biotechnology and Bioengineering
• In vitro modeling
• Multi-organ systems

Background:

• Cellular communication between tissues, like the gut and liver, is crucial for drug discovery.
• Understanding these interactions requires advanced in vitro models for human applications.
• Perturbations in one organ can significantly impact the function of another.

Purpose of the Study:

• To investigate human gut-liver tissue interactions under normal and inflammatory conditions.
• To develop and utilize an integrative multi-organ platform for studying gut-liver crosstalk.
• To gain insights into complex pathophysiological processes involving organ communication.

Main Methods:

• Developed an integrative multi-organ platform with human liver (hepatocytes, Kupffer cells) and intestinal (enterocytes, goblet cells, dendritic cells) models.
• Maintained long-term (>2 weeks) intestinal and hepatic functions in the co-culture system.
• Utilized gene expression analysis (RNA-seq) to compare interacting vs. isolated tissues and assess inflammatory responses.

Main Results:

• Demonstrated sustained intestinal barrier integrity and hepatic albumin production in the gut-liver model.
• Identified modulation of bile acid metabolism, including FGF19-mediated CYP7A1 inhibition, indicating functional crosstalk.
• Observed synergistic enhancement of CXCR3 ligand production and upregulation of interferon signaling during inflammatory interactions.
• Found that exacerbated inflammation negatively impacted tissue-specific functions, such as liver metabolism.

Conclusions:

• The developed multi-organ platform effectively models human gut-liver interactions, providing valuable insights.
• This platform can elucidate complex pathophysiological processes, including inflammatory organ crosstalk.
• Findings support the utility of integrated tissue models in drug discovery and understanding disease mechanisms.