# The potential mechanisms of reciprocal regulation of gut microbiota-liver immune signaling in metabolic dysfunction-associated steatohepatitis revealed in multi-omics analysis

## TL;DR

This study uses multi-omics to uncover how gut microbiota and liver immune signaling interact in MASH, revealing potential mechanisms for better disease management.

## Contribution

The study introduces a novel multi-omics approach to elucidate reciprocal regulation between gut microbiota and liver immune signaling in MASH.

## Key findings

- Disorders in lipid, amino acid, and glucose metabolism mediate interactions between gut microbiota and liver immune responses.
- JAK-STAT and NF-κB signaling pathways are activated in MASH through these interactions.
- The findings offer insights into microbiota-metabolite-immune signaling interactions for improved MASH management.

## Abstract

As a commonly known aggressive liver-related manifestation within the spectrum of metabolic syndrome with a significant risk of progressing to cirrhosis and hepatocellular carcinoma, metabolic dysfunction-associated steatohepatitis (MASH) is closely intertwined with obesity, insulin resistance, and dyslipidemia. Although the gut microbiota is implicated in MASH progression, the underlying mechanisms require further investigation. In this study, we sought to combine the analysis of the liver transcriptome, circulating metabolome, and gut microbiota to investigate the potential molecular mechanisms underlying the reciprocal regulation between gut microbiota and liver immune signaling. We utilized a high-fat and methionine/choline-deficient diet (HFMCD)-induced MASH model in a db/db mouse. Following annotation analysis using KEGG and Metorigin, a comprehensive correlation analysis was conducted among these genes and specific metabolites (such as L-glutamine, isocitric acid, putrescine, pyroglutamic acid, rhamnose) and gut microbiota genera (Enteroccus and Romboutsia). The results revealed intricate interactions among the liver’s immune microenvironment, the metabolome, and the gut microbiota. These interactions suggest a potential regulatory mechanism for metabolic disorders and immune responses.

Our multi-omics analysis showed that the interactions between gut microbiota and liver immune responses mediated by the disorders in lipid, amino acid, and glucose metabolism are associated with activation of the JAK-STAT and NF-κB signaling pathway in MASH. The multi-omics analysis provides valuable insights into the interactions among microbiota, circulating metabolites, and immune signaling. These insights can be harnessed to enhance the management of MASH.