# Mechanisms of gut microbiota/metabolite interface-mediated hepatic inflammation

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2024 · $397,590

## Abstract

Project Summary/Abstract
The liver is now recognized as an immunological organ with unique properties. Its immune response is tightly
controlled to ensure immune tolerance to microbial, dietary, and metabolic products flowing from gut to liver
through the portal vein. However, certain risk factors induce hepatic immune dysregulation, resulting in the
development of liver disease. A high-fat and high-sugar diet (HFS), a typical Western-type diet (WD), is
identified as a major risk factor contributing to the development of nonalcoholic fatty liver disease (NAFLD),
ranging from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH). Given dietary
changes worldwide, NAFLD is rapidly becoming the leading cause of liver disease affecting 25% of the
population worldwide. Mounting evidence indicates that the HFS and gut microbiota interaction generates a
spectrum of dietary and microbial components and outcome metabolites that can induce inappropriate hepatic
immune activation, suggesting a key role of the Diet/Gut/Liver/Immune axis in NASH . However, the underlying
mechanisms are poorly understood. Furthermore, very little is known about the specific microbes and
metabolites that regulate intrahepatic immunity. To address these major knowledge gaps, the investigators
have developed a NASH model by feeding wild-type mice with a choline-low HFS (CL-HFS) (0.05% choline)
which closely approximates a typical WD in composition. This model is characterized by gut dysbiosis,
metabolic disarray, abnormal hepatic immune response, and liver-resident macrophage (MΦ) and hepatic
stellate cell (HSC) activation, reflecting typical pathologic properties in human NASH patients. Using the model,
the investigators demonstrate that selective suppression of gut microbiota preventively and therapeutically
inhibits CL-HFS-induced NASH. Metagenomic and metabolomic analyses in combination with in vitro and in
vivo experiments identified Blautia producta (B. producta) and its product 2-oleoyglycerol (2-OG) as an
unrecognized bacterium and metabolite contributing to CL-HFS-induced abnormal hepatic immune response.
Of particular clinical relevance, enrichment of gut Blautia and high levels of hepatic 2-OG are found in human
NASH patients. Mechanistic studies suggest that 2-OG primes MΦs via G protein-coupled receptor 119
signaling, subsequently activating HSCs. These exciting results support the hypothesis: CL-HFS, B. producta,
and 2-OG, by activating MΦs through GPR119 signaling pathways, cause hepatic pathogenesis and HSC
activation. This hypothesis will be tested in the following Aims: Aim 1: Determine MΦ as a cellular basis of CL-
HFS-induced NASH pathogenesis mediating crosstalk between gut microbiota, HFS, and liver; Aim 2:
Determine GPR119 as a molecular basis of MΦ mediating hepatic pathogenesis induced by CL-HFS, B.
product, and 2-OG. This study will dissect the underlying cellular and molecular mechanisms to advance the
understanding of the role of...

## Key facts

- **NIH application ID:** 11094474
- **Project number:** 7R01DK130340-03
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Guangfu Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $397,590
- **Award type:** 7
- **Project period:** 2022-08-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11094474

## Citation

> US National Institutes of Health, RePORTER application 11094474, Mechanisms of gut microbiota/metabolite interface-mediated hepatic inflammation (7R01DK130340-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11094474. Licensed CC0.

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