# Gut-Liver Axis in the Pathogenesis of Alcohol-Associated Liver Disease: Protection by Betaine Treatment

> **NIH VA I01** · OMAHA VA  MEDICAL CENTER · 2024 · —

## Abstract

Alcoholic hepatitis, characterized by liver inflammation and hepatocyte injury, occurs in 10-20% of patients with
alcohol use disorder and accounts for significant mortality and financial burden to the VA healthcare system.
Currently, there is no FDA-approved therapy for such patients and treatment options remain as it was 40 years
ago. Therefore, it is imperative to develop new therapeutic strategies for which a better understanding of the
disease progression is required. There is robust evidence that gut microbial-derived components, such as
endotoxins, are the necessary cofactors for development of alcohol-associated liver disease (ALD) and their
increased serum levels correlate with disease severity. Further studies have demonstrated that elevated
serum levels of the gut luminal antigens occur through two main mechanisms: (i) compromised gut epithelial
barrier integrity that allows for increased paracellular translocation; and (ii) qualitative and quantitative changes
in the gut microbiota associated with an increased production of pathogenic antigens. These antigens normally
penetrate the intestinal epithelium in only trace amounts due to tightly regulated barrier integrity. The barrier is
mainly provided by the highly specialized intercellular multiprotein junctional complex, tight junctions (TJ),
located at the apical end of epithelial cells. Several studies have documented that ethanol disrupts the
structural integrity of TJ. The consequent loss of mucosal barrier allows for increased paracellular
translocation of gut luminal pathogenic molecules to travel through portal circulation and initiate a
necroinflammatory cascade in the liver. However, the molecular mechanism by which ethanol compromises TJ
integrity is incompletely understood.
We have previously shown that ethanol consumption alters the methionine metabolic pathway in the liver. The
consequent decline in the methylation index impairs crucial methylation reactions, leading to the generation of
many hallmark features of early alcohol-associated liver injury. We now present novel evidence that ethanol
administration alters the intestinal methionine metabolic pathway and lowers the methylation index in a manner
analogous to the liver. Further compelling evidence demonstrates that the consequent reduction in the
intestinal methylation reactions causes TJ disruption to promote paracellular leakage, endotoxemia and
progressive liver injury. Furthermore, associated with the alcohol-induced disruption of the gut barrier integrity
is gut microbial dysbiosis, marked by an increase in the Proteobacteria phylum and Gram-negative bacteria
that contribute to endotoxemia. More importantly, we show that co-treatment with betaine, a safe, bioavailable,
highly soluble, and naturally occurring methyl group donor, preserves intestinal barrier function and prevents
pathogenic gut microbiome changes to mitigate alcohol-induced endotoxemia and liver inflammation.
Based on these considerations, we put ...

## Key facts

- **NIH application ID:** 10801400
- **Project number:** 1I01BX006064-01A2
- **Recipient organization:** OMAHA VA  MEDICAL CENTER
- **Principal Investigator:** Kusum K. Kharbanda
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801400

## Citation

> US National Institutes of Health, RePORTER application 10801400, Gut-Liver Axis in the Pathogenesis of Alcohol-Associated Liver Disease: Protection by Betaine Treatment (1I01BX006064-01A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10801400. Licensed CC0.

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