Research Spotlight: Microbial Bile Acid Metabolism Regulates Gut Barrier Integrity and Liver Injury and Could Be a New Treatment Target

Darrick Li, MD, PhD, and Raymond Chung, MD, of the Mass General Liver Center, led a recent study in Science Advances, Inhibition of Microbial Deconjugation of Micellar Bile Acids Protects Against Intestinal Permeability and Liver Injury.

What was the question you set out to answer with this study?

Increased intestinal permeability play a role in the onset of diseases such as type 1 and 2 diabetes, inflammatory bowel disease and depression.

The gut microbial communities of these patients are altered compared to healthy individuals, and gut microbial imbalance has been proposed to contribute to the development of intestinal permeability.

However, the mechanisms by which intestinal microbes affect the integrity of the intestinal epithelium (the cells lining the intestinal wall) remains unclear.

In this study, we looked at the impact of bacterial metabolism of host-produced bile acid (BA) metabolites on epithelial barrier integrity.

What are two or three key takeaways?

In an established rat model of diet-induced cirrhosis that is characterized by disrupted epithelial barrier integrity, we showed that an abundant group of metabolites found in the human gut, conjugated bile acids, protect against pathogenic intestinal permeability.

In contrast, unconjugated bile acids, which are produced by the deconjugation of conjugated bile acids by human gut bacteria, damage the intestinal wall.

We elucidated a mechanism for this protection: conjugated bile acids form micelles (spherical arrangement of lipid molecules) and physically sequester unconjugated bile acids away from host intestinal cells. Our study identifies a signaling-independent, physicochemical mechanism for conjugated bile acid-mediated protection of epithelial barrier function.

Using a small molecule inhibitor of gut bacterial bile salt hydrolases (BSHs) that was previously developed in the laboratory of (co-corresponding author) A. Sloan Devin, PhD, we showed that inhibition of bacterial bile deconjugation prevents development of pathologic intestinal permeability and hepatic inflammation in a diet-induced animal model of disease.

What were your conclusions?

Our study identifies a signaling-independent, physicochemical mechanism for conjugated BA-mediated protection of epithelial barrier function and suggests that rational manipulation of microbial BA metabolism could be leveraged to regulate gut barrier integrity.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.