Researchers Identify Microbial Target for Treating Metabolic Diseases

A recent study led by researchers at the University of California San Diego has uncovered a potential microbial target for treating metabolic diseases. The research highlights the role of the gut microbiome, which significantly influences energy conversion from food. Specifically, the study focused on how rhythmic cycles of microbial activity can be disrupted by high-fat diets, contributing to metabolic disorders.

Restoring Microbial Rhythms with Time-Restricted Feeding

To explore solutions, the research team employed a method known as time-restricted feeding (TRF), which limits dietary intake to an eight-hour window each day. This approach was tested on mice consuming a high-fat diet. By analyzing daily fluctuations in microbial gene expression using metatranscriptomics, the researchers identified an enzyme called bile salt hydrolase (BSH) as pivotal in enhancing metabolic health.

Following TRF, the mice that received engineered gut bacteria expressing the bsh gene exhibited lower body fat, improved insulin sensitivity, and better glucose control. This mimicked the beneficial effects of the TRF intervention itself. The findings suggest a promising avenue for developing targeted therapies for conditions like obesity and diabetes.

The study was published in Cell Host & Microbe on June 18, 2025, providing a detailed account of how TRF can effectively modify microbial functions for metabolic improvements. The researchers conducted experiments involving three groups of mice to assess the impacts of TRF versus unrestricted feeding.

Dynamic Changes in Gut Microbiome

After eight weeks of observation, the researchers noted significant changes that were only detectable at the RNA level through metatranscriptomics. Traditional metagenomics, which maps genetic content, failed to capture these dynamic shifts. “By looking at RNA, we are able to capture the dynamic changes of these microbes compared to metagenomics,” stated Stephany Flores Ramos, Ph.D., a postdoctoral researcher at UC San Diego and first author of the study.

The investigation delved deeper into the specific activities of gut bacteria and their direct influence on metabolic health. Amir Zarrinpar, M.D., Ph.D., an associate professor of medicine at UC San Diego and senior author of the study, noted the importance of confirming the relationship between gut microbiome changes and metabolic benefits: “With this study, we were finally able to test that idea directly.”

The focus on BSH was crucial, as previous research suggested that this enzyme plays a role in fat digestion and glucose metabolism. The team established that TRF enhanced the expression of the bsh gene in the gut bacterium Dubosiella newyorkensis, which shares functional similarities with human gut bacteria.

Using this knowledge, researchers engineered various gut bacteria to express different versions of the bsh gene. Only the variant derived from D. newyorkensis, which was more active during TRF, led to significant metabolic enhancements in mice.

Mice administered these modified bacteria demonstrated improved blood sugar control, lower insulin levels, reduced body fat, and increased lean mass. “This demonstrates how metatranscriptomics can help identify time-dependent microbial functions that may be directly responsible for improving host metabolism,” Zarrinpar explained.

Next Steps for Research

The research team plans to further investigate the engineered bacteria in mice models with obesity or diabetes induced by high-fat diets to confirm the observed benefits. Zarrinpar expressed enthusiasm about future possibilities: “We also plan to explore other time-sensitive microbial genes uncovered by our data to develop additional engineered bacteria that could improve metabolic health.”

Additional co-authors of the study included researchers from UC San Diego and other institutions, such as Nicole Siguenza, Wuling Zhong, and Satchidananda Panda from the Salk Institute for Biological Studies. The study’s funding and affiliations were disclosed, highlighting potential conflicts of interest involving Zarrinpar and other researchers.

This groundbreaking research offers a fresh perspective on the intricate relationship between diet, gut microbiota, and metabolic health, pointing toward innovative strategies for treating metabolic diseases in humans.