Research led by scientists at the University of California San Diego has uncovered a new target for treating metabolic diseases by restoring microbial rhythms in the gut. The study, published in the journal Cell Host & Microbe on June 18, 2025, reveals how a specific enzyme may play a crucial role in metabolic health, especially in the context of high-fat diets.
The gut microbiome, a complex ecosystem of bacteria and other microorganisms residing in the digestive system, is essential for converting food into energy. Many of these microbes exhibit rhythmic cycles of activity that can be disrupted by unhealthy dietary habits, leading to metabolic disorders. To investigate this phenomenon, researchers employed a method known as time-restricted feeding (TRF), which limits food intake to a specific time window each day.
Through their innovative approach, the team analyzed daily variations in microbial gene expression using metatranscriptomics, which measures real-time gene activity in gut bacteria. They studied three groups of mice: one group fed a high-fat diet with TRF for eight hours daily, another group given the same diet without time restrictions, and a control group on a standard diet with unlimited access to food.
After an eight-week trial, the results indicated that only the TRF group showed significant functional changes at the RNA level. Traditional metagenomics, which identifies the presence of genes, failed to capture these dynamic shifts. “By looking at RNA, we are able to capture the dynamic changes of these microbes compared to metagenomics where we don’t see changes,” stated Stephany Flores Ramos, Ph.D., a postdoctoral researcher at UC San Diego and the study’s first author.
The research also investigated whether specific microbial activities were responsible for the observed metabolic benefits. Amir Zarrinpar, M.D., Ph.D., an associate professor of medicine at UC San Diego and the senior author of the study, emphasized the connection between TRF and changes in the gut microbiome. “With this study, we were finally able to test that idea directly,” he said.
Focusing on the enzyme bile salt hydrolase (BSH), known for its role in fat digestion and glucose metabolism, the researchers engineered the bsh gene into a harmless gut bacterium. They found that the version derived from the gut bacterium Dubosiella newyorkensis led to notable metabolic improvements when administered to mice. Those treated with the engineered bacteria exhibited better blood sugar control, reduced insulin levels, lower 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 noted. The findings pave the way for developing targeted microbial therapies aimed at obesity, diabetes, and other metabolic conditions.
Looking ahead, the researchers plan to test these engineered bacteria in models of obesity and diabetes induced by high-fat diets. Zarrinpar expressed enthusiasm about exploring additional time-sensitive microbial genes identified in their study to further enhance metabolic health through engineered strains.
The collaborative effort included contributions from various co-authors affiliated with UC San Diego, the Salk Institute for Biological Studies, and Arizona State University. Notably, the research team comprised Nicole Siguenza, Wuling Zhong, Amulya Lingaraju, and several others.
The study highlights the potential of leveraging gut microbiome research to create innovative strategies for addressing metabolic diseases, emphasizing the importance of understanding microbial functions in relation to diet and health.
