New Study Identifies Microbial Target for Metabolic Disease Treatment

Research from the University of California San Diego has unveiled a promising approach to treating metabolic diseases by restoring microbial rhythms in the gut. The study, published in Cell Host & Microbe on June 18, 2025, highlights the role of gut microbiomes in energy conversion and identifies an enzyme that may protect metabolic health.

The gut microbiome, composed of various bacteria and microorganisms, is essential for processing food into energy. Disruptions to this system, often caused by high-fat diets, can lead to metabolic disorders. The researchers employed a method known as time-restricted feeding (TRF), limiting dietary intake to a short time window each day, to observe its effects on mice subjected to a high-fat diet.

To investigate the impact of TRF on microbial function, the researchers analyzed gene expression in the gut bacteria using a technique called metatranscriptomics. This method allows for real-time measurements of microbial activity, in contrast to traditional metagenomics, which only identifies present genes. By focusing on RNA levels, the team was able to detect dynamic changes in microbial function that conventional methods missed.

After eight weeks of study, the results were clear. Mice on a high-fat diet with TRF demonstrated significant improvements in metabolic health compared to those with unrestricted food access. This included enhanced insulin sensitivity and reduced body fat, suggesting that the timing of food intake plays a crucial role in modulating gut microbiota activity.

Amir Zarrinpar, M.D., Ph.D., the senior author of the study, expressed enthusiasm for the findings, stating, “We’ve long suspected that the metabolic benefits of time-restricted feeding might be driven by changes in the gut microbiome. With this study, we were finally able to test that idea directly.”

The researchers specifically identified the enzyme bile salt hydrolase (BSH) as a key player in these metabolic improvements. BSH is known to aid in fat digestion and regulate glucose metabolism. The expression of the bsh gene increased during TRF in the gut bacteria Dubosiella newyorkensis, which shares functional similarities with human gut bacteria.

In a significant advancement, the team engineered gut bacteria to express various versions of the bsh gene. When these modified bacteria were introduced to mice, only the variant derived from D. newyorkensis, which showed increased expression during TRF, resulted in notable metabolic benefits. Mice receiving this engineered microbe exhibited better blood sugar control, lower insulin levels, and increased lean mass.

“This demonstrates how metatranscriptomics can help identify time-dependent microbial functions that may be directly responsible for improving host metabolism,” said Zarrinpar. He further emphasized the potential for developing targeted microbial therapies based on these insights.

Looking ahead, the research team plans to test the engineered bacteria in mice with obesity or diabetes induced by a high-fat diet to verify whether the observed benefits persist in disease models. Zarrinpar indicated a desire to explore additional time-sensitive microbial genes uncovered in their research to develop further engineered bacteria that could enhance metabolic health.

The study has garnered attention not only for its findings but also for the collaborative effort of numerous researchers, including Stephany Flores Ramos, Ph.D., the first author, and contributors from various institutions such as the Salk Institute for Biological Studies and Arizona State University.

These findings mark a significant step forward in understanding the intricate relationship between diet, gut microbiota, and metabolic health, potentially paving the way for innovative therapeutic strategies for conditions like obesity and diabetes.