New Study Reveals Microbial Enzyme Target for Metabolic Disease Treatment

Research from the University of California San Diego has unveiled a new target for treating metabolic diseases by restoring microbial rhythms in the gut. The study, published in *Cell Host & Microbe* on June 18, 2025, demonstrates how time-restricted feeding (TRF) can counteract the detrimental effects of high-fat diets on gut microbiota.

The gut microbiome, which comprises a diverse array of microorganisms, plays a crucial role in energy metabolism. Disruptions in microbial activity, often caused by unhealthy diets, can lead to metabolic disorders such as obesity and diabetes. The research team investigated how TRF, which limits food intake to a specified time each day, could help restore these beneficial microbial rhythms in mice subjected to a high-fat diet.

Using a technique called metatranscriptomics, the researchers analyzed the daily fluctuations in microbial gene expression. They discovered that TRF significantly impacted the expression of a specific enzyme known as bile salt hydrolase (BSH), which is essential for fat digestion and glucose metabolism. The team engineered the *bsh* gene into a non-pathogenic gut bacterium and found that mice receiving this modified microbe exhibited reduced body fat, improved insulin sensitivity, and enhanced glucose control, mirroring the effects of TRF.

Amir Zarrinpar, M.D., Ph.D., an associate professor at UC San Diego and the study’s senior author, emphasized the significance of these findings: “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.”

Investigating Microbial Functions

The study involved three groups of mice: one group on a high-fat diet with TRF, another on the same diet with unrestricted food access, and a control group on a standard diet. After eight weeks, the researchers found that while metagenomics only captured the presence of genes, metatranscriptomics provided insights into the dynamic changes in microbial functions.

Dr. Stephany Flores Ramos, a postdoctoral researcher and first author, pointed out that “by looking at RNA, we are able to capture the dynamic changes of these microbes compared to metagenomics where we don’t see changes.” The results indicated that TRF altered microbial function in ways that benefitted the host, paving the way for potential therapeutic applications.

The research team focused on how TRF influenced the transcription of the *bsh* gene in the gut bacteria *Dubosiella newyorkensis*, which has a human equivalent. They engineered various gut bacteria to express different versions of the *bsh* gene, leading to the discovery that only the variant from *D. newyorkensis*, expressed more during TRF, resulted in significant metabolic improvements.

“Mice given these engineered bacteria had better blood sugar control, lower insulin levels, less body fat, and more lean mass,” said Zarrinpar. This finding underscores the potential of metatranscriptomics in identifying time-sensitive microbial functions that could enhance host metabolism.

Future Directions

The next phase of research will involve testing the engineered bacteria in mice with obesity or diabetes induced by a high-fat diet to confirm the benefits observed in this study. Zarrinpar noted, “We also plan to explore other time-sensitive microbial genes uncovered by our data to develop additional engineered bacteria that could improve metabolic health.”

The study’s co-authors include notable researchers such as Nicole Siguenza, Wuling Zhong, and Rob Knight, among others, who contributed to the comprehensive investigation into gut microbiota dynamics and their implications for metabolic diseases.

Despite the promising results, the research team acknowledges the complexity of metabolic disorders and the need for further studies before these findings can transition into human therapies. The collaborative work highlights the critical intersection of microbiology, metabolism, and potential future treatments for metabolic diseases.