Scientists discover new molecule that naturally stimulates fat metabolism

Researchers have discovered that the body and gut microbes jointly regulate fat metabolism through BA-MCY, a molecule that balances bile.

” data-gt-translate-attributes=”({“attribute=”” tabindex=”0″ role=”link”>acid production. This discovery could lead to new treatments against metabolic diseases and highlights the role of diet on health.

Beneficial gut microbes and the human body work together to fine-tune fat metabolism and cholesterol levels, according to a recent preclinical study led by researchers at Weill Cornell Medicine and the Boyce Thompson Institute at the Ithaca campus of the Cornell University.

The human body evolved alongside beneficial microbes residing in the gut, collectively called the microbiota. This co-evolution has fostered a symbiotic relationship in which microbes help digest food and absorb essential nutrients, essential for both the survival of the host and the sustenance of the microbes.

A key aspect of this collaboration is the production of bioactive molecules that facilitate food breakdown and nutrient absorption by the host.

One of the largest groups of these molecules is called bile acids (also called “bile”) which are produced from cholesterol in the liver and then delivered to the intestine where they support the digestion of fats.

Scientists have known for some time that gut bacteria change bile acids into a form that stimulates a receptor called FXR, which reduces bile production. The new study, published January 8 in Naturereveals that an enzyme produced by intestinal cells converts bile acids into a different form that has the opposite effect. This modified form, called bile acid-methylcysteamine (BA-MCY), inhibits FXR to promote bile production and help boost fat metabolism.

“Our study reveals that there is a cross-talk between gut microbes and the body that is vital for regulating bile acid production,” said co-corresponding author Dr. David Artis, director of the Institute. Jill Roberts for inflammatory bowel disease research and the Friedman Center for Nutrition and Inflammation and Michael Kors Professor of Immunology at Weill Cornell Medicine.

Bile acids as signaling molecules

Bile acids help the digestive system break down fats into forms that the body can absorb and use. “But it is now clear that bile acids are more than just digestive aids; they act as signaling molecules, regulating cholesterol levels, fat metabolism, etc. said co-corresponding author Dr. Frank Schroeder, a Boyce Thompson Institute professor and professor in the Department of Chemistry and Chemical Biology in the College of Arts. and science at Cornell University. “They do all this by binding to FXR, which acts like a traffic light, controlling cholesterol metabolism and bile acid production to prevent excess buildup.”

Today, cross-campus collaboration between the laboratories of Dr. Schroeder and Dr. Artis has revealed the role of the host body in this fundamental biological process. The study was co-led by Dr. Tae Hyung Won, a former postdoctoral associate in Dr. Schroeder’s lab and now an assistant professor at Cha University in Korea; Dr. Christopher Parkhurst, professor of medicine at Weill Cornell Medicine, working in Dr. Artis’ laboratory; and Dr. Mohammad Arifuzzaman, assistant professor of immunology in medicine at Weill Cornell Medicine.

The multidisciplinary collaboration between Drs. Artis and Schroeder have successfully merged the biomedical disciplines of immunology, chemical biology, and host-microbiota interactions. In this study, they used a technique called untargeted metabolomics to identify all molecules produced by mice with and without gut microbes. By comparing the two, they were able to distinguish which molecules were made by gut microbes and which were produced by the body. BA-MCYs stood out as molecules produced by mice but nevertheless dependent on the presence of intestinal microbes.

“BA-MCYs demonstrate a new paradigm: molecules that are not produced by gut microbes but still depend on their presence,” said co-first author Dr. Won. Through a series of experiments, the researchers then showed how the body produces BA-MCY and how these molecules allow the body to counteract the microbe’s signals to produce less bile acid, thereby preventing cholesterol metabolism from slowing down. .

“This balancing act is crucial,” Dr. Schroeder said. “When gut bacteria produce lots of bile acids that strongly activate FXR, the body pushes back by producing BA-MCY, ensuring the bile acid system is balanced.”

Potential therapeutic implications

The researchers also showed in their preclinical model that increasing BA-MCY levels helped reduce fat accumulation in the liver and that increasing dietary fiber consumption also improved BA-MCY production. “Importantly, BA-MCY was also detected in human blood samples, indicating that a similar mechanism may occur in humans,” added Dr. Arifuzzaman.

The results may suggest potential therapeutic targets for metabolic disorders including hepatic steatosis, hypercholesterolemia and obesity-related disorders. They also suggest that dietary approaches such as increasing certain forms of fiber intake may help by supporting the body’s system of checks and balances. The next steps for the collaborators are to learn more about how these processes are regulated and study this type of microbe-gut crosstalk in different disease states.

The researchers suggested that their study approach could also help researchers study the role of the gut microbiota in a wide range of diseases, from chronic infections and inflammation to obesity and cancer.

“Our paper is a roadmap for using untargeted metabolomics and chemistry to better understand the impact of the crosstalk between the gut microbiota and the body on a range of diseases,” said Dr. Artis.

Reference: “Host metabolism balances microbial regulation of bile acid signaling” by Tae Hyung Won, Mohammad Arifuzzaman, Christopher N. Parkhurst, Isabella C. Miranda, Bingsen Zhang, Elin Hu, Sanchita Kashyap, Jeffrey Letourneau, Wen-Bing Jin, Yousi Fu, Douglas V. Guzior, JRI Live Cell Bank, Robert A. Quinn, Chun-Jun Guo, Lawrence A. David, David Artis and Frank C. Schroeder, January 8, 2025, Nature.
DOI: 10.1038/s41586-024-08379-9