Beneficial intestinal microbes and the body collaborate to finely adjust fat metabolism and cholesterol levels, based on a new preclinical investigation carried out by researchers from Weill Cornell Medicine and the Boyce Thompson Institute at Cornell University’s Ithaca location.
The human organism has co-evolved with the advantageous microbes residing in the gastrointestinal tract (referred to as the microbiota), resulting in mutually beneficial connections that assist in food digestion and absorption of vital nutrients needed for the survival of both the host and the gut microbes. A key element of these relationships is the generation of bioactive substances that facilitate food breakdown, making nutrient uptake possible by the host. One of the most significant groups of such substances are known as bile acids (also termed ‘bile’) which are synthesized from cholesterol in the liver and subsequently transported to the intestine where they enhance fat digestion.
Researchers have known for a while that gut bacteria transform bile acids into a version that activates a receptor known as FXR, which reduces bile synthesis. The new research, published on Jan. 8 in Nature, uncovers that an enzyme produced by intestinal cells alters bile acids into a different version with the contrary effect. This modified version, identified as bile acid-methylcysteamine (BA-MCY), suppresses FXR to stimulate bile production and assist in enhancing fat metabolism.
“Our study demonstrates that a communication is taking place between the gut microbes and the body that is essential for regulating bile acid synthesis,” stated co-corresponding author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Friedman Center for Nutrition and Inflammation, as well as the Michael Kors Professor in Immunology at Weill Cornell Medicine.
Bile acids facilitate the digestive system in breaking down fats into forms the body can absorb and utilize. “However, it has now become evident that bile acids are more than merely digestive aids; they function as signaling molecules, governing cholesterol levels, fat metabolism, and additional processes,” remarked co-corresponding author Dr. Frank Schroeder, a professor at the Boyce Thompson Institute and a professor in the Department of Chemistry and Chemical Biology in the College of Arts and Sciences at Cornell University. “They accomplish all of this by binding to FXR, which operates like a traffic light, managing cholesterol metabolism and bile acid production to prevent excess accumulation.”
The cross-campus collaboration among the laboratories of Dr. Schroeder and Dr. Artis has unveiled the host body’s involvement in this essential biological function. The study was co-led by Dr. Tae Hyung Won, a previous postdoctoral associate in Dr. Schroeder’s lab and currently an assistant professor at Cha University in Korea; Dr. Christopher Parkhurst, an instructor of medicine at Weill Cornell Medicine, working in Dr. Artis’s lab; and Dr. Mohammad Arifuzzaman, an assistant professor of immunology in medicine at Weill Cornell Medicine.
The interdisciplinary partnership between Drs. Artis and Schroeder has effectively integrated the biomedical fields of immunology, chemical biology, and host-microbiota interactions. In this study, they employed a method called untargeted metabolomics to identify all the molecules produced by mice with and without gut microbes. By analyzing the two groups, they could differentiate which molecules were synthesized by the gut microbes and which were generated by the organism. BA-MCYs emerged as substances that were created by the mice yet were nonetheless reliant on the existence of gut microbes.
The BA-MCYs illustrate a new paradigm: molecules that are not synthesized by the gut microbes but remain dependent on their presence.”
Dr. Tae Hyung Won, co-first author
Through a series of experiments, the researchers then demonstrated how the body synthesizes the BA-MCYs and how these substances enable the body to counter the microbes’ signals prompting decreased bile acid production, thereby preventing a slowdown in cholesterol metabolism.
“This balancing act is essential,” Dr. Schroeder affirmed. “When gut bacteria generate substantial amounts of bile acids that strongly activate FXR, the body responds by creating BA-MCYs, ensuring that the bile acid system remains equilibrated.”
The researchers also indicated in their preclinical model that elevating BA-MCY levels contributed to diminishing fat accumulation in the liver and that increased dietary fiber intake also enhanced BA-MCY production. “Notably, BA-MCYs were also identified in human blood samples, suggesting that a similar mechanism might occur in humans,” Dr. Arifuzzaman noted.
The findings may propose potential therapeutic targets for metabolic disorders, such as fatty liver disease, elevated cholesterol, and obesity-related conditions. They also imply that dietary strategies like increasing certain forms of fiber consumption may aid by bolstering the body’s regulatory mechanisms. The subsequent steps for the collaborators involve further understanding how these processes are regulated and examining this form of microbe-gut interaction in various disease states.
The researchers proposed that their study approach could also assist scientists in investigating the role of the gut microbiota in a broad spectrum of diseases, from infections and chronic inflammation to obesity and cancer.
“Our publication is a roadmap to employing untargeted metabolomics and chemistry to gain a deeper understanding of how the dialogue between the gut microbiota and the body influences a variety of diseases,” Dr. Artis stated.
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Journal reference:
Laumonnerie, C., et al. (2025). Siah2 antagonism of Pard3/JamC modulates Ntn1-Dcc signaling to regulate cerebellar granule neuron germinal zone exit. Nature Communications. doi.org/10.1038/s41467-024-55400-w.