Unlocking the Secrets: How Diet and Gut Microbes Regulate Body Fat and Cholesterol Levels

Beneficial gut microorganisms and the body collaborate to precisely regulate fat metabolism and cholesterol levels, as highlighted in a recent preclinical investigation conducted by researchers from Weill Cornell Medicine and the Boyce Thompson Institute at Cornell University’s Ithaca campus.

The human body has co-evolved with the advantageous microorganisms residing in the gut (known as microbiota), leading to reciprocal relationships that support food digestion and the absorption of vital nutrients essential for the survival of both the host and the gut microbes. A key element of these associations is the generation of bioactive compounds that facilitate food breakdown, allowing nutrient uptake by the host. Among the most significant groups of such compounds are identified as bile acids (also referred to as ‘bile’), produced from cholesterol in the liver before being sent to the intestine where they enhance fat digestion.

Researchers have been aware for some time that gut bacteria alter bile acids into a form that activates a receptor known as FXR, which diminishes bile production. The latest study, published on Jan. 8 in Nature, uncovers that an enzyme generated by intestinal cells transforms bile acids into another form that produces the opposite effect. This modified form, named bile acid-methylcysteamine (BA–MCY), inhibits FXR to stimulate bile production and assist in enhancing fat metabolism.

“Our research indicates that a communication is taking place between the gut microbes and the body that is essential for managing bile acid production,” remarked 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 assist the digestive system in breaking fats down into forms the body can absorb and utilize. “However, it is now evident that bile acids do more than just aid digestion; they function as signaling molecules, influencing cholesterol levels, fat metabolism, and more,” explained co-corresponding author Dr. Frank Schroeder, a professor at the Boyce Thompson Institute and a faculty member in the Department of Chemistry and Chemical Biology at Cornell University’s College of Arts and Sciences. “They perform all these functions by binding to FXR, which operates like a traffic signal, overseeing cholesterol metabolism and bile acid production to prevent excess buildup.”

Now, the cross-campus collaboration between the labs of Dr. Schroeder and Dr. Artis has unveiled the role of the host body in this essential biological process. The study was co-directed 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 teamwork between Drs. Artis and Schroeder has adeptly combined the biomedical fields of immunology, chemical biology, and host-microbiota interactions. In this investigation, they utilized a method called untargeted metabolomics to discern all the molecules produced by mice with and without gut microbes. By contrasting the two, they were able to identify which molecules originated from the gut microbes and which ones were generated by the body. BA-MCYs emerged as compounds that were synthesized by the mice but were still reliant on the presence of gut microbes.

“The BA-MCYs introduce a novel paradigm: molecules that are not synthesized by the gut microbes but depend on their presence,” co-first author Dr. Won stated. Through a series of experiments, the scientists demonstrated how the body produces the BA-MCYs and how these molecules offer a method for the body to counteract the microbes’ signals to synthesize less bile acid, thus preventing a slowdown in cholesterol metabolism.

“This balancing act is essential,” Dr. Schroeder stated. “When gut bacteria generate large amounts of bile acids that strongly activate FXR, the body responds by producing BA-MCYs, ensuring the bile acid system remains balanced.”

The researchers also indicated in their preclinical model that elevating BA-MCY levels contributed to reducing fat accumulation in the liver, and that increasing dietary fiber intake also promoted BA-MCY production. “Importantly, BA-MCYs were also discovered in human blood samples, suggesting that a similar mechanism might be at play in humans,” Dr. Arifuzzaman noted.

The findings may point to potential therapeutic targets for metabolic conditions, including fatty liver disease, elevated cholesterol levels, and obesity-related issues. They also imply that dietary strategies such as increasing specific forms of fiber intake may assist by bolstering the body’s regulatory systems. The next steps for the team involve gaining further insights into how these mechanisms are regulated and exploring this type of microbe-gut interaction across various disease states.

The researchers proposed that their study methodology could also aid scientists in examining the role of the gut microbiota across a wide spectrum of diseases, from infections and chronic inflammation to obesity and cancer.

“Our publication serves as a guide for utilizing untargeted metabolomics and chemistry to enhance our understanding of how the interaction between the gut microbiota and the body affects a multitude of diseases,” Dr. Artis remarked.

Many physicians and researchers at Weill Cornell Medicine maintain relationships and collaborate with external organizations to advance scientific innovation and provide expert advice. The institution publicly discloses these connections to promote transparency. For further information, see the profile for Dr. David Artis.

The research discussed in this article was partially funded by the National Institute for General Medical Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, all of which are part of the National Institutes of Health, through grant numbers GM131877, DK126871, AI151599, AI095466, AI095608, AI142213, AR070116, AI172027, DK132244. Additional support was given by the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised initiative of the Paul G. Allen Family Foundation; the Kenneth Rainin Foundation; Cure for IBD; Howard Hughes Medical Institute; the Sanders Family; the Rosanne H. Silbermann Foundation; Glenn Greenberg and Linda Vester Foundation; and Weill Cornell Medicine Jill Roberts Institute.