A study from Brigham and Women’s Hospital and Harvard Medical School has uncovered a molecular mechanism that may help to explain why type 2 diabetes goes into remission in patients who have undergone bariatric surgery. Published in Nature Chemical Biology in August, the study is the first to identify an anti-diabetic small molecule whose levels are increased by bariatric surgery.
Eric Sheu, MD, PhD, a gastrointestinal and bariatric surgeon at the Brigham’s Division of General and Gastrointestinal Surgery, led the study alongside A. Sloan Devlin, PhD, assistant professor in the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School.
“Bariatric surgery is the best treatment we currently have for obesity and type 2 diabetes,” Dr. Sheu said. “It leads to remission or improvement of the disease in almost all patients. This study sought to determine why this surgery works so well to control diabetes.”
Bile Acid Sets off Chain of Events
Bile acids help people digest fats and vitamins and convey signals that help regulate metabolic and immune functions. While previous studies indicated that bile acids as a group rise in the bloodstream after bariatric surgery, nobody had studied the effects of surgery on individual bile acids.
Drs. Sheu and Devlin discovered that one bile acid metabolite known as cholic acid 7-sulfate (CA7S) rises significantly after sleeve gastrectomy, a common bariatric surgery in which surgeons remove about 80 percent of the stomach. CA7S, which was previously thought to be a waste product, is produced in the liver and was found to set off a chain of biochemical events that lowers high blood sugar.
The research team analyzed intestinal samples from mice and studied human patients before and after sleeve gastrectomy surgery. They found elevated levels of the CA7S molecule in the mice’s intestines and patients’ stools. The molecule was noted to act on TGR5 intestinal receptors, which trigger the GLP-1 hormonal pathway that lowers blood sugar.
Promising Drug Therapy for Diabetes
According to Dr. Sheu, CA7S has potential as a therapeutic — or the foundation for one — for treating diabetes. The study showed that CA7S administration increased glucose metabolism and lowered blood sugar in insulin-resistant mice — a benefit that disappeared when they used synthetic genetic tools to prevent the mice from producing TGR5.
Furthermore, because the molecule doesn’t leave the gut and circulate in the bloodstream, it is less likely to cause side effects than other therapies that trigger the blood sugar-regulating TGR5 and the GLP-1 hormonal pathway.
“The molecule’s pathway is unique and may give us a safer, more effective way to regulate blood glucose levels,” Dr. Sheu said. “Dr. Devlin and I are currently studying this pathway in more detail to determine how it regulates production of CA7S and its relationship to the microbiome in the liver and gut. This will help us establish whether the molecule can be turned into an innovative drug that can be delivered safely and equitably to help patients.”
A Unique Collaboration
According to Dr. Sheu, this discovery would not have been possible without the close and unique collaboration between his lab and Dr. Devlin’s. He pointed to Dr. Devlin’s biochemical expertise and knowledge of the microbiome as an excellent complement to his group’s surgical skill set, access to patients and clinical knowledge.
“Brigham and Women’s has one of the largest academic bariatric programs in the country,” Dr. Sheu said. “Our research interests, understanding of surgical interventions and grounding in health policy make us incredibly productive and a leading GI center of excellence.”