Bariatric surgery is the leading treatment for obesity and metabolic diseases. The procedures, which generally involve changes to how a person’s digestive system takes in food, not only lead to significant weight loss, but also cause remission of type II diabetes within days of an operation by a mechanism that’s poorly understood. Now, researchers at Harvard Medical School have identified a single small molecule that could contribute to the surgery’s anti-diabetic effects and could point to a possible new treatment for the condition.
Medicinal chemists have long sought a pharmaceutical alternative to bariatric surgery to treat type II diabetes. One well-known drug target is glucagon-like peptide-1 (GLP-1), a hormone produced in the gut that increases insulin sensitivity and glucose tolerance. GLP-1 is secreted when a bile acid receptor called Takeda G-protein receptor 5 (TGR5) gets activated.
TGR5’s involvement in the hormone’s release inspired scientists to start looking at bile acids as a possible source of bariatric surgery’s anti-diabetic effects. Harvard chemical biologist Sloan Devlin was interested in them too, but wanted to study the molecules a little differently. Researchers, she says, had previously “been looking at bile acids in circulating blood after bariatric surgery.” Further, researchers “had been looking at pools of bile acids—up to 50 different molecules at a time—as opposed to individual bile acid metabolites.”
Devlin and Harvard bariatric surgeon Eric Sheu wanted to go to the source of bile acids, the gut, in their search for molecules with anti-diabetic effects. Because Devlin felt that single molecules, not groups of them, would play a significant role in those effects, the researchers interrogated the individual bile acids in the gut and feces of mice after sleeve gastrectomy—a common bariatric surgery that removes a portion of the stomach. Using ultra-high performance liquid chromatography–mass spectrometry, the team found a single compound with increased concentrations in the gut after surgery—cholic acid-7-sulfate (CA7S) (Nat. Chem. Biol. 2020, DOI: 10.1038/s41589-020-0604-z). “We found the same molecule was increased in [human] patients after surgery compared to before surgery,” Devlin says.
In experiments in both animal and human cell lines, the team showed that the sulfated bile acid activates TGR5, leading to the secretion of GLP-1. They also showed that CA7S increases the expression of TGR5, which makes the receptor more easily activated by other molecules in the gut. By making it easier for the receptor to turn on, CA7S could have long-term benefits on regulating blood glucose levels beyond a single dose.
In another experiment, when the team fed diabetic mice a sugary meal, those animals treated with CA7S cleared the glucose from their system faster than untreated mice. The research team thinks that finding suggests this molecule is a promising drug candidate for treating the disease.
Scientists had previously identified CA7S in the gut, but they didn’t study the molecule further because they thought that sulfated bile acids were waste products or surfactants without other biochemial functions. “People have thought of these molecules going in the garbage heap, not realizing that they might be active as they’re being excreted from the body,” Sheu says.
CA7S has a couple properties that suggest it could be a potential therapeutic for treating diabetes. Not only can the molecule be effective when swallowed, the researchers also found that it does not leave the gut and does not circulate in the bloodstream. As a result, the molecule probably would not cause side effects associated with TGR5 activation in other tissues such as gall stones and heart dysrhythmias.
John Chiang, a biochemist at Northeast Ohio Medical University who was not involved in the study, said in an email that CA7S derivatives have the potential to be “used as drug therapy to replace bariatric surgery,” but further tests in humans are required. He thinks that understanding how this molecule gets made will also be important to understanding its application to human medicine. “It cannot be ruled out that gut bacteria may be involved in synthesis of CA7S,” because microbial communities also change after bariatric surgery, Chiang says.
Devlin’s team agrees and is currently investigating the question. “What I can say right now is we do think the microbiome is involved,” Devlin says.