According to a study, bile acids — which are critical for digestion and absorption of fats and fat-soluble vitamins in the small intestine — could reduce the desire for cocaine. Researchers at Vanderbilt University Medical Center and the University of Alabama at Birmingham suggest that targeting bile acid signalling in the brain may be a novel way to treat cocaine abuse.
Vanderbilt investigators Charles (Robb) Flynn, and Naji Abumrad, John L. Sawyers Professor of Surgical Sciences, have long studied the metabolic changes associated with bariatric surgery for weight loss. “Surgical patients experience dramatic changes in glucose regulation and in taste preferences and food cravings while they are still in the recovery room,” Flynn said.
“These surgeries are doing something more than we understand. We wondered if elevated serum bile acids, a hallmark of bariatric surgery, were affecting the reward centres of the brain to blunt the pleasure of eating high-fat foods,” he said. If the surgery did affect the brain’s reward centres, he added, “How might it impact the rewarding properties of drugs of abuse?”
The most commonly performed bariatric surgery — Roux-en-Y gastric bypass — restricts the size of the stomach and alters the path of food through the digestive tract. It also changes the point where bile acids enter the small intestine, from the usual upper part of the small intestine to a site near the end. The change increases circulating levels of bile acids in the body.
To explore the effects of bariatric surgery and elevated bile acids, Flynn’s group developed a simpler surgical procedure in mice called bile diversion, in which the gallbladder is surgically connected to the end of the small intestine. Bile diversion in an obese mouse produces all of the beneficial effects of bariatric surgery: weight loss, reduced food intake and improved oral glucose tolerance, Flynn said.
With colleague Aurelio Galli, the investigators found that bile diversion surgery in normal-weight mice reduced cocaine-induced increases in brain dopamine release and reduced cocaine-associated behaviours. The researchers tested the effects of a synthetic bile acid drug called obeticholic acid (OCA), which is clinically approved to treat the chronic liver disease primary biliary cholangitis. In mice without surgery, OCA administration mimicked the effects of bile diversion surgery in reducing cocaine-associated behaviors.
The investigators further demonstrated that the bile acid receptor TGR5 mediates the effects of elevated bile acids and OCA in the nucleus accumbens, a brain region that plays a central role in reward circuitry. The study is the first to demonstrate a central nervous system role for bile acids in altering reward-related behaviors, and it opens the possibility of treating drug abuse in new ways.
“Will bile acids cure cocaine addiction in humans? We don’t know, but our research certainly suggests that bariatric surgery or consumption of bile acids may have beneficial effects,” Flynn said. The study appears in the journal PLOS Biology.