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Bariatric surgery, bile acids and cocaine

Bariatric surgery research links bile acids to cocaine reward

In bile diversion surgery - an experimental treatment for weight loss - bile is released at the end of the small intestine, increasing the amount of bile acids that enter the general circulation
Surgery produced an elevation of bile acids in the brain, resulting in a reduction in dopamine release in response to cocaine

Bile acids that aid fat digestion are also found to reduce the rewarding properties of cocaine use, according to a study by researchers at Vanderbilt University Medical Center and the University of Alabama at Birmingham, and could point to potential new strategies for treatment of cocaine abuse.

The study, ‘Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward’, publishing in PLOS Biology by Drs India Reddy, Nicholas Smith and Robb Flynn of Vanderbilt University, and Aurelio Galli of the University of Alabama at Birmingham, and colleagues -  builds on evidence that bile acids influence the brain's reward system.

Bile acids are normally released from the gall bladder into the upper part of the small intestine, where they emulsify fats for absorption, before being recycled further down the small intestine. In bile diversion surgery - an experimental treatment for weight loss - bile is released at the end of the small intestine, increasing the amount of bile acids that enter the general circulation. Mice treated with this surgery have less appetite for high-fat foods, which suggests that bile acids affect brain reward pathways.

Drs India Reddy (left), Nick Smith, Charles (Robb) Flynn (Credit: Anne Rayner)

To test this hypothesis, the authors first showed that surgery produced an elevation of bile acids in the brain, resulting in a reduction in dopamine release in response to cocaine. Mice receiving the surgery also showed less preference for the cocaine-associated chamber, indicating that cocaine was probably less rewarding.

The authors next administered a drug called obeticholic acid (OCA) that mimics the effect of bile at its receptor in the brain, called TGR5. They found that OCA mimicked the cocaine-related results of surgery in untreated mice, strengthening the case that the effects of surgery were due to elevated levels of bile acids. Knocking out TGR5 from the brain's nucleus accumbens, a central reward region, prevented bile acids from reducing cocaine's effects, confirming that signalling through this receptor was responsible for the cocaine-related results of bile acid elevation.

"These findings redefine the physiological significance of bile acid signalling and highlight the importance of determining whether bile acid analogues represent a viable pharmacological treatment for cocaine abuse," said Galli.

OCA, the compound that activated the bile acid receptor in this study, is approved for the treatment of primary biliary cirrhosis (Intercept Pharmaceuticals) offering fast translational opportunities for pharmacotherapies.

According to the research team, these findings redefine the physiological significance of bile acid signalling, highlight the importance of determining whether bile acid analogues represent a viable pharmacological treatment for cocaine abuse and also contributes to a greater understanding of how gut-based signalling influences higher order central functions such as reward.

"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," said Flynn.

The study is the first to demonstrate a central nervous system role for bile acids in altering reward-related behaviours, 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," added Flynn. "OCA is already clinically approved, so it might be possible to move quickly to clinical trials of its efficacy in treating addiction."

To access this paper, please click here

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