Morphine’s Bad Influence on the Microbiome

800px-pseudomonasPainkillers are an important tool in the hospital. After major surgery, relieving a patient’s pain using morphine and other opiates helps their recovery and quality of life while the body heals. But these drugs are not without their side effects and risks, from the potential for dependence to symptoms such as nausea, constipation, and itching. More recently, researchers have found that morphine may have more serious consequences, such as promoting tumor growth. A new study, conducted by surgeons from the University of Chicago Medicine, adds another warning to the list, revealing the bad influence of morphine upon normally harmless bacteria living in the human gut.

As discussed last week, the bacterial species Pseudomonas aeruginosa is a frequent inhabitant of the human body, usually colonizing the intestinal lining under peaceful conditions. But when that comfortable environment is disrupted by illness or surgery, what John Alverdy, professor of surgery at University of Chicago Medicine, calls “molecular diplomacy” can break down, causing the bacteria to turn violent and attack its host. Alverdy’s laboratory has studied various causes of this hostility, focusing primarily on the native biological signals that are thrown out of whack after the traumatic experience of surgery. But in a paper published last month in Annals of Surgery, Alverdy’s group found for the first time that a substance used to treat the after-effects of a procedure could also trigger P. aeruginosa virulence.

“Morphine is nothing we ever factored in,” Alverdy said. “The other triggers are endogenous signals, while morphine is both exogenous and endogenous. You make morphine-like substances from your body tissues, but we also give a boatload of them, clinically, and that’s the biggest difference.”

In the experiments, led by first author Trissa Babrowski, laboratory mice were given either morphine or placebo, and half of the animals in each group were inoculated with P. aeruginosa. The researchers then watched for signs of sepsis, the extreme immune response that accompanies the most serious infections. The difference between groups was striking — all of the mice given both the bacteria and morphine died within two days, while the mice who only received one or the other (or neither) survived.

Looking closer at the behavior of the bacteria when exposed to morphine, the researchers found a long chain of catastrophe. Activated by morphine, P. aeruginosa suppressed the natural production of mucus in the intestine, disrupted the epithelial cells that line the gut, and provoked the immune system to release various immune factors. In morphine-treated mice, the bacteria also released a protein called PA-IL and exhibited “clumping” behavior, signs that they had changed in personality from pacifists to aggressors.

But despite these worrisome results demonstrating the combustible mixture of morphine and P. aeruginosa, Alverdy said that there was no cause for alarm yet.

“Remember that most people get morphine, and most people have Pseudomonas, but most people don’t get an infection,” Alverdy said. “It’s easy to take away from a paper like this, ‘oh, if you have both, you’re dead meat.’ But not most of the time.”

Understanding why P. aeruginosa chooses to go berserk in some cases but not others will require a bit of bacterial psychoanalysis, Alverdy continued.

“We’ve discounted how the microbes are thinking,” he said. “We tend to think very simply there are microbes lurching everywhere trying to attack you at any minute. We’re just this giant defense system, and the minute our defenses go down, they attack. It just doesn’t happen that way.”

Nevertheless, if physicians want to prevent any potential negative influence of morphine on gut bacteria, there may already be a tool.

Methylnaltrexone, a drug developed in part by the University of Chicago Medicine’s Jonathan Moss, is a form of morphine that can be given at the same time to block the opiate’s effects outside of the nervous system, leaving only the pain relief minus the side effects. When mice given both P. aeruginosa and morphine were co-treated with methylnaltrexone, levels of the virulence protein PA-IL were reduced, suggesting an interruption of the morphine’s instigation of gut bacteria. Intriguingly, in a recent observational study of 7,000 patients treated with a drug similar to methylnaltrexone, postoperative infections were significantly reduced.

“These human findings…suggest that colonizing microbes can be shielded, in part, from the effects of host activating signals released during surgical injury by using opioid antagonists,” the authors wrote.

Regardless of how the mouse research translates to humans, Alverdy said that this new dangerous side effect of morphine should add even more caution to the use of opiate painkillers in the hospital and even more so in less regulated and monitored settings. Citing the recent deaths of Michael Jackson and Whitney Houston, both of which were thought to be caused by inappropriate use of prescription painkillers, Alverdy said that the potentially deadly influence of these drugs on gut bacteria offer yet another warning about their misuse.

“Our society is moving to becoming very dependent on pain medication. We have a whole group of pain clinics out there where people are getting Oxycontin and all these other things,” Alverdy said. “These are the things we worry about.”

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Babrowski T, Holbrook C, Moss J, Gottlieb L, Valuckaite V, Zaborin A, Poroyko V, Liu DC, Zaborina O, & Alverdy JC (2012). Pseudomonas aeruginosa virulence expression is directly activated by morphine and is capable of causing lethal gut-derived sepsis in mice during chronic morphine administration. Annals of surgery, 255 (2), 386-93 PMID: 21989372

[Photo: A scanning electron micrograph (SEM) of a number of Pseudomonas aeruginosa bacteria. (CDC/ Janice Haney Carr)]

About Rob Mitchum (518 Articles)
Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.
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