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Microbiome Disruptions and Opioid Dependence: What are the Links?

March 16, 2020
From opioid-induced alterations to dietary interventions for opioid withdrawal, researchers are making connections among gut health, mental health, and pain management.

Research on the gut microbiome has increased significantly in the past decade, with many scientists suggesting that disruption of the microbiome plays a key role not only in gastrointestinal illnesses, but also in emotional and behavioral health, and more recently, in pain prevalence. Emerging studies show that disruption of the gut microbiome may be a consequence of chronic opioid use as well. Now, manipulating the microbiome is being looked at as a means of calming the negative emotions influencing the behaviors contributing to substance use disorders, including opioid use disorder (OUD).

When it comes to mental health, studies have suggested that probiotics can have positive effects on depression, and that diets rich in fiber and omega-3 fatty acids may reduce the risk of depression, anxiety, and stress.1 Emerging evidence of the role that gut dysbiosis plays in the pathogenesis of substance use disorders like OUD may offer a promising avenue for future therapeutic development.2

An inherent property of opioids is the high rate of relapse associated with chronic opioid use, due to mechanisms that maintain persistent drug-seeking. These mechanisms may lead to relapse even years after physical opioid dependence is no longer an issue, mostly due to the persistent anxiety and depression that may prevent someone with OUD from remaining opioid-free.3

In one study, sustained and intermittent morphine treatment altered the gut microbiota in mice. However, only intermittent morphine delivery produced the microglia-driven neuroinflammation, hyperalgesia, and impaired reward processing associated with opioid use. (Image: iStock)

Opioid-Induced Alterations in the Gut

In a recent animal study exploring the relationship between opioid use and misuse, Lee and colleagues found a causal link between morphine-induced alterations in the gut microbiota and the symptoms of opioid dependence; they suggested that targeting these changes may alleviate the side effects of both opioid dependence and opioid withdrawal.4  In a discussion about the study, lead investigator Anna Taylor, PhD, of the University of Alberta, Canada told PPM that “opioid withdrawal is associated with changes in the microbiome and loss of integrity of the gut barrier. There is evidence that restoring the microbiome can relieve the anxiety and depression associated with opioid withdrawal.”

Dr. Taylor’s group showed that both sustained and intermittent morphine treatment altered the gut microbiota in mice. However, only intermittent morphine, in which administration of the drug was alternated with daily periods of morphine withdrawal, produced the microglia-driven neuroinflammation, hyperalgesia, and impaired reward processing that are associated with opioid use. They confirmed their findings by transferring microbiota from the intermittent morphine-treated mice to opioid-naïve mice, which replicated their results and confirmed a causal connection between an altered gut microbiota resulting from morphine use and the negative effects of the drug.

The group assessed three major opioid side effects: tolerance, hyperalgesia, and altered reward processing. Both sustained and intermittent delivery produced opioid tolerance, but only the intermittent group exhibited hyperalgesia, while the sustained group showed hyperalgesia only after drug withdrawal. The intermittent group also was the only group to show an impaired reward response, which is thought to be associated with the anhedonia seen in opioid dependence.

Following these studies, the team looked for signs of inflammation to help explain the findings. Only the intermittent group showed significant increases in microglial cell size in the spinal dorsal horn and the ventral tegmental area, indicating an increase in inflammation that the other groups did not exhibit.

When asked where her research is leading, Dr. Taylor said her group was exploring strategies to restore GI health and microbiome. One strategy may be to administer the locally acting opioid antagonist methylnaltrexone, along with morphine, to prevent opioid effects on intestinal motility. This leads one to consider whether naltrexone could also have an effect on opioid withdrawal. In a related study of patients undergoing short-term in-patient treatment of opioid use disorder, Nunes and colleagues found that adding extended-release injection naltrexone to counseling alone decreased relapse rates in those completing the in-patient treatment.5

Dietary Interventions: Can They Undo OUD Damage?

Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 polyunsaturated fatty acids (n-3 PUFAs), may reduce substance misuse liability. Hakimian and colleagues developed a model of chronic opioid exposure that mirrors the pattern of relapses observed in human opioid addiction – alternating periods of abstinence and relapse. They hypothesized that n-3 PUFA  could induce a beneficial shift in gut microbiome composition to normalize the bacteria that become overgrown as a result of chronic relapsing opioid use. They sought to determine whether altering the microbiome would lead to central nervous system changes that could relieve the anxiety and depression driving opioid use relapses. Their research showed that a diet enriched with omega-3 polyunsaturated fatty acids ameliorates the opioid-seeking behaviors that occur in the absence of drug availability and reduces anxiety, by altering the composition of the microbiome as well as by reducing microglial activation.

Hakimian and colleagues further showed that opioid withdrawal led to a depletion of specific microbiota and that omega-3 supplementation could restore microbial richness and diversity.6 “It is certainly interesting to look at dietary interventions, such as omega-3s and probiotics, to restore the integrity of the gut barrier that is lost during opioid withdrawal,” Dr. Taylor told PPM. “While the evidence is still lacking in humans, the inflammation that occurs following withdrawal may be relieved with an anti-inflammatory diet that is rich in fiber. As the fiber is fermented by gut bacteria into short-chain fatty acids, it, along with other anti-inflammatory foods, can help restore microbial diversity and ultimately restore gut barrier integrity,” she concluded.

Last updated on: April 1, 2020
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