The gut and the brain are 2 organs that are far apart, anatomically speaking, yet so close in other respects. Metabolic and neural crosstalk between the gut microbiome and brain has important implications for brain function, mood and behavior. A growing body of research has associated gut microbiome composition and function with substance use disorders (SUDs). Scientists are disentangling the nuances of these ties, with the hopes of using this knowledge to develop microbiome-informed strategies for managing SUDs.

The Gut-Brain Axis and Substance Use Disorders

SUDs are characterized by chronic dependence on a substance (e.g., alcohol, opioids and/or other drugs) despite negative mental, physical and social consequences. They have socioeconomic, biochemical, genetic and, increasingly, microbiological underpinnings. “It is widely understood that the brain is an important organ that mediates parameters of addiction,” said Shahrdad Lotfipour, Ph.D., an assistant professor of emergency medicine, pathology and pharmaceutical sciences at the University of California, Irvine. However, he noted that studying addiction through a microbial lens offers “a novel way of thinking about how other factors associated with the body could work hand in hand with the brain to mediate the motivation to attain drugs of abuse.”

The gut and the brain communicate across a bidirectional, biochemical and neural highway (the gut-brain axis). Nerve endings below the intestinal epithelium receive metabolic signals from the gut microbiota, which may influence behaviors, such as stress or anxiety. In addition to other metabolites implicated in central nervous system (CNS) development and brain function, like short chain fatty acids (SCFAs), gut microbes help produce an array of neurotransmitters  associated with mood, cognition and reward (e.g., serotonin and dopamine).

These neurotransmitters are particularly relevant in the context of SUDs; many substances of abuse hijack the brain’s reward system by triggering a deluge of dopamine into the reward pathway. The feelings of pleasure resulting from this dopamine deluge eventually abate, and individuals may repeatedly take the substance to experience those feelings again. Research indicates that gut microbes are involved in reward perceptions for both natural (e.g., food) and artificial rewards, including drugs, suggesting there are ties between SUD development/progression and gut microbiome composition.

Indeed, drugs of abuse are associated with changes in the composition of the microbiome. Though the specifics of these alterations vary depending on the substance, there is generally a decrease in microbes associated with a “healthy” community and increase in those considered pro-inflammatory, such as Proteobacteria. These changes are accompanied by a reduction in key microbial metabolites, like SCFAS, with various systemic and local effects (e.g., disruption of intestinal barrier integrity).

Often, SUDs are characterized by increased intestinal inflammation, in part from this leaky intestinal barrier that allows microbes and their products to interact with underlying immune cells. Upon activation, these immune cells produce cytokines that not only spark local inflammation, but can enter circulation and cross the blood-brain barrier. The resulting neuroinflammation alters neuronal activity, including within the brain’s reward pathway, and may influence responses to and tolerance of the substances themselves.

Microbes and Morphine: The Gut Microbiome and Opioid Use

Of the substances with known microbial ties, opioids—a class of drugs used to reduce pain—are some of the most devastating. Most drug overdose deaths in the U.S. involve an opioid (nearly 75% in 2020). Managing the “opioid epidemic” is a public health challenge and, according to Lotfipour, whose lab focuses on opioids, understanding factors influencing their abuse potential is key for developing therapeutic interventions.

Opioids, including substances like morphine, fentanyl and heroin, bind cellular receptors sprinkled throughout the CNS, as well as in other body regions like the gut. Binding these receptors decreases an individual’s perception of pain and boosts their feelings of pleasure and a sense of well-being. These effects make opioids incredibly addictive. Over time, someone may become tolerant to the initial dose of an opioid; they need a higher dose to feel the euphoric effects. The need to increase dosage raises the potential for overdose.

Preclinical research from Lotfipour’s lab, led by first-author, Michelle Ren, Ph.D., a former graduate student in the lab, demonstrates that microbes are involved in opioid-seeking behavior. Using a rat model of fentanyl self-administration, the researchers showed that depleting the animals’ gut microbiota with antibiotics altered how much fentanyl they self-administered. “Remarkably, we found that knock-down of the gut microbiome, or the reduction of the diversity that's present in [the] normal host microbiome, significantly potentiates the motivation to attain fentanyl,” Lotfipour explained. Notably, administering SCFAs to the animals could reduce this potentiation, suggesting that bacterial fermentation products can regulate the reward response to opioids.

It is reasonable that the microbiome would modulate opioid use, as there are well-established ties between opioids and gut function. Opioid receptors are widely expressed throughout the gastrointestinal tract, and opioids are notorious for causing constipation. They are also associated with shifts in gut microbiota structure, including decreased microbial diversity (a hallmark of microbiota health) and increases in potentially pathogenic species like Staphyloccocus and Enterococcus. “Having a healthy, diverse microbiome appears to be important, in [that] not having this [may reinforce] properties of drugs of abuse,” Lotfipour said.

Still, while researchers think microbes help mediate opioid use, and they have an idea about what opioid-associated microbiota changes look like, how these 2 factors relate is less clear. Lotfipour acknowledged that understanding the mechanisms mediating these relationships is a critical next step.

Managing Substance Use Disorders—with Gut Microbes?

Strategies for treating SUDs vary depending on the person and the substance, but may involve medication (e.g., opioid antagonists), counseling and behavioral care. However, these tactics may not always work, and relapses are possible. The current success rates for drug addiction treatment interventions are low, and about 40-60% of individuals who undergo treatment eventually relapse and return to using drugs of abuse. Given the emerging intersection between the gut microbiota and SUDs, Lotfipour highlighted that supplementing the gut microbiome with certain bacteria, or as shown by his lab’s research, their fermentation products like SCFAs, could potentially reduce the impacts of substances of abuse.

For example, one study found that probiotics enriched in Bifidobacteria and Lactobacillaeae reversed tolerance to morphine in mice. Fecal microbiota transplants (FMTs) could also be an option. A phase 1 clinical trial showed that individuals with alcohol use disorder who received an FMT enriched in Lachnospiraceae and Ruminococcaceae had a reduction in alcohol cravings after 15 days compared to the placebo group (90% versus 30% reduction, respectively). In morphine-dependent mice, FMT attenuated withdrawal symptoms triggered by an opioid antagonist. As opioid tolerance predisposes to dose escalation and overdose potential, these findings suggest microbes could prolong the efficacy of the drugs. Ultimately, they may have “big applications for the future of the gut microbiome, and how it could impact health and wellbeing,” said Lotfipour, especially as it pertains to SUDs. “It’s a very, very exciting area to be in.”

Besides SUDs, gut microbes are also implicated in neurodegenerative diseases. Check out this next article to learn more: