Opioid agonist and antagonist use and the gut microbiota: associations among people in addiction treatment

Abstract

Murine models suggest that opioids alter the gut microbiota, which may impact opioid tolerance and psychopathology. We examined how gut microbiota characteristics related to use of opioid agonists and antagonists among people receiving outpatient addiction treatment. Patients (n = 46) collected stool samples and were grouped by use of opioid agonists (heroin, prescription opioids), antagonists (naltrexone), agonist–antagonist combinations (buprenorphine–naloxone), or neither agonists nor antagonists within the month before enrollment. We sequenced the V4 region of the 16S rRNA gene using Illumina MiSeq to examine how alpha diversity, enterotypes, and relative abundance of bacterial genera varied by opioid agonist and antagonist exposures. Compared to 31 participants who used neither agonists nor antagonists, 5 participants who used opioid agonists (without antagonists) had lower microbiota diversity, Bacteroides enterotypes, and lower relative abundance of Roseburia, a butyrate producing genus, and Bilophila, a bile acid metabolizing genus. There were no differences in gut microbiota features between those using agonist + antagonists (n = 4), antagonists only (n = 6), and neither agonists nor antagonists. Similar to murine morphine exposure models, opioid agonist use was associated with lower microbiota diversity. Lower abundance of Roseburia and Bilophila may relate to the gut inflammation/permeability and dysregulated bile acid metabolism observed in opioid-exposed mice.

Drugs and Bugs: The Gut-Brain Axis and Substance Use Disorders

“…Patients using opioid agonists exhibit a lower abundance of Roseburia (SCFA producer) and Bilophila (bile acid metabolizer), but there were no differences in patients using opioid antagonists. This finding parallels work in preclinical models that demonstrate drug use disrupts SCFA production and bile acid balance which are crucial reducing inflammation in the gut, and contribute to changes in drug-taking behavior (Gicquelais et al 2020).…”

“…Systemic inflammatory factors originating in the gut might result in central nervous system effects through a compromised blood-brain barrier caused by chronic opioid use. Similar to shifts in Roseburia and Bilophila observed by Gicquelais et al (2020) levels of SCFA's are reduced by the peripheral μ-opioid receptor agonist and anti-diarrheal agent loperamide, perhaps due to a decrease in butyrateproducing bacteria (Touw et al 2017). In the periphery, SCFAs act on GPCR's free fatty acid receptors 2 (FFAR2) and 3 (FFAR3) to regulate leucocyte functions, such as the production of eicosanoids, chemokines, and cytokines involved in inflammatory responses (Vinolo et al 2011b).…”

Spontaneous and Naloxone-Precipitated Withdrawal Behaviors From Chronic Opiates are Accompanied by Changes in N-Oleoylglycine and N-Oleoylalanine Levels in the Brain and Ameliorated by Treatment With These Mediators

“…Interestingly, the reduction of N -acyl-serotonin levels in intestinal tissues following chronic heroin administration is similar to that observed in mice following 1 week treatment with a cocktail of antibiotics ( Guida et al, 2018 ), and hence is again potentially indicative of the occurrence of opiate-induced intestinal dysbiosis. Indeed, chronic treatment with, and development of tolerance to and addiction from, opiates is now well established to be accompanied by changes in the gut microbiota composition ( Banerjee et al, 2016 ; Wang et al, 2018 ; Gicquelais et al, 2020 ; see Salavrakos et al, 2021 for review). Opiates do not need to be administered orally in order for such changes to be observed, and it has been suggested that an altered gut microbiota composition may participate in morphine addiction ( Wang et al, 2018 ).…”

“…Recent studies in both rodents and humans have suggested that gut microbiota might be modulated by chronic opiate use and intervene in tolerance to and dependence from opiates ( Banerjee et al, 2016 ; Kang et al, 2017 ; Wang et al, 2018 ; Acharya et al, 2017 ; Gicquelais et al, 2020 ; see Meckel and Kiraly 2019 for a review). Indeed, the gut microbiota is increasingly being suggested to play a role in behavior and its disturbances induced by psychotropics (see Cussotto et al, 2019 for a review) and to interact with eCBome signaling in both the brain and gut ( Manca et al, 2020a ; Manca et al, 2020b ; see Iannotti and Di Marzo, 2021 for review).…”

Individual differences in members of Actinobacteria, Bacteroidetes, and Firmicutes is associated with resistance or vulnerability to addiction-like behaviors in heterogeneous stock rats

“…The genus Roseburia is a well-known producer of Butyrate and is associated with positive health outcomes (Tamanai-Shacoori et al, 2017). In other drugs of abuse, the depletion of Roseburia is associated with increase alcohol intake (Seo et al, 2020), and decreased Roseburia may relate to increased gut permeability/inflammation and dysregulation of bile acids (Gicquelais et al, 2020). A higher abundance of butyrate producing Clostridia in the Resistant animals is also protective as depletion of Clostridia can increase aerobic expansion of opportunist microbes and increase inflammation (Rivera-Chavez et al, 2016).…”