Chronic opioid use modulates human enteric microbiota and intestinal barrier integrity

Abstract

Over the past three decades the United States has experienced a devastating opioid epidemic. One of the many debilitating side effects of chronic opioid use is opioid-induced bowel dysfunction. We investigated the impact of methadone maintenance treatment (MMT) on the gut microbiome, the gut bacterial metabolite profile, and intestinal barrier integrity. An imbalance in key bacterial communities required for production of short-chain fatty acids (SCFAs), mucus degradation, and maintenance of barrier integrity was identified. Consistent with dysbiosis, levels of fecal SCFAs were reduced in MMT. We demonstrated that metabolites synthesized by Akkermansia muciniphila modulate intestinal barrier integrity in vitro by strengthening the pore pathway and regulating tight junction protein expression. This study provides essential information about the therapeutic potential of A. muciniphila and warrants development of new clinical strategies that aim to normalize the gut microbiome in individuals affected by chronic opioid use.

Hydrogen Sulfide Increases the Analgesic Effects of µ- and δ-Opioid Receptors during Neuropathic Pain: Pathways Implicated

“…Furthermore, it is worth noting that the reconstitution of intestinal microbiota biofilm [ 63 , 64 ] is another important pathophysiological feature of H 2 S. Therefore, we postulate that the reversion of gut dysbiosis exerted by H 2 S might also contribute to their analgesic effects. Furthermore, the co-administration of low doses of H 2 S donors and opioids might also avoid the dysbiosis [ 51 ] and bacterial translocation [ 65 , 66 ] induced by high doses of opioids, thus maintaining the homeostasis of gut microbiota. Nevertheless, further studies are needed to demonstrate this hypothesis.…”

Unique Pharmacology, Brain Dysfunction, and Therapeutic Advancements for Fentanyl Misuse and Abuse

“…Gut microbiota and gut-brain communication also play a critical role in opioid use and opioid tolerance [ 85 , 86 ]. Chronic opioid use alters fecal microbial diversity and composition and induces gut microbial dysbiosis in both rodents and humans, accompanied by increases in peripheral and central inflammation [ 87 – 89 ]. Moreover, microbial metabolites, such as short-chain fatty acids, are reduced, and intestinal and blood-brain barrier integrity is disrupted after opioid use, which could modulate the development, maturation, and function of microglia and exacerbate the neuroimmune responses [ 87 , 89 , 90 ].…”

“…Chronic opioid use alters fecal microbial diversity and composition and induces gut microbial dysbiosis in both rodents and humans, accompanied by increases in peripheral and central inflammation [ 87 – 89 ]. Moreover, microbial metabolites, such as short-chain fatty acids, are reduced, and intestinal and blood-brain barrier integrity is disrupted after opioid use, which could modulate the development, maturation, and function of microglia and exacerbate the neuroimmune responses [ 87 , 89 , 90 ]. Neuroinflammation that is induced by alterations of the microbiota can ultimately contribute to behaviors that are associated with opioid dependence [ 91 , 92 ].…”

Opioid-Use, COVID-19 Infection, and Their Neurological Implications

“…Opioid use has also been shown to increase susceptibility to several pathogenic infections, including Pseudomonas aeruginosa, Enterococcus faecalis , and Listeria monocytogenes , thereby predisposing toward sepsis and immune dysregulation ( 90 – 94 ). A recent clinical study identified an enrichment of family Bifidobacteriaceae and depletion of Akkermansiaceae among opioid users, along with a significant reduction in fecal SCFA levels ( 95 ). Opioid treatment has also been shown to change the level of bacterial metabolites.…”