Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome

Abstract

Opioids are highly addictive substances with a relapse rate of over 90%. While preclinical models of chronic opioid exposure exist for studying opioid dependence, none recapitulate the relapses observed in human opioid addiction. The mechanisms associated with opioid dependence, the accompanying withdrawal symptoms, and the relapses that are often observed months or years after opioid dependence are poorly understood. Therefore, we developed a novel model of chronic opioid exposure whereby the level of administration is self-directed with periods of behavior acquisition, maintenance, and then extinction alternating with reinstatement. This profile arguably mirrors that seen in humans, with initial opioid use followed by alternating periods of abstinence and relapse. Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 polyunsaturated fatty acids (n-3 PUFAs), may reduce substance misuse liability. Using the self-directed intake model, we characterize the observed profile of opioid use and demonstrate that an n-3-PUFA-enriched diet ameliorates oxycodone-seeking behaviors in the absence of drug availability and reduces anxiety. Guided by the major role gut microbiota have on brain function, neuropathology, and anxiety, we profile the microbiome composition and the effects of chronic opioid exposure and n-3 PUFA supplementation. We demonstrate that the withdrawal of opioids led to a significant depletion in specific microbiota genera, whereas n-3 PUFA supplementation increased microbial richness, phylogenetic diversity, and evenness. Lastly, we examined the activation state of microglia in the striatum and found that n-3 PUFA supplementation reduced the basal activation state of microglia. These preclinical data suggest that a diet enriched in n-3 PUFAs could be used as a treatment to alleviate anxiety induced opioid-seeking behavior and relapse in human opioid addiction.

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

“…Given current research in the area of psychopathology and the gut microbiota, Lactobacillus and Bifidobacterium, though Bifidobacterium was not included among the differentially abundant genera in the present analysis, may warrant further study. Opioid-related alterations in these genera were found to be reversible by omega-3 polyunsaturated fatty acid 19 and probiotic administration 11 , and they exhibited bile-salt hydrolase activity 54 in prior work. Moreover, certain Lactobacillus and Bifidobacterium species may impact anxiety and depressive symptoms 55 – 57 .…”

“…Our study was unable to perform the metabolomic analysis required to confirm that the lower abundance of Roseburia species observed in participants exposed to opioid agonists related to lower levels of butyrate in the gut environment. However, recent studies using murine models highlight that probiotic administration 11 and potentially butyrate 6 are associated with decreased opioid antinociceptive tolerance and that supplementation with omega-3 polyunsaturated fatty acids attenuates opioid-seeking behaviors and anxiety symptoms during opioid withdrawal 19 . These findings underscore the potential importance of modulating the gut environment to mitigate overdose risk and support OUD recovery.…”

“…hypothesize that gut leakiness from chronic drinking and the release of bacterial products into the bloodstream could promote a neuro-inflammatory state that influences mood and drinking behaviors 5 . In the context of OUD, a murine model suggests that dietary supplementation with anti-inflammatory omega-3 polyunsaturated fatty acids alter the gut microbiota and reduce anxiety symptoms and opioid-seeking behaviors 19 .…”

“…In addition to omega-3 polyunsaturated fatty acids 19 , some of the negative consequences associated with opioid exposure may be preventable by co-treatment with probiotics 11 and opioid antagonists, such as naltrexone 7,8 . For example, mice co-treated with morphine and naltrexone do not exhibit the increases in E. faecalis or disruptions to bile acid metabolism observed in morphine treated mice 7 .…”

Beneficial effects of omega-3 fatty acid supplementation in schizophrenia: possible mechanisms

“…This difference may modulate brain function through microbiota-gut-brain axis, and affect symptoms [201]. Increasing evidence has shown that dietary supplementation with omega-3 fatty acids affects gut microbiome [202,203], which in turn, affects neurofunction and mental behaviors [204,205].…”