Alterations in microbiome composition and metabolic byproducts drive behavioral and transcriptional responses to morphine

Hofford, Rebecca S.; Mervosh, Nicholas L.; Euston, Tanner J.; Meckel, Katherine; Orr, Amon T; Kiraly, Drew D.

doi:10.1038/s41386-021-01043-0

Cited by 51 publications

(58 citation statements)

References 67 publications

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“…The increase in alpha diversity after fentanyl IVSA in males is surprising and does not mimic results found in prior work focused on chronic morphine treatment in mice [10,12,13,45]. There are major differences in methodology from the animals examined, both in species and model, (e.g., opioid-dependent, self-administering), and drugs used.…”

Section: Discussioncontrasting

confidence: 64%

Dose- and Sex-Dependent Bidirectional Relationship between Intravenous Fentanyl Self-Administration and Gut Microbiota

Ren

Lotfipour

2022

Microorganisms

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Gut bacteria influence neural circuits in addiction-related behaviors. Given the association between opioid use, gastrointestinal distress, and microbial dysbiosis in humans and mice, we test the hypothesis that interactions between gut bacteria and the brain mediate the rewarding and reinforcing properties of fentanyl. We implant rats with intravenous catheters in preparation for fentanyl intravenous self-administration (IVSA) on an escalating schedule of reinforcement to determine factors that influence fentanyl intake, including sex, dose, and gut microbiota. Our data show the impact of fentanyl IVSA on gut microbiota diversity, as well as the role of gut microbiota on fentanyl IVSA, in Sprague Dawley rats in a sex- and dose-dependent manner (n = 10–16/group). We found that the diversity of gut microbiota within females dose-dependently predicts progressive but not fixed ratio schedules of fentanyl IVSA. Depending on sex and fentanyl dose, alpha diversity (richness and evenness measured with Shannon index) is either increased or decreased following fentanyl IVSA and predicts progressive ratio breakpoint. Our findings collectively suggest a role of gut bacteria in drug-related behavior, including motivation and reinforcement. This work provides feasibility for an intravenous fentanyl self-administration model and uncovers potential factors mediating drug use, which may lead to the development of effective addiction interventions.

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Section: Discussioncontrasting

confidence: 64%

Dose- and Sex-Dependent Bidirectional Relationship between Intravenous Fentanyl Self-Administration and Gut Microbiota

Ren

Lotfipour

2022

Microorganisms

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“…Additionally, although there were intestinal and blood–brain barriers, bacterial metabolic byproducts could also be mediators to exert gut–brain communication, and the modification of SCFA generation was demonstrated to be an effective way to manage neuropathologies. 33 In particular, SCFAs, the major metabolites largely originated from bacterial fermentation of dietary fiber, were accepted to play a role in brain physiology through gut–brain interactions. 34 This hypothesis was demonstrated by our study in mice exhibiting that gut microbiota byproduct SCFAs were reduced in the d -gal-induced aging d -gal group in association with brain decline.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-gallate alleviates galactose-induced aging impairment via gut–brain communication

et al. 2022

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“…Mice from Control and BDPP treatment groups were injected with 2.5, 5, or 15mg/kg morphine and underwent morphine conditioned place preference (CPP) largely as described previously [36]. Detailed methods in Supplemental Methods .…”

Section: Methodsmentioning

confidence: 99%

Dietary polyphenols drive alterations in behavior, transcriptional regulation, and commensal microbiota in models of opioid use

Osman

Hofford

Meckel

et al. 2022

Preprint

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Opioid Use Disorder (OUD) is a neuropsychiatric condition associated with tremendous medical and social consequences. Despite this burden, current pharmacotherapies for OUD are ineffective or intolerable for many patients. As such, interventions aimed at promoting overall health and resilience against OUD are of immense clinical and societal interest. Recently, treatment with a Bioactive Dietary Polyphenol Preparation (BDPP) was shown to promote behavioral resilience and adaptive neuroplasticity in multiple models of neuropsychiatric disease. Here, we assessed effects of BDPP treatment on behavioral and molecular responses to repeated morphine treatment. We find that BDPP pre-treatment alters responses across the dose range for both locomotor sensitization and conditioned place preference. Most notably, polyphenol treatment consistently reduced formation of preference at low dose (5mg/kg) morphine but enhanced it at high dose (15mg/kg). In parallel, we performed transcriptomic profiling of the nucleus accumbens, which again showed a dose x polyphenol interaction. At high dose morphine, BDPP pre-treatment potentiated gene expression changes induced by morphine particularly for genes related to synaptic function. We also profiled microbiome composition and function, as polyphenols are metabolized by the microbiome and can act as prebiotics. The profile revealed polyphenol treatment markedly altered microbiome composition and function, particularly in the low dose morphine group. Finally, we investigated involvement of the SIRT1 histone deacetylase, and the role of specific polyphenol metabolites in these behavioral phenotypes. Taken together, these results demonstrate that polyphenols have robust dose-dependent effects on behavioral and physiological responses to morphine and lay the foundation for future translational work.

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Alterations in microbiome composition and metabolic byproducts drive behavioral and transcriptional responses to morphine

Cited by 51 publications

References 67 publications

Dose- and Sex-Dependent Bidirectional Relationship between Intravenous Fentanyl Self-Administration and Gut Microbiota

Dose- and Sex-Dependent Bidirectional Relationship between Intravenous Fentanyl Self-Administration and Gut Microbiota

Epigallocatechin-3-gallate alleviates galactose-induced aging impairment via gut–brain communication

Dietary polyphenols drive alterations in behavior, transcriptional regulation, and commensal microbiota in models of opioid use

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