Identification of pre-existing microbiome and metabolic vulnerabilities to escalation of oxycodone self-administration and identification of a causal role of short-chain fatty acids in addiction-like behaviors

Abstract

The gut brain axis is thought to play a role in behavior and physiological responses through chemical, immunological, and metabolite signaling. Antibiotics, diet, and drugs can alter the transit time of gut contents as well as the makeup of the microbiome. Heterogeneity in genetics and environment are also well-known factors involved in the initiation and perpetuation of substance use disorders. Few viable genetic or biological markers are available to identify individuals who are at risk of escalating opioid intake. Primarily, the addiction field has focused on the nervous system, limiting the discovery of peripheral factors that contribute to addiction. To address this gap, we characterized the microbiome before and after drug exposure, and after antibiotics depletion in male and female heterogenous stock rats to determine if microbiome constituents are protective of escalation. We hypothesized that individuals that are prone to escalation of opioid self-administration will have distinct microbial and metabolic profiles. The fecal microbiome and behavioral responses were measured over several weeks of oxycodone self-administration and after antibiotic treatment. Antibiotic treatment reduces circulating short-chain fatty acids (SCFA) by depleting microbes that ferment fiber into these essential signaling molecules for the gut-brain axis. Depletion of the microbiome increased oxycodone self-administration in a subpopulation of animals (Responders). Supplementation of SCFAs in antibiotic depleted animals decreased elevated oxycodone self-administration. Phylogenetic functional analysis reveals distinct metabolic differences in the subpopulations of animals that are sensitive to antibiotic depletion and animals rescued by SCFA supplementation. In conclusion, this study identifies pre-existing microbiome and metabolic vulnerabilities to escalation of oxycodone self-administration, demonstrates that escalation of oxycodone self-administration dysregulates the microbiome and metabolic landscape, and identifies a causal role of short-chain fatty acids in addiction-like behaviors.

Microbiome Depletion Increases Fentanyl Self-Administration and Alters the Striatal Proteome Through Short-Chain Fatty Acids

“…In recent years the understanding of the microbiome as a regulator of brain and behavior has increased markedly ( Meckel and Kiraly, 2019 ; Rea et al, 2020 ; Lucerne et al, 2021 ). Recent work by our group and others has shown that alterations to the microbiome of rodents can affect cocaine ( Kiraly et al, 2016 ; Lee et al, 2018 ) and opioid reward and reinforcement ( Hofford et al, 2021b ; Simpson et al, 2022 ), can influence tolerance to opioids ( Kang et al, 2017 ; Zhang et al, 2019 ), and can alter cellular and molecular responses to opioids ( Simpson et al, 2020 ; Hofford et al, 2021b ). Previous work from our group measured morphine reward in mice after microbiome knockdown and found that mice with a reduced microbiome displayed reduced morphine place preference at higher doses ( Hofford et al, 2021b ).…”

Changes in gut microbiome composition drive fentanyl intake and striatal proteomic changes

“…In recent years the understanding of the microbiome as a regulator of brain and behavior has increased markedly [3][4][5] . Recent work by our group and others has shown that alterations to the microbiome of rodents can affect cocaine 6,7 and opioid reward and reinforcement 8,9 , can influence tolerance to opioids 10,11 , and can alter neuronal activation and transcriptional responses to opioids 8,12 . While this work was critical in establishing the role for gut-brain signaling in models of OUD, previous work has relied on transcriptional profiles and indirect measures of opioid reward as readouts for effects of the microbiome on brain and behavior.…”