Date of Award

Spring 2025

Project Type

Dissertation

Program or Major

Molecular and Evolutionary Systems Biology

Degree Name

Doctor of Philosophy

First Advisor

Cheryl A Whistler

Second Advisor

Jennifer L Whistler

Third Advisor

W. Kelley Thomas

Abstract

Opioids are highly effective analgesics for acute and chronic pain management but carry dangerous side effects that limit their utility and increase the risk of opioid use disorder (OUD). Yet not all individuals prescribed opioids develop an OUD, presenting a conundrum: why are so some individuals develop an OUD and others do not? While genetics, social environment, and behavior contribute to risk, they fail to explain why some individuals transition from prescribed use to an OUD. My doctoral research investigates an increasingly likely culprit that is also a promising therapeutic target: the gut microbiota. The gut microbiota is essential for neurological function, and dysbiosis is linked to numerous neurological disorders. Opioid-induced dysbiosis associates with behaviors contributing to OUD, including tolerance, dependence, and drug-seeking. But the contribution of microbiota to variable outcomes of opioid use is unclear in part because previous studies collapse natural variation in both microbiota and behavior. And yet natural variation may be the key to unlocking how the power of microbes may be harnessed to predict and reduce risk of OUD. In my research, I applied an oral opioid self-administration paradigm to model the transition from impulsive to compulsive drug-seeking in mice, reflecting human behaviors used to diagnose OUD. By examining gut microbiota in feces archived from mice during the paradigm, I can correlate microbiota composition and changes with diverse aspects of OUD, and through microbiota manipulation, define mechanisms of promotion of, or protection from, OUD. My work seeks to fill fundamental gaps of knowledge and answer the question: Do differences in the gut microbiota influence OUD development? This dissertation begins with a literature review (Chapter 1) examining the complex relationship between the gut microbiota and OUD development. Chapter 2 examines microbiota signatures of tolerance and mechanisms of protection. Chapter 3 identifies microbiota patterns associated with the risk for compulsive drug-seeking. Chapter 4 evaluates procedural and analytical methods for fecal microbiota transplantation that impact the success of microbiota engraftment. These findings underscore the importance of models that capture the complexity of OUD by preserving natural variation in microbiota and behavior and identify promising areas for further investigation.

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