Author ORCID Identifier

https://orcid.org/0000-0002-2054-7316

Date of Award

8-13-2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Geert de Vries

Second Advisor

Benoit Chassaing

Third Advisor

Nancy Forger

Fourth Advisor

Anne Murphy

Abstract

The gut microbiome is a complex community featuring a bewildering array of microbial species. Over the past couple decades, there has been an explosion of research demonstrating that the gut microbiota plays critical roles in a variety of host functions, including immune modulation, metabolism, brain function, and behavior. Mechanistic approaches such as fecal microbiota transfer from disease models into healthy animals have demonstrated direct effects of gut microbiota on host parameters but sequencing of fecal samples from similar subjects across different cohorts often reveals wide differences in microbial composition. This wide variability is also seen in clinical subjects within specific disease states postulated to be influenced by gut microbiota. Nevertheless, there are likely core features of the gut microbiota that may be modulated across different disease conditions to transmit similar signals to the host.

In this dissertation, I focus on potential core features of gut dysbiosis, or alterations in gut microbiota associated with various disease states. In Chapter 2, I will explore variations in gut microbiota observed across a genetic model exhibiting varying behavioral profiles, namely Brattleboro rats. In Chapter 3, I explore the potential mechanistic links between gut microbiota and host behavior, using a treatment that compromises the integrity of the gut barrier (namely, adding food emulsifiers to the diet). Compromising the gut barrier allows increased access of microbial byproducts that affect the CNS. I explored this potential mechanism in Chapter 4 by testing the effects of gut-derived LPS on host behavior, as LPS can compromise gut barrier integrity even further and act on immune cells and vagal gut innervations that communicate with the CNS to affect host behavior. In Chapter 5, I discuss the tools and multivariate investigative approaches employed in the studies discussed in this dissertation, and how multivariate approaches lend required dimensionality to studying a complex gut-brain signaling axis. Gut barrier dysfunction is a common theme observed in various disorders exhibiting altered anxiety behavior and gut dysbiosis of widely-varying microbial compositions. Understanding core functional features of gut dysbiosis will provide an important handle on ameliorating the gut environment in future attempts to treat CNS disorders.

DOI

https://doi.org/10.57709/14866301

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