Gut Microbiome Modulates Microglia Physiology in Homeostatic and Disease States

Author: Abdel-Haq, Reem

Year: 2022

Degree: Dissertation (Ph.D.)

Advisor: Mazmanian, Sarkis K.

Committee Members: Gradinaru, Viviana; Mazmanian, Sarkis K.; Thomson, Matthew; Chan, David C.

Option: Biology

DOI: 10.7907/ht1j-2461

Abstract

The gastrointestinal tract (GI) harbors a complex community of ~100 trillion bacteria, fungi, and viruses collectively referred to as the gut microbiome. Through direct and indirect signaling mechanisms, the gut microbiome exerts its effects on almost every organ system, including the brain. Constant, bi-directional communication along the gut-brain axis is required for the normal and healthy development of the host Central Nervous System (CNS). One of the cells in the CNS shaped by microbial-derived cues is microglia, the resident immune cells in the brain. Aberrant microglia activity is a driving force of several neurological diseases in which the gut microbiome plays a role, including Parkinson’s disease (PD).

In this thesis, we explore the interplay between gut microbiota signaling and microglia physiology during homeostatic and disease states. We first detail how microbial signaling along the gut-brain axis shapes microglial development and function. Next, we explore how the gut microbiome composition influences microglial activation states in the context of disease. Leveraging a preclinical mouse model of PD, we show that dietary-driven changes to the gut microbiome through the use of prebiotics attenuates motor deficits and α-synuclein aggregation. These effects result from changes in microglial gene expression and activation status. Collectively, these findings have broad implications for the gut microbiome research community and highlight potential for development of microbiome-based therapies for diseases of the brain.

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