Engineering the Gut Microbiome for Metabolic, Reproductive, and Cognitive Health
- Maissy, Erica Shanee
- Advisor(s): Zarrinpar, Amir
Abstract
Recent advancements in microbiome research have unveiled promising avenues for therapeutic interventions while underscoring the need for mechanistic studies of microbiome function and temporal dynamics. This dissertation explores the interplay between the gut microbiome, luminal bile acid modifications, and circadian dynamics in the context of women's health and neurodegenerative disease.
Chapter 1 reviews the current research on engineered microbial strains as novel therapeutics for gynecological health, including polycystic ovary syndrome (PCOS). Engineered probiotics, designed to express specific therapeutic functions such as antiviral peptides and anti-biofilm agents, offer targeted approaches for treating conditions like HIV and Candida albicans infections. The chapter underscores the integration of synthetic biology with clinical medicine, highlighting the therapeutic potential of targeting the microbiome.
Chapter 2 delves into one of these specific microbiome functions that impacts metabolism and the hypothalamic-gonadal-pituitary axis in the context of PCOS. Through murine models, this chapter demonstrates how bacterial bile acid modifications by bile salt hydrolase (BSH) can ameliorate metabolic dysfunction and some reproductive parameters associated with PCOS. This mechanistic insight illustrates the therapeutic promise of microbiome-targeted therapies, and highlights the role of bile acid receptors FXR and TGR5 in glucose homeostasis and hormonal regulation.
Chapter 3 explores the impact of time-restricted feeding (TRF) on the gut microbiome in an Alzheimer's disease (AD) mouse model. The study reveals that TRF modulates gut microbial composition, function, and rhythmicity, influencing metabolites crucial for regulating metabolism, neuroinflammation, and amyloid pathology. The microbiome emerges as a key player contributing to the mechanism of TRF’s mitigation of AD-related cognitive decline and neuropathology.
Together, these chapters contribute to a deeper understanding of how characterization and manipulation of the microbiome can elucidate mechanisms of disease and shape therapeutic strategies across diverse health conditions, from reproductive health challenges like PCOS to neurodegenerative diseases such as Alzheimer's. Continued research using synthetic biology and multi-omic analyses to elucidate mechanistic functions of the microbiome will further contribute to improved scientific tools and healthcare outcomes.