Author ORCID Identifier

https://orcid.org/0000-0003-3344-8031

Date of Award

8-13-2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Andrew Gewirtz, PhD

Second Advisor

Benoit Chassaing, PhD

Third Advisor

Timothy Denning, PhD

Fourth Advisor

Hang Shi, PhD

Abstract

Metabolic syndrome (MetS) is the collective term for the interrelated abnormalities associated with obesity. Features of MetS promote a variety of chronic diseases that are amongst humanity’s most pressing public-health problems. MetS is increasingly appreciated to be associated with chronic inflammation driven by an imbalance of host immune cells and expression of pro-inflammatory cytokines. While numerous genetic factors influence the development of MetS, the increased incidence of this disorder occurring amidst changes in food production and dietary habits has led to the presumption that diet and the intestinal microbiota is a major determinant of MetS. The overall goal of my studies was to investigate this hypothesis.

First, I sought to identify microbiota-based markers that might predict diet-induced obesity. Targeted and untargeted approaches were utilized including 16S rRNA gene amplicon sequencing for microbiome profiling and a TMT-based multiplexed mass spectrometry approach for analysis of the fecal metaproteome. Notably, we show that the fecal metaproteome appears to be a promising candidate for distinguishing differential responses to high-fat diets (HFD) and provides insight into potential mechanisms regarding the host-microbiota interactions mediating response to HFD exposure and highlights putative biomarkers for predicting obesity.

Next, I explored gut-bacterial derived activators of innate-immune signaling as key drivers of adipose inflammation and insulin resistance that results from HFD. Hence, another goal of this study was to examine how ablation of gut microbiota influenced HFD-induced inflammation utilizing three approaches to alter microbiota; antibiotics, germ-free mice, and Altered Schaedler Flora mice. We described HFD–induced, microbiota-dependent changes in immune cell populations in adipose tissue that associated with pro-inflammatory gene expression and features of MetS.

Lastly, I sought to ameliorate the inflammation that promotes MetS. One common feature of inflammation-associated microbiotas is increased levels of flagellin believed to cause intestinal inflammation due to flagellin’s ability to activate pro-inflammatory gene expression. Hence, I hypothesize that boosting levels of flagellin-specific IgA may help regulate flagellated bacteria and, protect against development of intestinal inflammation. Herein, we describe that administration of purified flagellin elicits a robust anti-flagellin fecal IgA response that reshapes microbiota composition, reduces flagellin expression, and protects against experimental colitis and MetS.

DOI

https://doi.org/10.57709/14986337

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