Genetic and environmental contributions to gastrointestinal health Open Access
Shaw, Kelly Ann (2017)
Published
Abstract
More than 60 million people in the United States (US) are affected by gastrointestinal (GI) diseases. An estimated $100 billion is spent on direct costs for medical care and indirect costs from morbidity and mortality. Genetics, diet, and microbes all play interconnected roles in the development and normal functioning of the GI tract. Through my dissertation work I sought to address the relationship between these factors and GI symptoms and disease. First, I tested a hypothesis generated from parents of individuals with a rare single-gene metabolic disease, classic galactosemia (CG). These parents anecdotally reported their children suffered from GI symptoms. Using an online survey, I found that individuals with CG were 4.5 times more likely to report constipation and 4.2 times more likely to report nausea compared to controls. There were no significant effects of predicted residual GALT activity or dietary galactose restriction, two known modifiers of other long-term outcomes in CG. Secondly, I sought to identify rare genetic variants that may contribute to increased susceptibility to pediatric inflammatory bowel disease (IBD). We found overlap with well-established IBD genes and evidence supporting the contribution of neutrophil function to disease. We also found variants in several extracellular matrix proteins, which have been of recent interest in the field. Finally, I studied gut bacteria in IBD, because host immune response to microbes likely plays a role in disease etiology. Previous work found increases and decreases in specific bacterial families in patients compared to controls. I expanded on their work by studying these bacteria longitudinally. I found that this imbalance in bacteria decreased over time but remained higher than in controls. While abundance of these IBD-associated bacteria was associated with a marker of gut inflammation, it did not differ between patients with and without mucosal healing, a marker of response to treatment. I discovered other bacterial groups that better separated responders to treatment from non-responders; a larger study is needed to follow up on these findings. My dissertation work focused on these two diseases to advance our knowledge of GI health and potentially lead to better prevention, prognosis, and treatment of disease.
Table of Contents
Chapter I.
Introduction
1
References
11
Chapter II.
Gastrointestinal Health in Classic Galactosemia
Summary
23
Introduction
24
Materials and methods
25
Results
28
Discussion
32
References
36
Tables
39
Supplemental tables
41
Supplemental figures
46
Supplemental file: gastrointestinal health survey
48
Chapter III.
Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort
Abstract
57
Introduction
58
Methods
60
Results
64
Discussion
65
References
69
Tables
74
Figures
81
Supplemental tables
84
Supplemental figures
91
Chapter IV.
Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease
Abstract
95
Background
96
Methods
99
Results
104
Discussion
111
Conclusions
116
References
118
Tables
125
Figures
126
Supplemental tables
130
Supplemental figures
139
Supplemental files
145
Chapter V.
Discussion
155
References
160
About this Dissertation
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Primary PDF
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Genetic and environmental contributions to gastrointestinal health () | 2018-08-28 10:49:44 -0400 |
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Supplemental Files
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