Genetic and environmental contributions to gastrointestinal health Open Access

Shaw, Kelly Ann (2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/h128nd88s?locale=en
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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