Biological Insights from Integrative Genetic, Epigenetic and Microbial analysis of Inflammatory Bowel Disease translation missing: zh.hyrax.visibility.files_restricted.text

Somineni, Hari (Summer 2019)

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Inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract, that are therapeutically or surgically manageable but not curable. The pathogenesis of inflammatory bowel disease is hypothesized to involve complex interactions between genetic, immunologic and environmental factors, including the microbiota, that remain largely undescribed. Although some of these pathological components, including common variants and the microbiome, were extensively studied in isolation, the lack of translation of these associations into biological insights has been a roadblock to understanding disease biology and for subsequent targeted prevention and therapy. During the course of this study, we first aimed: i) to facilitate new locus discovery of common and rare variants in a population that remains understudied; ii) to define DNA methylation signatures that might play a causal role in the development of Crohn’s disease; iii) to provide a state-of-the art review on the current understanding of the role of the gut microbiota in disease pathogenesis, diagnosis, and therapeutic management; and iv) to gain preliminary insights into the spatial and temporal dynamics of the oral microbiota in the pathogenesis and diagnosis of inflammatory bowel disease, and its relation to inflammation. Second, whenever possible, we performed integrative analyses of some of these pathogenetic datasets to facilitate biological insights into the underpinnings of inflammatory bowel disease, and propose that future studies could use this conceptual framework for integrating genetic, epigenetic and transcriptomic or microbial data. Lastly, based on the knowledge gained over the course of this study, and acknowledging the current gaps in our understanding, we provide a futuristic perspective on how to gain deeper biological insights in order to systematically tackle some of the over-arching objectives that have crystallized in the past decade.

Table of Contents

Chapter 1: Overview and Current Understanding of Inflammatory Bowel Disease 1

Introduction 2

Clinical and epidemiological overview of inflammatory bowel disease 2

Genetics of inflammatory bowel disease 2

Environmental component of inflammatory bowel disease 3

Epigenetics of inflammatory bowel disease 4

The microbiome of inflammatory bowel disease 5

Integration of distinct data types in inflammatory bowel disease 6

Overview of current study 7

References 9

Chapter 2: Whole-Genome Sequencing of African Americans Identifies Novel Rare Variants Associated with Inflammatory Bowel Disease 12

Abstract 13

Introduction 13

Methods 14

Results 18

Discussion 23

References 41

Chapter 3: Blood-derived DNA Methylation Signatures of Crohn’s Disease and Severity of Intestinal Inflammation 43

Abstract 44

Introduction 45

Methods 46

Results 54

Discussion 62

References 87

Chapter 4: The Microbiome in Patients with Inflammatory Diseases 90

Abstract 91

Introduction 91

What is currently known from inflammatory bowel disease microbiome research in humans 93

Causal potential of the gut microbiome in human inflammatory bowel disease 95

Dysbiosis in diagnosing inflammatory bowel disease 96

Targeting of dysbiosis for therapy 98

Probiotics 98

Prebiotics 101

Synbiotics 102

Other microbiome-based therapeutic interventions for the management of inflammatory bowel disease 104

Do IBD patients benefit from butyrate replacement? 104

Do IBD patients benefit from sulfate-reduction? 105

Do IBD patients benefit from fecal microbiota transplantation? 106

Discussion 107

Future directions 108

Need for large, well-designed prospective trials 108

Mendelian randomization to identify causal associations. 109

Role of the gut microbiome in disease course. 109

References 114

Chapter 5: Site- and Taxa-specific Disease-Associated Oral Microbial Structures Distinguish Patients with Inflammatory Bowel Disease 120

Abstract 121

Introduction 122

Methods 123

Results 127

Discussion 133

References 156

Chapter 6: Lessons learnt and Recommendations for Future Studies 159

Need for large, case-control cohorts of non-European ancestry 160

Leveraging the genetic heterogeneity across populations to understand widening ethnic disparities in IBD 160

Un-interpreted genetic signals, and trans-ethnic summary statistic fine-mapping analysis of causal variants in IBD 161

DNA methylation data as a functional tool to identify critical variants in IBD risk loci 162

Integrative epigenetic and transcriptomic analysis of genetic associations to gain molecular insights into GWAS signals 163

Quantifying the impact of environmental exposures on the epigenome and establishing the causal potential of exposure-associated DNA methylation in IBD 164

Genetics of microbiome and its integration with the epigenome and transcriptome to gain causal and molecular insights 165

References 166

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