Nutritional and Metabolic Profiling of Pulmonary Tuberculosis Open Access

Frediani, Jennifer (2014)

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The purpose of this dissertation was to explore 1) dietary intake in patients with pulmonary tuberculosis (TB) through use of a novel dietary intake assessment instrument; 2) serial dietary and body composition indices over time in recently diagnosed TB patients, and to examine differences between those with multidrug resistant TB (MDR-TB) and drug-sensitive TB and those receiving or not receiving high-dose vitamin D3 (cholecalciferol) therapy; and 3) the metabolic relationships between subjects with active TB disease and control. All data were derived from a double-blind, randomized, placebo-controlled trial of high-dose vitamin D3 therapy in patients with recently diagnosed pulmonary TB in Tbilisi, Georgia.

The dietary intake assessment instrument was validated in this population of Georgia TB disease patients by comparison with 24-recalls. Adjunctive high-dose vitamin D therapy did not affect changes in macronutrient intake or body composition over the course of treatment; however, total kilocalorie, protein and fat intake increased over the 16-week period in the TB patients overall. Body composition also improved over time with concurrent increases in body weight, BMI, fat mass and fat-free mass. Although not statistically significant, there was a trend that suggested higher intakes of macronutrients but concomitantly lower body weight and fat-free mass over time in those with MDR-TB compared to their drug-sensitive TB counterparts.

We then incorporated dietary intake data with high-resolution LC-MS plasma metabolomics in 17 patients with TB disease and their matched household contacts. In this study, mean 3-day daily total caloric and carbohydrate intake was significantly higher per kg body weight in TB disease subjects than their household contacts, and total fat and protein intake tended to be higher. Overall, our metabolomics study results did not appear to be a function of individual diets of subjects with TB or the healthy controls. We were able to differentiate metabolic profiles between those with TB disease and apparently healthy controls using high-resolution plasma metabolomics in human plasma. We were able to identify multiple metabolites relevant to Mtb disease and its unique metabolism, as well as D-series resolvins that may reflect a pathophysiologic response to TB disease in humans.

Table of Contents

Table of Contents

Chapter 1: Introduction - 1

History and Epidemiology of Tuberculosis - 1

Nutrition Status and TB - 3

Pathogenesis and Immune Response - 7

The Role of Vitamin D Deficiency in TB Pathophysiology - 9

Potential Utility of Metabolomics and TB - 13

Purpose of Research - 16

Chapter 2: Methods - 18

Objectives and Hypotheses - 18

Summary of Methods - 19

Overall RCT Study Design - 19

Data Collection and Measurements - 21

Chapter 3 Specific Methods - 23

Nutrient Intake Assessment - 23

Validation methodology - 25

Statistical analysis - 26

Chapter 4 Specific Methods - 27

Nutrition and Body Composition Assessment - 27

Statistical Analysis - 28

Chapter 5 Specific Metabolomics Analysis - 30

Metabolomics Analysis - 30

Statistical Analysis - 33

Metabolite Annotation and Pathway Analysis - 34

Chapter 3 - A Culture-Specific Nutrient Intake Assessment Instrument in Patients with Pulmonary Tuberculosis - 36

Abstract - 38

Introduction - 39

Methods - 41

Results - 46

Discussion - 47

Chapter 4 - Macronutrient intake and body composition over time among adults with active pulmonary tuberculosis - 57

Abstract - 59

Introduction - 61

Methods - 62

Results - 66

Discussion - 72

Chapter 5 - Plasma Metabolomics of Human Pulmonary Tuberculosis - 91

Abstract - 92

Introduction - 94

Methods - 97

Results - 103

Discussion - 107

Chapter 6: Summary, Conclusions, and Future Directions - 129

Key findings - 129

Strengths and limitations - 133

Implications of this research - 135

Future directions - 137

References - 139

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