Nutritional Metabolomics in Human Catabolic States Restricted; Files Only
Gonzalez Ramirez, Lucia Amor (Summer 2026)
Abstract
Catabolic metabolism is a hallmark of both acute and chronic diseases, characterized by profound metabolic dysregulation that contributes to a wide range of adverse clinical outcomes, including impaired muscle health, infection, and mortality. Amino acids play a central role in metabolic homeostasis; however, the metabolic pathways linking specific amino acid signatures to clinical outcomes remain unclear. To address this gap, this dissertation investigated clinical and metabolic alterations across two clinical models of catabolic stress: chronic disease, represented by adults with cystic fibrosis, and acute critical illness, represented by surgical intensive care unit patients. Using an integrated approach that combines targeted plasma amino acid profiling and untargeted high-resolution metabolomics (HRM), this work characterized plasma AA signatures and associated metabolic pathways in these distinct yet related catabolic states.
In adults with cystic fibrosis, amino acid profiles demonstrated disease-specific associations with skeletal muscle quantity, quality, and strength, as well as clinical outcomes including lung function, physical performance, and glucose metabolism. Essential amino acids and glutamate emerged as central features linking metabolic signatures to muscle health and clinical outcomes. Network and pathway analyses further identified coordinated alterations in amino acid metabolism, nitrogen balance, and energy-related pathways, reflecting broader metabolic dysregulation in this chronic catabolic state.
In critically ill surgical patients, distinct plasma amino acid signatures were associated with adverse outcomes. Elevated concentrations of essential amino acids were consistently observed among non-survivors, whereas reduced levels of both essential and non-essential amino acids were associated with hospital-acquired infections. These unique amino acid signatures demonstrated good discrimination of outcomes, which varied across time points. Integration with high-resolution metabolomics revealed time-dependent pathway alterations, with mortality associated with disruptions in lipid, amino acid, urea cycle, and redox metabolism, and infections associated with pathways related to energy metabolism, including the tricarboxylic acid cycle and antioxidant systems.
These novel findings demonstrate that plasma amino acid profiles and untargeted metabolic features capture distinct yet overlapping metabolic signatures across acute and chronic catabolic states that are linked to clinical outcomes. Together, the data from this dissertation provide insight into the underlying nutritional pathophysiology and identify potential targets for precision nutrition intervention strategies in future research.
Keywords: Acute Disease, Amino Acid Metabolism, Catabolism, Chronic Disease, Clinical Outcomes, Nutritional Metabolomics
Table of Contents
CHAPTER 1
Introduction 1
Overarching Goal 3
Specific Aims and Hypothesis 3
Chapter 1 References 6
CHAPTER 2
Background 8
Catabolic Metabolism in Disease 8
Chronic Catabolic State: Cystic Fibrosis 9
Acute Catabolic State: Post-Surgical Critical Illness 12
Amino Acids and Metabolic Regulation 15
Nutritional Metabolomics 16
Chapter 2 References 19
CHAPTER 3 Relationship between skeletal muscle indicators and clinical outcomes in cystic fibrosis is modified by adiposity and CFTR modulator use: A cross-sectional analysis 27
Abstract 28
Introduction 32
Material and Methods 33
Results 38
Discussion 40
Chapter 3 References 46
CHAPTER 4 Amino acid signatures linked to muscle health and clinical outcomes in adults with cystic fibrosis 61
Abstract 62
Introduction 66
Methods 67
Results 71
Discussion 73
Chapter 4 References 80
CHAPTER 5 Metabolism associated with skeletal muscle health in adults with cystic fibrosis: An integrative network analysis 109
Abstract 110
Introduction 114
Materials and Methods 115
Results 119
Discussion 121
Chapter 5 References 127
CHAPTER 6 Plasma amino acid profiles reveal metabolic signatures of mortality and infection in critically ill surgical patients: a longitudinal analysis 148
Abstract 150
Introduction 152
Materials and Methods 153
Results 156
Discussion 159
Chapter 6 References 164
CHAPTER 7 Integrated metabolomics reveals time-dependent metabolic pathways associated with mortality and infection in surgical ICU patients 184
Extended Abstract 186
Chapter 7 References 189
CHAPTER 8 Discussion 197
Skeletal muscle health as a clinical manifestation of chronic catabolic disease 197
Amino acid metabolism and clinical outcomes in chronic catabolic disease 198
Amino acid signatures associated with mortality and infection in acute catabolic disease 199
Metabolic pathways underlying catabolic disease 200
Clinical implications 201
Strengths and Limitations 203
Future directions 204
Conclusions 205
Chapter 8 References 206
About this Dissertation
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File download under embargo until 20 August 2027 | 2026-07-22 09:33:33 -0400 | File download under embargo until 20 August 2027 |
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