identification-quantification-deranged-metabolites-critically-ill

Identification and Quantification of Deranged Metabolites in Critically Ill Patients Using NMR-Based Metabolomics

Metabolomics is emerging as a significant approach to reflect the individual's response to pathophysiological conditions. Nuclear magnetic resonance (NMR) ...

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Critical illnesses contribute to the maximum morbidity and mortality of hospitalized patients. Acute respiratory distress syndrome (ARDS) and sepsis/septic shock are the two most common acute illnesses associated with intensive care unit (ICU) admission. Once triggered, both have an identical underlying mechanism, portrayed by inflammation and endothelial dysfunction. The diagnosis of ARDS is based on clinical findings, laboratory tests, and radiological imaging. Blood cultures remain the gold standard for the diagnosis of sepsis, with the limitation of time delay and low positive yield. A combination of biomarkers has been proposed to diagnose and prognosticate these acute disorders with strengths and limitations, but still, the gold standard has been elusive to clinicians. In this review article, we illustrate the potential of metabolomics to unravel biomarkers that can be clinically utilized as a rapid prognostic and diagnostic tool associated with specific patient populations (ARDS and sepsis/septic shock) based on the available scientific data.

Metabolomics: An emerging potential approach to decipher critical illnesses.

Diagnosis and management of patients with septic shock is still a significant challenge for clinicians with its high mortality amongst hospitalized patients. Septic shock is a heterogeneous condition and is usually accompanied by various underlying disease conditions. Dissecting the specific metabolic changes induced by these underlying disease conditions through metabolomics has shown the potential to improve our understanding of the disease's relevant pathophysiological mechanisms, leading to improved treatment. This study has shown the metabolic alterations caused due to co-morbid conditions like diabetes, hypertension, CAD, and CKD in septic shock. It has also shown the distinct metabolic profiles of septic shock patients with underlying respiratory illnesses and encephalopathy. Metabolic profiling of sera obtained from 50 septic shock patients and 20 healthy controls was performed using high-resolution 1D H CPMG and diffusion-edited NMR spectra. Univariate and multivariate statistical analyses were performed to identify the potential molecular biomarkers. Noted dysregulations in amino acids, carbohydrates, and lipid metabolism were observed in septic shock patients. Further stratification within the septic shock patients based on co-morbid conditions and primary diagnosis has shown their role in causing metabolic alterations. Evaluation of these compounds during treatment will help design a personalized treatment protocol for the patients, improving therapeutics.

Serum metabolic profiles of septic shock patients based upon co-morbidities and other underlying conditions.

: Sepsis and septic shock are still associated with a high mortality rate. The early-stage prediction of septic shock outcomes would be helpful to clinicians for designing their treatment protocol. In addition, it would aid clinicians in patient management by understanding gender disparity in terms of clinical outcomes of septic shock by identifying whether there are sex-based differences in sepsis-associated mortality. : This study aimed to test the hypothesis that gender-based metabolic heterogeneity is associated with sepsis survival and identify the biomarkers of mortality for septic shock in an Indian cohort. : The study was performed in an Indian population cohort diagnosed with sepsis/septic shock within 24 hours of admission. The study group was 50 patients admitted to intensive care, comprising 23 females and 27 males. Univariate and multivariate analysis were performed to identify the biomarkers for septic shock mortality and the gender-specific metabolic fingerprint in septic shock-associated mortality. : The energy-related metabolites, ketone bodies, choline, and NAG were found to be primarily responsible for differentiating survivors and non-survivors. The gender-based mortality stratification identified a female-specific association of the anti-inflammatory response, innate immune response, and β oxidation, and a male-specific association of the pro-inflammatory response to septic shock. : The identified mortality biomarkers may help clinicians estimate the severity of a case, as well as predict the outcome and treatment efficacy. The study underlines that gender is one of the most significant biological factors influencing septic shock metabolomic profiles. This understanding can be utilized to identify novel gender-specific biomarkers and innovative targets relevant for gender medicine.

Gender-specific association of oxidative stress and immune response in septic shock mortality using NMR-based metabolomics.

An early metabolic signature associated with the responsiveness to treatment can be useful in the better management of septic shock patients. This would help clinicians in designing personalized treatment protocols for patients showing non-responsiveness to treatment.

Metabolic fingerprint of patients showing responsiveness to treatment of septic shock in intensive care unit.

Bone is a living tissue made up of organic proteins, inorganic minerals, and water. The organic component of bone (mainly made up of Type-I collagen) provides flexibility and tensile strength. Solid-state nuclear magnetic resonance (ssNMR) is one of the few techniques that can provide atomic-level structural insights of such biomaterials in their native state. In the present article, we employed the variable contact time cross-polarization ( H- C CP) kinetics experiments to study the hydration-dependent atomic-level structural changes in the bone extracellular matrix (ECM). The natural abundant  C CP intensity of the bone ECM is measured by varying CP contact time and best fitted to the nonclassical kinetic model. Different relaxation parameters were measured by the best-fit equation corresponding to the different hydration conditions of the bone ECM. The associated changes in the measured parameters due to varying levels of hydration observed at different sites of collagen protein have provided its structural arrangements and interaction with water molecules in bone ECM. Overall, the present study reveals a better understanding of the kinetics of the organic part inside the bone ECM that will help in comprehending the disease-associated pathways.

 H- C cross-polarization kinetics to probe hydration-dependent organic components of bone extracellular matrix.

Analysis of the chemical composition of gallstones is vital for the etiopathogenesis of gallstone diseases that can ultimately help in the prevention of its formation. In the present study, gallstones from seven different regions of India were analyzed to highlight the major difference in their composition. Also, gallstones of different pathological conditions i.e., benign (chronic cholecystitis, CC) and malignant gallbladder disease (gallbladder cancer GBC) were characterized. The type of polymorphs of cholesterol molecules was also studied to provide insight into the structure of gallstones. 1H solution state NMR spectroscopy 1D experiments were performed on a total of 94 gallstone (GS) samples collected from seven different geographical regions of India. Solid-State NMR spectroscopy 13C cross-polarization magic angle spinning (CPMAS) experiments were done on the 20 CC GS samples and 20 GBC GS samples of two regions. 1H NMR spectra from the solution state NMR of all the stones reveal that cholesterol was a major component of the maximum stones of the north India region while in south Indian regions, GS had very less cholesterol. 13C CPMAS experiments reveal that the quantity of cholesterol was significantly more in the GS of CC in the Lucknow region compared with GBC stones of Lucknow and Chandigarh. Our study also revealed that GS of the Lucknow region of both malignant and benign gallbladder diseases belong to the monohydrate crystalline form of cholesterol while GS of Chandigarh region of both malignant and benign gallbladder diseases exists in both monohydrate crystalline form with the amorphous type and anhydrous form. Gallstones have a complicated and poorly understood etiology. Therefore, it is important to understand the composition of gallstones, which can be found in various forms and clinical conditions. Variations in dietary practices, environmental conditions, and genetic factors may influence and contribute to the formation of GS. Prevention of gallstone formation may help in decreasing the cases of gallbladder cancer.

NMR spectroscopy-based analysis of gallstones of cancerous and benign gallbladders from different geographical regions of the Indian subcontinent.

Acute respiratory distress syndrome (ARDS) is associated with high mortality rates, which are further exacerbated when accompanied by acute kidney injury (AKI). Presently, there is a lack of comprehensive studies thoroughly elucidating the metabolic dysregulation in ARDS patients with AKI leading to poor outcomes. We hypothesized that metabolomics can be a potent tool to highlight the differences in the metabolic profile unraveling unidentified pathophysiological mechanisms of ARDS patients with and without AKI. H nuclear magnetic resonance spectroscopy was used to identify key metabolites in the serum samples of 75 patients. Distinct clusters of both groups were obtained as the study's primary outcome using multivariate analysis. Notable alternations in the levels of nine metabolites were identified. Pathway analysis revealed the dysregulation of five significant cycles, which resulted in various complications, such as hyperammonemia, higher energy requirements, and mitochondrial dysfunction causing oxidative stress. Identified metabolites also showed a significant correlation with clinical scores, indicating severity. This study shows the alterations in the metabolite concentration highlighting the difference in the pathophysiology of both patient groups and its association with outcome, pointing in the direction of a personalized medicine approach and holding significant promise for application in critical care settings to improve clinical outcomes.

Article	Year
Metabolomics: An emerging potential approach to decipher critical illnesses. Biophysical chemistry\| PubMed ID: 32911125	2020
Serum metabolic profiles of septic shock patients based upon co-morbidities and other underlying conditions. Molecular omics\| PubMed ID: 33399607	2021
Gender-specific association of oxidative stress and immune response in septic shock mortality using NMR-based metabolomics. Molecular omics\| PubMed ID: 34881387	2022
Metabolic fingerprint of patients showing responsiveness to treatment of septic shock in intensive care unit. Magma (New York, N.Y.)\| PubMed ID: 36449125	2023
H- C cross-polarization kinetics to probe hydration-dependent organic components of bone extracellular matrix. Magnetic resonance in chemistry : MRC\| PubMed ID: 36946081	2023
NMR spectroscopy-based analysis of gallstones of cancerous and benign gallbladders from different geographical regions of the Indian subcontinent. PloS one\| PubMed ID: 37352214	2023
Unveiling Pathophysiological Insights: Serum Metabolic Dysregulation in Acute Respiratory Distress Syndrome Patients with Acute Kidney Injury. Journal of proteome research\| PubMed ID: 39078945	2024

Mohd Adnan Siddiqui

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