Browsing by Subject "Metabolomics"
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Item A Metabolomics Approach to Identify Metabolites Associated With Mortality in Patients Receiving Maintenance Hemodialysis(Elsevier, 2024-06-29) Al Awadhi, Solaf; Myint, Leslie; Guallar, Eliseo; Clish, Clary B.; Wulczyn, Kendra E.; Kalim, Sahir; Thadhani, Ravi; Segev, Dorry L.; McAdams DeMarco, Mara; Moe, Sharon M.; Moorthi, Ranjani N.; Hostetter, Thomas H.; Himmelfarb, Jonathan; Meyer, Timothy W.; Powe, Neil R.; Tonelli, Marcello; Rhee, Eugene P.; Shafi, Tariq; Medicine, School of MedicineIntroduction: Uremic toxins contributing to increased risk of death remain largely unknown. We used untargeted metabolomics to identify plasma metabolites associated with mortality in patients receiving maintenance hemodialysis. Methods: We measured metabolites in serum samples from 522 Longitudinal US/Canada Incident Dialysis (LUCID) study participants. We assessed the association between metabolites and 1-year mortality, adjusting for age, sex, race, cardiovascular disease, diabetes, body mass index, serum albumin, Kt/Vurea, dialysis duration, and country. We modeled these associations using limma, a metabolite-wise linear model with empirical Bayesian inference, and 2 machine learning (ML) models: Least absolute shrinkage and selection operator (LASSO) and random forest (RF). We accounted for multiple testing using a false discovery rate (pFDR) adjustment. We defined significant mortality-metabolite associations as pFDR < 0.1 in the limma model and metabolites of at least medium importance in both ML models. Results: The mean age of the participants was 64 years, the mean dialysis duration was 35 days, and there were 44 deaths (8.4%) during a 1-year follow-up period. Two metabolites were significantly associated with 1-year mortality. Quinolinate levels (a kynurenine pathway metabolite) were 1.72-fold higher in patients who died within year 1 compared with those who did not (pFDR, 0.009), wheras mesaconate levels (an emerging immunometabolite) were 1.57-fold higher (pFDR, 0.002). An additional 42 metabolites had high importance as per LASSO, 46 per RF, and 9 per both ML models but were not significant per limma. Conclusion: Quinolinate and mesaconate were significantly associated with a 1-year risk of death in incident patients receiving maintenance hemodialysis. External validation of our findings is needed.Item A multimodal and integrated approach to interrogate human kidney biopsies with rigor and reproducibility: guidelines from the Kidney Precision Medicine Project(American Physiological Society, 2021) El-Achkar, Tarek M.; Eadon, Michael T.; Menon, Rajasree; Lake, Blue B.; Sigdel, Tara K.; Alexandrov, Theodore; Parikh, Samir; Zhang, Guanshi; Dobi, Dejan; Dunn, Kenneth W.; Otto, Edgar A.; Anderton, Christopher R.; Carson, Jonas M.; Luo, Jinghui; Park, Chris; Hamidi, Habib; Zhou, Jian; Hoover, Paul; Schroeder, Andrew; Joanes, Marianinha; Azeloglu, Evren U.; Sealfon, Rachel; Winfree, Seth; Steck, Becky; He, Yongqun; D’Agati, Vivette; Iyengar, Ravi; Troyanskaya, Olga G.; Barisoni, Laura; Gaut, Joseph; Zhang, Kun; Laszik, Zoltan; Rovin, Brad H.; Dagher, Pierre C.; Sharma, Kumar; Sarwal, Minnie M.; Hodgin, Jeffrey B.; Alpers, Charles E.; Kretzler, Matthias; Jain, Sanjay; Medicine, School of MedicineComprehensive and spatially mapped molecular atlases of organs at a cellular level are a critical resource to gain insights into pathogenic mechanisms and personalized therapies for diseases. The Kidney Precision Medicine Project (KPMP) is an endeavor to generate three-dimensional (3-D) molecular atlases of healthy and diseased kidney biopsies by using multiple state-of-the-art omics and imaging technologies across several institutions. Obtaining rigorous and reproducible results from disparate methods and at different sites to interrogate biomolecules at a single-cell level or in 3-D space is a significant challenge that can be a futile exercise if not well controlled. We describe a “follow the tissue” pipeline for generating a reliable and authentic single-cell/region 3-D molecular atlas of human adult kidney. Our approach emphasizes quality assurance, quality control, validation, and harmonization across different omics and imaging technologies from sample procurement, processing, storage, shipping to data generation, analysis, and sharing. We established benchmarks for quality control, rigor, reproducibility, and feasibility across multiple technologies through a pilot experiment using common source tissue that was processed and analyzed at different institutions and different technologies. A peer review system was established to critically review quality control measures and the reproducibility of data generated by each technology before their being approved to interrogate clinical biopsy specimens. The process established economizes the use of valuable biopsy tissue for multiomics and imaging analysis with stringent quality control to ensure rigor and reproducibility of results and serves as a model for precision medicine projects across laboratories, institutions and consortia.Item Adverse Effects of Fenofibrate in Mice Deficient in the Protein Quality Control Regulator, CHIP(MDPI, 2018-08) Ravi, Saranya; Parry, Traci L.; Willis, Monte S.; Lockyer, Pamela; Patterson, Cam; Bain, James R.; Stevens, Robert D.; Ilkayeva, Olga R.; Newgard, Christopher B.; Schisler, Jonathan C.; Pathology and Laboratory Medicine, School of MedicineWe previously reported how the loss of CHIP expression (Carboxyl terminus of Hsc70-Interacting Protein) during pressure overload resulted in robust cardiac dysfunction, which was accompanied by a failure to maintain ATP levels in the face of increased energy demand. In this study, we analyzed the cardiac metabolome after seven days of pressure overload and found an increase in long-chain and medium-chain fatty acid metabolites in wild-type hearts. This response was attenuated in mice that lack expression of CHIP (CHIP-/-). These findings suggest that CHIP may play an essential role in regulating oxidative metabolism pathways that are regulated, in part, by the nuclear receptor PPARα (Peroxisome Proliferator-Activated Receptor alpha). Next, we challenged CHIP-/- mice with the PPARα agonist called fenofibrate. We found that treating CHIP-/- mice with fenofibrate for five weeks under non-pressure overload conditions resulted in decreased skeletal muscle mass, compared to wild-type mice, and a marked increase in cardiac fibrosis accompanied by a decrease in cardiac function. Fenofibrate resulted in decreased mitochondrial cristae density in CHIP-/- hearts as well as decreased expression of genes involved in the initiation of autophagy and mitophagy, which suggests that a metabolic challenge, in the absence of CHIP expression, impacts pathways that contribute to mitochondrial quality control. In conclusion, in the absence of functional CHIP expression, fenofibrate results in unexpected skeletal muscle and cardiac pathologies. These findings are particularly relevant to patients harboring loss-of-function mutations in CHIP and are consistent with a prominent role for CHIP in regulating cardiac metabolism.Item Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease(MDPI, 2022-03-30) Collins, Kimberly S.; Eadon, Michael T.; Cheng, Ying-Hua; Barwinska, Daria; Ferreira, Ricardo Melo; McCarthy, Thomas W.; Janosevic, Danielle; Syed, Farooq; Maier, Bernhard; El-Achkar, Tarek M.; Kelly, Katherine J.; Phillips, Carrie L.; Hato, Takashi; Sutton, Timothy A.; Dagher, Pierre C.; Medicine, School of MedicineDiabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography-mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD.Item Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome(Elsevier, 2019-01) MahmoudianDehkordi, Siamak; Arnold, Matthias; Nho, Kwangsik; Ahmad, Shahzad; Jia, Wei; Xie, Guoxiang; Louie, Gregory; Kueider‐Paisley, Alexandra; Moseley, M. Arthur; Thompson, J. Will; St John Williams, Lisa; Tenenbaum, Jessica D.; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Bhattacharyya, Sudeepa; Toledo, Jon B.; Schafferer, Simon; Klein, Sebastian; Koal, Therese; Risacher, Shannon L.; Kling, Mitchel Allan; Motsinger‐Reif, Alison; Rotroff, Daniel M.; Jack, John; Hankemeier, Thomas; Bennett, David A.; De Jager, Philip L.; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; van Duijn, Cornelia M.; Saykin, Andrew J.; Kastenmüller, Gabi; Kaddurah‐Daouk, Rima; Radiology and Imaging Sciences, School of MedicineIntroduction Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut‐brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). Methods Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD‐related genetic variants, adjusting for confounders and multiple testing. Results In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α‐dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response–related genes implicated in AD showed associations with BA profiles. Discussion We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut‐liver‐brain axis in the pathogenesis of AD.Item Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers(Elsevier, 2019-02) Nho, Kwangsik; Kueider-Paisley, Alexandra; MahmoudianDehkordi, Siamak; Arnold, Matthias; Risacher, Shannon L.; Louie, Gregory; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Kastenmüller, Gabi; Jia, Wei; Xie, Guoxiang; Ahmad, Shahzad; Hankemeier, Thomas; van Duijn, Cornelia M.; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Radiology and Imaging Sciences, School of MedicineINTRODUCTION: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-β deposition. METHOD: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION: This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.Item Altered metabolite levels and correlations in patients with colorectal cancer and polyps detected using seemingly unrelated regression analysis(Springer Nature, 2017-11) Chen, Chen; Gowda, G. A. Nagana; Zhu, Jiangjiang; Deng, Lingli; Gu, Haiwei; Chiorean, E. Gabriela; Zaid, Mohammad Abu; Harrison, Marietta; Zhang, Dabao; Zhang, Min; Raftery, Daniel; Graduate Medical Education, IU School of MedicineIntroduction: Metabolomics technologies enable the identification of putative biomarkers for numerous diseases; however, the influence of confounding factors on metabolite levels poses a major challenge in moving forward with such metabolites for pre-clinical or clinical applications. Objectives: To address this challenge, we analyzed metabolomics data from a colorectal cancer (CRC) study, and used seemingly unrelated regression (SUR) to account for the effects of confounding factors including gender, BMI, age, alcohol use, and smoking. Methods: A SUR model based on 113 serum metabolites quantified using targeted mass spectrometry, identified 20 metabolites that differentiated CRC patients (n = 36), patients with polyp (n = 39), and healthy subjects (n = 83). Models built using different groups of biologically related metabolites achieved improved differentiation and were significant for 26 out of 29 groups. Furthermore, the networks of correlated metabolites constructed for all groups of metabolites using the ParCorA algorithm, before or after application of the SUR model, showed significant alterations for CRC and polyp patients relative to healthy controls. Results: The results showed that demographic covariates, such as gender, BMI, BMI2, and smoking status, exhibit significant confounding effects on metabolite levels, which can be modeled effectively. Conclusion: These results not only provide new insights into addressing the major issue of confounding effects in metabolomics analysis, but also shed light on issues related to establishing reliable biomarkers and the biological connections between them in a complex disease.Item AMP deamination is sufficient to replicate an atrophy-like metabolic phenotype in skeletal muscle(Elsevier, 2021) Miller, Spencer G.; Hafen, Paul S.; Law, Andrew S.; Springer, Catherine B.; Logsdon, David L.; O’Connell, Thomas M.; Witczak, Carol A.; Brault, Jeffrey J.; Anatomy, Cell Biology and Physiology, School of MedicineBackground: Skeletal muscle atrophy, whether caused by chronic disease, acute critical illness, disuse or aging, is characterized by tissue-specific decrease in oxidative capacity and broad alterations in metabolism that contribute to functional decline. However, the underlying mechanisms responsible for these metabolic changes are largely unknown. One of the most highly upregulated genes in atrophic muscle is AMP deaminase 3 (AMPD3: AMP → IMP + NH3), which controls the content of intracellular adenine nucleotides (AdN; ATP + ADP + AMP). Given the central role of AdN in signaling mitochondrial gene expression and directly regulating metabolism, we hypothesized that overexpressing AMPD3 in muscle cells would be sufficient to alter their metabolic phenotype similar to that of atrophic muscle. Methods: AMPD3 and GFP (control) were overexpressed in mouse tibialis anterior (TA) muscles via plasmid electroporation and in C2C12 myotubes using adenovirus vectors. TA muscles were excised one week later, and AdN were quantified by UPLC. In myotubes, targeted measures of AdN, AMPK/PGC-1α/mitochondrial protein synthesis rates, unbiased metabolomics, and transcriptomics by RNA sequencing were measured after 24 h of AMPD3 overexpression. Media metabolites were measured as an indicator of net metabolic flux. At 48 h, the AMPK/PGC-1α/mitochondrial protein synthesis rates, and myotube respiratory function/capacity were measured. Results: TA muscles overexpressing AMPD3 had significantly less ATP than contralateral controls (-25%). In myotubes, increasing AMPD3 expression for 24 h was sufficient to significantly decrease ATP concentrations (-16%), increase IMP, and increase efflux of IMP catabolites into the culture media, without decreasing the ATP/ADP or ATP/AMP ratios. When myotubes were treated with dinitrophenol (mitochondrial uncoupler), AMPD3 overexpression blunted decreases in ATP/ADP and ATP/AMP ratios but exacerbated AdN degradation. As such, pAMPK/AMPK, pACC/ACC, and phosphorylation of AMPK substrates, were unchanged by AMPD3 at this timepoint. AMPD3 significantly altered 191 out of 639 detected intracellular metabolites, but only 30 transcripts, none of which encoded metabolic enzymes. The most altered metabolites were those within purine nucleotide, BCAA, glycolysis, and ceramide metabolic pathways. After 48 h, AMPD3 overexpression significantly reduced pAMPK/AMPK (-24%), phosphorylation of AMPK substrates (-14%), and PGC-1α protein (-22%). Moreover, AMPD3 significantly reduced myotube mitochondrial protein synthesis rates (-55%), basal ATP synthase-dependent (-13%), and maximal uncoupled oxygen consumption (-15%). Conclusions: Increased expression of AMPD3 significantly decreased mitochondrial protein synthesis rates and broadly altered cellular metabolites in a manner similar to that of atrophic muscle. Importantly, the changes in metabolites occurred prior to reductions in AMPK signaling, gene expression, and mitochondrial protein synthesis, suggesting metabolism is not dependent on reductions in oxidative capacity, but may be consequence of increased AMP deamination. Therefore, AMP deamination in skeletal muscle may be a mechanism that alters the metabolic phenotype of skeletal muscle during atrophy and could be a target to improve muscle function during muscle wasting.Item The Application of Metabolomics to Probiotic and Prebiotic Interventions in Human Clinical Studies(MDPI, 2020-03) O’Connell, Thomas M.; Otolaryngology -- Head and Neck Surgery, School of MedicineThere is an ever-increasing appreciation for our gut microbiota that plays a crucial role in the maintenance of health, as well as the development of disease. Probiotics are live bacteria that are consumed to increase the population of beneficial bacteria and prebiotics are dietary substrates intended to promote the propagation of beneficial bacteria. In order to optimize the use of probiotics and prebiotics, a more complete biochemical understanding of the impact that these treatments have on the community and functioning of the gut microbiota is required. Nucleic acid sequencing methods can provide highly detailed information on the composition of the microbial communities but provide less information on the actual function. As bacteria impart much of their influence on the host through the production of metabolites, there is much to be learned by the application of metabolomics. The focus of this review is on the use of metabolomics in the study of probiotic and prebiotic treatments in the context of human clinical trials. Assessment of the current state of this research will help guide the design of future studies to further elucidate the biochemical mechanism by which probiotics and prebiotics function and pave the way toward more personalized applications.Item Author Correction: Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations(Springer Nature, 2023-10-19) Feofanova, Elena V.; Brown, Michael R.; Alkis, Taryn; Manuel, Astrid M.; Li, Xihao; Tahir, Usman A.; Li, Zilin; Mendez, Kevin M.; Kelly, Rachel S.; Qi, Qibin; Chen, Han; Larson, Martin G.; Lemaitre, Rozenn N.; Morrison, Alanna C.; Grieser, Charles; Wong, Kari E.; Gerszten, Robert E.; Zhao, Zhongming; Lasky-Su, Jessica; NHLBI Trans-Omics for Precision Medicine (TOPMed); Yu, Bing; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthCorrection to: Nature Communications 10.1038/s41467-023-38800-2, published online 30 May2023 In this article, the author name Robert E. Gerszten was incorrectly written as Robert E. Gersztern. The original article has been corrected.