August 2023 Publication List of Studies Using Metabolon’s Platform and Services

Metabolon’s significant impact on scientific exploration through data and services is evident, with citations in over 3,000 scientific posters and publications. In August 2023, data generated from our platforms took center stage in 54 published studies, spanning diverse topics from the effects of human milk sugars on the gut microbiota to the impact of diabetes on pregnancy to the effects of antibiotics on cancer relapse.

The Metabolon Global Discovery Panel boasts an impressive ability to detect and identify over 5,400 metabolites in serum, tissue, and fecal samples. Leveraging more than two decades of experience and an unrivaled library, Metabolon stands at the forefront with the widest coverage and capability to uncover potential biomarkers in your data.

For a convenient resource, you can access a searchable directory of metabolomics-related publications here.

Highlighted Publications

1. Metabolomic insights into maternal and neonatal complications in pregnancies affected by type 1 diabetes

Meek CL, Stewart ZA, Feig DS, et al. Metabolomic insights into maternal and neonatal complications in pregnancies affected by type 1 diabetes [published online ahead of print, 2023 Aug 24]. Diabetologia. 2023;10.1007/s00125-023-05989-2. doi:10.1007/s00125-023-05989-2

In response to unfavorable environmental conditions, the embryonic development process can temporarily halt, a phenomenon known as diapause. Recent studies have linked this phenomenon to how tumors respond to chemotherapy in non-genetic ways, but the specific mechanisms involved remain poorly understood. In this study, the researchers unveiled a multifaceted role for SMC4 in the transition of colorectal cancer cells into a state resembling diapause using Metabolon’s Global Discovery Panel and Complex Lipids Targeted Panel.

The reduction of SMC4 levels promotes the expression of three key glycolysis enzymes associated with the investment phase, leading to increased lactate production while concurrently inhibiting PGAM1. This elevated lactate production subsequently triggers the upregulation of ABC transporters through histone lactylation, rendering tumor cells resistant to chemotherapy. SMC4 also functions as a co-activator for PGAM1 transcription, and the simultaneous loss of SMC4 and PGAM1 disrupts F-actin assembly, resulting in cytokinesis failure and polyploidy. Consequently, these events hinder cell proliferation.

These findings shed light on the mechanisms that underlie non-genetic resistance to chemotherapy, potentially holding significant implications for the field. They enhance our comprehension of how aerobic glycolysis functions in tumors and could inform future therapeutic strategies.

2. Prebiotic proanthocyanidins inhibit bile reflux-induced esophageal adenocarcinoma through reshaping the gut microbiome and esophageal metabolome

Weh KM, Howard CL, Zhang Y, et al. Prebiotic proanthocyanidins inhibit bile reflux-induced esophageal adenocarcinoma through reshaping the gut microbiome and esophageal metabolome. Preprint. bioRxiv. 2023;2023.08.22.554315. Published 2023 Aug 23. doi:10.1101/2023.08.22.554315

The gut and local esophageal microbiome undergo a gradual transformation in patients with gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma (EAC), shifting from a healthy population of commensal bacteria to a group of pathogenic bacteria associated with inflammation. However, our understanding of how microbial communities and metabolites contribute to the development of EAC driven by reflux remains incomplete and poses challenges for targeted intervention.

In this study, the researchers employed a rat model of reflux-induced EAC to investigate the potential of cranberry proanthocyanidins (C-PAC) in targeting the gut microbiome-esophageal metabolome axis to inhibit EAC progression. Sprague Dawley rats, with or without induced reflux, were provided with either water or C-PAC ad libitum (700 µg/rat/day) for 25 or 40 weeks.

Metabolon’s Global Discovery Panel used untargeted metabolomics to reveal that C-PAC exhibited prebiotic activity, counteracting reflux-induced dysbiosis and mitigating alterations in bile acid metabolism and transport. These effects culminated in a significant inhibition of EAC progression through the TLR/NF-κB/P53 signaling cascades. At the species level, C-PAC reversed the overgrowth of reflux-induced pathogenic bacteria such as Clostridium perfringens, Escherichia coli, and Proteus mirabilis.

C-PAC specifically reversed the changes induced by reflux in bacterial composition, inflammatory markers, and genes implicated in immune response, including Ccl4, Cd14, Crp, Cxcl1, Il6, Il1β, Lbp, Lcn2, Myd88, Nfkb1, Tlr2, and Tlr4. These findings align with observed changes in human EAC progression, as confirmed through publicly available databases.

C-PAC represents a safe and promising dietary component that can be used either alone or potentially as an adjunct to existing therapies to prevent the progression of EAC. It achieves this by ameliorating reflux-induced dysbiosis, inflammation, and cellular damage.

3. Precision modulation of dysbiotic adult microbiomes with a human-milk-derived synbiotic reshapes gut microbial composition and metabolites

Button JE, Cosetta CM, Reens AL, et al. Precision modulation of dysbiotic adult microbiomes with a human-milk-derived synbiotic reshapes gut microbial composition and metabolites. Cell Host Microbe. 2023;31(9):1523-1538.e10. doi:10.1016/j.chom.2023.08.004

The utilization of live biotherapeutic products to manipulate the gut microbiome holds promise for clinical applications but remains a challenging endeavor. In this study, the researchers deliberately induced dysbiosis in a group of 56 healthy volunteers through the administration of antibiotics. Their aim was to evaluate the effectiveness of a synbiotic intervention consisting of Bifidobacterium longum subspecies infantis (B. infantis), a microbe commonly found in infant gut microbiota, and human milk oligosaccharides (HMOs).

Remarkably, B. infantis successfully established itself in 76% of the subjects, with its engraftment being reliant on the presence of HMOs. In some cases, B. infantis reached a relative abundance of up to 81%. The changes observed in the composition of the gut microbiome and the profile of gut metabolites indicated distinct alterations in the recovery process of the engrafted subjects compared to the control group.

The researchers used Metabolon’s Global Discovery Panel to associate the engraftment of B. infantis with several noteworthy outcomes, including an increase in lactate-consuming Veillonella, a more rapid recovery of acetate levels, and changes in metabolites like indolelactate and p-cresol sulfate. These metabolites are known to have an impact on the host’s inflammatory status.

Furthermore, the study revealed that in both in vitro and in vivo settings, Veillonella, when co-cultured with B. infantis and HMOs, converted the lactate produced by B. infantis into propionate, a vital mediator of host physiology.

Collectively, these findings indicate that this synbiotic approach consistently and predictably influences the recovery process of a dysbiotic microbiome.

4. A human milk oligosaccharide alters the microbiome, circulating hormones, cytokines and metabolites in a randomized controlled trial of older individuals

Carter MM, Demis D, Perelman D, et al. A human milk oligosaccharide alters the microbiome, circulating hormones, cytokines and metabolites in a randomized controlled trial of older individuals. medRxiv. 2023:2023.08.18.23294085. doi:10.1101/2023.08.18.23294085

Aging’s negative effect on immune function is linked to various diseases, including cancer, atherosclerosis, and neurodegenerative conditions. This study aimed to enhance the gut microbiota and immune system in aging individuals by introducing a prebiotic oligosaccharide called 2-fucosyllactose (2’-FL), which is naturally abundant in human breast milk and known for its established health benefits in infants and animal models.

In a 6-week randomized controlled trial involving 89 healthy older individuals (average age = 67.3 years), 2’-FL was administered at two different doses, as well as a placebo. While the primary endpoint, a significant change in the cytokine response score, was not achieved, individuals who consumed the prebiotic exhibited notable increases in Bifidobacterium levels within their gut microbiota. Additionally, they showed elevated serum levels of insulin, high-density lipoprotein (HDL) cholesterol, and the fibroblast growth factor 21 (FGF21) hormone.

Furthermore, a comprehensive multi-omics analysis including Metabolon’s Short Chain Fatty Acids Targeted Panel revealed a systemic response to 2’-FL, which could be detected in both blood and urine samples. These findings underscore the potential of this prebiotic to offer a wide range of benefits to aging individuals.

5. Circulating T cell profiles associate with enterotype signatures underlying hematological malignancy relapses

Vallet N, Salmona M, Malet-Villemagne J, et al. Circulating T cell profiles associate with enterotype signatures underlying hematological malignancy relapses. Cell Host Microbe. 2023;31(8):1386-1403.e6. doi:10.1016/j.chom.2023.06.009

Administering azithromycin shortly after allogeneic hematopoietic stem cell transplantation has been demonstrated to elevate the risk of hematological malignancy relapse. In order to ascertain the effects of azithromycin on the post-transplant gut environment and its potential impact on relapse, we conducted a comprehensive analysis of the evolving gut bacteriome, virome, and metabolome in 55 patients who received either azithromycin or a placebo. Using our Global Discovery Panel, we identified four distinct enterotypes, elucidating the interconnections between bacteriophage species and metabolic pathways associated with each. One of these enterotypes demonstrated a strong association with sustained remission, while a specific taxon from Bacteroides was linked to relapse, and two taxa from Bacteroides and Prevotella were correlated with complete remission. These taxa were further linked to metabolic pathways involving lipids, pentoses, branched-chain amino acids, and various bacteriophage species. Additionally, these enterotypes and taxa showed connections to exhausted T cells and the functional state of circulating immune cells. These findings shed light on the intricate ways in which antibiotics can impact the intricate network of gut bacteria, viruses, and metabolites, potentially contributing to cancer relapse by influencing the behavior of immune cells.

Agriculture

6. Zubiri-Gaitán A, Blasco A, Hernández P. Plasma metabolomic profiling in two rabbit lines divergently selected for intramuscular fat content. Commun Biol. 2023;6(1):893. Published 2023 Aug 31. doi:10.1038/s42003-023-05266-3
7. Han S, Xu X, Yuan H, et al. Integrated Transcriptome and Metabolome Analysis Reveals the Molecular Mechanism of Resistance (Youkang) and Susceptive (Tengjiao) Zanthoxylum armatum Cultivars Rust. Preprints: Preprints; 2023.
8. Wang J, Li L, Wang Z, et al. Integrative analysis of the metabolome and transcriptome reveals the molecular regulatory mechanism of isoflavonoid biosynthesis in Ormosia henryi Prain. Int J Biol Macromol. 2023;246:125601. doi:10.1016/j.ijbiomac.2023.125601
9. Eichenberger M, Schwander T, Hüppi S, et al. The catalytic role of glutathione transferases in heterologous anthocyanin biosynthesis. Nature Catalysis. 2023/08/31 2023;doi:10.1038/s41929-023-01018-y
10. Zhang T, Peng JT, Klair A, Dickinson AJ. Non-canonical and developmental roles of the TCA cycle in plants. Curr Opin Plant Biol. 2023;74:102382. doi:10.1016/j.pbi.2023.102382
11. Srivastava V, Gross E. Mitophagy-promoting agents and their ability to promote healthy-aging [published online ahead of print, 2023 Aug 31]. Biochem Soc Trans. 2023;BST20221363. doi:10.1042/BST20221363

Cancer

12. Weston WC, Hales KH, Hales DB. Flaxseed Reduces Cancer Risk by Altering Bioenergetic Pathways in Liver: Connecting SAM Biosynthesis to Cellular Energy. Metabolites. 2023;13(8):945. Published 2023 Aug 14. doi:10.3390/metabo13080945
13. Gnanaprakasam JNR, Kushwaha B, Liu L, et al. Asparagine restriction enhances CD8⁺T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response. Nat Metab. 2023;5(8):1423-1439. doi:10.1038/s42255-023-00856-1
14. Cooper AJL, Dorai T, Pinto JT, Denton TT. Metabolic Heterogeneity, Plasticity, and Adaptation to “Glutamine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase-ω-Amidase (Glutaminase II)] Pathway. Biology (Basel). 2023;12(8):1131. Published 2023 Aug 14. doi:10.3390/biology12081131

Cardiovascular Disease

15. Gao Y, Huang F, Ruan F, et al. Multi-omics map revealed PPARα activation protecting against myocardial ischemia-reperfusion injury by maintaining cardiac metabolic homeostasis. bioRxiv. 2023:2023.08.17.551936. doi:10.1101/2023.08.17.551936

COVID-19 and Infectious Diseases

16. Hensen T, Fässler D, O’Mahony L, et al. The Effects of Hospitalisation on the Serum Metabolome in COVID-19 Patients. Metabolites. 2023;13(8):951. Published 2023 Aug 16. doi:10.3390/metabo13080951
17. Rasmussen KK, dos Santos Q, MacPherson CR, Zucco AG, Gjærde LK, Ilett EE, Lodding I, Helleberg M, Lundgren JD, Nielsen SD, et al. Metabolic Profiling Early Post-Allogeneic Haematopoietic Cell Transplantation in the Context of CMV Infection. Metabolites. 2023; 13(9):968. https://doi.org/10.3390/metabo13090968

Diabetes

18. Fernandes Silva L, Hokkanen J, Vangipurapu J, Oravilahti A, Laakso M. Metabolites as Risk Factors for Diabetic Retinopathy in Patients with Type 2 Diabetes: a 12-year Follow-up Study [published online ahead of print, 2023 Aug 10]. J Clin Endocrinol Metab. 2023;dgad452. doi:10.1210/clinem/dgad452
19. Naja K, Anwardeen N, Al-Hariri M, Al Thani AA, Elrayess MA. Pharmacometabolomic Approach to Investigate the Response to Metformin in Patients with Type 2 Diabetes: A Cross-Sectional Study. Biomedicines. 2023;11(8):2164. Published 2023 Aug 1. doi:10.3390/biomedicines11082164

Gastrointestinal

20. Wu Q, Boonma P, Badu S, et al. Donor-recipient specificity and age-dependency in fecal microbiota therapy and probiotic resolution of gastrointestinal symptoms. NPJ Biofilms Microbiomes. 2023;9(1):54. Published 2023 Aug 3. doi:10.1038/s41522-023-00421-4
21. Jacobs JP, Sauk JS, Ahdoot AI, et al. Microbial and Metabolite Signatures of Stress Reactivity in Ulcerative Colitis Patients in Clinical Remission Predict Clinical Flare Risk [published online ahead of print, 2023 Aug 31]. Inflamm Bowel Dis. 2023;izad185. doi:10.1093/ibd/izad185
22. Kierans SJ, Fagundes RR, Malkov MI, et al. Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression. Proc Natl Acad Sci U S A. 2023;120(35):e2208117120. doi:10.1073/pnas.2208117120

Inflammation

23. Komaravolu RK, Mehta-D’souza P, Conner T, et al. -specific effects of injury and beta-adrenergic activation on metabolic and inflammatory mediators in a murine model of post-traumatic osteoarthritis. bioRxiv. 2023:2023.08.15.553402. doi:10.1101/2023.08.15.553402
24. Almuraikhy S, Anwardeen N, Doudin A, et al. Antioxidative Stress Metabolic Pathways in Moderately Active Individuals. Metabolites. 2023; 13(9):973. doi:10.3390/metabo13090973
25. Palmieri EM, Holewinski R, McGinity CL, et al. Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming. Nat Commun. 2023;14(1):5114. Published 2023 Aug 22. doi:10.1038/s41467-023-40738-4
26. Tang C, Xie AX, Liu EM, et al. Immunometabolic coevolution defines unique microenvironmental niches in ccRCC. Cell Metab. 2023;35(8):1424-1440.e5. doi:10.1016/j.cmet.2023.06.005
27. Nogal A, Asnicar F, Vijay A, et al. Genetic and gut microbiome determinants of SCFA circulating and fecal levels, postprandial responses and links to chronic and acute inflammation. Gut Microbes. 2023;15(1):2240050. doi:10.1080/19490976.2023.2240050

Liver Disease

28. Elvira Mass, Hao Huang, Iva Splichalova et al. Developmental programming of Kupffer cells by maternal obesity causes fatty liver disease in the offspring, 11 August 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3242837/v1]

Neuroscience

29. Novotny BC, Fernandez MV, Wang C, et al. Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer’s disease brains. Alzheimers Dement. 2023;19(5):1785-1799. doi:10.1002/alz.12800
30. Patel V, Mill J, Okonkwo OC, et al. Global Energy Metabolism Deficit in Alzheimer Disease Brain. The Journal of Prevention of Alzheimer’s Disease. 2023/08/04 2023;doi:10.14283/jpad.2023.91
31. Gusdon AM, Savarraj JP, Redell JB, et al. Lysophospholipids are Associated with Outcomes after Mild Traumatic Brain Injury in Humans [published online ahead of print, 2023 Aug 8]. J Neurotrauma. 2023;10.1089/neu.2023.0046. doi:10.1089/neu.2023.0046
32. Coletto E, Savva GM, Latousakis D, et al. Role of mucin glycosylation in the gut microbiota-brain axis of core 3 O-glycan deficient mice. Sci Rep. 2023;13(1):13982. Published 2023 Aug 26. doi:10.1038/s41598-023-40497-8
33. Ratovitski T, Kamath SV, O’Meally RN, et al. Arginine methylation of RNA-binding proteins is impaired in Huntington’s disease [published online ahead of print, 2023 Aug 3]. Hum Mol Genet. 2023;ddad125. doi:10.1093/hmg/ddad125
34. Majhi BB, Gélinas SE, Mérindol N, Ricard S, Desgagné-Penix I. Characterization of norbelladine synthase and noroxomaritidine/norcraugsodine reductase reveals a novel catalytic route for the biosynthesis of Amaryllidaceae alkaloids including the Alzheimer’s drug galanthamine. Front Plant Sci. 2023;14:1231809. Published 2023 Aug 30. doi:10.3389/fpls.2023.1231809
35. Srivastava V, Gross E. Mitophagy-promoting agents and their ability to promote healthy-aging [published online ahead of print, 2023 Aug 31]. Biochem Soc Trans. 2023;BST20221363. doi:10.1042/BST20221363
36. Chaby LE, Lasseter HC, Contrepois K, et al. Correction: Chaby et al. Cross-Platform Evaluation of Commercially Targeted and Untargeted Metabolomics Approaches to Optimize the Investigation of Psychiatric Disease. Metabolites2021, 11, 609. Metabolites. 2023;13(8):933. Published 2023 Aug 9. doi:10.3390/metabo13080933

Nutrition

37. Bernard L, Chen J, Kim H, et al. Serum Metabolomic Markers of Dairy Consumption: Results from the Atherosclerosis Risk in Communities Study and the Bogalusa Heart Study [published online ahead of print, 2023 Aug 3]. J Nutr. 2023;S0022-3166(23)72524-8. doi:10.1016/j.tjnut.2023.08.001
38. Reay WR, Kiltschewskij DJ, Biase MAD, et al. Genetic influences on circulating retinol and its relationship to human health. medRxiv. 2023:2023.08.07.23293796. doi:10.1101/2023.08.07.23293796
39. Jackson MI, Jewell DE. Feeding of fish oil and medium-chain triglycerides to canines impacts circulating structural and energetic lipids, endocannabinoids, and non-lipid metabolite profiles. Front Vet Sci. 2023;10:1168703. Published 2023 Aug 24. doi:10.3389/fvets.2023.1168703
40. Jacobs JP, Lee ML, Rechtman DJ, et al. Human milk oligosaccharides modulate the intestinal microbiome of healthy adults. Scientific Reports. 2023/08/31 2023;13(1):14308. doi:10.1038/s41598-023-41040-5
41. Hughes DA, Li-Gao R, Bull CJ, et al. The association between body mass index and metabolite response to a liquid mixed meal challenge. medRxiv. 2023:2023.08.21.23294369. doi:10.1101/2023.08.21.23294369
42. Naik J, Rajput R, Stracke R, Pandey A. The HSF–DREB–MYB transcriptional regulatory module regulates flavonol biosynthesis and flavonoid B-ring hydroxylation in banana (<em>Musa acuminata</em>). bioRxiv. 2023:2023.08.23.554507. doi:10.1101/2023.08.23.554507
43. Prabhakaran P, Nazir MYM, Thananusak R, et al. Uncovering global lipid accumulation routes towards docosahexaenoic acid (DHA) production in Aurantiochytrium sp. SW1 using integrative proteomic analysis [published online ahead of print, 2023 Aug 23]. Biochim Biophys Acta Mol Cell Biol Lipids. 2023;159381. doi:10.1016/j.bbalip.2023.159381

Renal and Urological Disorders

44. Guardado M, Steurer M, Chapin C, et al. The Urinary Metabolomic Fingerprint in Extremely Preterm Infants on Total Parenteral Nutrition vs. Enteral Feeds. Metabolites. 2023; 13(9):971. doi:3390/metabo13090971

Respiratory Disorders

45. Sevelsted A, Pedersen CT, Gürdeniz G, et al. Exposures to perfluoroalkyl substances and asthma phenotypes in childhood: an investigation of the COPSAC2010 cohort. EBioMedicine. 2023;94:104699. doi:10.1016/j.ebiom.2023.104699
46. Diallo D, Sun S, Somboro AM, et al. Metabolic and Immune Consequences of Antibiotic Related Microbiome Alterations during first-line Tuberculosis Treatment in Bamako, Mali. Preprint. Res Sq. 2023;rs.3.rs-3232670. Published 2023 Aug 11. doi:10.21203/rs.3.rs-3232670/v1

Other

47. Pasquale LR, Khawaja AP, Wiggs JL, et al. Metabolite and Lipid Biomarkers Associated With Intraocular Pressure and Inner Retinal Morphology: 1H NMR Spectroscopy Results From the UK Biobank. Invest Ophthalmol Vis Sci. 2023;64(11):11. doi:10.1167/iovs.64.11.11
48. Amin N, Kaddurah-Daouk R, van Duijn CM. Leveraging Health Linkage Data From the UK Biobank-With Great Power Comes Great Responsibility-Reply [published online ahead of print, 2023 Aug 23]. JAMA Psychiatry. 2023;10.1001/jamapsychiatry.2023.2969. doi:10.1001/jamapsychiatry.2023.2969
49. Weinisch P, Raffler J, Römisch-Margl W, et al. The HuMet Repository: Watching human metabolism at work. Preprint. bioRxiv. 2023;2023.08.08.550079. Published 2023 Aug 9. doi:10.1101/2023.08.08.550079
50. Hajjar G, Barros Santos MC, Bertrand-Michel J, et al. Scaling-up metabolomics: Current state and perspectives. TrAC Trends in Analytical Chemistry. 2023/10/01/ 2023;167:117225. doi: 10.1016/j.trac.2023.117225
51. Yang H, Li X, Jin H, et al. Longitudinal metabolomics analysis reveals the acute effect of cysteine and NAC included in the combined metabolic activators. Free Radic Biol Med. 2023;204:347-358. doi:10.1016/j.freeradbiomed.2023.05.013
52. Jia F, Zhao X, Zhao Y. Advancements in ToF-SIMS imaging for life sciences. Front Chem. 2023;11:1237408. Published 2023 Aug 24. doi:10.3389/fchem.2023.1237408
53. Miranda-Cervantes A, Fritzen AM, Raun SH, et al. Pantothenate Kinase 4 controls efficient skeletal muscle energy substrate metabolism via acetyl-CoA. bioRxiv. 2023:2023.08.14.551603. doi:10.1101/2023.08.14.551603
54. Brown AA, Fernandez-Tajes JJ, Hong MG, et al. Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits. Nat Commun. 2023;14(1):5062. Published 2023 Aug 21. doi:10.1038/s41467-023-40569-3