{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:27:52Z","timestamp":1780511272932,"version":"3.54.1"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T00:00:00Z","timestamp":1754179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Secondary (nosocomial) bacterial meningitis remains a serious problem in patients with severe brain damage. The aim of this study was to assess the differences in the aromatic metabolites of tryptophan, phenylalanine, and tyrosine, in serum and cerebrospinal fluid (CSF) samples collected simultaneously from patients with long-term sequelae of severe brain damage with suspected secondary bacterial meningitis. Methods: Group I included 16 paired serum and CSF samples from patients (N = 11) without secondary bacterial meningitis; group II included 13 paired serum and CSF samples from patients (N = 4) with secondary bacterial meningitis. Results: The median concentrations of serum 5-hydroxyindole-3-acetic, CSF 4-hydroxyphenyllactic (p-HPhLA), CSF 4-hydroxyphenylacetic, CSF phenyllactic, and indole-3-lactic acids in serum and CSF were statistically higher in group II compared to group I (p-value \u2264 0.03), while 4-hydroxyphenylpropionic and indole-3-acetic in serum were lower in group II compared to group I (p-value = 0.04). In group I, p-HPhLA serum concentrations were greater than or equal to its CSF concentrations in 14 paired samples; in group II, p-HPhLA concentrations in serum were lower than in CSF in all paired samples. Conclusions: The obtained results demonstrate the differences in the profile of aromatic metabolites in serum and CSF and may confirm the hypothesis of the p-HPhLA microbial origin in the CSF of patients with secondary bacterial meningitis.<\/jats:p>","DOI":"10.3390\/metabo15080527","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T07:49:58Z","timestamp":1754380198000},"page":"527","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Differences in the Profile of Aromatic Metabolites in the Corresponding Blood Serum and Cerebrospinal Fluid Samples of Patients with Secondary Bacterial Meningitis"],"prefix":"10.3390","volume":"15","author":[{"given":"Alisa K.","family":"Pautova","sequence":"first","affiliation":[{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Petrovka Street, 25-2, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"Meinarovich","sequence":"additional","affiliation":[{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Petrovka Street, 25-2, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladislav E.","family":"Zakharchenko","sequence":"additional","affiliation":[{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Petrovka Street, 25-2, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel D.","family":"Sobolev","sequence":"additional","affiliation":[{"name":"Exacte Labs Bioanalytical Laboratory, 20-2 Nauchny Proezd, 117246 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia A.","family":"Burnakova","sequence":"additional","affiliation":[{"name":"Exacte Labs Bioanalytical Laboratory, 20-2 Nauchny Proezd, 117246 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2328-1610","authenticated-orcid":false,"given":"Natalia V.","family":"Beloborodova","sequence":"additional","affiliation":[{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Petrovka Street, 25-2, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e34","DOI":"10.1093\/cid\/ciw861","article-title":"2017 Infectious Diseases Society of America\u2019s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis","volume":"64","author":"Tunkel","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jcrc.2018.01.022","article-title":"Healthcare-Associated Ventriculitis and Meningitis in a Neuro-ICU: Incidence and Risk Factors Selected by Machine Learning Approach","volume":"45","author":"Savin","year":"2018","journal-title":"J. Crit. Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3892\/wasj.2024.274","article-title":"Risk Factors for Mortality in Patients with Bacterial Meningitis Following a Neurosurgical Procedure: A Meta-analysis","volume":"6","author":"Suryaningtyas","year":"2024","journal-title":"World Acad. Sci. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ajic.2008.03.002","article-title":"CDC\/NHSN Surveillance Definition of Health Care-Associated Infection and Criteria for Specific Types of Infections in the Acute Care Setting","volume":"36","author":"Horan","year":"2008","journal-title":"Am. J. Infect. Control"},{"key":"ref_5","unstructured":"Centers for Disease Control and Prevention (CDC) (2025, May 02). CDC\/NHSN Surveillance Definitions for Specific Types of Infections, Available online: https:\/\/www.cdc.gov\/nhsn\/pdfs\/pscmanual\/17pscnosinfdef_current.pdf."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"497","DOI":"10.3109\/02688697.2013.771138","article-title":"Conservative Antibiotic Policy in Patients Undergoing Non-Trauma Cranial Surgery Does Not Result in Higher Rates of Postoperative Meningitis: An Audit of Nine Years of Narrow-Spectrum Prophylaxis","volume":"27","author":"Moorthy","year":"2013","journal-title":"Br. J. Neurosurg."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Barker, F.G. (2007). Efficacy of Prophylactic Antibiotics against Meningitis after Craniotomy: A Meta-Analysis. Neurosurgery, 60.","DOI":"10.1227\/01.NEU.0000255425.31797.23"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.cmi.2017.05.013","article-title":"Management of Post-Neurosurgical Meningitis: Narrative Review","volume":"23","author":"Hussein","year":"2017","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Borowiak, A., Safranow, K., Sarna, A., and \u0141oniewska, B. (2025). Diagnostic Utility of Procalcitonin and Lactate Determination in Cerebrospinal Fluid for the Diagnosis of Neonatal Meningitis. J. Clin. Med., 14.","DOI":"10.3390\/jcm14020414"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wang, Q., Wang, Y., Yang, Y., Kong, Y., and Peng, Y. (2023). The Value of Elevated Cerebrospinal Fluid Lactate Concentrations in Post-Neurosurgical Bacterial Meningitis. BMC Neurol., 23.","DOI":"10.1186\/s12883-023-03428-8"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s11916-024-01262-2","article-title":"Lumbar Puncture Complications: A Review of Current Literature","volume":"28","author":"Reis","year":"2024","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1007\/s10877-015-9663-1","article-title":"Early Monitoring of Ventriculostomy-Related Infections with Procalcitonin in Patients with Ventricular Drains","volume":"29","author":"Omar","year":"2015","journal-title":"J. Clin. Monit. Comput."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Alnomasy, S.F., Alotaibi, B.S., Mujamammi, A.H., Hassan, E.A., and Ali, M.E. (2021). Microbial Aspects and Potential Markers for Differentiation between Bacterial and Viral Meningitis among Adult Patients. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0251518"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1227\/neu.0000000000003021","article-title":"Cerebrospinal Fluid Neutrophil Gelatinase-Associated Lipocalin as a Novel Biomarker for Postneurosurgical Bacterial Meningitis: A Prospective Observational Cohort Study","volume":"95","author":"Lin","year":"2024","journal-title":"Neurosurgery"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9302","DOI":"10.1007\/s12035-024-04144-1","article-title":"Brain Immune Cell Infiltration and Serum Metabolomic Characteristics Reveal That Lauric Acid Promotes Immune Cell Infiltration in Brain and Streptococcus Suis Meningitis in Mice","volume":"61","author":"Jiang","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Himmelreich, U., Malik, R., K\u00fchn, T., Daniel, H.-M., Somorjai, R.L., Dolenko, B., and Sorrell, T.C. (2009). Rapid Etiological Classification of Meningitis by NMR Spectroscopy Based on Metabolite Profiles and Host Response. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005328"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/s41390-020-0816-7","article-title":"Derivation of a Metabolic Signature Associated with Bacterial Meningitis in Infants","volume":"88","author":"Gordon","year":"2020","journal-title":"Pediatr. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.chroma.2013.04.005","article-title":"Characterization of Cerebrospinal Fluid by Comprehensive Two-Dimensional Gas Chromatography Coupled to Time-of-Flight Mass Spectrometry","volume":"1293","author":"Hartonen","year":"2013","journal-title":"J. Chromatogr. A"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rogachev, A.D., Alemasov, N.A., Ivanisenko, V.A., Ivanisenko, N.V., Gaisler, E.V., Oleshko, O.S., Cheresiz, S.V., Mishinov, S.V., Stupak, V.V., and Pokrovsky, A.G. (2021). Correlation of Metabolic Profiles of Plasma and Cerebrospinal Fluid of High-Grade Glioma Patients. Metabolites, 11.","DOI":"10.3390\/metabo11030133"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Murgia, F., Lorefice, L., Poddighe, S., Fenu, G., Secci, M.A., Marrosu, M.G., Cocco, E., and Atzori, L. (2020). Multi-Platform Characterization of Cerebrospinal Fluid and Serum Metabolome of Patients Affected by Relapsing\u2013Remitting and Primary Progressive Multiple Sclerosis. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030863"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/nature24661","article-title":"A Gut Bacterial Pathway Metabolizes Aromatic Amino Acids into Nine Circulating Metabolites","volume":"551","author":"Dodd","year":"2017","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Pautova, A.K., Samokhin, A.S., Beloborodova, N.V., and Revelsky, A.I. (2022). Multivariate Prognostic Model for Predicting the Outcome of Critically Ill Patients Using the Aromatic Metabolites Detected by Gas Chromatography-Mass Spectrometry. Molecules, 27.","DOI":"10.3390\/molecules27154784"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1134\/S106193482470117X","article-title":"Prospects for Monitoring Aromatic and Mitochondrial Metabolites Using Gas Chromatography\u2013Mass Spectrometry during Extracorporeal Blood Purification in Patients with Sepsis","volume":"79","author":"Pautova","year":"2024","journal-title":"J. Anal. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4","DOI":"10.15360\/1813-9779-2025-1-4-14","article-title":"Prediction of Local Infectious and Inflammatory Complications after Reconstructive Surgery of Aorta","volume":"21","author":"Grin","year":"2025","journal-title":"Gen. Reanimatol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Pautova, A.K., Meglei, A.Y., Chernevskaya, E.A., Alexandrova, I.A., and Beloborodova, N.V. (2022). 4-Hydroxyphenyllactic Acid in Cerebrospinal Fluid as a Possible Marker of Post-Neurosurgical Meningitis: Retrospective Study. J. Pers. Med., 12.","DOI":"10.3390\/jpm12030399"},{"key":"ref_26","unstructured":"FDA (2025, May 02). Bioanalytical Method Validation Guidance Industry Biopharmaceutics Bioanalytical Method Validation Guidance Industry Biopharmaceutics Contains Nonbinding Recommendations, Available online: https:\/\/www.fda.gov\/files\/drugs\/published\/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf."},{"key":"ref_27","unstructured":"(2025, May 02). EMEA\/CHMP, ICH Guideline M10 Bioanalytical Method Validation Study Sample Analysis\u2014Committee Medicinal Products Human Use (CHMP). European Medicines Agency 2022. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/ich-guideline-m10-bioanalytical-method-validation-step-5_en.pdf."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sobolev, P.D., Burnakova, N.A., Beloborodova, N.V., Revelsky, A.I., and Pautova, A.K. (2023). Analysis of 4-Hydroxyphenyllactic Acid and Other Diagnostically Important Metabolites of \u03b1-Amino Acids in Human Blood Serum Using a Validated and Sensitive Ultra-High-Pressure Liquid Chromatography-Tandem Mass Spectrometry Method. Metabolites, 13.","DOI":"10.3390\/metabo13111128"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sobolev, P.D., Burnakova, N.A., Revelsky, A.I., Zakharchenko, V.E., Beloborodova, N.V., and Pautova, A.K. (2025). A Sensitive Method for the Profiling of Phenyl- and Indole-Containing Metabolites in Blood Serum and Cerebrospinal Fluid Samples of Patients with Severe Brain Damage Using Ultra-High-Pressure Liquid Chromatography-Tandem Mass Spectrometry. J. Pharm. Biomed. Anal., 260.","DOI":"10.1016\/j.jpba.2025.116803"},{"key":"ref_30","first-page":"2825","article-title":"Scikit-Learn: Machine Learning in Python","volume":"12","author":"Pedregosa","year":"2011","journal-title":"J. Mach. Learn. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1023\/A:1012487302797","article-title":"Gene Selection for Cancer Classification using Support Vector Machines","volume":"46","author":"Guyon","year":"2002","journal-title":"Mach. Learn."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v036.i11","article-title":"Feature Selection Boruta Package","volume":"36","author":"Kursa","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_33","unstructured":"Raschka, S. (2018). Model Evaluation, Model Selection, and Algorithm Selection in Machine Learning. arXiv."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Likhvantsev, V.V., Berikashvili, L.B., Yadgarov, M.Y., Yakovlev, A.A., and Kuzovlev, A.N. (2024). The Tri-Steps Model of Critical Conditions in Intensive Care: Introducing a New Paradigm for Chronic Critical Illness. J. Clin. Med., 13.","DOI":"10.3390\/jcm13133683"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"39","DOI":"10.17116\/anaesthesiology202402139","article-title":"Prevention of Nosocomial Pneumonia Recurrence Using a Bacteriophage Cocktail in Intensive Care Unit","volume":"2","author":"Grechko","year":"2024","journal-title":"Anesteziol. Reanimatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1089\/sur.2015.060","article-title":"Empirical Combination Antibiotic Therapy Improves the Outcome of Nosocomial Meningitis or Ventriculitis in Neuro-Critical Care Unit Patients","volume":"17","author":"Li","year":"2016","journal-title":"Surg. Infect."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chernevskaya, E., Klimenko, N., Pautova, A., Buyakova, I., Tyakht, A., and Beloborodova, N. (2021). Host-Microbiome Interactions Mediated by Phenolic Metabolites in Chronically Critically Ill Patients. Metabolites, 11.","DOI":"10.3390\/metabo11020122"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1111\/j.1365-2982.2009.01370.x","article-title":"Understanding the Role of Tryptophan and Serotonin Metabolism in Gastrointestinal Function","volume":"21","author":"Keszthelyi","year":"2009","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3698","DOI":"10.1073\/pnas.0812874106","article-title":"Metabolomics Analysis Reveals Large Effects of Gut Microflora on Mammalian Blood Metabolites","volume":"106","author":"Wikoff","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.ymgme.2015.01.005","article-title":"Perturbations of Tyrosine Metabolism Promote the Indolepyruvate Pathway via Tryptophan in Host and Microbiome","volume":"114","author":"Gertsman","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3085","DOI":"10.1093\/eurheartj\/ehad333","article-title":"Atlas of Gut Microbe-Derived Products from Aromatic Amino Acids and Risk of Cardiovascular Morbidity and Mortality","volume":"44","author":"Nemet","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3465","DOI":"10.1038\/s41467-025-58459-1","article-title":"Relationships between Brain Activity, Tryptophan-Related Gut Metabolites, and Autism Symptomatology","volume":"16","author":"Ringold","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"105637","DOI":"10.1016\/j.ejps.2020.105637","article-title":"Inhibition of NLRP3-Inflammasome Mediated IL-1\u03b2 Release by Phenylpropanoic Acid Derivatives: In-Silico and in-Vitro Approach","volume":"157","author":"Kinra","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2429754","DOI":"10.1080\/19490976.2024.2429754","article-title":"Dysrupted Microbial Tryptophan Metabolism Associates with SARS-CoV-2 Acute Inflammatory Responses and Long COVID","volume":"16","author":"Yao","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.cmet.2023.12.026","article-title":"Psychological Stress-Induced Microbial Metabolite Indole-3-Acetate Disrupts Intestinal Cell Lineage Commitment","volume":"36","author":"Wei","year":"2024","journal-title":"Cell Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.celrep.2018.03.109","article-title":"Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages","volume":"23","author":"Krishnan","year":"2018","journal-title":"Cell Rep."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ehrlich, A.M., Pacheco, A.R., Henrick, B.M., Taft, D., Xu, G., Huda, M.N., Mishchuk, D., Goodson, M.L., Slupsky, C., and Barile, D. (2020). Indole-3-Lactic Acid Associated with Bifidobacterium-Dominated Microbiota Significantly Decreases Inflammation in Intestinal Epithelial Cells. BMC Microbiol., 20.","DOI":"10.1186\/s12866-020-02023-y"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"374","DOI":"10.15171\/apb.2019.044","article-title":"5-HIAA as a Potential Biological Marker for Neurological and Psychiatric Disorders","volume":"9","author":"Jayamohananan","year":"2019","journal-title":"Adv. Pharm. Bull."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Zaragoz\u00e1, R. (2020). Transport of Amino Acids Across the Blood-Brain Barrier. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00973"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0070-2153(07)80004-4","article-title":"Organic anion-transporting polypeptides at the blood-brain and blood-cerebrospinal fluid barriers","volume":"80","author":"Westholm","year":"2007","journal-title":"Curr. Top. Dev. Biol."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/8\/527\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:22:18Z","timestamp":1760034138000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/8\/527"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,3]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["metabo15080527"],"URL":"https:\/\/doi.org\/10.3390\/metabo15080527","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,3]]}}}