{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:09:20Z","timestamp":1784264960145,"version":"3.55.0"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Growing evidence implicates neuroinflammation, gut-derived endotoxemia, and dysregulated lipid metabolism in the pathogenesis of Parkinson\u2019s disease (PD). However, the relationships among circulating lipopolysaccharide (LPS), LPS-handling proteins, systemic inflammatory activation, and lipid fractions remain insufficiently characterized. The aim of this study was to compare LPS levels, LPS-related inflammatory mediators, and plasma lipid parameters between PD patients and matched controls, and to explore correlations among these biomarkers. Twenty PD patients and twenty matched controls underwent fasting venous sampling. Circulating LPS, lipopolysaccharide binding protein (LBP), soluble cluster of differentiation 14 (sCD14), high-sensitivity C-reactive protein (hsCRP), and phospholipid transfer protein (PLTP) were quantified via LAL assay and ELISAs. Serum cholesterol, HDL cholesterol (HDL-C), phospholipids (PLs), HDL-PLs and triacylglycerols (TAGs) were assessed using validated biochemical techniques. LPS concentrations did not differ between groups. However, PD patients showed elevated sCD14 and hsCRP levels, reduced LBP, and increased PLTP. Lipid profiling revealed lower total cholesterol and reduced HDL-associated cholesterol and phospholipids in PD, while TAG levels remained unchanged. Correlation analyses indicated coordinated associations between inflammatory markers and lipid fractions, with distinct interaction patterns in PD compared with controls. These findings support a mechanistic interplay among endotoxemia, innate immune activation, and lipid dysregulation in the pathophysiology of PD.<\/jats:p>","DOI":"10.3390\/ijms27093711","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T09:01:24Z","timestamp":1776848484000},"page":"3711","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Systemic Endotoxemia, Inflammatory Activation, and Lipid Dysregulation in Parkinson\u2019s Disease: Evidence from Circulating LPS-Related Biomarkers and Plasma Lipids"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1984-1614","authenticated-orcid":false,"given":"Matteo","family":"Della Porta","sequence":"first","affiliation":[{"name":"Department of Biomedical & Clinical Sciences, Universit\u00e0 di Milano, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Barichella","sequence":"additional","affiliation":[{"name":"Fondazione Pezzoli per la Malattia di Parkinson, 20125 Milan, Italy"},{"name":"ASST Gaetano Pini-CTO, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Pezzoli","sequence":"additional","affiliation":[{"name":"Fondazione Pezzoli per la Malattia di Parkinson, 20125 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0778-8529","authenticated-orcid":false,"given":"Roberta","family":"Cazzola","sequence":"additional","affiliation":[{"name":"Department of Biomedical & Clinical Sciences, Universit\u00e0 di Milano, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ebrahim, G., Hutchinson, H., Gonzalez, M., and Dagra, A. (2025). Central and Peripheral Immunity Responses in Parkinson\u2019s Disease: An Overview and Update. Neuroglia, 6.","DOI":"10.3390\/neuroglia6020017"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3527","DOI":"10.1007\/s00204-025-04088-y","article-title":"An Update on the Involvement of Inflammatory Mediators in Parkinson\u2019s Disease Pathogenesis","volume":"99","author":"Verma","year":"2025","journal-title":"Arch. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Conte, C., Ingrassia, A., Breve, J., Bol, J.J., Timmermans-Huisman, E., van Dam, A.M., Beccari, T., and van de Berg, W.D.J. (2023). Toll-like Receptor 4 Is Upregulated in Parkinson\u2019s Disease Patients and Co-Localizes with PSer129\u03b1Syn: A Possible Link with the Pathology. Cells, 12.","DOI":"10.3390\/cells12101368"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1177\/0968051907085986","article-title":"From Therapy to Experimental Model: A Hundred Years of Endotoxin Administration to Human Subjects","volume":"13","author":"Bahador","year":"2007","journal-title":"J. Endotoxin Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12468","DOI":"10.1073\/pnas.1511003112","article-title":"Imaging Robust Microglial Activation after Lipopolysaccharide Administration in Humans with PET","volume":"112","author":"Sandiego","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1002\/mds.27815","article-title":"Alterations in Blood Monocyte Functions in Parkinson\u2019s Disease","volume":"34","author":"Nissen","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1136\/gutjnl-2018-316844","article-title":"Role of TLR4 in the Gut-Brain Axis in Parkinson\u2019s Disease: A Translational Study from Men to Mice","volume":"68","author":"Dodiya","year":"2019","journal-title":"Gut"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1212\/01.wnl.0000266593.50534.e8","article-title":"Patient-Reported Autonomic Symptoms in Parkinson Disease","volume":"69","author":"Verbaan","year":"2007","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Hasegawa, S., Goto, S., Tsuji, H., Okuno, T., Asahara, T., Nomoto, K., Shibata, A., Fujisawa, Y., Minato, T., and Okamoto, A. (2015). Intestinal Dysbiosis and Lowered Serum Lipopolysaccharide-Binding Protein in Parkinson\u2019s Disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142164"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Forsyth, C.B., Shannon, K.M., Kordower, J.H., Voigt, R.M., Shaikh, M., Jaglin, J.A., Estes, J.D., Dodiya, H.B., and Keshavarzian, A. (2011). Increased Intestinal Permeability Correlates with Sigmoid Mucosa Alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson\u2019s Disease. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028032"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.parkreldis.2015.02.004","article-title":"Increased Urinary Indoxyl Sulfate (Indican): New Insights into Gut Dysbiosis in Parkinson\u2019s Disease","volume":"21","author":"Cassani","year":"2015","journal-title":"Park. Relat. Disord."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18682","DOI":"10.1074\/jbc.272.30.18682","article-title":"Lipopolysaccharide (LPS)-Binding Proteins BPI and LBP Form Different Types of Complexes with LPS","volume":"272","author":"Tobias","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"28367","DOI":"10.1074\/jbc.M302921200","article-title":"Lipopolysaccharide (LPS)-Binding Protein Inhibits Responses to Cell-Bound LPS","volume":"278","author":"Thompson","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12172","DOI":"10.1074\/jbc.271.21.12172","article-title":"Neutralization and Transfer of Lipopolysaccharide by Phospholipid Transfer Protein","volume":"271","author":"Hailman","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1128\/IAI.68.5.2410-2417.2000","article-title":"Lipopolysaccharide-Binding Protein and Phospholipid Transfer Protein Release Lipopolysaccharides from Gram-Negative Bacterial Membranes","volume":"68","author":"Vesy","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neurobiolaging.2025.07.004","article-title":"Serum HDL-Cholesterol Is Associated with the Clinical-Biological Profile of Early-Stage Parkinson\u2019s Disease Patients Independently of APOE","volume":"155","author":"Mascioli","year":"2025","journal-title":"Neurobiol. Aging"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cannas, F., Kope\u0107, K.K., Zuddas, N., Cesare Marincola, F., Arcara, G., Loi, M., Mussap, M., and Fanos, V. (2025). Parkinson\u2019s Disease Through the Lens of Metabolomics: A Targeted Systematic Review on Human Studies (2019\u20132024). J. Clin. Med., 14.","DOI":"10.3390\/jcm14176277"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41531-023-00511-2","article-title":"Gastrointestinal Disorders in Parkinson\u2019s Disease and Other Lewy Body Diseases","volume":"9","author":"Hirayama","year":"2023","journal-title":"npj Park. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s40035-023-00392-8","article-title":"Parkinson\u2019s Disease and Gut Microbiota: From Clinical to Mechanistic and Therapeutic Studies","volume":"12","author":"Zhang","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eabe6729","DOI":"10.1126\/science.abe6729","article-title":"Enterically Derived High-Density Lipoprotein Restrains Liver Injury via the Portal Vein","volume":"373","author":"Han","year":"2021","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s12974-023-02846-2","article-title":"Lipopolysaccharide-Binding Protein and Future Parkinson\u2019s Disease Risk: A European Prospective Cohort","volume":"20","author":"Zhao","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yang, R., Gao, G., and Yang, H. (2022). The Pathological Mechanism Between the Intestine and Brain in the Early Stage of Parkinson\u2019s Disease. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.861035"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pal, G.D., Shaikh, M., Forsyth, C.B., Ouyang, B., Keshavarzian, A., and Shannon, K.M. (2015). Abnormal Lipopolysaccharide Binding Protein as Marker of Gastrointestinal Inflammation in Parkinson Disease. Front. Neurosci., 9.","DOI":"10.3389\/fnins.2015.00306"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3472","DOI":"10.1093\/brain\/awac176","article-title":"Lipid Pathway Dysfunction Is Prevalent in Patients with Parkinson\u2019s Disease","volume":"145","author":"Galper","year":"2022","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/s41531-025-00955-8","article-title":"Investigating Plasma Lipid Profiles in Association with Parkinson\u2019s Disease Risk","volume":"11","author":"Zhang","year":"2025","journal-title":"npj Park. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"31","DOI":"10.36922\/AN025320086","article-title":"Lipid Metabolism Dysregulation in Parkinson\u2019s Disease: Mechanistic Insights and Therapeutic Implications","volume":"4","author":"Wang","year":"2025","journal-title":"Adv. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.2217\/nnm-2023-0222","article-title":"Phospholipids Impact the Protective Effects of HDL-Mimetic Nanodiscs against Lipopolysaccharide-Induced Inflammation","volume":"18","author":"Kim","year":"2023","journal-title":"Nanomedicine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1194\/jlr.M060285","article-title":"The Effect of Phospholipid Composition of Reconstituted HDL on Its Cholesterol Efflux and Anti-Inflammatory Properties","volume":"56","author":"Schwendeman","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1093\/eurheartj\/ehac605","article-title":"High-Density Lipoprotein Revisited: Biological Functions and Clinical Relevance","volume":"44","author":"Nordestgaard","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bonizzi, A., Piuri, G., Corsi, F., Cazzola, R., and Mazzucchelli, S. (2021). HDL Dysfunctionality: Clinical Relevance of Quality Rather Than Quantity. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070729"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1194\/jlr.P076463","article-title":"Plasma Cholesterol Homeostasis, HDL Remodeling and Function during the Acute Phase Reaction","volume":"58","author":"Zimetti","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1097\/MOL.0000000000000382","article-title":"Inflammation, Remodeling and Other Factors Affecting HDL Cholesterol Efflux","volume":"28","author":"Ronsein","year":"2017","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41577-022-00684-6","article-title":"Inflammation and Immune Dysfunction in Parkinson Disease","volume":"22","author":"Tansey","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Qin, Y., Wang, L., Song, J., Quan, W., Xu, J., and Chen, J. (2024). Plasma Lipidome, Circulating Inflammatory Proteins, and Parkinson\u2019s Disease: A Mendelian Randomization Study. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1424056"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1212\/WNL.17.5.427","article-title":"Parkinsonism: Onset, Progression, and Mortality","volume":"17","author":"Hoehn","year":"1967","journal-title":"Neurology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A Simple Method for the Isolation and Purification of Total Lipides from Animal Tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/S0021-9258(18)70226-3","article-title":"Phosphorus Assay in Column Chromatography","volume":"234","author":"Bartlett","year":"1959","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/clinchem\/23.5.882","article-title":"Cholesterol Determination in High-Density Lipoproteins Separated by Three Different Methods","volume":"23","author":"Stone","year":"1977","journal-title":"Clin. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3711\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T09:04:18Z","timestamp":1776848658000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3711"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,22]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27093711"],"URL":"https:\/\/doi.org\/10.3390\/ijms27093711","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,22]]}}}