{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:52:26Z","timestamp":1793371946141,"version":"4.5.0"},"posted":{"date-parts":[[2025,6,24]]},"group-title":"Immunology","reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Imbalances in the gut microbiome have been linked to increased intestinal permeability and disease flares in systemic lupus erythematosus (SLE). Our study revealed that patients with flares of lupus nephritis (LN) and intestinal expansions of the anaerobic commensal,\n                  <jats:italic>Ruminococcus gnavus<\/jats:italic>\n                  (RG), displayed whole blood transcriptome profiles indicative of platelet, neutrophil, and myeloid cell activation, a profile reminiscent of sepsis. Serum analysis confirmed elevated serum levels of Platelet Factor 4 and neutrophil extracellular traps, which significantly correlated with levels of IgG-antibody to a novel lipoglycan (LG) produced by pathogenic RG strains, which was also documented in an independent LN cohort. To test for causality,\n                  <jats:italic>in vivo<\/jats:italic>\n                  mouse models further demonstrated that gut colonization with LG-producing RG strains, as well as a single intraperitoneal challenge with an LG preparation, caused platelet activation and megakaryocytosis in bone marrow and spleen. Mice colonized with RG strains that produce LG developed cellular infiltration of the kidneys by neutrophils and monocytes. Hence, RG expansions during renal flares may identify a specific LN flare endotype driven by thromboinflammatory mechanisms. Antibodies that arise from immune exposure to the RG lipoglycan may serve as a surrogate biomarker, helping to elucidate the impact of the relationship between gut microbiota communities and clinical outcomes in patients afflicted by LN. [208]\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"641288v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.06.20.641288","type":"posted-content","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T05:25:23Z","timestamp":1750742723000},"source":"Crossref","is-referenced-by-count":2,"title":["Pathogenic strains of a gut commensal drive systemic platelet activation and thromboinflammation in lupus nephritis"],"prefix":"10.64898","author":[{"given":"Abhimanyu","family":"Amarnani","sequence":"first","affiliation":[{"name":"Division of Rheumatology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristobal F.","family":"Rivera","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Macintosh","family":"Cornwell","sequence":"additional","affiliation":[{"name":"Division of Precision Medicine, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Weinstein","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan R.S.","family":"Gottesman","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Loomis","sequence":"additional","affiliation":[{"name":"Department of Pathology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zakia","family":"Azad","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Prasad","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betsy","family":"Barnes","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine, Feinstein Institutes, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Yi","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimat","family":"Ullah","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Gisch","sequence":"additional","affiliation":[{"name":"Division of Bioanalytical Chemistry, Research Center Borstel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Ruggles","sequence":"additional","affiliation":[{"name":"Division of Precision Medicine, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhama","family":"Ramkhelawon","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregg J.","family":"Silverman","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, NYU Grossman School of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041210041990000_2025.06.20.641288v1.1","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1136\/annrheumdis-2018-214856","article-title":"Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal","volume":"78","year":"2019","journal-title":"Annals of the rheumatic diseases"},{"key":"2026041210041990000_2025.06.20.641288v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0141-9"},{"key":"2026041210041990000_2025.06.20.641288v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-018-0152-z"},{"key":"2026041210041990000_2025.06.20.641288v1.4","doi-asserted-by":"crossref","unstructured":"Silverman, G. J. , Azzouz, D. F. , Gisch, N. & Amarnani, A . The gut microbiome in systemic lupus erythematosus: lessons from rheumatic fever. Nature Reviews Rheumatology (2024).","DOI":"10.1038\/s41584-023-01071-8"},{"key":"2026041210041990000_2025.06.20.641288v1.5","doi-asserted-by":"publisher","DOI":"10.2478\/rir-2023-0027"},{"key":"2026041210041990000_2025.06.20.641288v1.6","doi-asserted-by":"crossref","unstructured":"Gronke, K. et al. Translocating gut pathobiont Enterococcus gallinarum induces TH17 and IgG3 anti-RNA\u2013directed autoimmunity in mouse and human. Science translational medicine 17 (2025).","DOI":"10.1126\/scitranslmed.adj6294"},{"key":"2026041210041990000_2025.06.20.641288v1.7","doi-asserted-by":"crossref","unstructured":"Azzouz, D. et al. Longitudinal gut microbiome analyses and blooms of pathogenic strains during lupus disease flares. J Annals of the Rheumatic Diseases (2023).","DOI":"10.1136\/ard-2023-223929"},{"key":"2026041210041990000_2025.06.20.641288v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/art.41511"},{"key":"2026041210041990000_2025.06.20.641288v1.9","doi-asserted-by":"crossref","unstructured":"Toumi, E. et al. Gut microbiota in systemic lupus erythematosus patients and lupus mouse model: a cross species comparative analysis for biomarker discovery. Frontiers in immunology 13 (2022).","DOI":"10.3389\/fimmu.2022.943241"},{"key":"2026041210041990000_2025.06.20.641288v1.10","doi-asserted-by":"crossref","unstructured":"Juge, N . Microbe profile: Ruminococcus gnavus: the yin and yang of human gut symbionts. Microbiology 169, 001383 (2023).","DOI":"10.1099\/mic.0.001383"},{"key":"2026041210041990000_2025.06.20.641288v1.11","doi-asserted-by":"publisher","DOI":"10.1002\/acr2.70033"},{"key":"2026041210041990000_2025.06.20.641288v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50994-7"},{"key":"2026041210041990000_2025.06.20.641288v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.04.008"},{"key":"2026041210041990000_2025.06.20.641288v1.14","doi-asserted-by":"crossref","unstructured":"Martyanov, A. A. et al. Effects of bacterial lipopolysaccharides on platelet function: Inhibition of weak platelet activation. Scientific reports 10, 12296 (2020).","DOI":"10.1038\/s41598-020-69173-x"},{"key":"2026041210041990000_2025.06.20.641288v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2018.04.007"},{"key":"2026041210041990000_2025.06.20.641288v1.16","doi-asserted-by":"publisher","DOI":"10.1002\/art.42382"},{"key":"2026041210041990000_2025.06.20.641288v1.17","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042718-041607"},{"key":"2026041210041990000_2025.06.20.641288v1.18","doi-asserted-by":"publisher","DOI":"10.1002\/art.40930"},{"key":"2026041210041990000_2025.06.20.641288v1.19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0196117"},{"key":"2026041210041990000_2025.06.20.641288v1.20","doi-asserted-by":"crossref","first-page":"e01093","DOI":"10.1002\/cti2.1093","article-title":"Machine learning applied to whole-blood RNA-sequencing data uncovers distinct subsets of patients with systemic lupus erythematosus","volume":"8","year":"2019","journal-title":"Clinical & translational immunology"},{"key":"2026041210041990000_2025.06.20.641288v1.21","doi-asserted-by":"publisher","DOI":"10.1002\/art.38628"},{"key":"2026041210041990000_2025.06.20.641288v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.03.008"},{"key":"2026041210041990000_2025.06.20.641288v1.23","doi-asserted-by":"publisher","DOI":"10.1002\/art.38790"},{"key":"2026041210041990000_2025.06.20.641288v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00834-4"},{"key":"2026041210041990000_2025.06.20.641288v1.25","doi-asserted-by":"crossref","unstructured":"Silverman, G. J. , Deng, J. & Azzouz, D. F . Sex-dependent Lupus Blautia (Ruminococcus) gnavus strain induction of zonulin-mediated intestinal permeability and autoimmunity. Frontiers in immunology 13, 897971 (2022).","DOI":"10.3389\/fimmu.2022.897971"},{"key":"2026041210041990000_2025.06.20.641288v1.26","doi-asserted-by":"crossref","unstructured":"Ioannou, M. et al. Biomarkers of intestinal permeability in major psychiatric disorders: Distinct biological roles call for a more nuanced application. Progress in Neuro- Psychopharmacology and Biological Psychiatry, 111405 (2025).","DOI":"10.1016\/j.pnpbp.2025.111405"},{"key":"2026041210041990000_2025.06.20.641288v1.27","first-page":"3381","article-title":"Expansion of the neonatal platelet mass is achieved via an extension of platelet lifespan. Blood","volume":"123","year":"2014","journal-title":"The Journal of the American Society of Hematology"},{"key":"2026041210041990000_2025.06.20.641288v1.28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02061"},{"key":"2026041210041990000_2025.06.20.641288v1.29","doi-asserted-by":"crossref","unstructured":"Zhu, X.-W. et al. Comprehensive Assessment of the Association between FCGR s polymorphisms and the risk of systemic lupus erythematosus: Evidence from a Meta- Analysis. Scientific reports 6, 31617 (2016).","DOI":"10.1038\/srep31617"},{"key":"2026041210041990000_2025.06.20.641288v1.30","first-page":"331","article-title":"The Gp1ba-Cre transgenic mouse: a new model to delineate platelet and leukocyte functions. Blood","volume":"133","year":"2019","journal-title":"The Journal of the American Society of Hematology"},{"key":"2026041210041990000_2025.06.20.641288v1.31","doi-asserted-by":"crossref","unstructured":"Matta, B. , Battaglia, J. & Barnes, B. J . Detection of neutrophil extracellular traps in patient plasma: method development and validation in systemic lupus erythematosus and healthy donors that carry IRF5 genetic risk. Frontiers in immunology 13, 951254 (2022).","DOI":"10.3389\/fimmu.2022.951254"},{"key":"2026041210041990000_2025.06.20.641288v1.32","first-page":"e4701","article-title":"A new methodology for the quantification of neutrophil extracellular traps in patient plasma","volume":"13","year":"2023","journal-title":"Bio-protocol"},{"key":"2026041210041990000_2025.06.20.641288v1.33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0188863"},{"key":"2026041210041990000_2025.06.20.641288v1.34","unstructured":"Amarnani, A. , Rivera-Martinez, C , Scherlinger, M , Azzouz, D , Lee, A , Trujillo, K , Cornwell, M , Weinstein, T , Borja, T , Matta, B , Chung, S , Cooney, L , Chaudhary, U , Medvedovsky, S , Izmirly, P , Buyon, J , Blanco, P , Barnes, B , Ramkhelawon, B , Ruggles, K , Silverman, G . A Human Gut Pathobiont Drives Platelet Activation with Microparticle Release and NETosis During Lupus Nephritis Flares. Arthritis Rheumatol. 76 (2024)."},{"key":"2026041210041990000_2025.06.20.641288v1.35","unstructured":"Amarnani, A. , Azzouz, D , Cornwell, M , Mieles, D , Izmirly, P , Buyon, J , Ruggles, K , Silverman, G . Lupus Nephritis Flares Linked to Platelet Activation During Gut Pathobiont Blooms [abstract]. Arthritis Rheumatol. 75 (2023)."},{"key":"2026041210041990000_2025.06.20.641288v1.36","first-page":"394","volume":"43","year":"2009","journal-title":"Modified PAXgene\u2122 method allows for isolation of high-integrity total RNA from microlitre volumes of mouse whole blood"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.06.20.641288","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T17:04:31Z","timestamp":1776013471000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.06.20.641288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,24]]},"references-count":36,"URL":"https:\/\/doi.org\/10.1101\/2025.06.20.641288","relation":{},"subject":[],"published":{"date-parts":[[2025,6,24]]},"subtype":"preprint"}}