{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T16:03:42Z","timestamp":1784736222914,"version":"3.55.0"},"posted":{"date-parts":[[2026,4,15]]},"group-title":"Immunology","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL069438"],"award-info":[{"award-number":["R01HL069438"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U01DE035632"],"award-info":[{"award-number":["U01DE035632"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30 AI124414"],"award-info":[{"award-number":["P30 AI124414"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32GM149364"],"award-info":[{"award-number":["T32GM149364"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Sickle cell disease (SCD) is a chronic, inherited condition rising across the globe. Prior studies revealed a direct link between the gut microbiome and disease micropathology via aged-like (ANs) neutrophils in mouse models. In SCD patients community-level shifts in the gut microbiome included decreases in diversity and the Firmicutes\/Bacteroidetes (F:B) ratio, coupled to a loss of short chain fatty acid producing microbes and a shift to non-canonical butyrate production and aerobic fatty acid oxidation pathways. ANs and the proviral microbiome associate with multiple blood cytokines, while bacterial gut microbiome features largely do not. Prophages depleted of genes related to lysis, transcriptional regulation, and host takeover were enriched in SCD patient guts, pointing to domestication of these elements, and 25% of prophages were shared at high identity between study patients. In sum, we identify prophage associated immune signatures and taxonomic and functional alterations to the gut microbiome that associate with SCD pathophysiology in a heterogeneous chronic disease both affected by and affecting microbiome composition and function.<\/jats:p>","DOI":"10.64898\/2026.04.13.718288","type":"posted-content","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T04:05:18Z","timestamp":1776312318000},"source":"Crossref","is-referenced-by-count":0,"title":["Bacterial and viral gut microbiome alterations characterize microbiome-immune-pathophysiology axes in sickle cell disease"],"prefix":"10.64898","author":[{"given":"Zachary N.","family":"Flamholz","sequence":"first","affiliation":[{"name":"Department of Systems and Computational Biology, Albert Einstein College of Medicine; Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer De","family":"Los Santos","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Montefiore Health System and Albert Einstein College of Medicine; Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Ireland","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Montefiore Health System and Albert Einstein College of Medicine; Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Keenan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Montefiore Health System and Albert Einstein College of Medicine; Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob S.","family":"Kazmi","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine; Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aakash Mahant","family":"Mahant","sequence":"additional","affiliation":[{"name":"Department of Hematology, St Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anayeli","family":"Correa","sequence":"additional","affiliation":[{"name":"Department of Hematology, St Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"Frenette","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine; Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9974-0786","authenticated-orcid":false,"given":"Betsy C.","family":"Herold","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Montefiore Health System and Albert Einstein College of Medicine; Bronx, New York, USA"},{"name":"Department of Hematology, St Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa","family":"Manwani","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Montefiore Health System and Albert Einstein College of Medicine; Bronx, New York, USA"},{"name":"Department of Hematology, St Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7303-1022","authenticated-orcid":false,"given":"Libusha","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Systems and Computational Biology, Albert Einstein College of Medicine; Bronx, New York, USA"},{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine; Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072208351066000_2026.04.13.718288v2.1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-99-119420"},{"key":"2026072208351066000_2026.04.13.718288v2.2","doi-asserted-by":"crossref","unstructured":"A. T. N. Ho et al. Trends in hospitalizations for sickle cell disease related-complications in usa 2004 - 2012. Journal of Hematology, 8(1), 2019.","DOI":"10.14740\/jh475"},{"issue":"2","key":"2026072208351066000_2026.04.13.718288v2.3","first-page":"380","article-title":"High-priced sickle cell gene therapies threaten to exacerbate us health disparities and establish new pricing precedents for molecular medicine. Journal of Law","volume":"50","year":"2022","journal-title":"Medicine and Ethics"},{"key":"2026072208351066000_2026.04.13.718288v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/s2352-3026(23)00118-7"},{"key":"2026072208351066000_2026.04.13.718288v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/nature15367"},{"issue":"1","key":"2026072208351066000_2026.04.13.718288v2.6","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s12967-019-1938-8","article-title":"Intestinal injury and gut permeability in sickle cell disease","volume":"17","year":"2019","journal-title":"Journal of Translational Medicine"},{"issue":"12","key":"2026072208351066000_2026.04.13.718288v2.7","first-page":"E325","article-title":"Rifaximin for sickle cell disease","volume":"94","year":"2019","journal-title":"American Journal of Hematology"},{"issue":"6","key":"2026072208351066000_2026.04.13.718288v2.8","first-page":"E175","article-title":"Effects of rifaximin on circulating aged neutrophils in sickle cell disease","volume":"94","year":"2019","journal-title":"American Journal of Hematology"},{"issue":"1","key":"2026072208351066000_2026.04.13.718288v2.9","first-page":"2282","article-title":"Effects of Rifaximin on Intestinal Pathophysiologic Changes Associated with Sickle Cell Disease (SCD)","volume":"134","year":"2019","journal-title":"Blood"},{"issue":"4","key":"2026072208351066000_2026.04.13.718288v2.10","first-page":"E91","article-title":"Intestinal microbiome analysis revealed dysbiosis in sickle cell disease","volume":"93","year":"2018","journal-title":"American Journal of Hematology"},{"key":"2026072208351066000_2026.04.13.718288v2.11","doi-asserted-by":"crossref","unstructured":"S. Mohandas et al. Differences in gut microbiome in hospitalized immunocompetent vs. immunocompromised children, including those with sickle cell disease. Frontiers in Pediatrics, 8, 2020.","DOI":"10.3389\/fped.2020.583446"},{"key":"2026072208351066000_2026.04.13.718288v2.12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0249644"},{"key":"2026072208351066000_2026.04.13.718288v2.13","doi-asserted-by":"crossref","unstructured":"R. E. Ley et al. Human gut microbes associated with obesity. Nature, 444(7122):1022\u20131023, Dec 2006.","DOI":"10.1038\/4441022a"},{"key":"2026072208351066000_2026.04.13.718288v2.14","doi-asserted-by":"publisher","DOI":"10.1111\/JCMM.17402"},{"issue":"1","key":"2026072208351066000_2026.04.13.718288v2.15","first-page":"2021","article-title":"Comparison between 16S rRNA and shotgun sequencing data for the taxonomic characterization of the gut microbiota","volume":"11","year":"3030","journal-title":"Scientific Reports"},{"issue":"1","key":"2026072208351066000_2026.04.13.718288v2.16","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1038\/s41467-017-01682-2","article-title":"Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment","volume":"8","year":"2017","journal-title":"Nature Communications"},{"key":"2026072208351066000_2026.04.13.718288v2.17","doi-asserted-by":"crossref","unstructured":"P. Muscolino et al. Potential predictive role of gut microbiota to immunotherapy in hcc patients: a brief review. Frontiers in Oncology, 13, 2023.","DOI":"10.3389\/fonc.2023.1247614"},{"key":"2026072208351066000_2026.04.13.718288v2.18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2023202118"},{"key":"2026072208351066000_2026.04.13.718288v2.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.10.009"},{"key":"2026072208351066000_2026.04.13.718288v2.20","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.65088"},{"key":"2026072208351066000_2026.04.13.718288v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-023-00933-y"},{"key":"2026072208351066000_2026.04.13.718288v2.22","doi-asserted-by":"crossref","unstructured":"S. Khan and L. Kelly . Oral microbes are a signature of disease in the gut. 2023.","DOI":"10.21203\/rs.3.rs-1631596\/v2"},{"key":"2026072208351066000_2026.04.13.718288v2.23","doi-asserted-by":"crossref","unstructured":"A. P. Camargo et al. Identification of mobile genetic elements with genomad. Nature Biotechnology, Sep 2023.","DOI":"10.1101\/2023.03.05.531206"},{"issue":"7","key":"2026072208351066000_2026.04.13.718288v2.24","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1038\/ismej.2017.16","article-title":"Lysogeny in nature: mechanisms, impact and ecology of temperate phages","volume":"11","year":"2017","journal-title":"The ISME Journal"},{"key":"2026072208351066000_2026.04.13.718288v2.25","doi-asserted-by":"crossref","unstructured":"K. Kieft et al. Deciphering active prophages from metagenomes. mSystems, 0(0):e00084\u201322, 2022.","DOI":"10.1128\/msystems.00084-22"},{"issue":"1","key":"2026072208351066000_2026.04.13.718288v2.26","first-page":"3893","article-title":"Individuals with sickle cell disease have decreased intestinal microbial diversity compared to healthy related and unrelated black individuals without sickle cell disease","volume":"144","year":"2024","journal-title":"Blood"},{"issue":"1","key":"2026072208351066000_2026.04.13.718288v2.27","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1038\/s41467-017-01973-8","article-title":"Meta-analysis of gut microbiome studies identifies disease-specific and shared responses","volume":"8","year":"2017","journal-title":"Nature Communications"},{"issue":"6","key":"2026072208351066000_2026.04.13.718288v2.28","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1016\/j.ekir.2025.04.007","article-title":"Gut microbiome as a risk factor for future ckd","volume":"10","year":"2025","journal-title":"Kidney International Reports"},{"key":"2026072208351066000_2026.04.13.718288v2.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-022-00540-9"},{"key":"2026072208351066000_2026.04.13.718288v2.30","doi-asserted-by":"crossref","unstructured":"A. L. Silva-Junior et al. Immunological hallmarks of inflammatory status in vaso-occlusive crisis of sickle cell anemia patients. Frontiers in Immunology, 12:559925, 3 2021.","DOI":"10.3389\/fimmu.2021.559925"},{"key":"2026072208351066000_2026.04.13.718288v2.31","doi-asserted-by":"crossref","first-page":"4585704","DOI":"10.1155\/2020\/4585704","article-title":"Sickle cell anemia patients display an intricate cellular and serum biomarker network highlighted by tcd4+cd69+ lymphocytes, il-17\/mip-1\u00a1i\u00bf\u03b2\u00a1\/i\u00bf, il-12\/vegf, and il-10\/ip-10 axis","volume":"2020","year":"2020","journal-title":"Journal of Immunology Research"},{"issue":"3","key":"2026072208351066000_2026.04.13.718288v2.32","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1002\/jha2.712","article-title":"Levels of inflammatory markers are differentially expressed in sickle cell anemia and sickle cell trait","volume":"4","year":"2023","journal-title":"eJHaem"},{"key":"2026072208351066000_2026.04.13.718288v2.33","doi-asserted-by":"crossref","unstructured":"S. R. Stockdale et al. Interpersonal variability of the human gut virome confounds disease signal detection in ibd. Communications Biology, 6(1):221, Feb 2023.","DOI":"10.1038\/s42003-023-04592-w"},{"key":"2026072208351066000_2026.04.13.718288v2.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.11.055"},{"key":"2026072208351066000_2026.04.13.718288v2.35","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00889&ndash;14"},{"issue":"8","key":"2026072208351066000_2026.04.13.718288v2.36","doi-asserted-by":"crossref","first-page":"2976","DOI":"10.4049\/jimmunol.1700105","article-title":"Microbial-derived butyrate promotes epithelial barrier function through il-10 recep-tor\u2013dependent repression of claudin-2","volume":"199","year":"2017","journal-title":"The Journal of Immunology"},{"key":"2026072208351066000_2026.04.13.718288v2.37","doi-asserted-by":"publisher","DOI":"10.1099\/00207713-24-2-260"},{"key":"2026072208351066000_2026.04.13.718288v2.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2025.08.012"},{"key":"2026072208351066000_2026.04.13.718288v2.39","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2024.2361493"},{"key":"2026072208351066000_2026.04.13.718288v2.40","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021115-105202"},{"key":"2026072208351066000_2026.04.13.718288v2.41","doi-asserted-by":"crossref","unstructured":"S. Krakau et al. nf-core\/mag: a best-practice pipeline for metagenome hybrid assembly and binning. NAR Genomics and Bioinformatics, 4(1):lqac007, 02 2022.","DOI":"10.1093\/nargab\/lqac007"},{"key":"2026072208351066000_2026.04.13.718288v2.42","unstructured":"S. Krakau , et al. nf-core\/mag: mag 2.5.1, November 2023."},{"key":"2026072208351066000_2026.04.13.718288v2.43","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv033"},{"key":"2026072208351066000_2026.04.13.718288v2.44","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-119"},{"key":"2026072208351066000_2026.04.13.718288v2.45","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-020-00867-0"},{"issue":"11","key":"2026072208351066000_2026.04.13.718288v2.46","first-page":"1","article-title":"Multivariable association discovery in population-scale meta-omics studies","volume":"17","year":"2021","journal-title":"PLOS Computational Biology"},{"key":"2026072208351066000_2026.04.13.718288v2.47","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3988"},{"key":"2026072208351066000_2026.04.13.718288v2.48","doi-asserted-by":"crossref","unstructured":"A. A. Hagberg et al. Exploring network structure, dynamics, and function using networkx. In G. Varoquaux et al., editors, Proceedings of the 7th Python in Science Conference, pp. 11 \u2013 15, Pasadena, CA USA, 2008.","DOI":"10.25080\/TCWV9851"},{"key":"2026072208351066000_2026.04.13.718288v2.49","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"},{"issue":"2","key":"2026072208351066000_2026.04.13.718288v2.50","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/s41564-023-01584-8","article-title":"Large language models improve annotation of prokaryotic viral proteins","volume":"9","year":"2024","journal-title":"Nature Microbiology"},{"key":"2026072208351066000_2026.04.13.718288v2.51","unstructured":"T. pandas development team. pandas-dev\/pandas: Pandas, February 2020."},{"key":"2026072208351066000_2026.04.13.718288v2.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2649-2"},{"key":"2026072208351066000_2026.04.13.718288v2.53","first-page":"2825","article-title":"Scikit-learn: Machine learning in Python","volume":"12","year":"2011","journal-title":"Journal of Machine Learning Research"},{"key":"2026072208351066000_2026.04.13.718288v2.54","doi-asserted-by":"publisher","DOI":"10.1109\/mcse.2007.55"},{"key":"2026072208351066000_2026.04.13.718288v2.55","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","article-title":"SciPy 1.0: Fundamental Algorithms for Scientific Computing in Python","volume":"17","year":"2020","journal-title":"Nature Methods"},{"issue":"60","key":"2026072208351066000_2026.04.13.718288v2.56","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.21105\/joss.03021","article-title":"seaborn: statistical data visualization","volume":"6","year":"2021","journal-title":"Journal of Open Source Software"},{"key":"2026072208351066000_2026.04.13.718288v2.57","unstructured":"F. Charlier et al. Statannotations, October 2022."}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.13.718288","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T15:35:24Z","timestamp":1784734524000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.04.13.718288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,15]]},"references-count":57,"URL":"https:\/\/doi.org\/10.64898\/2026.04.13.718288","relation":{"has-version":[{"id-type":"doi","id":"10.7554\/eLife.111630.1","asserted-by":"object"}]},"subject":[],"published":{"date-parts":[[2026,4,15]]},"subtype":"preprint"}}