{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:36:29Z","timestamp":1788971789546,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health~Holland","award":["LSHM20104"],"award-info":[{"award-number":["LSHM20104"]}]},{"name":"Health~Holland","award":["LSHM20068"],"award-info":[{"award-number":["LSHM20068"]}]},{"name":"Novartis","award":["LSHM20104"],"award-info":[{"award-number":["LSHM20104"]}]},{"name":"Novartis","award":["LSHM20068"],"award-info":[{"award-number":["LSHM20068"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>An estimated 10% of COVID-19 survivors have been reported to suffer from complaints after at least three months. The intestinal microbiome has been shown to impact long COVID through the gut\u2013lung axis and impact the severity. We aimed to investigate the relationship between the gut microbiome and clinical characteristics, exploring microbiome heterogeneity through clustering. Seventy-nine patients with long COVID evaluated at 3 to 6 months after infection were sampled for fecal metagenome analysis. Patients were divided into two distinct hierarchical clusters, based solely on the microbiome composition. Compared to cluster 1 (n = 67), patients in cluster 2 (n = 12) showed a significantly reduced lung function (FEV1, FVC, and DLCO) and during acute COVID-19 showed a longer duration of hospital admissions (48 compared to 7 days) and higher rates of ICU admissions (92% compared to 22%). Additionally, the microbiome composition showed a reduced alpha diversity and lower proportion of butyrate-producing bacteria in cluster 2 together with higher abundances of Ruminococcus gnavus, Escherichia coli, Veillonella spp. and Streptococcus spp. and reduced abundances of Faecalibacterium prausnitzii and Eubacteria spp. Further research could explore the effect of pre- and pro-biotic supplementation and its impact on lung function and societal participation in long COVID.<\/jats:p>","DOI":"10.3390\/ijms26041781","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T11:49:27Z","timestamp":1739965767000},"page":"1781","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Exploring Heterogeneity of Fecal Microbiome in Long COVID Patients at 3 to 6 Months After Infection"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2047-0888","authenticated-orcid":false,"given":"Jelle M.","family":"Blankestijn","sequence":"first","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Baalbaki","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8192-0543","authenticated-orcid":false,"given":"Rosanne J. H. C. G.","family":"Beijers","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5707-4673","authenticated-orcid":false,"given":"Merel E. B.","family":"Cornelissen","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Joost","family":"Wiersinga","sequence":"additional","affiliation":[{"name":"Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Internal Medicine, Division of Infectious Diseases, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9263-7137","authenticated-orcid":false,"given":"Mahmoud I.","family":"Abdel-Aziz","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health, 1081 HV Amsterdam, The Netherlands"},{"name":"Department of Clinical Pharmacy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0414-3442","authenticated-orcid":false,"given":"Anke H.","family":"Maitland-van der Zee","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health, 1081 HV Amsterdam, The Netherlands"},{"name":"Department of Pediatric Respiratory Medicine, Emma Children\u2019s Hospital, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"ref_1","unstructured":"World Health Orginazation (2024, September 01). WHO Coronavirus (COVID-19) Dashboard 2024. Available online: https:\/\/data.who.int\/dashboards\/covid19\/cases."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41579-022-00846-2","article-title":"Long COVID: Major findings, mechanisms and recommendations","volume":"21","author":"Davis","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sk Abd Razak, R., Ismail, A., Abdul Aziz, A.F., Suddin, L.S., Azzeri, A., and Sha\u2019ari, N.I. (2024). Post-COVID syndrome prevalence: A systematic review and meta-analysis. BMC Public Health, 24.","DOI":"10.1186\/s12889-024-19264-5"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Baalbaki, N., Blankestijn, J.M., Abdel-Aziz, M.I., de Backer, J., Bazdar, S., Beekers, I., Beijers, R.J.H.C.G., van den Bergh, J.P., Bloemsma, L.D., and Jan Bogaard, H. (2023). Precision Medicine for More Oxygen (P4O2)-Study Design and First Results of the Long COVID-19 Extension. J. Pers. Med., 13.","DOI":"10.3390\/jpm13071060"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/S0140-6736(24)01136-X","article-title":"Long COVID: A clinical update","volume":"404","author":"Greenhalgh","year":"2024","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lymberopoulos, E., Gentili, G.I., Budhdeo, S., and Sharma, N. (2022). COVID-19 severity is associated with population-level gut microbiome variations. Front. Cell Infect Microbiol., 12.","DOI":"10.3389\/fcimb.2022.963338"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1136\/gutjnl-2021-325989","article-title":"Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome","volume":"71","author":"Liu","year":"2022","journal-title":"Gut"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ma, P.J., Wang, M.M., and Wang, Y. (2022). Gut microbiota: A new insight into lung diseases. Biomed. Pharmacother., 155.","DOI":"10.1016\/j.biopha.2022.113810"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1136\/gutjnl-2015-309728","article-title":"The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia","volume":"65","author":"Schuijt","year":"2016","journal-title":"Gut"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/s41385-019-0160-6","article-title":"Microbes, metabolites, and the gut-lung axis","volume":"12","author":"Dang","year":"2019","journal-title":"Mucosal Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1111\/joim.13458","article-title":"Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations","volume":"291","author":"Vestad","year":"2022","journal-title":"J. Intern. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2351478","DOI":"10.1080\/19490976.2024.2351478","article-title":"Pathogenesis and therapeutic opportunities of gut microbiome dysbiosis in critical illness","volume":"16","author":"Cho","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.chom.2020.09.001","article-title":"Recovery of the Gut Microbiota after Antibiotics Depends on Host Diet, Community Context, and Environmental Reservoirs","volume":"28","author":"Ng","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.chom.2024.04.005","article-title":"The gut microbiome associates with phenotypic manifestations of post-acute COVID-19 syndrome","volume":"32","author":"Su","year":"2024","journal-title":"Cell Host Microbe"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/j.1365-2036.2007.03562.x","article-title":"Review article: The role of butyrate on colonic function","volume":"27","author":"Hamer","year":"2008","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1111\/all.13660","article-title":"High levels of butyrate and propionate in early life are associated with protection against atopy","volume":"74","author":"Roduit","year":"2019","journal-title":"Allergy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"100864","DOI":"10.1016\/S2666-5247(24)00079-X","article-title":"Association between butyrate-producing gut bacteria and the risk of infectious disease hospitalisation: Results from two observational, population-based microbiome studies","volume":"5","author":"Kullberg","year":"2024","journal-title":"Lancet Microbe"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mancilla-Ceballos, R., Milne, K.M., Guenette, J.A., and Cortes-Telles, A. (2023). Inflammation associated with lung function abnormalities in COVID-19 survivors. BMC Pulm. Med., 23.","DOI":"10.1186\/s12890-023-02521-5"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/S1473-3099(23)00685-0","article-title":"A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): A randomised, double-blind, placebo-controlled trial","volume":"24","author":"Lau","year":"2024","journal-title":"Lancet Infect Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1001\/archneur.1989.00520460115022","article-title":"The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus","volume":"46","author":"Krupp","year":"1989","journal-title":"Arch. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1007\/s11136-009-9496-9","article-title":"Development of physical and mental health summary scores from the patient-reported outcomes measurement information system (PROMIS) global items","volume":"18","author":"Hays","year":"2009","journal-title":"Qual. Life Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1007\/s11136-011-9903-x","article-title":"Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)","volume":"20","author":"Herdman","year":"2011","journal-title":"Qual. Life Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.clineuro.2006.10.002","article-title":"Checklist for cognitive and emotional consequences following stroke (CLCE-24): Development, usability and quality of the self-report version","volume":"109","author":"Rasquin","year":"2007","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"752","DOI":"10.2340\/16501977-0589","article-title":"Reproducibility of three self-report participation measures: The ICF Measure of Participation and Activities Screener, the Participation Scale, and the Utrecht Scale for Evaluation of Rehabilitation-Participation","volume":"42","author":"Priesterbach","year":"2010","journal-title":"J. Rehabil. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1600-0447.1983.tb09716.x","article-title":"The hospital anxiety and depression scale","volume":"67","author":"Zigmond","year":"1983","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_26","unstructured":"WHO Working Group on the Clinical Characterisation and Management of COVID-19 Infection (2020). A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis., 20, e192\u2013e197."},{"key":"ref_27","unstructured":"Andrews, S. (2024, July 22). FastQC: A Quality Control Tool for High Throughput Sequence Data 2010. Available online: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1126\/science.abj6987","article-title":"The complete sequence of a human genome","volume":"376","author":"Nurk","year":"2022","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1038\/s41587-023-01688-w","article-title":"Extending and improving metagenomic taxonomic profiling with uncharacterized species using MetaPhlAn 4","volume":"41","author":"Beghini","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"ref_32","unstructured":"R Core Team (2013). R: A Language and Environment for Statistical Computing, Foundation for Statistical Computing."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"McMurdie, P.J., and Holmes, S. (2013). phyloseq: An R package for reproducible interactive analysis and graphics of microbiome census data. PLoS ONE., 8.","DOI":"10.1371\/journal.pone.0061217"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3514","DOI":"10.1038\/s41467-020-17041-7","article-title":"Analysis of compositions of microbiomes with bias correction","volume":"11","author":"Lin","year":"2020","journal-title":"Nat. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/4\/1781\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:38:09Z","timestamp":1760027889000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/4\/1781"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,19]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ijms26041781"],"URL":"https:\/\/doi.org\/10.3390\/ijms26041781","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,19]]}}}