Lower Airway and Oral Microbiome Dysbiosis in Patients with Long COVID Post-Hospitalisation: A UK Multicentre, Prospective Cohort Study.

Abstract

Background: Acute COVID-19 alters the airway microbiota. Whether these changes persist post-COVID-19 and contribute to Long COVID (LC) is unknown. We aimed to describe the microbiota based on LC severity and subtype; and identify links with inflammation to find potential therapeutic targets. Method(s): Adults were prospectively recruited to the longitudinal UK Post-hospitalisation COVID-19 study (PHOSP-COVID). Patients were grouped by previously described 'severity clusters' (of ongoing health impairments) and symptom subgroups. Oral and lower airway microbiota (at six-months post-discharge) were characterised through 16S rRNA sequencing, and microbiota diversity was assessed. Co-occurrence network analysis identified influential taxa. Associations between influential taxa and inflammatory proteins from plasma were assessed through Spearman's rank correlations. Finding(s): 771 participants had their microbiota assessed. Of participants with oral rinses and 'severity cluster' assignment (mean age: 57.5), 278/722 (38.5%) were women. The very severe cluster was associated with microbiota dysbiosis post-COVID-19. Persistent neurocognitive symptoms were associated with oral microbiota dysbiosis, while gastrointestinal symptoms were associated with lower airway microbiota dysbiosis. Microbiota influential taxa shifted to a higher prevalence of lactic acid bacteria (LAB) associated with worse health outcomes. LAB abundance was associated with elevated inflammatory proteins. Interpretation(s): The association of microbial dysbiosis with neurocognitive and gastrointestinal symptoms suggests potential oral-brain and gut-lung crosstalk in LC. Shifts in influential microbiota taxa, and their link to inflammation based on worse health outcomes, suggest a potential LAB role change which may be associated with the host immune response. Funding(s): UK Research and Innovation and National Institute for Health Research. Declaration of Interest: ADS reports their institution was awarded grants from GSK, 30T, Sanofi and Boehringer Ingelheim; personal consultations fees were received from 30T, Insmed, AstraZeneca, Sanofi; payment for lectures, presentations, speakers' bureaus, manuscript writing or educational events were received from AstraZeneca, Bayer, GSK, Insmed, Zambon, Sanofi, Fisher & Paykel and Inogen. RAE declares grant awards from UKRI/MRC/NIHR to complete this work; the author reports that their institute was awarded grants from Wolfson Foundation and Genentech/Roche; personal consultation fees were received from Astrazenica/Evidera for Long-COVID unrelated to this work; personal speaker fee from Moderna in April 2023 for non- promotional symposium lecture on Long-COVID; and unpaid roles as ERS Group 01.02 Pulmonary Rehabilitation and Chronic Care Chair and ATS Pulmonary Rehabilitation Assembly Chair. MJ reports grants awarded from Medical Research Council Asthma+Lung UK, Royal Society, AAIR Charity, Boehringher Ingelheim and GSK; and consultation fees received from Skyhawk Therapeutics. IDS reports an advanced research fellowship from the Rayne Foundation; participation on a data safety monitoring or advisory board from patientMpower; and stock or stock options from patientMpower. JJ declares grant awarded from Wellcome Trust to complete this work; the author reports grants awarded from Microsoft Research, GlaxoSmithKline, Gilead Sciences, Cancer Research UK, Rosetrees Trust, Cystic Fibrosis Trust, Chan Zuckerberg Initiative; consultation fees received from Boehringer Ingelheim, Roche, GlaxoSmithKline, NHSX; payment for lectures, presentations, speakers' bureaus, manuscript writing or educational events received from Boehringer Ingelheim, Roche, GlaxoSmithKline, Takeda; support for attending meetings and/or travel from Boehringer Ingelheim and Takeda; UK patent application numbers 2113765.8 and GB2211487.0; and participation on data safety monitoring/advisory boards from Boehringer Ingelheim and Roche. AShe declares that their institute was awarded a grant from NIHR to complete this work; and unpaid role with UK COVID-19 advisory bodies. GPMC declares a grant to their institute from UKRI to complete this work; the author reports grants awarded from BHF, MRC and NIHR. MJD reports grants awarded from AstraZenaca, Boehringer Ingelheim and Novo Nordisk; consultations fees received from Boehringer Ingelheim, Lilly, Novo Nordisk and Sanofi; payment for lectures, presentations, speakers' bureaus, manuscript writing or educational events received from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Sanofi and Lilly; support for attending meetings and/or travel from Boehringer Ingelheim, Novo Nordisk, Lilly, Amgen, AstraZeneca, Biomea Fusion, Regeneron and Zealand Pharma; and participation on data safety monitoring/advisory boards from Amgen, AstraZeneca, Biomea Fusion, Sanofi, Zealand Pharma, Carmot/Roche, Regeneron, EktaH, Abbvie and GSK. WDCM reports that their institute was awarded a grant from National Institute for Health Research; and an unpaid role as President of the Association for Respiratory Technology and Physiology (ARTP). BGG reports a Sir Henry Wellcome trust Postdoctoral Fellowship (Grant number 221680/Z/20/Z). CEBo declares that their institute was awarded grants from NIHR/UKRI and NIHR Nottingham BRC to complete this work; the author reports that their institute was awarded grants from Nottingham Hospitals Charity, University of Nottingham and NUH Trust R&I for this work. CEB declares that their institute was awarded a grant from NIHR/MRC to complete this work; the author reports grants awarded and consultancy fees to their institution from 4D Pharma, Areteia, AstraZeneca, Chiesi, Genentech, GlaxoSmithKline, Mologic, Novartis, Regeneron Pharmaceuticals, Roche and Sanofi. DP declares that their institute was awarded grants from UKRI and NIHR to complete this work. ABD reports a Wellcome trust personal Fellowship (Grant number 227856/Z/23/Z). AH declares that their institute was awarded grants from UK Research and Innovation and NIHR Manchester BRC to complete this work; and an unpaid role with NIHR Respiratory Translational Research Collaboration. JKQ reports that their institute was awarded grants from UKRI, NIHR, Health Data Research UK, BI, AZ and Insmed; and consultation fees were received from GlaxoSmithKline and BI. MS declares that their institute was awarded grants from UKRI -MRC / DHSC- NIHR to complete this work. PP reports a grant awarded from NIHR for project titled Supported remote rehabilitation post Covid-19: development, deployment and evaluation of a digitally-enabled rehabilitation programme. LVW declares grants awarded from UK Research and Innovation and National Institute of Health Research, as well as a professorship from GSK/Asthma + Lung UK to complete this work; the author reports that their institute was awarded grants from Orion Pharma, GSK, Genentech and contract from AstraZeneca; receipt of consultancy fees paid to institution from Galapagos, Boehringer Ingelheim and GSK; support for a San Francisco site visit from Genentech in September 2019; role in advisory board for Galapagos; role as associate editor for European Respiratory Journal. PLM declares medical writing support provided by Fleishman-Hillard from Boehringer Ingelheim Pharmaceuticals, Inc.; the author reports grants awarded to their institute from AstraZeneca, GSK, Asthma & lung UK AND Action for Pulmonary Fibrosis; advisory board fees from Hoffman-La Roche, Boehringer Ingelheim, AstraZeneca, Trevi, Qureight, Endevour and Redx; speaker fees from Boehringer Ingelheim and Hoffman-La Roche; fees paid to author from participation on Data Safety Monitoring Board or Advisory Board from United Therapeutics; stock options from Qureight. JCP declares funding from Breathing Matters, UCLH Charitable Fund and UCLH BRC/NIHR to complete this work; grants awarded from GSK as part of MRC Eminent consortium UKRI paid to their institute; roles as Medical Director of Breathing Matters Charity and Chair of NIHR UK National Research Strategy Group in ILD. JRH reports grant awarded from AstraZeneca for clinical trials; consulting fees for advisory and educational work from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Sanofi- Regeneron, Takeda; support for attending meetings and/or travel from AstraZeneca. MM declares that their institute was awarded a grant from UKRI/NIHR to complete this work. MTo declares grant awarded from NIHR Cambridge BRC and MRC to complete this work; personal payments for advisory board from Jansen, Apollo Therapeutics, Merck and personal consultancy fees payment from Merck, RxPx and uMed; support for attending meetings and/or travel from GSK and Jansen; participation on Data Safety Monitoring Boards or Advisory Boards of ComCov and FluCov. TC declares salary support awarded to their institution from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London; the author reports grants awarded from BMA foundation, GSST and NIHR; payment for workshops to clinicians in UK and Iceland as well as travel expenses and subsistence to Conferences and meetings abroad; participation on a data safety monitoring board or advisory board DMEC of NIHR grant unrelated to this work; and an unpaid role on the scientific committee of the BABCP. MJR reports being substantively employed as Senior Clinical Development Medical Director from Novartis Pharmaceuticals. GC reports grants awarded from GSK, AstraZeneca and CSO Scotland; consulting fees and honorariums for speaker sessions and advisory board role from AstraZeneca, GSK, Chiesi and Sanofi; support for an ERS industry funded trip; participation as a chair Act on COPD advisory board in Scotland for AstraZeneca. JDC reports grants awarded from Astrazeneca, Boehringer Ingelheim, Chiesi, Genentech, Gilead, Grifols, Insmed and Trudell; consulting fees received from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, Glaxosmithkline, Grifols, Insmed, Janssen, Novartis, Pfizer and Zambon. MGS declares grants awarded from National Institute of Health Research UK, Medical Research Council UK and Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool to complete this work; unpaid role as an independent external and member of Pfizer's External Data Monitoring Committee for their mRNA vaccine program(s) and role is RSV Vaccine Advisory Board; role as Chair of Infectious Disease Scientific Advisory Board for Integrum Scientific LLC, Greensboro, NC, USA and Director of MedEx Solutions Ltd; minority owner in Integrum Scientific LLC, Greensboro, NC, USA and majority owner in MedEx Solutions Ltd; a receipt of a gift to their Institution of Clinical Trial Investigational Medicinal Product without encumbrance and distribution of same to trial sites from Chiesi Farmaceutici S.p.A.; unpaid roles as an independent member for HMG UK Scientific Advisory Group for Emergencies (SAGE), COVID-19 Response from March 2020 to March 2022 and as an independent member of HMG UK New Emerging Respiratory Virus Threats Advisory Group (NERVTAG) from 2014 to June 2023. All other authors declare no competing interests. Ethical Approval: Written informed consent was obtained from all patients. The study was approved by the Leeds West Research Ethics Committee (20/YH/0225). Copyright © 2025, The Authors. All rights reserved.