The Perfect Enemy | Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia
July 10, 2025
Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia
Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia
  • Fajgenbaum, D. C. & June, C. H. Cytokine storm. N. Engl. J. Med. 383, 2255–2273 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lucas, C. et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 584, 463–469 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zuo, T. et al. Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology 159, 944–955.e8 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Yeoh, Y. K. et al. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut 70, 698–706 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Gu, S. et al. Alterations of the gut microbiota in patients with coronavirus disease 2019 or H1N1 influenza. Clin. Infect. Dis. 71, 2669–2678 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Liu, Q. et al. Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome. Gut 71, 544–552 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Zhang, F. et al. Prolonged impairment of short-chain fatty acid and L-isoleucine biosynthesis in gut microbiome in patients with COVID-19. Gastroenterology 162, 548–561.e4 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Vestad, B. et al. Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations. J. Intern. Med.https://doi.org/10.1111/joim.13458 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  • Nori, P. et al. Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge. Infect. Control Hosp. Epidemiol. 42, 84–88 (2021).

    Article  PubMed  Google Scholar 

  • Grasselli, G. et al. Hospital-acquired infections in critically Ill patients With COVID-19. Chest 160, 454–465 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Yu, D. et al. Low prevalence of bloodstream infection and high blood culture contamination rates in patients with COVID-19. PLoS One 15, e0242533 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Langford, B. J. et al. Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin. Microbiol. Infect. 26, 1622–1629 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shafran, N. et al. Secondary bacterial infection in COVID-19 patients is a stronger predictor for death compared to influenza patients. Sci. Rep. 11, 12703 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar, N. P. et al. Systemic inflammation and microbial translocation are characteristic features of SARS-CoV-2-related multisystem inflammatory syndrome in children.Open Forum Infect. Dis. 8, ofab279 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  • Buffie, C. G. et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517, 205–208 (2015).

    Article  ADS  CAS  PubMed  Google Scholar 

  • Buffie, C. G. & Pamer, E. G. Microbiota-mediated colonization resistance against intestinal pathogens. Nat. Rev. Immunol. 13, 790–801 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Modi, S. R., Collins, J. J. & Relman, D. A. Antibiotics and the gut microbiota. J. Clin. Investig. 124, 4212–4218 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  • Shimasaki, T. et al. Increased relative abundance of Klebsiella pneumoniaecarbapenemase-producing klebsiella pneumoniae within the gut microbiota is associated with risk of bloodstream infection in long-term acute care hospital patients. Clin. Infect. Dis. 68, 2053–2059 (2019).

    Article  PubMed  Google Scholar 

  • Kim, S., Covington, A. & Pamer, E. G. The intestinal microbiota: Antibiotics, colonization resistance, and enteric pathogens. Immunol. Rev. 279, 90–105 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morjaria, S. et al. Antibiotic-induced shifts in fecal microbiota density and composition during hematopoietic stem cell transplantation. Infect. Immun. 87, e00206-19 (2019).

  • Niehus, R. et al. Quantifying antibiotic impact on within-patient dynamics of extended-spectrum beta-lactamase resistance. Elife 9, e49206 (2020).

  • Taur, Y. et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin. Infect. Dis. 55, 905–914 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taur, Y. et al. Reconstitution of the gut microbiota of antibiotic-treated patients by autologous fecal microbiota transplant. Sci. Transl. Med. 10, eaap9489 (2018).

  • Liao, C. et al. Compilation of longitudinal microbiota data and hospitalome from hematopoietic cell transplantation patients. Sci. Data 8, 71 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  • Peled, J. U. et al. Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation. N. Engl. J. Med. 382, 822–834 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pamer, E. G., Taur, Y., Jenq, R. & van den Brink, M. R. M. Impact of the intestinal microbiota on infections and survival following hematopoietic stem cell transplantation. Blood 124, SCI-48-SCI-48 (2014).

    Article  Google Scholar 

  • Chanderraj, R. et al. The bacterial density of clinical rectal swabs is highly variable, correlates with sequencing contamination, and predicts patient risk of extraintestinal infection. Microbiome 10, 2 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCullers, J. A. The co-pathogenesis of influenza viruses with bacteria in the lung. Nat. Rev. Microbiol. 12, 252–262 (2014).

    Article  CAS  PubMed  Google Scholar 

  • Wang, D. et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 323, 1061–1069 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Westblade, L. F., Simon, M. S. & Satlin, M. J. Bacterial coinfections in coronavirus disease 2019. Trends Microbiol 29, 930–941 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sepulveda, J. et al. Bacteremia and blood culture utilization during COVID-19 surge in New York City. J. Clin. Microbiol. 58, e00875-20 (2020).

  • Lansbury, L., Lim, B., Baskaran, V. & Lim, W. S. Co-infections in people with COVID-19: a systematic review and meta-analysis. J. Infect. 81, 266–275 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sieswerda, E. et al. Recommendations for antibacterial therapy in adults with COVID-19 – an evidence based guideline. Clin. Microbiol. Infect. 27, 61–66 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Zhai, B. et al. High-resolution mycobiota analysis reveals dynamic intestinal translocation preceding invasive candidiasis. Nat. Med. 26, 59–64 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gago, J. et al. Pathogen species is associated with mortality in nosocomial bloodstream infection in patients with COVID-19. Open Forum Infect. Dis. 9, ofac083 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  • Haak, B. W. et al. Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT. Blood 131, 2978–2986 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deriu, E. et al. Influenza virus affects intestinal microbiota and secondary Salmonella infection in the gut through type i interferons. PLoS Pathog. 12, e1005572 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  • Yildiz, S., Mazel-Sanchez, B., Kandasamy, M., Manicassamy, B. & Schmolke, M. Influenza A virus infection impacts systemic microbiota dynamics and causes quantitative enteric dysbiosis. Microbiome 6, 9 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • Sencio, V. et al. Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production. Cell Rep. 30, 2934–2947.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Steed, A. L. et al. The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science 357, 498–502 (2017).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Abt, M. C. et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37, 158–170 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl Acad. Sci. USA 108, 5354–5359 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Sencio, V. et al. Influenza virus infection impairs the gut’s barrier properties and favors secondary enteric bacterial infection through reduced production of short-chain fatty acids. Infect. Immun. 89, e0073420 (2021).

    Article  PubMed  Google Scholar 

  • Wang, J. et al. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation. J. Exp. Med. 211, 2397–2410 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winkler, E. S. et al. SARS-CoV-2 causes lung infection without severe disease in human ACE2 knock-in mice. J. Virol. 96, e0151121 (2022).

    Article  PubMed  Google Scholar 

  • Yinda, C. K. et al. K18-hACE2 mice develop respiratory disease resembling severe COVID-19. PLoS Pathog. 17, e1009195 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng, J. et al. COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice. Nature 589, 603–607 (2021).

    Article  ADS  CAS  PubMed  Google Scholar 

  • Golden, J. W. et al. Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease. JCI Insight 5, e142032 (2020).

  • Bao, L. et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature 583, 830–833 (2020).

    Article  ADS  CAS  PubMed  Google Scholar 

  • Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuzawa-Ishimoto, Y. et al. Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium. J. Exp. Med. 214, 3687–3705 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schluter, J. et al. The gut microbiota is associated with immune cell dynamics in humans. Nature 588, 303–307 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).

    Article  ADS  CAS  PubMed  Google Scholar 

  • Diefenbach, C. S. et al. Microbial dysbiosis is associated with aggressive histology and adverse clinical outcome in B-cell non-Hodgkin lymphoma. Blood Adv. 5, 1194–1198 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731–16736 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Wrzosek, L. et al. Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent. BMC Biol. 11, 61 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  • Seibert, B. et al. Mild and severe SARS-CoV-2 infection induces respiratory and intestinal microbiome changes in the K18-hACE2 transgenic mouse model. Microbiol. Spectr. 9, e0053621 (2021).

    Article  PubMed  Google Scholar 

  • Sencio, V. et al. Alteration of the gut microbiota following SARS-CoV-2 infection correlates with disease severity in hamsters. Gut Microbes 14, 2018900 (2022).

    Article  PubMed  Google Scholar 

  • Sokol, H. et al. SARS-CoV-2 infection in nonhuman primates alters the composition and functional activity of the gut microbiota. Gut Microbes 13, 1–19 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Gaebler, C. et al. Evolution of antibody immunity to SARS-CoV-2. Nature 591, 639–644 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Park, S.-K. et al. Detection of SARS-CoV-2 in fecal samples from patients with asymptomatic and Mild COVID-19 in Korea. Clin. Gastroenterol. Hepatol. 19, 1387–1394.e2 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Xiao, F. et al. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 158, 1831–1833.e3 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Cheung, K. S. et al. Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong Cohort: systematic review and meta-analysis. Gastroenterology 159, 81–95 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Lamers, M. M. et al. SARS-CoV-2 productively infects human gut enterocytes. Science 369, 50–54 (2020).

    Article  ADS  CAS  PubMed  Google Scholar 

  • Cao, J. et al. Integrated gut virome and bacteriome dynamics in COVID-19 patients. Gut Microbes 13, 1–21 (2021).

    Article  PubMed  Google Scholar 

  • Klag, T., Stange, E. F. & Wehkamp, J. Defective antibacterial barrier in inflammatory bowel disease. Dig. Dis. 31, 310–316 (2013).

    Article  PubMed  Google Scholar 

  • Ramanan, D. & Cadwell, K. Intrinsic defense mechanisms of the intestinal epithelium. Cell Host Microbe 19, 434–441 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schluter, J. & Foster, K. R. The evolution of mutualism in gut microbiota via host epithelial selection. PLoS Biol. 10, e1001424 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McLoughlin, K., Schluter, J., Rakoff-Nahoum, S., Smith, A. L. & Foster, K. R. Host selection of microbiota via differential adhesion. Cell Host Microbe 19, 550–559 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Castañer, M. et al. Evaluation of B-cell function in diabetics by C-peptide determination in basal and postprandial urine. Diabete Metab. 13, 538–542 (1987).

    PubMed  Google Scholar 

  • Yu, S. et al. Paneth cell-derived lysozyme defines the composition of mucolytic microbiota and the inflammatory tone of the intestine. Immunity 53, 398–416.e8 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salzman, N. H. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010).

    Article  CAS  PubMed  Google Scholar 

  • van der Lugt, B. et al. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice. Immun. Ageing 16, 6 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    Article  ADS  CAS  PubMed  Google Scholar 

  • Wang, C., Hu, J., Blaser, M. J. & Li, H. Estimating and testing the microbial causal mediation effect with high-dimensional and compositional microbiome data. Bioinformatics 36, 347–355 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Zhang, X.-S. et al. Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity. Elife 7, e37816 (2018).

  • Schulfer, A. F. et al. The impact of early-life sub-therapeutic antibiotic treatment (STAT) on excessive weight is robust despite transfer of intestinal microbes. ISME J. 13, 1280–1292 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, L. et al. An observational cohort study of bacterial co-infection and implications for empirical antibiotic therapy in patients presenting with COVID-19 to hospitals in North West London. J. Antimicrob. Chemother. 76, 796–803 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Labarta-Bajo, L. et al. Type I IFNs and CD8 T cells increase intestinal barrier permeability after chronic viral infection. J. Exp. Med. 217, e20192276 (2020).

  • Karki, R. et al. Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell 184, 149–168.e17 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Giron, L. B. et al. Plasma markers of disrupted gut permeability in severe COVID-19 patients. Front. Immunol. 12, 686240 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ubeda, C. et al. Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J. Clin. Investig. 120, 4332–4341 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dickson, R. P. et al. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat. Microbiol. 1, 16113 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yelin, I. et al. Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients. Nat. Med. 25, 1728–1732 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie, X. et al. An Infectious cDNA Clone of SARS-CoV-2. Cell Host Microbe 27, 841–848.e3 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gohl, D. M. et al. Systematic improvement of amplicon marker gene methods for increased accuracy in microbiome studies. Nat. Biotechnol. 34, 942–949 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Wang, Q., Garrity, G. M., Tiedje, J. M. & Cole, J. R. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73, 5261–5267 (2007).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Pawlowsky-Glahn, V., Egozcue, J. J. & Tolosana-Delgado, R. Modelling and Analysis of Compositional Data. (John Wiley & Sons, Ltd, 2015). https://doi.org/10.1002/9781119003144

  • Kruschke, J. K. Bayesian estimation supersedes the t test. J. Exp. Psychol. Gen. 142, 573–603 (2013).

    Article  PubMed  Google Scholar 

  • Homan, M. D. & Gelman, A. The No-U-Turn sampler: adaptively setting path lengths in Hamiltonian Monte Carlo. J. Mach. Learn. Res. 15, 1593–1623 (2014).

    MathSciNet  MATH  Google Scholar