The ability to predict invasive fungal infections (IFI) in patients with hematological malignancies is fundamental for successful therapy. Although gut dysbiosis is known to occur in hematological patients, whether airway dysbiosis also contributes to the risk of IFI has not been investigated. Nasal and oropharyngeal swabs were collected for functional microbiota characterization in 173 patients with hematological malignancies recruited in a multicenter, prospective, observational study and stratified according to the risk of developing IFI. A lower microbial richness and evenness were found in the pharyngeal microbiota of high-risk patients that were associated with a distinct taxonomic and metabolic profile. A murine model of IFI provided biologic plausibility for the finding that loss of protective anaerobes, such as Clostridiales and Bacteroidetes, along with an apparent restricted availability of tryptophan, is causally linked to the risk of IFI in hematologic patients and indicates avenues for antimicrobial stewardship and metabolic reequilibrium in IFI.

Department of Medicine and Surgery University of Perugia Perugia Italy

Department of Pharmaceutical Science University of Perugia Perugia Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

Haematology and Bone Marrow Transplant Unit Department of Medicine and Surgery University of Parma Parma Italy

Hematology and Stem Cell Transplant Unit IRCCS Regina Elena National Cancer Institute Rome Italy

Hematology AUSL IRCCS Reggio Emilia Italy

Hematology S Giovanni Rotondo Hospital San Giovanni Rotondo Italy

Hematology University of Verona Verona Italy

Istituto di Ematologia Università Cattolica del Sacro Cuore Rome Italy

RECETOX Faculty of Science Masaryk University Brno Czech Republic

Singapore Centre for Environmental Life Sciences Engineering Nanyang Technological University Singapore

University Research Center on Functional Genomics University of Perugia Perugia Italy

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Ananda-Rajah MR, Cheng A, Morrissey CO, Spelman T, Dooley M, Neville AM, Slavin M. 2011. Attributable hospital cost and antifungal treatment of invasive fungal diseases in high-risk hematology patients: an economic modeling approach. Antimicrob Agents Chemother 55:1953–1960. 10.1128/AAC.01423-10. PubMed DOI PMC

Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. 2012. Hidden killers: human fungal infections. Sci Transl Med 4:165rv13. 10.1126/scitranslmed.3004404. PubMed DOI

Pagano L, Busca A, Candoni A, Cattaneo C, Cesaro S, Fanci R, Nadali G, Potenza L, Russo D, Tumbarello M, Nosari A, Aversa F, et al. 2017. Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM recommendations. Blood Rev 31:17–29. 10.1016/j.blre.2016.09.002. PubMed DOI

Oliveira-Coelho A, Rodrigues F, Campos A, Jr, Lacerda JF, Carvalho A, Cunha C. 2015. Paving the way for predictive diagnostics and personalized treatment of invasive aspergillosis. Front Microbiol 6:411. 10.3389/fmicb.2015.00411. PubMed DOI PMC

Stanzani M, Lewis RE, Fiacchini M, Ricci P, Tumietto F, Viale P, Ambretti S, Baccarani M, Cavo M, Vianelli N. 2013. A risk prediction score for invasive mold disease in patients with hematological malignancies. PLoS One 8:e75531. 10.1371/journal.pone.0075531. PubMed DOI PMC

Staffas A, Burgos da Silva M, van den Brink MR. 2017. The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease. Blood 129:927–933. 10.1182/blood-2016-09-691394. PubMed DOI PMC

Harris B, Morjaria SM, Littmann ER, Geyer AI, Stover DE, Barker JN, Giralt SA, Taur Y, Pamer EG. 2016. Gut microbiota predict pulmonary infiltrates after allogeneic hematopoietic cell transplantation. Am J Respir Crit Care Med 194:450–463. 10.1164/rccm.201507-1491OC. PubMed DOI PMC

McAleer JP, Kolls JK. 2018. Contributions of the intestinal microbiome in lung immunity. Eur J Immunol 48:39–49. 10.1002/eji.201646721. PubMed DOI PMC

O'Dwyer DN, Zhou X, Wilke CA, Xia M, Falkowski NR, Norman KC, Arnold KB, Huffnagle GB, Murray S, Erb-Downward JR, Yanik GA, Moore BB, Dickson RP. 2018. Lung dysbiosis, inflammation, and injury in hematopoietic cell transplantation. Am J Respir Crit Care Med 198:1312–1321. 10.1164/rccm.201712-2456OC. PubMed DOI PMC

Rizzatti G, Lopetuso LR, Gibiino G, Binda C, Gasbarrini A. 2017. Proteobacteria: a common factor in human diseases. Biomed Res Int 2017:9351507. 10.1155/2017/9351507. PubMed DOI PMC

Faner R, Sibila O, Agusti A, Bernasconi E, Chalmers JD, Huffnagle GB, Manichanh C, Molyneaux PL, Paredes R, Perez Brocal V, Ponomarenko J, Sethi S, Dorca J, Monso E. 2017. The microbiome in respiratory medicine: current challenges and future perspectives. Eur Respir J 49:1602086. 10.1183/13993003.02086-2016. PubMed DOI

Dickson RP, Erb-Downward JR, Freeman CM, McCloskey L, Beck JM, Huffnagle GB, Curtis JL. 2015. Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography. Annals ATS 12:821–830. 10.1513/AnnalsATS.201501-029OC. PubMed DOI PMC

Marsh RL, Kaestli M, Chang AB, Binks MJ, Pope CE, Hoffman LR, Smith-Vaughan HC. 2016. The microbiota in bronchoalveolar lavage from young children with chronic lung disease includes taxa present in both the oropharynx and nasopharynx. Microbiome 4:37. 10.1186/s40168-016-0182-1. PubMed DOI PMC

Man WH, de Steenhuijsen Piters WA, Bogaert D. 2017. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat Rev Microbiol 15:259–270. 10.1038/nrmicro.2017.14. PubMed DOI PMC

Gao Z, Kang Y, Yu J, Ren L. 2014. Human pharyngeal microbiome may play a protective role in respiratory tract infections. Genomics Proteomics Bioinformatics 12:144–150. 10.1016/j.gpb.2014.06.001. PubMed DOI PMC

Human Microbiome Project Consortium. 2012. Structure, function and diversity of the healthy human microbiome. Nature 486:207–214. 10.1038/nature11234. PubMed DOI PMC

Lemon KP, Klepac-Ceraj V, Schiffer HK, Brodie EL, Lynch SV, Kolter R. 2010. Comparative analyses of the bacterial microbiota of the human nostril and oropharynx. mBio 1:e00129-10. 10.1128/mBio.00129-10. PubMed DOI PMC

Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C. 2011. Metagenomic biomarker discovery and explanation. Genome Biol 12:R60. 10.1186/gb-2011-12-6-r60. PubMed DOI PMC

Knights D, Parfrey LW, Zaneveld J, Lozupone C, Knight R. 2011. Human-associated microbial signatures: examining their predictive value. Cell Host Microbe 10:292–296. 10.1016/j.chom.2011.09.003. PubMed DOI PMC

Flint HJ, Scott KP, Duncan SH, Louis P, Forano E. 2012. Microbial degradation of complex carbohydrates in the gut. Gut Microbes 3:289–306. 10.4161/gmic.19897. PubMed DOI PMC

Yun Y, Srinivas G, Kuenzel S, Linnenbrink M, Alnahas S, Bruce KD, Steinhoff U, Baines JF, Schaible UE. 2014. Environmentally determined differences in the murine lung microbiota and their relation to alveolar architecture. PLoS One 9:e113466. 10.1371/journal.pone.0113466. PubMed DOI PMC

Marsland BJ, Gollwitzer ES. 2014. Host-microorganism interactions in lung diseases. Nat Rev Immunol 14:827–835. 10.1038/nri3769. PubMed DOI

Morjaria S, Schluter J, Taylor BP, Littmann ER, Carter RA, Fontana E, Peled JU, van den Brink MRM, Xavier JB, Taur Y. 2019. Antibiotic-induced shifts in fecal microbiota density and composition during hematopoietic stem cell transplantation. Infect Immun 87:e00206-19. 10.1128/IAI.00206-19. PubMed DOI PMC

Scales BS, Dickson RP, Huffnagle GB. 2016. A tale of two sites: how inflammation can reshape the microbiomes of the gut and lungs. J Leukoc Biol 100:943–950. 10.1189/jlb.3MR0316-106R. PubMed DOI PMC

Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D'Angelo C, Massi-Benedetti C, Fallarino F, Carvalho A, Puccetti P, Romani L. 2013. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39:372–385. 10.1016/j.immuni.2013.08.003. PubMed DOI

Hong BY, Sobue T, Choquette L, Dupuy AK, Thompson A, Burleson JA, Salner AL, Schauer PK, Joshi P, Fox E, Shin DG, Weinstock GM, Strausbaugh LD, Dongari-Bagtzoglou A, Peterson DE, Diaz PI. 2019. Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis. Microbiome 7:66. 10.1186/s40168-019-0679-5. PubMed DOI PMC

Teufelberger AR, Broker BM, Krysko DV, Bachert C, Krysko O. 2019. Staphylococcus aureus orchestrates type 2 airway diseases. Trends Mol Med 25:696–707. 10.1016/j.molmed.2019.05.003. PubMed DOI

Teegavarapu PS, Puppala M, Pingali SR, Patel A, Ibrahim I, Mukherjee A, Rice L, Padmanabhan Iyer S. 2015. Staphylococcus species leads the Eskape infections in various hematological malignancies. Blood 126:4623–4623. 10.1182/blood.V126.23.4623.4623. DOI

Shelburne SA, Ajami NJ, Chibucos MC, Beird HC, Tarrand J, Galloway-Pena J, Albert N, Chemaly RF, Ghantoji SS, Marsh L, Pemmaraju N, Andreeff M, Shpall EJ, Wargo JA, Rezvani K, Alousi A, Bruno VM, Futreal PA, Petrosino JF, Kontoyiannis DP. 2015. Implementation of a pan-genomic approach to investigate holobiont-infecting microbe interaction: a case report of a leukemic patient with invasive mucormycosis. PLoS One 10:e0139851. 10.1371/journal.pone.0139851. PubMed DOI PMC

Fedosenko S, Karnaushkina M, Ogorodova L, Petrov V, Kulikov E, Kirillova N. 2017. Sources of origin of the oropharyngeal microbiota in patients with different phenotypes of COPD. Eur Resp J 50:OA1500. 10.1183/1393003.congress-2017.OA1500. DOI

Jovanovic M, Tosic T, Jovanovic S, Stosovic R, Stevanovic G, Velebit B, Zervos MJ. 2018. Presence of the esp gene in Enterococcus faecium derived from oropharyngeal microbiota of haematology patients. Arch Oral Biol 88:54–59. 10.1016/j.archoralbio.2018.01.008. PubMed DOI

Stein-Thoeringer CK, Nichols KB, Lazrak A, Docampo MD, Slingerland AE, Slingerland JB, Clurman AG, Armijo G, Gomes ALC, Shono Y, Staffas A, Burgos da Silva M, Devlin SM, Markey KA, Bajic D, Pinedo R, Tsakmaklis A, Littmann ER, Pastore A, Taur Y, Monette S, Arcila ME, Pickard AJ, Maloy M, Wright RJ, Amoretti LA, Fontana E, Pham D, Jamal MA, Weber D, Sung AD, Hashimoto D, Scheid C, Xavier JB, Messina JA, Romero K, Lew M, Bush A, Bohannon L, Hayasaka K, Hasegawa Y, Vehreschild M, Cross JR, Ponce DM, Perales MA, Giralt SA, Jenq RR, Teshima T, Holler E, Chao NJ, et al. 2019. Lactose drives Enterococcus expansion to promote graft-versus-host disease. Science 366:1143–1149. 10.1126/science.aax3760. PubMed DOI PMC

Bertolini M, Ranjan A, Thompson A, Diaz PI, Sobue T, Maas K, Dongari-Bagtzoglou A. 2019. Candida albicans induces mucosal bacterial dysbiosis that promotes invasive infection. PLoS Pathog 15:e1007717. 10.1371/journal.ppat.1007717. PubMed DOI PMC

Hamilton S, Bongaerts RJ, Mulholland F, Cochrane B, Porter J, Lucchini S, Lappin-Scott HM, Hinton JC. 2009. The transcriptional programme of Salmonella enterica serovar Typhimurium reveals a key role for tryptophan metabolism in biofilms. BMC Genomics 10:599. 10.1186/1471-2164-10-599. PubMed DOI PMC

Wellington S, Nag PP, Michalska K, Johnston SE, Jedrzejczak RP, Kaushik VK, Clatworthy AE, Siddiqi N, McCarren P, Bajrami B, Maltseva NI, Combs S, Fisher SL, Joachimiak A, Schreiber SL, Hung DT. 2017. A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase. Nat Chem Biol 13:943–950. 10.1038/nchembio.2420. PubMed DOI PMC

Agus A, Planchais J, Sokol H. 2018. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23:716–724. 10.1016/j.chom.2018.05.003. PubMed DOI

Dehhaghi M, Kazemi Shariat Panahi H, Guillemin GJ. 2019. Microorganisms, tryptophan metabolism, and kynurenine pathway: a complex interconnected loop influencing human health status. Int J Tryptophan Res 12:1178646919852996. 10.1177/1178646919852996. PubMed DOI PMC

Rao M, Dodoo E, Zumla A, Maeurer M. 2019. Immunometabolism and pulmonary infections: implications for protective immune responses and host-directed therapies. Front Microbiol 10:962. 10.3389/fmicb.2019.00962. PubMed DOI PMC

Galloway-Pena JR, Peterson CB, Malik F, Sahasrabhojane PV, Shah DP, Brumlow CE, Carlin LG, Chemaly RF, Im JS, Rondon G, Felix E, Veillon L, Lorenzi PL, Alousi AM, Jenq RR, Kontoyiannis DP, Shpall EJ, Shelburne SA, Okhuysen PC. 2019. Fecal microbiome, metabolites, and stem cell transplant outcomes: a single-center pilot study. Open Forum Infect Dis 6:ofz173. 10.1093/ofid/ofz173. PubMed DOI PMC

Stokes JM, Lopatkin AJ, Lobritz MA, Collins JJ. 2019. Bacterial metabolism and antibiotic efficacy. Cell Metab 30:251–259. 10.1016/j.cmet.2019.06.009. PubMed DOI PMC

Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ, Slingerland AE, Smith OM, Young LF, Gupta J, Lieberman SR, Jay HV, Ahr KF, Porosnicu Rodriguez KA, Xu K, Calarfiore M, Poeck H, Caballero S, Devlin SM, Rapaport F, Dudakov JA, Hanash AM, Gyurkocza B, Murphy GF, Gomes C, Liu C, Moss EL, Falconer SB, Bhatt AS, Taur Y, Pamer EG, van den Brink MRM, Jenq RR. 2016. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med 8:339ra71. 10.1126/scitranslmed.aaf2311. PubMed DOI PMC

Galloway-Pena JR, Shi Y, Peterson CB, Sahasrabhojane P, Gopalakrishnan V, Brumlow CE, Daver NG, Alfayez M, Boddu PC, Khan MAW, Wargo JA, Do KA, Jenq RR, Kontoyiannis DP, Shelburne SA. 2019. Gut microbiome signatures are predictive of infectious risk following induction therapy for acute myeloid leukemia. Clin Infect Dis 71:63–71. 10.1093/cid/ciz777. PubMed DOI PMC

Larsen JM. 2017. The immune response to Prevotella bacteria in chronic inflammatory disease. Immunology 151:363–374. 10.1111/imm.12760. PubMed DOI PMC

Gollwitzer ES, Saglani S, Trompette A, Yadava K, Sherburn R, McCoy KD, Nicod LP, Lloyd CM, Marsland BJ. 2014. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat Med 20:642–647. 10.1038/nm.3568. PubMed DOI

Budden KF, Shukla SD, Rehman SF, Bowerman KL, Keely S, Hugenholtz P, Armstrong-James DPH, Adcock IM, Chotirmall SH, Chung KF, Hansbro PM. 2019. Functional effects of the microbiota in chronic respiratory disease. Lancet Respir Med 7:907–920. 10.1016/S2213-2600(18)30510-1. PubMed DOI

Galloway-Pena JR, Smith DP, Sahasrabhojane P, Ajami NJ, Wadsworth WD, Daver NG, Chemaly RF, Marsh L, Ghantoji SS, Pemmaraju N, Garcia-Manero G, Rezvani K, Alousi AM, Wargo JA, Shpall EJ, Futreal PA, Guindani M, Petrosino JF, Kontoyiannis DP, Shelburne SA. 2016. The role of the gastrointestinal microbiome in infectious complications during induction chemotherapy for acute myeloid leukemia. Cancer 122:2186–2196. 10.1002/cncr.30039. PubMed DOI PMC

Huffnagle GB, Dickson RP, Lukacs NW. 2017. The respiratory tract microbiome and lung inflammation: a two-way street. Mucosal Immunol 10:299–306. 10.1038/mi.2016.108. PubMed DOI PMC

Scheich S, Koenig R, Wilke AC, Lindner S, Reinheimer C, Wichelhaus TA, Hogardt M, Kempf VAJ, Kessel J, Weber S, Martin H, Bug G, Serve H, Steffen B. 2018. Stenotrophomonas maltophilia colonization during allogeneic hematopoietic stem cell transplantation is associated with impaired survival. PLoS One 13:e0201169. 10.1371/journal.pone.0201169. PubMed DOI PMC

Al-Anazi KA, Al-Jasser AM. 2014. Infections caused by Acinetobacter baumannii in recipients of hematopoietic stem cell transplantation. Front Oncol 4:186. 10.3389/fonc.2014.00186. PubMed DOI PMC

Akmatov MK, Koch N, Vital M, Ahrens W, Flesch-Janys D, Fricke J, Gatzemeier A, Greiser H, Gunther K, Illig T, Kaaks R, Krone B, Kuhn A, Linseisen J, Meisinger C, Michels K, Moebus S, Nieters A, Obi N, Schultze A, Six-Merker J, Pieper DH, Pessler F. 2017. Determination of nasal and oropharyngeal microbiomes in a multicenter population-based study–findings from pretest 1 of the German National Cohort. Sci Rep 7:1855. 10.1038/s41598-017-01212-6. PubMed DOI PMC

Swimm A, Giver CR, DeFilipp Z, Rangaraju S, Sharma A, Ulezko Antonova A, Sonowal R, Capaldo C, Powell D, Qayed M, Kalman D, Waller EK. 2018. Indoles derived from intestinal microbiota act via type I interferon signaling to limit graft-versus-host disease. Blood 132:2506–2519. 10.1182/blood-2018-03-838193. PubMed DOI PMC

Borghi M, Pariano M, Solito V, Puccetti M, Bellet MM, Stincardini C, Renga G, Vacca C, Sellitto F, Mosci P, Brancorsini S, Romani L, Costantini C. 2019. Targeting the aryl hydrocarbon receptor with indole-3-aldehyde protects from vulvovaginal candidiasis via the IL-22-IL-18 cross-talk. Front Immunol 10:2364. 10.3389/fimmu.2019.02364. PubMed DOI PMC

Puccetti M, Paolicelli G, Oikonomou V, De Luca A, Renga G, Borghi M, Pariano M, Stincardini C, Scaringi L, Giovagnoli S, Ricci M, Romani L, Zelante T. 2018. Towards targeting the aryl hydrocarbon receptor in cystic fibrosis. Mediators Inflamm 2018:1601486. 10.1155/2018/1601486. PubMed DOI PMC

Zelante T, Puccetti M, Giovagnoli S, Romani L. 2021. Regulation of host physiology and immunity by microbial indole-3-aldehyde. Curr Opin Immunol 70:27–32. 10.1016/j.coi.2020.12.004. PubMed DOI

Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, Pastore D, Picardi M, Bonini A, Chierichini A, Fanci R, Caramatti C, Invernizzi R, Mattei D, Mitra ME, Melillo L, Aversa F, Van Lint MT, Falcucci P, Valentini CG, Girmenia C, Nosari A. 2006. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 91:1068–1075. PubMed

Romani L, Oikonomou V, Moretti S, Iannitti RG, D'Adamo MC, Villella VR, Pariano M, Sforna L, Borghi M, Bellet MM, Fallarino F, Pallotta MT, Servillo G, Ferrari E, Puccetti P, Kroemer G, Pessia M, Maiuri L, Goldstein AL, Garaci E. 2017. Thymosin alpha1 represents a potential potent single-molecule-based therapy for cystic fibrosis. Nat Med 23:590–600. 10.1038/nm.4305. PubMed DOI PMC

Barman M, Unold D, Shifley K, Amir E, Hung K, Bos N, Salzman N. 2008. Enteric salmonellosis disrupts the microbial ecology of the murine gastrointestinal tract. Infect Immun 76:907–915. 10.1128/IAI.01432-07. PubMed DOI PMC

A High-Risk Profile for Invasive Fungal Infections Is Associated with Altered Nasal Microbiota and Niche Determinants