In the present study, we characterized the microbiomes of acute leukemia (AL) patients who achieved complete remission following remission induction chemotherapy (RIC) as outpatients, but who did not receive antimicrobials to treat or prevent febrile neutropenia.
Saliva and stool samples from 9 patients with acute myeloid leukemia, 11 patients with acute lymphoblastic leukemia, and 5 healthy controls were subjected to 16S ribosomal RNA sequencing at baseline and at 3 months following RIC. Only patients who achieved remission at 3 months post-treatment were included. We excluded anyone who used antimicrobials within 2 months of enrollment or at any time during the study period.
At baseline, the relative abundances of species of Prevotella maculosa (P=0.001), Megasphaera micronuciformis (P=0.014), Roseburia inulinivorans (P=0.021), and Bacteroides uniformis (P=0.004) in saliva and Prevotella copri (P=0.002) in the stools of controls were significantly higher than in AL patients. Following RIC, the relative abundances of Eubacterium sp. oral clone DO008 (P=0.012), Leptotrichia sp. oral clone IK040 (P=0.002), Oribacterium sp. oral taxon 108 (P=0.029), Megasphaera micronuciformis (P=0.016), TM7 phylum sp. oral clone DR034 (P<0.001), Roseburia inulinivorans (P=0.034), Actinomyces odontolyticus (P=0.014), Leptotrichia buccalis (P=0.005), and Prevotella melaninogenica (P=0.046) in saliva and Lactobacillus fermentum (P=0.046), Coprococcus catus (P=0.050), butyrate-producing bacterium SS3/4 (P=0.013), and Bacteroides coprocola (P=0.027) in the stools of AL patients were significantly greater than in controls.
Following RIC, several taxa are changed in stool and salvia samples of AL patients. Our results warrant future large-scale multicenter studies to examine whether the microbiota might have an effect on clinical outcomes of AL patients.
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Akrami K, Sweeney D (2018) The microbiome of the critically ill patient. Curr Opin Crit Care 24:49–54. https://doi.org/10.1097/MCC.0000000000000469
Arthur JC et al (2012) Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338:120–123. https://doi.org/10.1126/science.1224820
Bindels LB, Porporato P, Dewulf EM, Verrax J, Neyrinck AM, Martin JC, Scott KP, Buc Calderon P, Feron O, Muccioli GG, Sonveaux P, Cani PD, Delzenne NM (2012) Gut microbiota-derived propionate reduces cancer cell proliferation in the liver. Brit J Cancer 107:1337–1344. https://doi.org/10.1038/bjc.2012.409
Bindels LB, Neyrinck AM, Claus SP, le Roy CI, Grangette C, Pot B, Martinez I, Walter J, Cani PD, Delzenne NM (2016) Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia. ISME J 10:1456–1470. https://doi.org/10.1038/ismej.2015.209
Boulangé CL, Neves AL, Chilloux J, Nicholson JK, Dumas M-E (2016) Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome Med 8:42. https://doi.org/10.1186/s13073-016-0303-2
Bow E, Meddings J (2006) Intestinal mucosal dysfunction and infection during remission-induction therapy for acute myeloid leukaemia. Leukemia 20:2087–2092. https://doi.org/10.1038/sj.leu.2404440
Bow EJ, Wingard J, Bowden R (2003) Infectious complications in patients receiving cytotoxic therapy for acute leukemia: history, background, and approaches to management. Manag Infect Oncol Patients:71–104
Brennan CA, Garrett WS (2016) Gut microbiota, inflammation, and colorectal cancer. Annu Rev Microbiol 70:395–411. https://doi.org/10.1146/annurev-micro-102215-095513
Couturier-Maillard A, Secher T, Rehman A, Normand S, de Arcangelis A, Haesler R, Huot L, Grandjean T, Bressenot A, Delanoye-Crespin A, Gaillot O, Schreiber S, Lemoine Y, Ryffel B, Hot D, Nùñez G, Chen G, Rosenstiel P, Chamaillard M (2013) NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest 123:700–711
de Castro JC, Ganc A, Ganc R, Petrolli M, Hamerschlack N (2015) Fecal microbiota transplant after hematopoietic SCT: report of a successful case. Bone Marrow Transplant 50:145
Ferreira RM, Pereira-Marques J, Pinto-Ribeiro I, Costa JL, Carneiro F, Machado JC, Figueiredo C (2018) Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut 67:226–236
Flowers C et al (2013) Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 31:794–810
Galloway-Peña 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. https://doi.org/10.1002/cncr.30039
Galloway-Peña JR, Smith DP, Sahasrabhojane P, Wadsworth WD, Fellman BM, Ajami NJ, Shpall EJ, Daver N, Guindani M, Petrosino JF, Kontoyiannis DP, Shelburne SA (2017) Characterization of oral and gut microbiome temporal variability in hospitalized cancer patients. Genome Med 9:21
Gardner A, Mattiuzzi G, Faderl S, Borthakur G, Garcia-Manero G, Pierce S, Brandt M, Estey E (2008) Randomized comparison of cooked and noncooked diets in patients undergoing remission induction therapy for acute myeloid leukemia. J Clin Oncol 26:5684–5688
Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA (2018) The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 33:570–580
Harata G, Kumar H, He F, Miyazawa K, Yoda K, Kawase M, Kubota A, Hiramatsu M, Rautava S, Salminen S (2017) Probiotics modulate gut microbiota and health status in Japanese cedar pollinosis patients during the pollen season. Eur J Nutr 56:2245–2253
Hefazi M, Patnaik M, Hogan W, Litzow M, Pardi D, Khanna S (2017) Safety and efficacy of fecal microbiota transplant for recurrent clostridium difficile infection in patients with cancer treated with cytotoxic chemotherapy: a single-institution retrospective case series. In: Mayo Clinic Proceedings, vol 11, p 1617
Jin C, Lagoudas GK, Zhao C, Bullman S, Bhutkar A, Hu B, Ameh S, Sandel D, Liang XS, Mazzilli S, Whary MT, Meyerson M, Germain R, Blainey PC, Fox JG, Jacks T (2019) Commensal microbiota promote lung cancer development via γδ T cells. Cell 176:998–1013
Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris MB, Maloney DG, Chauncey T, McSweeney PA, Storb R (2002) Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 8:512–520
Karlsson F, Tremaroli V, Nielsen J, Bäckhed F (2013) Assessing the human gut microbiota in metabolic diseases. Diabetes 62:3341–3349
Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, Aroniadis O, Barto A, Borody T, Giovanelli A, Gordon S, Gluck M, Hohmann EL, Kao D, Kao JY, McQuillen DP, Mellow M, Rank KM, Rao K, Ray A, Schwartz MA, Singh N, Stollman N, Suskind DL, Vindigni SM, Youngster I, Brandt L (2014) Fecal microbiota transplant for treatment of clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 109:1065–1071
Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, Gallagher J, Herrstedt J, Rapoport B, Rolston K, Talcott J, for the Study Section on Infections of Multinational Association for Supportive Care in Cancer (2000) The multinational association for supportive care in cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 18:3038–3051
Kroemer G, Zitvogel L (2018) Cancer immunotherapy in 2017: the breakthrough of the microbiota. Nat Rev Immunol 18:87–88
Lozupone CA, Hamady M, Kelley ST, Knight R (2007) Quantitative and qualitative β diversity measures lead to different insights into factors that structure microbial communities. Appl Environ Microbiol 73:1576–1585
Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, Lynfield R, Maloney M, McAllister-Hollod L, Nadle J, Ray SM, Thompson DL, Wilson LE, Fridkin SK, Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey Team (2014) Multistate point-prevalence survey of health care–associated infections. N Engl J Med 370:1198–1208
Murphy C, O’Toole P, Shanahan F (2019) The Gut microbiota in causation, detection, and treatment of cancer. Am J Gastroenterol 114:1036–1042
Ojima M, Motooka D, Shimizu K, Gotoh K, Shintani A, Yoshiya K, Nakamura S, Ogura H, Iida T, Shimazu T (2016) Metagenomic analysis reveals dynamic changes of whole gut microbiota in the acute phase of intensive care unit patients. Dig Dis Sci 61:1628–1634
Pamer EG (2016) Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science 352:535–538
Peled JU, Devlin SM, Staffas A, Lumish M, Khanin R, Littmann ER, Ling L, Kosuri S, Maloy M, Slingerland JB, Ahr KF, Porosnicu Rodriguez KA, Shono Y, Slingerland AE, Docampo MD, Sung AD, Weber D, Alousi AM, Gyurkocza B, Ponce DM, Barker JN, Perales MA, Giralt SA, Taur Y, Pamer EG, Jenq RR, van den Brink MRM (2017) Intestinal microbiota and relapse after hematopoietic-cell transplantation. J Clin Oncol 35:1650–1659
Peled JU et al (2019) Inferior survival after microbiota injury: a multicenter allo-HCT study. Am Soc Clin Oncol
Rajagopala S, Vashee S, Oldfield L, Suzuki Y, Venter J, Telenti A, Nelson K (2017) The Human microbiome and cancer. Cancer Prev Res 10:226–234
Rashidi A, Kaiser T, Shields-Cutler R, Graiziger C, Holtan SG, Rehman TU, Wasko J, Weisdorf DJ, Dunny G, Khoruts A, Staley C (2019a) Dysbiosis patterns during re-induction/salvage versus induction chemotherapy for acute leukemia. Sci Rep 9:6083
Rashidi A, Kaiser T, Shields-Cutler R, Graiziger C, Rehman TU, Holtan SG, Weisdorf DJ, Knights D, Khoruts A, Staley C (2019b) Outpatient-to-inpatient transition causes marked dysbiosis in allogeneic hematopoietic cell transplantation recipients. Biol Blood Marrow Tr 25:S47
Rogers G, Bruce K (2010) Next-generation sequencing in the analysis of human microbiota: essential considerations for clinical application. Mol Diagn Ther 14:343–350
Rooks MG, Garrett WS (2016) Gut microbiota, metabolites and host immunity. Nat Rev Immunol 16:341–352
Roy S, Trinchieri G (2017) Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer 17:271–285
Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C (2011) Metagenomic biomarker discovery and explanation. Genome Biol 12:R60
Shen X, Miao J, Wan Q, Wang S, Li M, Pu F, Wang G, Qian W, Yu Q, Marotta F, He F (2018) Possible correlation between gut microbiota and immunity among healthy middle-aged and elderly people in southwest China. Gut Pathog 10:4
Taplitz R et al (2018) Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol 36:3043–3054
Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J, Gobourne A, Lee YJ, Dubin KA, Socci ND, Viale A, Perales MA, Jenq RR, van den Brink MRM, Pamer EG (2012) Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 55:905–914
Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L, No D, Gobourne A, Viale A, Dahi PB, Ponce DM, Barker JN, Giralt S, van den Brink M, Pamer EG (2014) The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 124:1174–1182
Taur Y et al (2018) Reconstitution of the gut microbiota of antibiotic-treated patients by autologous fecal microbiota transplant. Sci Transl Med 10:eaap9489
Tilg H, Adolph T, Gerner R, Moschen A (2018) The intestinal microbiota in colorectal cancer. Cancer Cell 33:954–964
van Vliet MJ, Tissing WJE, Dun CAJ, Meessen NEL, Kamps WA, de Bont ESJM, Harmsen HJM (2009) Chemotherapy treatment in pediatric patients with acute myeloid leukemia receiving antimicrobial prophylaxis leads to a relative increase of colonization with potentially pathogenic bacteria in the gut. Clin Infect Dis 49:262–270. https://doi.org/10.1086/599346
Wang Z, Wang Q, Wang X, Zhu L, Chen J, Zhang B, Chen Y, Yuan Z (2019) Gut microbial dysbiosis is associated with development and progression of radiation enteritis during pelvic radiotherapy. J Cell Mol Med 23:3747–3756
Yu LC-H, Shih YA, Wu LL, Lin YD, Kuo WT, Peng WH, Lu KS, Wei SC, Turner JR, Ni YH (2014) Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis. Am J Physiol Gastrointest Liver Physiol 307:G824–G835
This research was supported by grants from the National Natural Science Foundation of China (grant no. 81360089), Science and Technology Program of Department of Science and Technology of Yunnan Province (grant no. 202001AY070001-070), and the Scientific and Technological Commission of Yunnan Province (grant nos. 2015FB072, 2017FE468 (-204), and 2018FE001 (-113)). The funders had no role in the design of the study or the collection, analysis and interpretation of data, or in writing the manuscript.
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The study was performed in accordance with the principles of the Declaration of Helsinki with regard to ethical research involving human subjects, and our protocols were approved by the Research Ethics Committee of Yunnan Cancer Hospital and Kunming Medical University.
Written informed consent was obtained from all participants or the parents/legally authorized representatives of participants prior to enrollment.
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Shen, Z., Gu, X., Cao, H. et al. Characterization of microbiota in acute leukemia patients following successful remission induction chemotherapy without antimicrobial prophylaxis. Int Microbiol 24, 263–273 (2021). https://doi.org/10.1007/s10123-021-00163-3
- Febrile neutropenia
- Induction chemotherapy