Skip to main content

Advertisement

SpringerLink
Log in

Persistent Gut Microbial Dysbiosis in Children with Acute Lymphoblastic Leukemia (ALL) During Chemotherapy

  • Human Microbiome
  • Published:
Microbial Ecology Aims and scope Submit manuscript

Abstract

Prophylactic or therapeutic antibiotic use along with chemotherapy treatment potentially has a long-standing adverse effect on the resident gut microbiota. We have established a case-control cohort of 32 pediatric and adolescent acute lymphoblastic leukemia (ALL) patients and 25 healthy siblings (sibling controls) to assess the effect of chemotherapy as well as antibiotic prophylaxis on the gut microbiota. We observe that the microbiota diversity and richness of the ALL group is significantly lower than that of the control group at diagnosis and during chemotherapy. The microbiota diversity is even lower in antibiotics-exposed ALL patients. Although the gut microbial diversity tends to stabilize after 1-year post-chemotherapy, their abundances were altered because of chemotherapy and prophylactic antibiotic treatments. Specifically, the abundances of mucolytic gram-positive anaerobic bacteria, including Ruminococcus gnavus and Ruminococcus torques, tended to increase during the chemotherapy regimen and continued to be elevated 1 year beyond the initiation of chemotherapy. This dysbiosis may contribute to the development of gastrointestinal complications in ALL children following chemotherapy. These findings set the stage to further understand the role of the gut microbiome dynamics in ALL patients and their potential role in alleviating some of the adverse side effects of chemotherapy and antibiotics use in immunocompromised children.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The 16S rRNA gene sequencing data utilized in the study is available via the NIH BioProject Accession PRJNA421352. The metadata is available in the supplementary files as well as available from the NIH Biosamples.

References

  1. Smith MA RL, Gurney JG, et al. (1999) Leukemia. In: Ries LA, Smith MA, Gurney JG, et al., eds Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program NIH PubNo 99-4649, pp 17-34.

  2. Ward E, DeSantis C, Robbins A, Kohler B, Jemal A (2014) Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64:83–103. https://doi.org/10.3322/caac.21219

    Article  PubMed  Google Scholar 

  3. Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, Friedman DL, Marina N, Hobbie W, Kadan-Lottick NS, Schwartz CL, Leisenring W, Robison LL, Childhood Cancer Survivor S (2006) Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355:1572–1582. https://doi.org/10.1056/NEJMsa060185

    Article  CAS  PubMed  Google Scholar 

  4. van Vliet MJ, Harmsen HJ, de Bont ES, Tissing WJ (2010) The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog 6:e1000879. https://doi.org/10.1371/journal.ppat.1000879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hudson MM, Ness KK, Gurney JG, Mulrooney DA, Chemaitilly W, Krull KR, Green DM, Armstrong GT, Nottage KA, Jones KE, Sklar CA, Srivastava DK, Robison LL (2013) Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309:2371–2381. https://doi.org/10.1001/jama.2013.6296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gibson TM, Ehrhardt MJ, Ness KK (2016) Obesity and metabolic syndrome among adult survivors of childhood leukemia. Curr Treat Options in Oncol 17:17. https://doi.org/10.1007/s11864-016-0393-5

    Article  Google Scholar 

  7. Rajagopala SV, Vashee S, Oldfield LM, Suzuki Y, Venter JC, Telenti A, Nelson KE (2017) The human microbiome and cancer. Cancer Prev Res (Phila) 10:226–234. https://doi.org/10.1158/1940-6207.CAPR-16-0249

    Article  Google Scholar 

  8. Karlsson F, Tremaroli V, Nielsen J, Backhed F (2013) Assessing the human gut microbiota in metabolic diseases. Diabetes 62:3341–3349. https://doi.org/10.2337/db13-0844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, Almeida M, Arumugam M, Batto JM, Kennedy S, Leonard P, Li J, Burgdorf K, Grarup N, Jorgensen T, Brandslund I, Nielsen HB, Juncker AS, Bertalan M, Levenez F, Pons N, Rasmussen S, Sunagawa S, Tap J, Tims S, Zoetendal EG, Brunak S, Clement K, Dore J, Kleerebezem M, Kristiansen K, Renault P, Sicheritz-Ponten T, de Vos WM, Zucker JD, Raes J, Hansen T, Meta HITc, Bork P, Wang J, Ehrlich SD, Pedersen O (2013) Richness of human gut microbiome correlates with metabolic markers. Nature 500:541–546. https://doi.org/10.1038/nature12506

    Article  CAS  PubMed  Google Scholar 

  10. Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BA, Forslund K, Hildebrand F, Prifti E, Falony G, Le Chatelier E, Levenez F, Dore J, Mattila I, Plichta DR, Poho P, Hellgren LI, Arumugam M, Sunagawa S, Vieira-Silva S, Jorgensen T, Holm JB, Trost K, Meta HITC, Kristiansen K, Brix S, Raes J, Wang J, Hansen T, Bork P, Brunak S, Oresic M, Ehrlich SD, Pedersen O (2016) Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535:376–381. https://doi.org/10.1038/nature18646

    Article  CAS  PubMed  Google Scholar 

  11. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI (2009) A core gut microbiome in obese and lean twins. Nature 457:480–484. https://doi.org/10.1038/nature07540

    Article  CAS  PubMed  Google Scholar 

  12. Fulde M, Hornef MW (2014) Maturation of the enteric mucosal innate immune system during the postnatal period. Immunol Rev 260:21–34. https://doi.org/10.1111/imr.12190

    Article  CAS  PubMed  Google Scholar 

  13. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084–1089. https://doi.org/10.1126/science.aac4255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Berard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350:1079–1084. https://doi.org/10.1126/science.aad1329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rajagopala SV, Yooseph S, Harkins DM, Moncera KJ, Zabokrtsky KB, Torralba MG, Tovchigrechko A, Highlander SK, Pieper R, Sender L, Nelson KE (2016) Gastrointestinal microbial populations can distinguish pediatric and adolescent acute lymphoblastic leukemia (ALL) at the time of disease diagnosis. BMC Genomics 17:635. https://doi.org/10.1186/s12864-016-2965-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S, Darling V, Johnson C, Karlsson EA, Chang TC, Jeha S, Pui CH, Sun Y, Pounds S, Hayden RT, Tuomanen E, Rosch JW (2018) Gut microbiome composition predicts infection risk during chemotherapy in children with acute lymphoblastic leukemia. Clin Infect Dis. https://doi.org/10.1093/cid/ciy153

  17. Edgar RC (2013) UPARSE: highly accurate OTU sequences from microbial amplicon reads. Nat Methods 10:996–998. https://doi.org/10.1038/nmeth.2604

    Article  CAS  PubMed  Google Scholar 

  18. Miquel S, Martin R, Rossi O, Bermudez-Humaran LG, Chatel JM, Sokol H, Thomas M, Wells JM, Langella P (2013) Faecalibacterium prausnitzii and human intestinal health. Curr Opin Microbiol 16:255–261. https://doi.org/10.1016/j.mib.2013.06.003

    Article  CAS  PubMed  Google Scholar 

  19. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 104:13780–13785. https://doi.org/10.1073/pnas.0706625104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, Ballet V, Claes K, Van Immerseel F, Verbeke K, Ferrante M, Verhaegen J, Rutgeerts P, Vermeire S (2014) A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63:1275–1283. https://doi.org/10.1136/gutjnl-2013-304833

    Article  CAS  PubMed  Google Scholar 

  21. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottiere HM, Dore J, Marteau P, Seksik P, Langella P (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 105:16731–16736. https://doi.org/10.1073/pnas.0804812105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chua LL, Rajasuriar R, Azanan MS, Abdullah NK, Tang MS, Lee SC, Woo YL, Lim YA, Ariffin H, Loke P (2017) Reduced microbial diversity in adult survivors of childhood acute lymphoblastic leukemia and microbial associations with increased immune activation. Microbiome 5:35. https://doi.org/10.1186/s40168-017-0250-1

    Article  PubMed  PubMed Central  Google Scholar 

  23. Pinheiro J, Bates D, DebRoy S, Sarkar D, Team RC (2018) nlme: linear and nonlinear mixed effects models. R package version 31-137

  24. Rekha R, Rizvi MA, Jaishree P (2006) Designing and validation of genus-specific primers for human gut flora study

  25. 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. https://doi.org/10.1002/cncr.30039

    Article  CAS  PubMed  Google Scholar 

  26. Montassier E, Gastinne T, Vangay P, Al-Ghalith GA, Bruley des Varannes S, Massart S, Moreau P, Potel G, de La Cochetiere MF, Batard E, Knights D (2015) Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment Pharmacol Ther 42:515–528. https://doi.org/10.1111/apt.13302

    Article  CAS  PubMed  Google Scholar 

  27. Hansen SG, Skov MN, Justesen US (2013) Two cases of Ruminococcus gnavus bacteremia associated with diverticulitis. J Clin Microbiol 51:1334–1336. https://doi.org/10.1128/JCM.03382-12

    Article  PubMed  PubMed Central  Google Scholar 

  28. Graziani F, Pujol A, Nicoletti C, Dou S, Maresca M, Giardina T, Fons M, Perrier J (2016) Ruminococcus gnavus E1 modulates mucin expression and intestinal glycosylation. J Appl Microbiol 120:1403–1417. https://doi.org/10.1111/jam.13095

    Article  CAS  PubMed  Google Scholar 

  29. Lee JY, Arai H, Nakamura Y, Fukiya S, Wada M, Yokota A (2013) Contribution of the 7beta-hydroxysteroid dehydrogenase from Ruminococcus gnavus N53 to ursodeoxycholic acid formation in the human colon. J Lipid Res 54:3062–3069. https://doi.org/10.1194/jlr.M039834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mohammed Saif M, Farid SF, Khaleel SA, Sabry NA, El-Sayed MH (2012) Hepatoprotective efficacy of ursodeoxycholic acid in pediatrics acute lymphoblastic leukemia. Pediatr Hematol Oncol 29:627–632. https://doi.org/10.3109/08880018.2012.713083

    Article  CAS  PubMed  Google Scholar 

  31. Dabard J, Bridonneau C, Phillipe C, Anglade P, Molle D, Nardi M, Ladire M, Girardin H, Marcille F, Gomez A, Fons M (2001) Ruminococcin A, a new lantibiotic produced by a Ruminococcus gnavus strain isolated from human feces. Appl Environ Microbiol 67:4111–4118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yooseph S, Kirkness EF, Tran TM, Harkins DM, Jones MB, Torralba MG, O’Connell E, Nutman TB, Doumbo S, Doumbo OK, Traore B, Crompton PD, Nelson KE (2015) Stool microbiota composition is associated with the prospective risk of Plasmodium falciparum infection. BMC Genomics 16:631. https://doi.org/10.1186/s12864-015-1819-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Lozupone CA, Turnbaugh PJ, Fierer N, Knight R (2011) Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc Natl Acad Sci U S A 108:4516–4522. https://doi.org/10.1073/pnas.1000080107

    Article  PubMed  Google Scholar 

  34. Turner S, Pryer KM, Miao VP, Palmer JD (1999) Investigating deep phylogenetic relationships among cyanobacteria and plastids by small subunit rRNA sequence analysis. J Eukaryot Microbiol 46:327–338

    Article  CAS  PubMed  Google Scholar 

  35. Kozich JJ, Westcott SL, Baxter NT, Highlander SK, Schloss PD (2013) Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol 79:5112–5120. https://doi.org/10.1128/AEM.01043-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cox MP, Peterson DA, Biggs PJ (2010) SolexaQA: At-a-glance quality assessment of Illumina second-generation sequencing data. BMC Bioinforma 11:485. https://doi.org/10.1186/1471-2105-11-485

    Article  Google Scholar 

  37. Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB, Lesniewski RA, Oakley BB, Parks DH, Robinson CJ, Sahl JW, Stres B, Thallinger GG, Van Horn DJ, Weber CF (2009) Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol 75:7537–7541. https://doi.org/10.1128/AEM.01541-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, Peplies J, Glockner FO (2013) The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 41:D590–D596. https://doi.org/10.1093/nar/gks1219

    Article  CAS  PubMed  Google Scholar 

  39. McMurdie PJ, Holmes S (2013) phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One 8:e61217. https://doi.org/10.1371/journal.pone.0061217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dehbi HM, Jones S, Sohaib SM, Finegold JA, Siggers JH, Stegemann B, Whinnett ZI, Francis DP (2015) A novel curve fitting method for AV optimisation of biventricular pacemakers. Physiol Meas 36:1889–1900. https://doi.org/10.1088/0967-3334/36/9/1889

    Article  PubMed  Google Scholar 

  41. Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550. https://doi.org/10.1186/s13059-014-0550-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, Rozen SG (2012) Primer3--new capabilities and interfaces. Nucleic Acids Res 40:e115. https://doi.org/10.1093/nar/gks596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This project was funded by Hyundai Motor America and Hyundai Hope on Wheels and J. Craig Venter Institute (JCVI).

Author information

Authors and Affiliations

  1. J. Craig Venter Institute (JCVI), Rockville, MD, USA

    Seesandra V. Rajagopala, Harinder Singh, Yanbao Yu, Bryan Frank, Rembert Pieper & Karen E. Nelson

  2. Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Seesandra V. Rajagopala

  3. Hyundai Cancer Genomics Center, Children’s Hospital Orange County (CHOC Children’s), Orange, CA, USA

    Keri B. Zabokrtsky & Leonard Sender

  4. Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of California-Irvine, Orange, CA, USA

    Keri B. Zabokrtsky & Leonard Sender

  5. J. Craig Venter Institute (JCVI), La Jolla, CA, USA

    Manolito G. Torralba, Kelvin J. Moncera & Karen E. Nelson

  6. Division of Oncology, Hyundai Cancer Institute, CHOC Children’s, Orange, CA, USA

    Leonard Sender

  7. Department of Pediatrics, School of Medicine, University of California-Irvine, Orange, CA, USA

    Leonard Sender

Authors
  1. Seesandra V. Rajagopala
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harinder Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanbao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keri B. Zabokrtsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manolito G. Torralba
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kelvin J. Moncera
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bryan Frank
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rembert Pieper
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Leonard Sender
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Karen E. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Managed study participant’s consent and sample collection: LS, KBZ. Performed experiments: SVR, YY, MT, KJM, BF, MT. Performed computational analysis: SVR, HS. Analyzed the data and provided input to the manuscript: SRV, HS, YY, KBZ, MT, BF, RP, LS, KEN. Wrote the paper: SVR, HS, KEN. Conceived, designed, and supervised: SVR, KEN, LS. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Harinder Singh.

Ethics declarations

Human subject protocols along with consent forms were established. Written informed consent was obtained from a parent and/or legal guardian for all the study participants, and all methods were performed in accordance with the relevant guidelines and regulations.

Competing Interests

The authors declare that they have no competing interests.

Consent for Publication

Informed consent (and assent, where appropriate) and authorization to use, create, and disclose health information for research was obtained from and documented for each research participant enrolled to study at the Hyundai Cancer Institute at CHOC Children’s.

Ethics Approval and Consent to Participate

This study was reviewed and approved by the In-House Institutional Review Board at CHOC Children’s (protocol number 120555).

Electronic supplementary material

ESM 1

(DOCX 530 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rajagopala, S.V., Singh, H., Yu, Y. et al. Persistent Gut Microbial Dysbiosis in Children with Acute Lymphoblastic Leukemia (ALL) During Chemotherapy. Microb Ecol 79, 1034–1043 (2020). https://doi.org/10.1007/s00248-019-01448-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00248-019-01448-x

Keywords

Search

Navigation