Supportive Care in Cancer

, Volume 26, Issue 2, pp 427–439 | Cite as

The gut microbiome, symptoms, and targeted interventions in children with cancer: a systematic review

  • Jinbing BaiEmail author
  • Madhusmita Behera
  • Deborah Watkins Bruner
Review Article



The gut microbiome plays a critical role in maintaining children’s health and in preventing and treating children’s disease. Current application of the gut microbiome in childhood cancer is still lacking. This study aimed to systematically review the following: (1) alternations in the gut microbiome throughout cancer treatment trajectories in children, (2) the associations between the gut microbiome and gastrointestinal (GI) symptoms and psychoneurological symptoms (PNS), and (3) the efficacy of therapeutic interventions in the gut microbiome in children with cancer.


PubMed, EMBASE, the Cochrane Library, and the American Society of Clinical Oncology abstract were searched. Eligible studies included all study types in which the gut microbiome was primarily reported in children with cancer. The Mixed Methods Assessment Tool was used to evaluate the methodology quality of included studies. Seven studies met our eligibility criteria, including two cohort studies, two case-control studies, and three randomized controlled trails.


The findings showed that the diversity estimates of the gut microbiome in children with cancer were lower than those of healthy controls both pre- and post-treatment. Children with cancer showed a significantly lower relative abundance of healthy gut microbiome (e.g., Clostridium XIVa and Bifidobacterium) during and after cancer treatment. No adequate literature was identified to support the associations between dysbiosis of the gut microbiome and GI symptoms/PNS. The use of prebiotics (fructooligosaccharides) and probiotics (Bifidobacterium or Lactobacilli) appears to improve the microenvironment of the gut around 1 month (4–5 weeks) during chemotherapy rather than at the beginning of treatment. Data also suggest that both prebiotic and probiotic interventions decrease clinical side effects (e.g., infection and morbidity risk) in children with cancer.


This study adds to the evidence that dysbiosis of the gut microbiome can be improved using prebiotic and probiotic supplementations in children with cancer. More well-designed experimental studies are needed to confirm this conclusion. Further studies are needed to examine the associations between the gut microbiome and GI symptoms/PNS in childhood cancer.


Cancer Children Gut microbiome Gastrointestinal symptoms Psychoneurological symptoms Prebiotics Probiotics 





Psychoneurological symptoms


Preferred Reporting Items for Systematic Reviews and Meta-Analyses


Acute lymphoblastic leukemia


Acute myeloid leukemia




Short-chain fatty acids





We thank Dr. Becky Kinkead and Ms. Rebecca Meador from Emory University for reviewing and editing this paper.

Author contributions

All the authors contributed to this paper and agreed with this publication.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

520_2017_3982_MOESM1_ESM.doc (68 kb)
Table S1 (DOC 68 kb)


  1. 1.
    Knight, R. and B. Buhler, Follow your gut : the enormous impact of tiny microbes. First TED Books hardcover edition. ed. 2015. 114 pagesGoogle Scholar
  2. 2.
    Savage DC (1977) Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol 31:107–133CrossRefPubMedGoogle Scholar
  3. 3.
    Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13(10):701–712CrossRefPubMedGoogle Scholar
  4. 4.
    Hollister EB et al (2015) Structure and function of the healthy pre-adolescent pediatric gut microbiome. Microbiome 3:36CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Lin A, Bik EM, Costello EK, Dethlefsen L, Haque R, Relman DA, Singh U (2013) Distinct distal gut microbiome diversity and composition in healthy children from Bangladesh and the United States. PLoS One 8(1):e53838. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Wilson M (2008) Bacteriology of humans: an ecological perspective. Blackwell Pub. x, Malden, MA, 351 pGoogle Scholar
  7. 7.
    Dethlefsen L, McFall-Ngai M, Relman DA (2007) An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature 449(7164):811–818. CrossRefPubMedGoogle Scholar
  8. 8.
    Schroeder BO, Backhed F (2016) Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 22(10):1079–1089CrossRefPubMedGoogle Scholar
  9. 9.
    Slattery J, MacFabe DF, Frye RE (2016) The significance of the enteric microbiome on the development of childhood disease: a review of prebiotic and probiotic therapies in disorders of childhood. Clin Med Insights Pediatr 10:91–107. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Li S, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K, Wang J (2012) A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490(7418):55–60. CrossRefPubMedGoogle Scholar
  11. 11.
    Morgan XC et al (2012) Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 13(9):R79CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hsiao EY et al (2013) Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155(7):1451–1463CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hill JM et al (2014) Pathogenic microbes, the microbiome, and Alzheimer’s disease (AD). Front Aging Neurosci 6:127PubMedPubMedCentralGoogle Scholar
  14. 14.
    Garrett WS (2015) Cancer and the microbiota. Science 348(6230):80–86. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bultman SJ (2014) Emerging roles of the microbiome in cancer. Carcinogenesis 35(2):249–255CrossRefPubMedGoogle Scholar
  16. 16.
    Kelly DL et al (2016) The microbiome and cancer: implications for oncology nursing science. Cancer Nurs 39(3):E56–E62CrossRefPubMedGoogle Scholar
  17. 17.
    Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R (2010) Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 107(26):11971–11975. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Jost T et al (2013) Assessment of bacterial diversity in breast milk using culture-dependent and culture-independent approaches. Br J Nutr 110(7):1253–1262CrossRefPubMedGoogle Scholar
  19. 19.
    Bezirtzoglou E, Tsiotsias A, Welling GW (2011) Microbiota profile in feces of breast- and formula-fed newborns by using fluorescence in situ hybridization (FISH). Anaerobe 17(6):478–482CrossRefPubMedGoogle Scholar
  20. 20.
    Lewis JD, Chen EZ, Baldassano RN, Otley AR, Griffiths AM, Lee D, Bittinger K, Bailey A, Friedman ES, Hoffmann C, Albenberg L, Sinha R, Compher C, Gilroy E, Nessel L, Grant A, Chehoud C, Li H, Wu GD, Bushman FD (2015) Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn’s disease. Cell Host Microbe 18(4):489–500. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Leonard MM et al (2015) Celiac disease genomic, environmental, microbiome, and metabolomic (CDGEMM) study design: approach to the future of personalized prevention of celiac disease. Nutrients 7(11):9325–9336CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Dąbrowska K, Witkiewicz W (2016) Correlations of host genetics and gut microbiome composition. Front Microbiol 7(1357)Google Scholar
  23. 23.
    Turpin W, Espin-Garcia O, Xu W, Silverberg MS, Kevans D, Smith MI, Guttman DS, Griffiths A, Panaccione R, Otley A, Xu L, Shestopaloff K, Moreno-Hagelsieb G, Abreu M, Beck P, Bernstein C, Dieleman L, Feagan B, Jacobson K, Kaplan G, Krause DO, Madsen K, Marshall J, Moayyedi P, Ropeleski M, Seidman E, Snapper S, Stadnyk A, Steinhart H, Surette M, Turner D, Walters T, Vallance B, Aumais G, Bitton A, Cino M, Critch J, Denson L, Deslandres C, el-Matary W, Herfarth H, Higgins P, Huynh H, Hyams J, Mack D, McGrath J, Paterson AD, Croitoru K (2016) Association of host genome with intestinal microbial composition in a large healthy cohort. Nat Genet 48(11):1413–1417. CrossRefPubMedGoogle Scholar
  24. 24.
    Turpin W et al (2016) Association of host genome with intestinal microbial composition in a large healthy cohort. Nat GenetGoogle Scholar
  25. 25.
    Yatsunenko T et al (2012) Human gut microbiome viewed across age and geography. Nature 486(7402):222–227PubMedPubMedCentralGoogle Scholar
  26. 26.
    David LA et al (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505(7484):559–563CrossRefPubMedGoogle Scholar
  27. 27.
    Kang SS et al (2014) Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition. Mol Neurodegener 9:36CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Xu Z, Knight R (2015) Dietary effects on human gut microbiome diversity. Br J Nutr 113(Suppl):S1–S5CrossRefPubMedGoogle Scholar
  29. 29.
    Touchefeu Y et al (2014) Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis—current evidence and potential clinical applications. Aliment Pharmacol Ther 40(5):409–421PubMedGoogle Scholar
  30. 30.
    Zitvogel L et al (2016) Microbiome and anticancer immunosurveillance. Cell 165(2):276–287CrossRefPubMedGoogle Scholar
  31. 31.
    Stringer AM et al (2013) Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases. Support Care Cancer 21(7):1843–1852CrossRefPubMedGoogle Scholar
  32. 32.
    Galloway-Pena JR et al (2016) The role of the gastrointestinal microbiome in infectious complications during induction chemotherapy for acute myeloid leukemia. CancerGoogle Scholar
  33. 33.
    Coller JK, White IA, Logan RM, Tuke J, Richards AM, Mead KR, Karapetis CS, Bowen JM (2015) Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer: a pilot study. Support Care Cancer 23(5):1233–1236. CrossRefPubMedGoogle Scholar
  34. 34.
    Manichanh C, Varela E, Martinez C, Antolin M, Llopis M, Dor J, Giralt J, Guarner F, Malagelada JR (2008) The gut microbiota predispose to the pathophysiology of acute postradiotherapy diarrhea. Am J Gastroenterol 103(7):1754–1761. CrossRefPubMedGoogle Scholar
  35. 35.
    van Vliet MJ et al (2010) The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog 6(5):1–7Google Scholar
  36. 36.
    Amaral FA et al (2008) Commensal microbiota is fundamental for the development of inflammatory pain. Proc Natl Acad Sci U S A 105(6):2193–2197CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Shen, S., et al., Gut microbiota is critical for the induction of chemotherapy-induced pain. Nat Neurosci, 2017. advance online publication Google Scholar
  38. 38.
    Hsu YJ et al (2015) Effect of intestinal microbiota on exercise performance in mice. J Strength Cond Res 29(2):552–558CrossRefPubMedGoogle Scholar
  39. 39.
    Naseribafrouei A et al (2014) Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil 26(8):1155–1162CrossRefPubMedGoogle Scholar
  40. 40.
    Foster JA, McVey Neufeld KA (2013) Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 36(5):305–312. CrossRefPubMedGoogle Scholar
  41. 41.
    Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ, MacQueen G, Sherman PM (2011) Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60(3):307–317. CrossRefPubMedGoogle Scholar
  42. 42.
    Wang A et al (2015) Gut microbial dysbiosis may predict diarrhea and fatigue in patients undergoing pelvic cancer radiotherapy: a pilot study. PLoS One 10(5):e0126312CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Dupuis LL et al (2016) Anxiety, pain, and nausea during the treatment of standard-risk childhood acute lymphoblastic leukemia: a prospective, longitudinal study from the Children’s Oncology Group. CancerGoogle Scholar
  44. 44.
    Heden L et al (2013) Parents’ perceptions of their child’s symptom burden during and after cancer treatment. J Pain Symptom Manag 46(3):366–375CrossRefGoogle Scholar
  45. 45.
    Van Vliet MJ et al (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(2):262–270CrossRefPubMedGoogle Scholar
  46. 46.
    Gibson GR, Probert HM, Loo JV, Rastall RA, Roberfroid MB (2004) Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev 17(2):259–275. CrossRefPubMedGoogle Scholar
  47. 47.
    Moher D et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Open Med 3(3):e123–e130PubMedPubMedCentralGoogle Scholar
  48. 48.
    Pluye P et al (2009) A scoring system for appraising mixed methods research, and concomitantly appraising qualitative, quantitative and mixed methods primary studies in Mixed Studies Reviews. Int J Nurs Stud 46(4):529–546CrossRefPubMedGoogle Scholar
  49. 49.
    Pace R et al (2012) Testing the reliability and efficiency of the pilot Mixed Methods Appraisal Tool (MMAT) for systematic mixed studies review. Int J Nurs Stud 49(1):47–53CrossRefPubMedGoogle Scholar
  50. 50.
    Cozen W, Yu G, Gail MH, Ridaura VK, Nathwani BN, Hwang AE, Hamilton AS, Mack TM, Gordon JI, Goedert JJ (2013) Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins. Br J Cancer 108(5):1163–1167. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Huang Y et al (2012) Effect of high-dose methotrexate chemotherapy on intestinal Bifidobacteria, Lactobacillus and Escherichia coli in children with acute lymphoblastic leukemia. Exp Biol Med 237(3):305–311CrossRefGoogle Scholar
  52. 52.
    Rajagopala SV et al (2016) Gastrointestinal microbial populations can distinguish pediatric and adolescent acute lymphoblastic leukemia (ALL) at the time of disease diagnosis. BMC Genomics 17(1):635CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Ekert H et al (1980) Prophylactic co-trimoxazole and lactobacilli preparation in neutropenic patients. Med Pediatr Oncol 8(1):47–51CrossRefPubMedGoogle Scholar
  54. 54.
    Zheng S et al (2006) Nutritional support of pediatric patients with cancer consuming an enteral formula with fructooligosaccharides. Nutr Res 26(4):154–162CrossRefGoogle Scholar
  55. 55.
    Wada M et al (2010) Effects of the enteral administration of Bifidobacterium breve on patients undergoing chemotherapy for pediatric malignancies. Support Care Cancer 18(6):751–759CrossRefPubMedGoogle Scholar
  56. 56.
    Zwielehner J et al (2011) Changes in human fecal microbiota due to chemotherapy analyzed by TaqMan-PCR, 454 sequencing and PCR-DGGE fingerprinting. PLoS One 6(12):e28654CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Richardson G, Dobish R (2007) Chemotherapy induced diarrhea. J Oncol Pharm Pract 13(4):181–198. CrossRefPubMedGoogle Scholar
  58. 58.
    Morturano, R., Managementof chemotherapy-induced diarrhea, in OncoLink, Penn Medicine,. 2012Google Scholar
  59. 59.
    Miller E, Jacob E, Hockenberry MJ (2011) Nausea, pain, fatigue, and multiple symptoms in hospitalized children with cancer. Oncol Nurs Forum 38(5):E382–E393CrossRefPubMedGoogle Scholar
  60. 60.
    Lyon D, Elmore L, Aboalela N, Merrill-Schools J, McCain N, Starkweather A, Elswick RK, Jackson-Cook C (2014) Potential epigenetic mechanism(s) associated with the persistence of psychoneurological symptoms in women receiving chemotherapy for breast cancer: a hypothesis. Biol Res Nurs 16(2):160–174. CrossRefPubMedGoogle Scholar
  61. 61.
    Bhatt AP, Redinbo MR, Bultman SJ (2017) The role of the microbiome in cancer development and therapy. CA Cancer J Clin 67(4):326–344CrossRefPubMedGoogle Scholar
  62. 62.
    Roy S, Trinchieri G (2017) Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer 17(5):271–285. CrossRefPubMedGoogle Scholar
  63. 63.
    Alexander, J.L., et al., Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol, 2017. advance online publication Google Scholar
  64. 64.
    Montassier E et al (2015) Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment Pharmacol Ther 42(5):515–528CrossRefPubMedGoogle Scholar
  65. 65.
    Fijlstra M, Ferdous M, Koning AM, Rings EH, Harmsen HJ, Tissing WJ (2014) Substantial decreases in the number and diversity of microbiota during chemotherapy-induced gastrointestinal mucositis in a rat model. Support Care Cancer 23(6):1513–1522. CrossRefPubMedGoogle Scholar
  66. 66.
    Montassier E et al (2014) 16S rRNA gene pyrosequencing reveals shift in patient faecal microbiota during high-dose chemotherapy as conditioning regimen for bone marrow transplantation. Microb Ecol 67(3):690–699CrossRefPubMedGoogle Scholar
  67. 67.
    Paulsen JA et al (2017) Gut microbiota composition associated with alterations in cardiorespiratory fitness and psychosocial outcomes among breast cancer survivors. Support Care CancerGoogle Scholar
  68. 68.
    Wong ML et al (2016) Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol Psychiatry 21(6):797–805CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Kennedy PJ, Cryan JF, Dinan TG, Clarke G (2016) Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology 112(Pt B):399–412. PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Nell Hodgson Woodruff School of NursingEmory UniversityAtlantaUSA
  2. 2.Department of Hematology and Oncology, School of MedicineEmory UniversityAtlantaUSA
  3. 3.Winship Research Informatics, Winship Cancer InstituteEmory UniversityAtlantaUSA
  4. 4.Education and Training, Winship Cancer InstituteEmory UniversityAtlantaUSA

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