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Abstract

Therapeutic food interventions have reduced mortality in children with severe acute malnutrition (SAM), but incomplete restoration of healthy growth remains a major problem1,2. The relationships between the type of nutritional intervention, the gut microbiota, and therapeutic responses are unclear. In the current study, bacterial species whose proportional representation define a healthy gut microbiota as it assembles during the first two postnatal years were identified by applying a machine-learning-based approach to 16S ribosomal RNA data sets generated from monthly faecal samples obtained from birth onwards in a cohort of children living in an urban slum of Dhaka, Bangladesh, who exhibited consistently healthy growth. These age-discriminatory bacterial species were incorporated into a model that computes a ‘relative microbiota maturity index’ and ‘microbiota-for-age Z-score’ that compare postnatal assembly (defined here as maturation) of a child’s faecal microbiota relative to healthy children of similar chronologic age. The model was applied to twins and triplets (to test for associations of these indices with genetic and environmental factors, including diarrhoea), children with SAM enrolled in a randomized trial of two food interventions, and children with moderate acute malnutrition. Our results indicate that SAM is associated with significant relative microbiota immaturity that is only partially ameliorated following two widely used nutritional interventions. Immaturity is also evident in less severe forms of malnutrition and correlates with anthropometric measurements. Microbiota maturity indices provide a microbial measure of human postnatal development, a way of classifying malnourished states, and a parameter for judging therapeutic efficacy. More prolonged interventions with existing or new therapeutic foods and/or addition of gut microbes may be needed to achieve enduring repair of gut microbiota immaturity in childhood malnutrition and improve clinical outcomes.

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Accessions

Primary accessions

European Nucleotide Archive

Data deposits

16S rRNA sequences, generated from faecal samples in raw format prior to post-processing and data analysis, have been deposited at the European Nucleotide Archive (accession number PRJEB5482).

References

  1. 1.

    et al. Mortality in severely malnourished children with diarrhoea and use of a standardised management protocol. Lancet 353, 1919–1922 (1999)

  2. 2.

    et al. A follow-up experience of 6 months after treatment of children with severe acute malnutrition in Dhaka, Bangladesh. J. Trop. Pediatr. 58, 253–257 (2012)

  3. 3.

    World Health Organization Department of Nutrition for Health and Development WHO child growth standards growth velocity based on weight, length and head circumference: methods and development. (World Health Organization, 2009)

  4. 4.

    , , , & Worldwide timing of growth faltering: revisiting implications for interventions. Pediatrics 125, e473–e480 (2010)

  5. 5.

    & Badiuzzaman, Ali, M. & Fuchs, G. Management of severe malnutrition and diarrhea. Indian J. Pediatr. 68, 45–51 (2001)

  6. 6.

    et al. P0580 Use of a standardized protocol based on local diet results in satisfactory rates of weight gain of severely malnourished children undergoing nutritional rehabilitation. J. Pediatr. Gastroenterol. Nutr. 39, S277 (2004)

  7. 7.

    , & Specially formulated foods for treating children with moderate acute malnutrition in low- and middle-income countries. Cochrane Database Syst. Rev. CD009584 (2013)

  8. 8.

    et al. Critical windows for nutritional interventions against stunting. Am. J. Clin. Nutr. 97, 911–918 (2013)

  9. 9.

    et al. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332, 970–974 (2011)

  10. 10.

    et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011)

  11. 11.

    et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012)

  12. 12.

    et al. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 339, 548–554 (2013)

  13. 13.

    et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014)

  14. 14.

    et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013)

  15. 15.

    et al. The long-term stability of the human gut microbiota. Science 341, (2013)

  16. 16.

    Random Forests. Mach. Learn. 45, 5–32 (2001)

  17. 17.

    et al. Infant weight-for-length is positively associated with subsequent linear growth across four different populations. Matern. Child Nutr. 1, 11–20 (2005)

  18. 18.

    et al. Distinct distal gut microbiome diversity and composition in healthy children from Bangladesh and the United States. PLoS ONE 8, e53838 (2013)

  19. 19.

    et al. Effects of a community-based approach of food and psychosocial stimulation on growth and development of severely malnourished children in Bangladesh: a randomised trial. Eur. J. Clin. Nutr. 66, 701–709 (2012)

  20. 20.

    , & lme4: Linear mixed-effects models using S4 classes. (2011)

  21. 21.

    et al. Contribution of enteric infection, altered intestinal barrier function, and maternal malnutrition to infant malnutrition in Bangladesh. Clin. Infect. Dis. 54, 185–192 (2012)

  22. 22.

    et al. Diarrheal illness in a cohort of children 0-2 years of age in rural Bangladesh: I. Incidence and risk factors. Acta Paediatr. 95, 430–437 (2006)

  23. 23.

    et al. Quality-filtering vastly improves diversity estimates from Illumina amplicon sequencing. Nature Meth. 10, 57–59 (2013)

  24. 24.

    et al. QIIME allows analysis of high-throughput community sequencing data. Nature Meth. 7, 335–336 (2010)

  25. 25.

    et al. An improved Greengenes taxonomy with explicit ranks for ecological and evolutionary analyses of bacteria and archaea. ISME J. 6, 610–618 (2012)

  26. 26.

    & Classification and regression by randomForest. R package version 4.6-7. R News 2, 18–22 (2002)

  27. 27.

    , & lmerTest: tests for random and fixed effects for linear mixed effect models (lmer objects of lme4 package). (2013)

  28. 28.

    National Institute of Population Research and Training (NIPORT), Mitra and Associates, and ICF International. Bangladesh Demographic and Health Survey 2011. Dhaka, Bangladesh and Calverton, Maryland, USA: NIPORT, Mitra and Associates, and ICF International (2013)

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Acknowledgements

We thank the parents and children from Dhaka, Bangladesh for their participation in this study, J. Hoisington-López and S. Deng for technical assistance, and N. Griffin, A. Kau, N. Dey and J. Faith for suggestions during the course of this work. This work was supported by the Bill & Melinda Gates Foundation. The clinical component of the SAM study was funded by the International Atomic Energy Agency. The birth cohort study of singletons was supported in part by the NIH (AI043596). S.S. is a member of the Washington University Medical Scientist Training Program. A.B. is the recipient of an SBE Doctoral Dissertation Research Improvement Grant (NSF Award no. SES-1027035).

Author information

Affiliations

  1. Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, Missouri 63108, USA

    • Sathish Subramanian
    • , Tanya Yatsunenko
    • , Amber Benezra
    • , Joseph DeStefano
    • , Martin F. Meier
    • , Brian D. Muegge
    • , Michael J. Barratt
    • , Laura G. VanArendonk
    •  & Jeffrey I. Gordon
  2. Centre for Nutrition and Food Security, International Centre for Diarrhoeal Disease Research, Dhaka 1212, Bangladesh

    • Sayeeda Huq
    • , Rashidul Haque
    • , Mustafa Mahfuz
    • , Mohammed A. Alam
    •  & Tahmeed Ahmed
  3. Department of Anthropology, New School for Social Research, New York, New York 10003, USA

    • Amber Benezra
  4. Division of Statistical Genomics, Washington University in St. Louis, St. Louis, Missouri 63108, USA

    • Qunyuan Zhang
    •  & Michael A. Province
  5. Departments of Medicine, Microbiology and Pathology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA

    • William A. Petri Jr

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Contributions

S.S. and J.I.G. designed the metagenomic study, S.H., T.A., R.H., M.A.A., M.M., W.A.P. Jr designed and implemented the clinical monitoring and sampling for the SAM trial, participated in patient recruitment, sample collection, sample preservation and/or clinical evaluations; S.S. generated the 16S rRNA data with assistance from M.F.M. and B.D.M.; A.B. and J.D. performed the anthropology study; S.S., T.Y., Q.Z., L.G.V., M.J.B., M.A.P. and J.I.G. analysed the data; S.S. and J.I.G. wrote the paper.

Competing interests

J.I.G. is cofounder of Matatu Inc., a company that characterizes the role of diet-by-microbiota interactions in defining health. The other authors declare no competing interests.

Corresponding author

Correspondence to Jeffrey I. Gordon.

Extended data

Supplementary information

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    Supplementary Information

    This file contains Supplementary Notes and a list of the Supplementary Tables 1-19, which are in a separate excel file.

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    Supplementary Tables

    This file contains Supplementary Tables 1-19.

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DOI

https://doi.org/10.1038/nature13421

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