Cited by 1,270Gut microbiota and healthChild Nutrition and Water AccessInfant Nutrition and Health

The DOI matches its Crossref record; 26 of the 28 references it cites were found in a registry or an index; none of the 25 sources its claims cite is checked for support yet.

Persistent gut microbiota immaturity in malnourished Bangladeshi children

Open access

Abstract

Therapeutic food interventions have reduced mortality in children with severe acute malnutrition (SAM), but incomplete restoration of healthy growth remains a major problem. 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.

Overview

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TL;DR

A machine-learning model based on age-discriminatory fecal bacterial taxa defines gut microbiota maturation in healthy Bangladeshi children and shows that severe acute malnutrition (SAM) is associated with marked microbiota immaturity that is only partially and transiently improved by two food interventions. The same immaturity is seen in moderate acute malnutrition and correlates with anthropometric status.

Key findings

  • A Random Forests model using the top 24 age-discriminatory 97% ID OTUs explained 73% of variance in chronologic age in healthy Bangladeshi children and generalized to independent healthy singleton and twin/triplet validation sets (r² = 0.71 and 0.68, respectively).
  • In 64 children with SAM (mean enrollment WHZ −4.2 ± 0.7), relative microbiota maturity and microbiota-for-age Z-scores were significantly lower than in healthy children at enrollment and end of nutritional rehabilitation (Dunnett’s p < 0.0001 for both treatment groups); improvements after RUTF or Khichuri-Halwa were not durable, with regression to significant immaturity beyond 4 months after treatment stopped.
  • RUTF and Khichuri-Halwa did not differ significantly in weight gain (10.9 ± 4.6 vs 10.4 ± 5.4 g/kg/day; p = 0.7), and WHZ remained lower than healthy children during follow-up (−2.1 ± 1.2 Khichuri-Halwa; −2.4 ± 0.8 RUTF vs −0.5 ± 1.1 healthy; p < 0.0001).
  • In a cross-sectional analysis at 18 months, children with MAM had significantly lower relative microbiota maturity and MAZ scores than healthy children, and these metrics correlated with WHZ (Spearman rho = 0.62 and 0.63; p < 0.001); 220 bacterial taxa differed in SAM vs healthy, with 165 significantly diminished during longer-term follow-up in both treatment groups.

Methods

  • Healthy Bangladeshi birth cohorts in Mirpur, Dhaka: 50 children followed monthly for up to ~24 months (25 singletons, 11 twin pairs, 1 triplet set; 996 fecal samples), plus twins/triplets for validation; SAM trial enrolled 64 children aged 6–20 months randomized to imported RUTF (Plumpy’Nut) or locally produced Khichuri-Halwa; MAM analysis used 33 children at 18 months.
  • Fecal bacterial communities were profiled by V4-16S rRNA sequencing (1,897 fecal DNA samples total; 1,222 97% ID OTUs passing detection filters), with Random Forests regression against chronologic age to identify age-discriminatory taxa and a sparse 24-taxon model to compute relative microbiota maturity and microbiota-for-age Z-score.
  • Associations with clinical/dietary factors used linear mixed models, Dunnett’s post-hoc comparisons, Spearman correlations, and Mann-Whitney/Wilcoxon tests; antibiotic effects were assessed in a subset of nine children with pre-antibiotic samples.

Limitations

  • The paper states that most children with SAM could not provide fecal samples before antibiotics, so effects of other antibiotics consumed singly or in combinations could not be measured; it also notes that functional roles of age-discriminatory taxa need clarification and that more clinical studies are needed to test whether microbiota immaturity persists beyond childhood.
  • The paper notes that systematic analyses across different populations may show a need for geographic specificity when constructing microbiota-based models or diagnostics.
  • Evident from the text: the main findings are associational, sample sizes for some subgroups are small (e.g., nine children with pre-antibiotic samples; 10 children with MAM), and treatment effects on microbiota maturity were not durable, limiting conclusions about causality or long-term therapeutic repair.

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Integrity signals

Registry

Crossref · 10.1038/nature13421

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26 of 26 references verified0 citation errors · 0 not checkable

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    The relationships among nutritional intervention type, gut microbiota, and therapeutic responses are unclear.

    “The relationships between the type of nutritional intervention, the gut microbiota, and therapeutic responses are unclear.”
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Metadata

Authors
Subramanian, S., Huq, S., Yatsunenko, T., Haque, R., Mahfuz, M., Alam, M. A., Benezra, A., DeStefano, J., Meier, M. F., Muegge, B. D., Barratt, M. J., VanArendonk, L. G., Zhang, Q., Province, M. A., Petri Jr, W. A., Ahmed, T., & Gordon, J. I.
Affiliations
  • Washington University in St. Louis (US)
  • International Centre for Diarrhoeal Disease Research (BD)
  • The New School (US)
Corresponding author
Gordon, Jeffrey I.
Venue
Nature
Published
2014-06
Volume
510
Issue
7505
Pages
417-421
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2151241623
Cited by
1,270
References
28
Citations by year
2026: 83 · 2025: 91 · 2024: 101 · 2023: 118 · 2022: 126 · 2021: 159 · 2020: 131 · 2019: 101 · 2018: 89 · 2017: 87 · 2016: 94 · 2015: 66 · 2014: 23
FWCI
36.93
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • International Atomic Energy Agency
  • National Institute of General Medical Sciences (T32GM007067)
  • National Institute of Allergy and Infectious Diseases (AI 043596, R01AI043596)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Nursing › Nutrition and Dietetics › Child Nutrition and Water Access
  • Health Sciences › Nursing › Nutrition and Dietetics › Infant Nutrition and Health
Keywords
gut microbiota, severe acute malnutrition, child malnutrition, food-based interventions, probiotics, prebiotics, fecal microbiota transplantation, diarrhea, twins and triplets, Bangladesh, low-income countries, 16S rRNA
MeSH terms
Bacteria, Bangladesh, Feces, Female, Humans, Infant, Infant Nutrition Disorders, Male, Models, Biological, Nutritional Status, RNA, Ribosomal, 16S, Bacterial Physiological Phenomena, Gastrointestinal Tract, Biodiversity, Microbiota

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