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Therapeutic interventions targeting enteropathy in severe acute malnutrition modulate systemic and vascular inflammation and epithelial regeneration.

  • 2025-01
  • EBioMedicine 111
    • Jonathan P Sturgeon
    • Kuda Mutasa
    • Mutsa Bwakura-Dangarembizi
    • Beatrice Amadi
    • Deophine Ngosa
    • Anesu Dzikiti
    • Kanta Chandwe
    • Ellen Besa
    • Batsirai Mutasa
    • Simon H Murch
    • Susan Hill
    • Raymond J Playford
    • Kelley VanBuskirk
    • Paul Kelly
    • Andrew J Prendergast

Study Design

Type
Randomized Controlled Trial (RCT)
Sample size
n = 122
Population
122 children (57% male) with SAM randomised following stabilisation
Methods
multiplex biomarkers measured in a phase II multi-centre trial; randomised to one of four interventions for 14 days: budesonide, N-acetylglucosamine, colostrum, or teduglutide, compared with standard-of-care
Duration
14 days
Funding
Mixed (industry + independent)
  • Large Human Trial

Background

Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition, and children hospitalised with complications have unacceptably high mortality. Complicated SAM is a multisystem disease characterised pathophysiologically by muscle wasting, systemic inflammation, metabolic dysfunction, and malnutrition enteropathy including epithelial barrier dysfunction. There is a clear need for novel interventions to address the underlying pathogenic perturbations of complicated SAM.

Methods

In this analysis of tertiary outcomes from a phase II multi-centre trial in Zambia and Zimbabwe, multiplex biomarkers were measured in 122 children (57% male) with SAM randomised following stabilisation ('baseline') to one of four interventions for 14 days to treat malnutrition enteropathy: budesonide, N-acetylglucosamine, colostrum, or teduglutide, compared with standard-of-care. Following measurement of 35 biomarkers from day 15 plasma samples using Luminex and ELISA, the dimensionality of biomarker data was reduced using principal component analysis.

Findings

Both budesonide and colostrum reduced systemic inflammation (as measured by CD14, IL1-ra, CRP, and LBP), while children receiving colostrum had higher GLP2 and angiopoietin, and lower circulating lipopolysaccharide, suggesting better restoration of epithelial barrier function. N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF), and circulating growth factors (angiopoietin, IGFBP-3, and GCSF).

Interpretation

Interventions aimed at ameliorating malnutrition enteropathy showed plausible effects on biomarkers of inflammation and epithelial regeneration, demonstrating an interdependence of systemic inflammation and enteropathy markers seen in structural analysis. Given the interplay between inflammation and tissue restoration in malnutrition, this mechanism of action supports larger trials to determine the clinical benefits of interventions, either alone or in combination, in children with complicated SAM.

Funding

This analysis of tertiary outcomes for the TAME trial was funded by a Wellcome grant to JPS (220566/Z/20/Z). The TAME trial was funded by a grant from the Medical Research Council (UK), number MR/P024033/1. AJP is funded by Wellcome (108065/Z/15/Z). Takeda UK provided teduglutide at a discounted price.

Research Insights

  • Colostrum→Increased Angiopoietin Level

    N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF), and circulating growth factors (angiopoietin, IGFBP-3, and GCSF).

    Effect
    Beneficial
    Effect size
    Small
  • Colostrum→Increased GLP-2 Level

    children receiving colostrum had higher GLP2 and angiopoietin

    Effect
    Beneficial
    Effect size
    Small
  • Colostrum→Reduced Inflammation

    Both budesonide and colostrum reduced systemic inflammation (as measured by CD14, IL1-ra, CRP, and LBP)

    Effect
    Beneficial
    Effect size
    Small
  • Colostrum→Reduced Lipopolysaccharide Level

    children receiving colostrum had higher GLP2 and angiopoietin, and lower circulating lipopolysaccharide

    Effect
    Beneficial
    Effect size
    Small
  • N-Acetyl Glucosamine→Increased Angiopoietin Level

    N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF), and circulating growth factors (angiopoietin, IGFBP-3, and GCSF).

    Effect
    Beneficial
    Effect size
    Small
  • N-Acetyl Glucosamine→Increased EGF Level

    N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF)

    Effect
    Beneficial
    Effect size
    Small
  • N-Acetyl Glucosamine→Increased GCSF Level

    N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF), and circulating growth factors (angiopoietin, IGFBP-3, and GCSF).

    Effect
    Beneficial
    Effect size
    Small
  • N-Acetyl Glucosamine→Increased IGFBP-3 Level

    N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF), and circulating growth factors (angiopoietin, IGFBP-3, and GCSF).

    Effect
    Beneficial
    Effect size
    Small
  • N-Acetyl Glucosamine→Increased VEGF Level

    N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF)

    Effect
    Beneficial
    Effect size
    Small
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