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Long-Term Intestinal Epithelial Remodeling Induced by Acute Protein-Energy Malnutrition.

Fenja A Schuran1, Neha Mishra1, Víctor A López-Agudelo1

  • 1Institute of Clinical Molecular Biology, University of Kiel and University Hospital Schleswig-Holstein, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany.

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Summary

Protein-energy malnutrition (PEM) causes lasting intestinal changes, depleting Paneth cells and altering gene expression. These effects persist due to DNA methylation, highlighting new therapeutic targets for malnutrition consequences.

Keywords:
GDF15Paneth cellProtein energy malnutritionintestinal epitheliumintestinal inflammationmicrobiome

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Area of Science:

  • Gastroenterology
  • Nutritional Science
  • Microbiology

Background:

  • Protein-energy malnutrition (PEM) is a significant global health issue with long-term health implications.
  • The persistent effects of a single PEM episode on the intestinal epithelium and microbiota are not fully understood.

Purpose of the Study:

  • To investigate the long-term structural and functional consequences of PEM on the intestinal epithelium and microbiota.
  • To identify molecular mechanisms driving persistent changes post-PEM.

Main Methods:

  • Utilized a multi-omics approach: spatial transcriptomics, DNA methylation analysis, fecal metagenomics, and metabolomics.
  • Employed germ-free mice models to differentiate host-microbe interactions.

Main Results:

  • PEM persistently alters the intestinal epithelium, characterized by Paneth cell depletion and suppressed antimicrobial gene expression.
  • These epithelial changes are linked to persistent DNA methylation alterations and are microbiota-dependent.
  • Identified microbial metabolite 9-HODE and host GDF15 expression as key drivers of Paneth cell dysfunction.

Conclusions:

  • Long-term intestinal consequences of PEM are driven by persistent epigenetic alterations and host-microbe interactions.
  • Targeting microbial lipid metabolism and the GDF15 pathway presents potential therapeutic avenues for malnutrition-related diseases.