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Schuran, F.A.* ; Sommer, F.* ; Mishra, N.* ; Lopez-Agudelo, V.* ; Hinrichsen, F.* ; Walker, A. ; Bernardes, J.P.* ; Gilbert, F.* ; Bhardwaj, A.* ; Kuenzel, S.* ; Sommer, N.* ; Gong, T.* ; Hamm, J.* ; Schroeder, L.* ; Weber-Stiehl, S.* ; Ito, G.* ; Klischies, K.* ; Tran, F.* ; Penninger, J.M.* ; Blumberg, R.* ; Franke, A.* ; Schmitt-Kopplin, P. ; Baines, J.F.* ; Rosenstiel, P.*

Protein-Energy Malnutrition Induces Microbiome-Dependent Long-Lasting Changes in Intestinal Epithelial Composition.

J. Crohns Colitis 19, i349-i349 (2025)
DOI
Background: Protein-energy malnutrition (PEM) in childhood is associated with increased susceptibility to infections, endocrine disorders, meta-bolic syndrome and organ dysfunction later in life1-4. However, the mechanisms behind these long-term effects are poorly understood. While the gutmicrobiome plays an important role in the aetiology of PEM, little is known about the long-term epithelial changes caused by the microbiome 5-7 . Theaim of this project was to analyse the effects of PEM on the intestinal epithelium in the presence and absence of the microbiome.Methods: Conventionally maintained (CONV-R) and germ-free (GF) mice were exposed to isocaloric PEM (0.7% protein) for 4 weeks, followedby a 6-week recovery period (20% protein). Multi-omics was used to analyse the effects of PEM. Changes in the composition of the intestinal epi-thelium were validated by immunostaining. An organoid differentiation model was used to analyse the hypotheses formulated under ex vivo PEMconditions.Results: PEM caused a long-lasting reduction in body weight in CONV-R mice and extensive changes in the intestinal epithelium, including a sig-nificant depletion of Paneth cells, compared to GF mice. Furthermore, PEM disrupted microbiota composition and function, particularly affectingamino acid and lipid metabolism. Using a multi-omics approach, we identified the microbiota-derived PPAR-GDF15 axis as a critical mediator ofPEM-induced Paneth cell dysfunction. These findings were validated using an ex vivo intestinal organoid model of PEM, which revealed that Panethcell depletion requires not only the stress-induced cytokine GDF15 as a mediator of PEM, but also a secondary microbiota-dependent hit includinglipid metabolites such as 9-HODE and 12,13-diHOME, which act as PPAR agonists.Conclusion: PEM induces long-term microbiome-dependent changes in the intestinal epithelium. This malnutrition-microbiome-host axis may be apromising target for therapeutic intervention to counteract the persistent effects of malnutrition.
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Publication type Article: Journal article
Document type Meeting abstract
ISSN (print) / ISBN 1873-9946
e-ISSN 1876-4479
Journal Journal of Crohn's and Colitis
Quellenangaben Volume: 19, Issue: , Pages: i349-i349 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Reviewing status Peer reviewed
Institute(s) Research Unit BioGeoChemistry and Analytics (BGC)