P0013 Protein-Energy Malnutrition Induces Microbiome-Dependent Long-Lasting Changes in Intestinal Epithelial Composition
Authors: Schuran F A , Sommer F , Mishra N , López-Agudelo V , Hinrichsen F , Walker A , Bernardes J P , Gilbert F , Bhardwaj A , Künzel S , Sommer N , Gong T , Hamm J , Schröder 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 
Published: January 2025

Background

Protein-energy malnutrition (PEM) in childhood is associated with increased susceptibility to infections, endocrine disorders, metabolic syndrome and organ dysfunction later in life1-4. However, the mechanisms behind these long-term effects are poorly understood. While the gut microbiome plays an important role in the aetiology of PEM, little is known about the long-term epithelial changes caused by the microbiome5-7. The aim 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, followed by a 6-week recovery period (20% protein). Multi-omics was used to analyse the effects of PEM. Changes in the composition of the intestinal epithelium were validated by immunostaining. An organoid differentiation model was used to analyse the hypotheses formulated under ex vivo PEM conditions.

Results

PEM caused a long-lasting reduction in body weight in CONV-R mice and extensive changes in the intestinal epithelium, including a significant depletion of Paneth cells, compared to GF mice. Furthermore, PEM disrupted microbiota composition and function, particularly affecting amino acid and lipid metabolism. Using a multi-omics approach, we identified the microbiota-derived PPAR-GDF15 axis as a critical mediator of PEM-induced Paneth cell dysfunction. These findings were validated using an ex vivo intestinal organoid model of PEM, which revealed that Paneth cell depletion requires not only the stress-induced cytokine GDF15 as a mediator of PEM, but also a secondary microbiota-dependent hit including lipid 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 a promising target for therapeutic intervention to counteract the persistent effects of malnutrition.

References

1.World Health Organization (2024). World health statistics 2024: monitoring health for the SDGs, Sustainable Development Goals.

2.UNICEF, WHO, and WORLD BANK (2023). Level and trend in child malnutrition. World Health Organization, 4.

3.Soeters, P., Bozzetti, F., Cynober, L., Forbes, A., Shenkin, A., and Sobotka, L. (2017). Defining malnutrition: A plea to rethink. Clinical Nutrition 36, 896–901. https://doi.org/10.1016/J.CLNU.2016.09.032.

4.Bhutta, Z., Berkley, J., Bandsma, R. et al. Severe childhood malnutrition. Nat Rev Dis Primers 3, 17067 (2017). https://doi.org/10.1038/nrdp.2017.67

5.Smith, M.I., Yatsunenko, T., Manary, M.J., Trehan, I., Mkakosya, R., Cheng, J., Kau, A.L., Rich, S.S., Concannon, P., Mychaleckyj, J.C., et al. (2013). Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science (1979) 339, 548–554. https://doi.org/10.1126/science.1229000.

6.Gordon, J.I., Dewey, K.G., Mills, D.A., and Medzhitov, R.M. (2012). The Human Gut Microbiota and Undernutrition. Sci Transl Med 4. https://doi.org/10.1126/SCITRANSLMED.3004347.

7.Barratt, M.J., Ahmed, T., and Gordon, J.I. (2022). Gut microbiome development and childhood undernutrition. Cell Host Microbe 30, 617–626. https://doi.org/10.1016/J.CHOM.2022.04.002.