Translational control of innate barrier defense by the gut microbiota

Li, Y.; Wu, R.; Ma, X.; Zhang, J.; Ma, J.; Duan, Y.; Hassell, B.; Ruhn, K.; Behrendt, C. L.; Dende, C.; Wang, L.; Lemoff, A.; Raj, P.; Kuang, Z.; Hooper, L. N.

doi:10.1101/2025.08.11.668728

bioRxiv · 10.1101/2025.08.11.668728

Translational control of innate barrier defense by the gut microbiota

Li, Y.·Wu, R.·Ma, X.·Zhang, J.·Ma, J.·Duan, Y.·Hassell, B.·Ruhn, K.·Behrendt, C. L.·Dende, C.·Wang, L.·Lemoff, A.·Raj, P.·Kuang, Z.·Hooper, L. N.

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Abstract

The intestinal epithelium is protected by a mucus barrier, infused with antimicrobial proteins, that restricts microbial access to host tissue. Because assembling this barrier is energetically costly, its production must be tightly regulated. Here, we show that the microbiota regulates the translation of key mucus barrier components, including the structural glycoprotein mucin 2 and the antimicrobial enzyme lysozyme. This process is initiated by microbial induction of histone deacetylase 5 (HDAC5) in secretory epithelial cells of the intestine. HDAC5 promotes deacetylation of 14-3-3 proteins, enabling activation of the energy sensing kinase mTOR which enhances translation of mucus and antimicrobial proteins. These findings reveal a mechanism by which the microbiota controls barrier immunity at the level of protein synthesis and suggest that the HDAC5-mTOR axis integrates microbial and energetic signals to regulate intestinal defense. One sentence summaryThe gut microbiota enhances translation of innate barrier defense proteins through HDAC5-mediated activation of mTORC1 signaling.

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Li, Y., Wu, R., Ma, X., Zhang, J., Ma, J., Duan, Y., Hassell, B., Ruhn, K., Behrendt, C. L., Dende, C., Wang, L., Lemoff, A., Raj, P., Kuang, Z., Hooper, L. N.. 2025-08-11. Translational control of innate barrier defense by the gut microbiota. https://doi.org/10.1101/2025.08.11.668728

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