Abstract
L-Amino acids are the building blocks for proteins synthesized in ribosomes in all kingdoms of life, but d-amino acids (d-aa) have important non-ribosome-based functions1. Mammals synthesize d-Ser and d-Asp, primarily in the central nervous system, where d-Ser is critical for neurotransmission2. Bacteria synthesize a largely distinct set of d-aa, which become integral components of the cell wall and are also released as free d-aa3,4. However, the impact of free microbial d-aa on host physiology at the host–microbial interface has not been explored. Here, we show that the mouse intestine is rich in free d-aa that are derived from the microbiota. Furthermore, the microbiota induces production of d-amino acid oxidase (DAO) by intestinal epithelial cells, including goblet cells, which secrete the enzyme into the lumen. Oxidative deamination of intestinal d-aa by DAO, which yields the antimicrobial product H2O2, protects the mucosal surface in the small intestine from the cholera pathogen. DAO also modifies the composition of the microbiota and is associated with microbial induction of intestinal sIgA. Collectively, these results identify d-aa and DAO as previously unrecognized mediators of microbe–host interplay and homeostasis on the epithelial surface of the small intestine.
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Acknowledgements
The authors thank M. Nakane (Shiseido) for technical support with 2D-HPLC, L. Comstock for help with anaerobic cultures, R. Konno for providing DAOG181R mice, Waldor laboratory colleagues and M. Silverman for their comments on the manuscript, Q. Wang for help creating the ΔoxyR strain, L. Bry for germ-free mice, G. Abu-Ali/Huttenhower Group for assistance with LEfSe and 16S metagenomic analysis and S. Aiso for support. This work was supported by the Howard Hughes Medical Institute (M.K.W.), NIH grant no. R37 AI-042347 (M.K.W.) and the Moritani Scholarship Foundation (J.S.).
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J.S. and M.K.W. conceived and designed the study. J.S. carried out histological experiments, biochemical analyses, microbiological studies, sequence analyses, animal experiments with T.Z., and figure preparation. Y.M. and K.H. performed HPLC quantifications of chiral amino acids with technical support by M.M. S.R.-N. and B.M.D. provided scientific advice. M.K.W. supervised the experiments and directed the analysis. J.S., S.R.-N., B.M.D. and M.K.W. wrote the manuscript.
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Sasabe, J., Miyoshi, Y., Rakoff-Nahoum, S. et al. Interplay between microbial d-amino acids and host d-amino acid oxidase modifies murine mucosal defence and gut microbiota. Nat Microbiol 1, 16125 (2016). https://doi.org/10.1038/nmicrobiol.2016.125
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DOI: https://doi.org/10.1038/nmicrobiol.2016.125