Interplay between microbial d-amino acids and host d-amino acid oxidase modifies murine mucosal defence and gut microbiota.
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 functions(1). Mammals synthesize d-Ser and d-Asp, primarily in the central nervous system, where d-Ser is critical for neurotransmission(2). Bacteria synthesize a largely distinct set of d-aa, which become integral components of the cell wall and are also released as free d-aa(3,4). 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.
Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.|Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Jumpei
J
Sasabe
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Yurika
Y
Miyoshi
Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Seth
S
Rakoff-Nahoum
Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Ting
T
Zhang
Shiseido Co., Ltd, Minato-ku, Tokyo 105-0021, Japan.
Masashi
M
Mita
Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Brigid M
BM
Davis
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Kenji
K
Hamase
Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Matthew K
MK
Waldor
D000596:Amino Acids / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001419:Bacteria / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D003605:D-Amino-Acid Oxidase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000069196:Gastrointestinal Microbiome / Q000276:immunology; D020397:Goblet Cells / Q000201:enzymology; D006706:Homeostasis; D054884:Host-Pathogen Interactions; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D018928:Immunity, Mucosal; D007071:Immunoglobulin A, Secretory / Q000032:analysis; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D007422:Intestines / Q000166:cytology / Q000201:enzymology; D051379:Mice; D012336:RNA, Ribosomal, 16S; D014734:Vibrio cholerae / Q000254:growth & development / Q000378:metabolism
D000596:Amino Acids; D007071:Immunoglobulin A, Secretory; D012336:RNA, Ribosomal, 16S; D006861:Hydrogen Peroxide; D003605:D-Amino-Acid Oxidase
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