Lypd8 promotes the segregation of flagellated microbiota and colonic epithelia

• Published in: Nature (London) Vol. 532; no. 7597; pp. 117 - 121
• Main Authors: Okumura, Ryu, Kurakawa, Takashi, Nakano, Takashi, Kayama, Hisako, Kinoshita, Makoto, Motooka, Daisuke, Gotoh, Kazuyoshi, Kimura, Taishi, Kamiyama, Naganori, Kusu, Takashi, Ueda, Yoshiyasu, Wu, Hong, Iijima, Hideki, Barman, Soumik, Osawa, Hideki, Matsuno, Hiroshi, Nishimura, Junichi, Ohba, Yusuke, Nakamura, Shota, Iida, Tetsuya, Yamamoto, Masahiro, Umemoto, Eiji, Sano, Koichi, Takeda, Kiyoshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-04-2016; Nature Publishing Group
• Subjects: 631/250/262; 631/250/347; Animals; Bacteria; Bacterial Adhesion; Barriers; Caco-2 Cells; Cell Line; Colitis - chemically induced; Colitis - drug therapy; Colitis - genetics; Colon; Colon (Anatomy); Colon - microbiology; Dextran Sulfate; Epithelial cells; Epithelium - microbiology; Female; Flagella; GPI-Linked Proteins - deficiency; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; GPI-Linked Proteins - secretion; Gram-Negative Bacteria - drug effects; Gram-Negative Bacteria - metabolism; Gram-Negative Bacteria - pathogenicity; Gram-Negative Bacteria - physiology; Homeostasis; Humanities and Social Sciences; Humans; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - genetics; Inflammatory bowel disease; Intestinal Mucosa - cytology; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Intestinal Mucosa - secretion; Large intestine; letter; Male; Mice; Microbiota (Symbiotic organisms); Molecular weight; Motility; multidisciplinary; Pathogenesis; Peptides; Physiological aspects; Proteins; Proteus mirabilis - drug effects; Proteus mirabilis - metabolism; Proteus mirabilis - pathogenicity; Rodents; Science; Small intestine; Symbiosis
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature17406

Lypd8 protein derived from intestinal epithelial cells binds to flagellated bacteria to reduce their motility, which limits the entry of Gram-negative bacteria into the inner colonic mucus and prevents invasion of colonic epithelia.
Lypd8 separates microbiota from epithelia
This paper shows that the intestinal epithelial cell derived protein Lypd8, a member of member of the Ly6/PLAUR superfamily, binds to flagellated bacteria. In doing so it reduces the bacteria's motility, limits the entry of Gram-negative bacteria into the inner colonic mucus, and prevents invasion into colonic epithelium.
Colonic epithelial cells are covered by thick inner and outer mucus layers
1
,
2
. The inner mucus layer is free of commensal microbiota, which contributes to the maintenance of gut homeostasis
3
,
4
,
5
,
6
. In the small intestine, molecules critical for prevention of bacterial invasion into epithelia such as Paneth-cell-derived anti-microbial peptides and regenerating islet-derived 3 (RegIII) family proteins have been identified
7
,
8
,
9
,
10
,
11
. Although there are mucus layers providing physical barriers against the large number of microbiota present in the large intestine, the mechanisms that separate bacteria and colonic epithelia are not fully elucidated. Here we show that Ly6/PLAUR domain containing 8 (Lypd8) protein prevents flagellated microbiota invading the colonic epithelia in mice. Lypd8, selectively expressed in epithelial cells at the uppermost layer of the large intestinal gland, was secreted into the lumen and bound flagellated bacteria including
Proteus mirabilis
. In the absence of Lypd8, bacteria were present in the inner mucus layer and many flagellated bacteria invaded epithelia.
Lypd8
−/−
mice were highly sensitive to intestinal inflammation induced by dextran sulfate sodium (DSS). Antibiotic elimination of Gram-negative flagellated bacteria restored the bacterial-free state of the inner mucus layer and ameliorated DSS-induced intestinal inflammation in
Lypd8
−/−
mice. Lypd8 bound to flagella and suppressed motility of flagellated bacteria. Thus, Lypd8 mediates segregation of intestinal bacteria and epithelial cells in the colon to preserve intestinal homeostasis.