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. 2010 Apr 20;107(16):7419-24.
doi: 10.1073/pnas.1001061107. Epub 2010 Apr 1.

Indigenous opportunistic bacteria inhabit mammalian gut-associated lymphoid tissues and share a mucosal antibody-mediated symbiosis

Takashi Obata  1 , Yoshiyuki Goto, Jun Kunisawa, Shintaro Sato, Mitsuo Sakamoto, Hiromi Setoyama, Takahiro Matsuki, Kazuhiko Nonaka, Naoko Shibata, Masashi Gohda, Yuki Kagiyama, Tomonori Nochi, Yoshikazu Yuki, Yoshiko Fukuyama, Akira Mukai, Shinichiro Shinzaki, Kohtaro Fujihashi, Chihiro Sasakawa, Hideki Iijima, Masatoshi Goto, Yoshinori Umesaki, Yoshimi Benno, Hiroshi Kiyono
Affiliations

Indigenous opportunistic bacteria inhabit mammalian gut-associated lymphoid tissues and share a mucosal antibody-mediated symbiosis

Takashi Obata et al. Proc Natl Acad Sci U S A. .

Abstract

The indigenous bacteria create natural cohabitation niches together with mucosal Abs in the gastrointestinal (GI) tract. Here we report that opportunistic bacteria, largely Alcaligenes species, specifically inhabit host Peyer's patches (PPs) and isolated lymphoid follicles, with the associated preferential induction of antigen-specific mucosal IgA Abs in the GI tract. Alcaligenes were identified as the dominant bacteria on the interior of PPs from naïve, specific-pathogen-free but not from germ-free mice. Oral transfer of intratissue uncultured Alcaligenes into germ-free mice resulted in the presence of Alcaligenes inside the PPs of recipients. This result was further supported by the induction of antigen-specific Ab-producing cells in the mucosal (e.g., PPs) but not systemic compartment (e.g., spleen). The preferential presence of Alcaligenes inside PPs and the associated induction of intestinal secretory IgA Abs were also observed in both monkeys and humans. Localized mucosal Ab-mediated symbiotic immune responses were supported by Alcaligenes-stimulated CD11c(+) dendritic cells (DCs) producing the Ab-enhancing cytokines TGF-beta, B-cell-activating factor belonging to the TNF family, and IL-6 in PPs. These CD11c(+) DCs did not migrate beyond the draining mesenteric lymph nodes. In the absence of antigen-specific mucosal Abs, the presence of Alcaligenes in PPs was greatly diminished. Thus, indigenous opportunistic bacteria uniquely inhabit PPs, leading to PP-DCs-initiated, local antigen-specific Ab production; this may involve the creation of an optimal symbiotic environment on the interior of the PPs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Microbial distribution in the GI immune compartment. (A) Microbial composition at the surface and on the interior of PPs was examined by 16S rRNA gene clone library analysis. (B) The presence of Alcaligenes was visually analyzed by whole-mount FISH at the surface and on the interior of PPs and LP. Data are representative of five independent experiments. [Scale bars, 100 μm (PP), 150 μm (LP).]
Fig. 2.
Fig. 2.
PP-MLN migration axis for Alcaligenes-ingested GI tract DCs. (A) CD11c+ DCs were isolated from the PPs and MLNs. Bacterial composition was determined by 16S rRNA gene clone library analysis. (B) Whole-mount FISH was performed to detect Alcaligenes (yellow) in the MLNs of PP-intact and PP-null mice. The confocal images were sequentially captured at 20-μm intervals along the z axis. Data are representative of five independent experiments. (Scale bars, 300 μm.)
Fig. 3.
Fig. 3.
Preferential induction of Alcaligenes-specific mucosal Ab responses in the PPs. (A) Alcaligenes-specific fecal IgA and serum IgG Ab responses were determined by ELISA. Data are means ± SD (n = 4). (B) The numbers of Alcaligenes inside PPs were counted in 10 randomly chosen PPs of CBA/N xid and WT mice. Data are representative of three independent experiments. Horizontal bar indicates the mean. (C) Bacterial distribution on the interior of PPs of GF mice. AB, antibiotic-treated mice. Data are representative of three independent experiments. (Scale bars, 100 μm.) (D) Alcaligenes-specific fecal IgA and serum IgG Ab responses in the Alcaligenes-associated ex-GF mice were measured by ELISA. Data are means ± SD (n = 6). **P < 0.01.
Fig. 4.
Fig. 4.
Intratissue habitation of Alcaligenes inside nonhuman primate and human PPs. (A and B) Alcaligenes were detected on the interior of monkey and human PPs by whole-mount FISH (Left). Alcaligenes-specific fecal IgA Ab responses in monkeys and human were examined by ELISA [Right; n = 10 (A), n = 14 (B)]. Horizontal bar indicates the mean. (Scale bars, 100 μm.) (C) Immunohistochemical analysis was conducted in monkey and human PPs with Alcaligenes-reactive #11E-8C-7A mAb and phycoerythrin-labeled anti-mouse IgM Ab. Open circles indicate the presence of Alcaligenes. (Scale bars, 100 μm.)
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