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Oral administration of the lactic acid bacterium Pediococcus acidilactici attenuates atherosclerosis in mice by inducing tolerogenic dendritic cells

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Abstract

The intestinal microbiota appears to play an important role in the development of atherosclerosis. We investigated the effect of the probiotic lactic acid bacterium Pediococcus acidilactici R037 on atherosclerosis using apolipoprotein E-deficient (ApoE −/−) mice. Six-week-old ApoE −/− mice were orally administered R037 six times a week. Mice treated with R037 for 12 weeks exhibited markedly attenuated atherosclerotic lesions in the aortic root (2.3 ± 0.15 × 105 µm2 vs. 3.3 ± 0.29 × 105 µm2, respectively; P < 0.01; n = 15–17 each group). The expression of Ki-67 in CD4+ T cells, the population of interferon γ-producing CD4+ T cells in the spleen, and pro-inflammatory cytokine production from splenic lymphocytes were significantly decreased in R037-treated mice. Interestingly, splenic dendritic cells (DCs) isolated from R037-treated mice suppressed CD4+ T-cell proliferation and pro-inflammatory cytokine production ex vivo, suggesting that R037 treatment induced tolerogenic DCs. Programmed cell death ligand 1 expression in DCs was significantly enhanced in R037-treated mice, which might explain the immunosuppressive effect of DCs at least in part. These results indicate that R037 attenuates atherosclerosis by inducing tolerogenic DCs, which suppress Th1-driven inflammation and the proliferative activity of CD4+ T cells. Our findings may provide a novel therapeutic approach for the prevention of atherosclerosis based on dietary supplementation with probiotics.

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Acknowledgements

We wish to thank Airo Tategaki and Tomohiro Ueda (Kaneka CO., Japan) for providing us with R037.

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    Authors and Affiliations

    1. Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

      Taiji Mizoguchi, Kazuyuki Kasahara, Tomoya Yamashita, Naoto Sasaki, Keiko Yodoi, Takuya Matsumoto, Takuo Emoto, Tomohiro Hayashi, Naoki Kitano, Naofumi Yoshida, Hilman Zulkifli Amin & Ken-ichi Hirata

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    1. Taiji Mizoguchi
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    2. Kazuyuki Kasahara
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    Correspondence to Tomoya Yamashita.

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    Funding

    This work was supported by Japan Society for the Promotion of Science KAKENHI Grant No. 24591114 (T. Y.), Takeda Scientific Foundation (T. Y. and N. S.), Mochida Memorial Foundation (T. Y.), Suzuken Memorial Foundation (T. Y. and N. S.), Senshin Medical Research Foundation (T. Y. and N. S.), Yakult Bioscience Research Foundation (T. Y.), Uehara Memorial Foundation (K. H. and N. S.), Hyogo Science and Technology Association (T. Y.), The Japanese Circulation Society Translational Research Foundation (K. H.), and Banyu Life Science Foundation International (K. K.).

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    All authors declare that they have no conflict of interest.

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    Taiji Mizoguchi and Kazuyuki Kasahara contributed equally to this article.

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    Mizoguchi, T., Kasahara, K., Yamashita, T. et al. Oral administration of the lactic acid bacterium Pediococcus acidilactici attenuates atherosclerosis in mice by inducing tolerogenic dendritic cells. Heart Vessels 32, 768–776 (2017). https://doi.org/10.1007/s00380-017-0949-8

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