Oral administration of the lactic acid bacterium Pediococcus acidilactici attenuates atherosclerosis in mice by inducing tolerogenic dendritic cells.
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 × 105µm2vs. 3.3 ± 0.29 × 105µm2, 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.
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
T
Mizoguchi
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.
Kazuyuki
K
Kasahara
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. tomoya@med.kobe-u.ac.jp.
Tomoya
T
Yamashita
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.
Naoto
N
Sasaki
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.
Keiko
K
Yodoi
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.
Takuya
T
Matsumoto
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.
Takuo
T
Emoto
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.
Tomohiro
T
Hayashi
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.
Naoki
N
Kitano
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.
Naofumi
N
Yoshida
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.
Hilman Zulkifli
HZ
Amin
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.
Ken-Ichi
KI
Hirata
D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D051379:Mice; D000074085:Mice, Knockout, ApoE; D000070016:Pediococcus acidilactici; D019936:Probiotics / Q000008:administration & dosage*
Atherosclerosis; Dendritic cells; Probiotic; Programmed death ligand 1