Date Published: June 17, 2019
Publisher: Public Library of Science
Author(s): Kentaro Arakawa, Tomoaki Ishigami, Michiko Nakai-Sugiyama, Lin Chen, Hiroshi Doi, Tabito Kino, Shintaro Minegishi, Sae Saigoh-Teranaka, Rie Sasaki-Nakashima, Kiyoshi Hibi, Kazuo Kimura, Kouichi Tamura, Michael Bader.
The interaction between atherosclerosis and commensal microbes through leaky gut syndrome (LGS), which is characterized by impaired intestinal permeability and the introduction of undesired pathogens into the body, has not been fully elucidated. Our aim was to investigate the potential role of a ClC-2 chloride channel activator, lubiprostone, which is reported to have beneficial effects on LGS, in the development of atherosclerosis in apolipoprotein E–deficient (ApoE-/-) mice. After a 15-week feeding period of a Western diet (WD), ApoE-/- mice were treated with a Western-type diet (WD) alone or WD with oral supplementation of lubiprostone for 10 weeks. This feeding protocol was followed by experimental evaluation of LGS and atherosclerotic lesions in the aorta. In mice with lubiprostone, in vivo translocation of orally administered 4-kDa FITC-dextran was significantly improved, and RNA expression of the epithelial tight junction proteins, Zo-1 and occludin, was significantly up-regulated in the ileum, compared to the WD alone group, suggesting a possible reversal of WD-induced intestinal barrier dysfunction. As a result, WD-induced exacerbation of atherosclerotic lesion formation was reduced by 69% in longitudinally opened aortas and 26% in aortic root regions. In addition, there was a significant decrease in circulating immunoglobulin level, followed by an attenuation of inflammatory responses in the perivascular adipose tissue, as evidenced by reduced expression of pro-inflammatory cytokines and chemokines. Lubiprostone attenuates atherosclerosis by ameliorating LGS-induced inflammation through the restoration of the intestinal barrier. These findings raise the possibility of targeting LGS for the treatment of atherosclerosis.
Atherosclerosis is the leading cause of cardiovascular mortality and morbidity worldwide. Recent studies have revealed that atherosclerosis arises from a systemic inflammatory process, including the accumulation and the activities of immune cells [1, 2]. In our previous work, we reported that atherosclerotic development, caused by intestinal microbiome, is due to the recruitment and ectopic activation of B2 cells in the perivascular adipose tissue and an increase in circulating immunoglobulin (IgG and IgG3) [3,4]. This inflammatory pathway can be inhibited by antibiotic-induced elimination of the intestinal microbiome, as well as by depletion of B2 cells with antibodies against the cell surface antigen CD23. These findings underline a possible persistent inflammatory process in atherosclerosis, centered on a pathological humoral immunity between commensal microbes and activated sub-populations of substantial B cells in the vicinity of the arterial adventitia.
The findings reported in this study demonstrate the potential role of lubiprostone in attenuating atherosclerotic lesions through the amelioration of LGS-induced inflammation by restoring the functional barrier of the gut. WD-induced changes in intestinal barrier function (reduction in intestinal tight junction proteins resulting in increased in vivo permeability) led to increased activation of B2 cells and an increment in circulating IgG, accompanied by an up-regulation of pro-inflammatory cytokines and chemokines in the spleen and PVAT. Oral supplementation of lubiprostone attenuated these inflammatory sequelae and suppressed WD-induced exacerbation of atherosclerotic lesion formation, which would be considered to have substantial clinical value.