Lubiprostone as a potential therapeutic agent to improve intestinal permeability and prevent the development of atherosclerosis in apolipoprotein E-deficient mice

Abstract

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.

The Types and Proportions of Commensal Microbiota Have a Predictive Value in Coronary Heart Disease

“…This barrier is efficient when the microbiome is complex and stable; however, under certain conditions, such as those induced by diets high in fat and cholesterol or in certain diseases, major alterations to the composition of the host microbiota can occur, which have in turn been associated with increased intestinal permeability [ 35 , 36 , 37 , 38 ]. When the intestinal mucosal barrier becomes compromised, commensal microbes or commensal microbe-derived molecules can readily enter the bloodstream and exert systemic effects, which include the induction of infection or chronic low-grade inflammation and immunoreactivity, affecting multiple immune cell populations; this phenomenon has been found to be prevalent in atherosclerosis [ 39 ]. However, the presence of Streptococcus in the blood was not identified in at least two of the relevant studies included in our analysis.…”

Gut microbiota and atherosclerosis: role of B cell for atherosclerosis focusing on the gut-immune-B2 cell axis

“…However, the role of the TLR signaling pathway in B2 cells during atherosclerosis development is not fully elucidated. Nevertheless, in our previous study, we found that under hyperlipidemic conditions, signals driven by the microbiota via the TLR signaling pathway may cause B2 cells to become functionally active, potentially leading to the generation of active antibodies, cytokines, and chemokines, thereby providing a mechanism in which they may be contributing to atherosclerosis development [1,8,53].…”

“…Additionally, interventional approaches can also be applied to enhance the intestinal function of subjects with atherosclerosis. For instance, patients with coronary heart disease and constipation might present interventional opportunities involving the use of laxative agents for improving intestinal commensal microbiota [53,127,128].…”

“…In follow-up experiments, it was confirmed that the obese mice exhibited the highest levels of intestinal permeability; moreover, obesity-prone rats were also found to exhibit increased gut permeability, plasma LPS, and inflammation, albeit with reduced epithelial barrier function as compared with obesity-resistant rats [ 50 – 52 ]. In addition, our group also found that lubiprostone attenuates the development of atherosclerotic lesions by ameliorating leaky gut syndrome-induced inflammation through the restoration of the intestinal barrier [ 53 ]. Consistent with these observations, individuals with inflammatory bowel disease were at higher risk of developing coronary artery disease, despite having lower rates of traditional risk factors than their age-matched controls, in a longitudinal cohort study [ 39 ].…”

Successful prediction of clinical outcomes using arterial velocity pulse index, a new non-invasive vascular index, in Japan

“…Currently, lifestyle-related diseases, such as hypertension (HT), diabetes mellitus (DM), and hyperlipidemia (HL), are considered common risk factors for CV complications. Vascular inflam-mation with immunological background [2][3][4] has also been recently recognized as a basic pathological condition in CV diseases, which remains to be elucidated in terms of unknown treatable risks, i.e., "residual risks. "…”