Abstract
Atherosclerosis (AS) is closely associated with abnormally chronic low-grade inflammation and gut dysbiosis. Flaxseed oil (FO) rich in omega-3 polyunsaturated fatty acids (PUFAs), which are mainly composed of alpha-linolenic acid (ALA, 18:3 omega-3), has been demonstrated to exhibit pleiotropic benefits in chronic metabolic diseases. However, the impact of dietary ALA-rich FO on AS and its associated underlying mechanisms remain poorly understood. Thus, the present study was designed as two phases to investigate the effects in atherosclerotic Apolipoprotein E (ApoE)−/− mice. In the initial portion, the ApoE−/− mice were randomly allocated to three groups: control group (CON), model group (MOD), and FO-fed model group (MOD/FO) and were treated for 12 weeks. The second phase used antibiotic (AB)-treated ApoE−/− mice were divided into two groups: AB-treated model group (AB/MOD) and FO-fed AB-treated model group (AB/FO). In the results, the dietary ALA-rich FO administration ameliorated atherosclerotic lesion, as well as the parameters of AS (body weights (BWs) and the total bile acids (TBA). Chronic systemic/vascular inflammatory cytokines and in situ macrophages (Mψs) were reduced with FO intervention. In addition, the FO improved the gut integrity and permeability by decreasing the plasma lipopolysaccharide (LPS). Moreover, gut dysbiosis and metabolites [short-chain fatty acids (SCFAs) and bile acids (BAs)] in AS were modulated after FO treatment. Intriguingly, during an AB-treated condition, a significantly weakened amelioration of FO-treated on AS proposed that the intestinal microbiota contributed to the FO effects. A correlation analysis showed close relationships among gut bacteria, metabolites, and inflammation. Collectively, these results suggested that the dietary ALA-rich FO ameliorated the AS in ApoE−/− mice via the gut microbiota-inflammation-artery axis.
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Key Points
Gut microbiota plays a vital role in the progression of AS. Emerging studies have suggested that gut dysbiosis provokes the damage of intestinal mucosal barriers and enhances the intestinal permeability, thus, leading to the translocations of pathogenic bacteria and their metabolites (such as LPS) into the plasma via the gut-heart axis, for triggering blood vessel chronic inflammation. Flaxseed oil (FO), rich in α-linolenic acid (ALA, 18:3 ω-3) has been demonstrated to exhibit pleiotropic benefits in chronic metabolic diseases. However, the effects of the dietary ALA-rich FO on AS and the underlying mechanisms remain elusive. Thus, this study was aimed to investigate the effectiveness of the dietary ALA-rich FO on the occurrence and the development of AS in ApoE−/− mice, with or without gut microbiota, which may potentially contribute to the further understanding of complicated mechanisms among AS, gut microbiota, and inflammation.
In clinical and experimental studies, the consumption of ω-3 PUFAs has exhibited pleiotropic benefits in the control of chronic diseases. This study mainly explored the protective effects of dietary FO intervention on HFD-induced AS and the underlying gut microbiota-inflammation-artery axis in this effectiveness.
The mice lacking an apolipoprotein E are especially vulnerable to a series of complex vascular lesion symptoms under the stimulation of HFD, which were comparable to human lesions. In this study, we confirmed that FO could improve the AS pathological injury in atherosclerotic ApoE−/− mice with HFD. The FO intervention on the food intake in our study showed a limited influence, which indicated that the effectiveness of FO treatment on AS was not dependent on nutrients absorption and on the efficiency of calorie utilization in the gastrointestinal tract in AS, which was consistent with previous reports. To further reveal the underlying mechanisms of dietary FO amelioration on AS, the gut microbiota alterations due to a critical role of gut dysbiosis in the pathogenesis of AS was assessed. I was found that phyla Bacteriodetes and Firmicutes were kept predominantly in diverse groups, which are paralleled with previous studies. An increase in Firmicutes/Bacteriodetes ratio is closely related to chronic metabolic diseases. In this study, the increased ratio of Firmicutes/Bacteriodetes in AS was rectified by the dietary FO administration, suggesting that FO could markedly modulate the gut microbiota by decreasing the predominant Firmicutes/Bacteriodetes in phylum level.