| Hypertension is an important risk factor for cardiovascular disease,characterized by high morbidity and mortality,and is directly responsible for more than 10.8 million deaths worldwide each year.In China,due to the improvement of people’s living standards and changes in living habits,the number of patients with hypertension and related cardiovascular diseases has increased sharply year by year.However,due to the lack of understanding of the pathological mechanism of hypertension and the lack of early prevention awareness and intervention methods,the control rate of the disease in China and even the world has not been significantly improved in recent years.In addition,at present,calcium channel inhibitors,angiotensin inhibitors and other drugs are mainly used for antihypertensive treatment.However,because the targets of these antihypertensive drugs are spread throughout the body and various types of cells,they are prone to systemic side effects.Therefore,based on the above reasons,in-depth analysis of cardiovascular health maintenance and cardiovascular disease risk factors,and the development of new antihypertensive drugs or special medical foods with high safety and good antihypertensive effect are important scientific fields to achieve early prevention,early intervention,risk reduction,social and economic burden,improve quality of life and build a moderately prosperous society of cardiovascular disease.Intestinal endophytes and their metabolites participate in the maintenance of many physiological functions of the body,and the development of disease treatment methods related to intestinal endophytes has become a hot topic in disease mechanism research and treatment methods research in recent years.Studies have pointed out that Bacteroides vulgaris(B.vulgatus)is one of the dominant bacteria in the intestine,which is involved in regulating cardiovascular health,nutrient metabolism,immunity and other physiological functions.Previous studies in this laboratory found that in the process of inducing blood pressure increase in mice through high-salt diet,the abundance of B.vulgatus in the intestines of mice decreased with the increase of blood pressure,and the abundance of B.vulgatus increased again after blood pressure was lowered,suggesting that B.vulgatus was related to the hypertensive process caused by high-salt diet.In this study,we carried out verification work,constructed a mouse model of hypertension with high-salt feed,and used B.vulgatus to gavage mice and monitor blood pressure changes,and it was found that B.vulgatus gavage can significantly slow down the process of hypertension caused by high-salt diet in mice,so the antihypertensive effect of B.vulgatus was confirmed.Based on the results of plasma metabolomics analysis and literature research of mice before and after Gavage of B.vulgatus,we propose that B.vulgatus may regulate the content of adenosine(ADO),a common vasodilating factor,in plasma,thereby realizing the role of blood pressure regulation.To confirm this hypothesis,we detected the changes in plasma adenosine content in mice before and after treatment by high performance liquid chromatography(HPLC),and confirmed that the plasma adenosine content of B.vulgatus was accompanied by an increase in plasma during the relieving of hypertension.The intestine colonized by B.vulgatus is a major site of adenosine synthesis in the body,and we confirmed through HPLC that B.vulgatus does not produce adenosine itself,so we infer that part of the increased adenosine in plasma comes from the interaction with intestinal cells after colonization by B.vulgatus.Subsequently,in order to analyze the mechanism by which B.vulgatus promotes adenosine synthesis in intestinal epithelial cells,we sequenced the m RNA of intestinal epithelial cells before and after culture of B.vulgatus and found that B.vulgatus promoted the significant enrichment of nucleotide metabolism pathways and energy metabolism pathways related to adenosine synthesis in intestinal epithelial cells,especially the expression of adenosine synthesis-related genes such as Adcy9,Prps1l3,Adarb2 and Entpd1 in intestinal epithelial cells treated with B.vulgatus were upregulated.Based on the above sequencing results,we then examined and analyzed the activity of CD39,a key protein for adenosine synthesis,namely CD39,a product of the Entpd1 gene,and the activity of CD73,a downstream protein of its pathway.Using real-time PCR experiments,Western Blot experiments,immunohistochemistry experiments and immunofluorescence experiments,we found that in primary cultured intestinal epithelial cells,intestinal epithelial cells of high-salt diet hypertensive mice had lower CD39 and CD73 expression levels compared with normal mice,while co-incubation of B.vulgatus could significantly increase the expression of CD39 and CD73 in mouse intestinal epithelial cells.Similarly,in vivo experiments,after gavage of B.vulgatus,the expression of CD39 and CD73 in mouse intestinal epithelial cells was significantly increased.Therefore,the results suggest that B.vulgatus can promote the activation of the adenosine synthesis pathway in intestinal epithelial cells.Subsequently,we analyzed the correlation between the plasma adenosine content and the expression of CD39 and CD73 in intestinal epithelial cells,and found that there was a significant correlation between the two,suggesting that the plasma adenosine content of mice was significantly correlated with the activation of adenosine synthesis pathway in intestinal epithelial cells.In summary,this article found the regulatory effect of B.vulgatus on hypertension in mice under a high-salt diet,and proved that B.vulgatus increased the content of plasma adenosine,accompanied by the activation of adenosine synthesis pathways mediated by CD39 and CD73 in intestinal epithelial cells,and there was a correlation between the two.The results of this study provide a theoretical basis for elucidating the mechanism of endophytic bacteria regulating cardiovascular health and developing new antihypertensive drugs. |
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