Heart Failure Research Group (D.M.K., W.A.S., H.A.J., D.H., B.G., A.F., F.Z.M.), Baker Heart and Diabetes Institute, Melbourne, Australia.
Central Clinical School, Faculty of Medicine Nursing and Health Sciences (D.M.K.).
Circulation. 2020 Apr 28;141(17):1393-1403. doi: 10.1161/CIRCULATIONAHA.119.043081. Epub 2020 Feb 25.
High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites.
One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg·d). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined.
Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation.
The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.
高血压（BP）仍然是心血管死亡的主要、控制不良但可改变的危险因素之一。在西方主要生活方式因素中，膳食纤维含量低的饮食与高血压的流行有关。缺乏益生元纤维的影响以及导致更高血压的相关机制尚不清楚。在这里，我们表明缺乏膳食纤维会导致高血压生成的肠道微生物群的发展、高血压及其并发症，并证明了感应肠道代谢物的 G 蛋白偶联受体（GPCR）的作用。
包括 C57BL/6J、无菌 C57BL/6J 和 GPR41、GPR43、GPR109A 和 GPR43/109A 基因敲除品系在内的 179 只小鼠被纳入研究。C57BL/6J 小鼠植入含有生理盐水或低剂量血管紧张素 II（0.25mg·kg·d）的微量输液泵。给予缺乏益生元纤维的饮食，或添加在大肠发酵过程中产生的短链脂肪酸（[SCFA）等肠道代谢物，或高益生元纤维饮食。测定心脏组织学和功能、血压、钠和钾排泄、肠道微生物组、流式细胞术、儿茶酚胺和甲基化全谱变化。
缺乏益生元纤维使小鼠在轻度高血压刺激下易患高血压，导致病理性心脏重塑。将高血压生成的微生物群转移到无菌小鼠中重现了膳食纤维缺乏性高血压表型，包括心脏表现。将 SCFA 重新引入到膳食纤维缺乏的小鼠中对高血压、心脏肥大和纤维化的发展具有保护作用。SCFA 的心脏保护作用是通过其同源 SCFA 受体 GPR43/GPR109A 介导的，并调节 DNA 甲基化调节的 L-3,4-二羟苯丙氨酸水平和 T 调节细胞的丰度。
低纤维西方化饮食的有害影响可能是通过缺乏 SCFA 产生和 GPR43/109A 信号导致高血压。维持健康的、产生 SCFA 的微生物群对心血管健康很重要。
