Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease
Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease
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DOI：
10.1161/circulationaha.119.043081
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发表时间：
2020-04-28
期刊：
影响因子：
37.8
通讯作者：
Marques, Francine Z.
中科院分区：
文献类型：
--
作者：
Kaye, David M.;Shihata, Waled A.;Marques, Francine Z.
背景：高血压（BP）仍然是心血管死亡的一个主要的、控制不佳但可改变的危险因素。在西方的关键生活方式因素中，缺乏纤维的饮食与高血压的患病率有关。缺乏益生元纤维的影响以及导致血压升高的相关机制尚不清楚。在这里，我们证明缺乏益生元膳食纤维会导致高血压肠道微生物群、高血压及其并发症的发展，并证明了感知肠道代谢物的 G 蛋白偶联受体 (GPCR) 的作用。方法：179 只小鼠，包括 C57BL/6J、限菌 C57BL/6J 以及 GPR41、GPR43、GPR109A 和 GPR41、GPR43、GPR109A 和GPR43/109A 也包括在内。 C57BL/6J小鼠被植入含有盐水或缓慢升压剂量的血管紧张素II（0.25mg中心点kg(-1)中心点d(-1)）的微型泵。给小鼠喂食缺乏益生元纤维的饮食，添加或不添加肠道代谢物（称为短链脂肪酸（[SCFA）]，是在大肠中益生元纤维发酵过程中产生的），或喂食高益生元纤维饮食。确定了心脏组织学和功能、血压、钠和钾排泄、肠道微生物组、流式细胞术、儿茶酚胺和甲基化范围的变化。结果：缺乏益生元纤维使小鼠在轻度高血压刺激下易患高血压，从而导致病理性心脏重塑。将致高血压微生物群转移至无菌小鼠体内，重现了缺乏益生元的高血压表型，包括心脏表现。将短链脂肪酸重新引入纤维耗尽的小鼠体内对高血压、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同源 SCFA 受体 GPR43/GPR109A 介导的，并调节 L-3,4-二羟基苯丙氨酸水平和受 DNA 甲基化调节的 T 调节细胞的丰度。结论：低纤维西化饮食的有害影响可能是通过 SCFA 产生不足和 GPR43/109A 信号传导导致高血压的原因。维持健康的、产生 SCFA 的微生物群对于心血管健康非常重要。
Background: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.Methods: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 center dot kg(-1)center dot d(-1)). 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.Results: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.Conclusions: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.