肠道微生物群缺失会改变免疫系统组成并削弱心肌梗死后的心脏修复。

Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair.

机构信息

Program in Molecular Medicine, National Yang Ming University and Academia Sinica, Taipei, Taiwan (T.W.H.T., P.C.C.H.).

Institute of Biomedical Sciences (T.W.H.T., H.C.-C., C.-Y.C., C.Y.T.Y., C.-J.L., R.P.P., L.-L.C., S.-C.R., J.-H.L., P.-J.L., H.-H.L., J.-W.S., P.C.H.H.), Academia Sinica, Taipei, Taiwan.

出版信息

Circulation. 2019 Jan 29;139(5):647-659. doi: 10.1161/CIRCULATIONAHA.118.035235.

DOI:10.1161/CIRCULATIONAHA.118.035235

PMID:30586712

Abstract

BACKGROUND

The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated.

METHODS

To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI.

RESULTS

Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate.

CONCLUSIONS

Gut microbiota-derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.

摘要

背景

肠道微生物群对宿主生理调节的影响最近引起了广泛关注，特别是在免疫系统和代谢等关键领域。这些领域对于心肌梗死（MI）的病理生理学和修复也至关重要。然而，肠道微生物群在 MI 背景下的作用仍有待充分阐明。

方法

为了研究肠道微生物群在 MI 后心脏修复中的作用，C57BL/6J 小鼠在 MI 前 7 天接受抗生素治疗以耗尽小鼠肠道微生物群。流式细胞术用于检测心脏中免疫细胞组成的变化。16S rDNA 测序作为肠道微生物组成变化的检测指标。通过高效液相色谱法鉴定抗生素处理后改变的短链脂肪酸（SCFA）种类。进行粪便再定植、单核细胞移植、膳食 SCFA 或乳杆菌益生菌补充，以评估微生物群对 MI 后小鼠的心脏保护作用。

结果

接受抗生素治疗的小鼠在 MI 后表现出明显的、剂量依赖性的死亡率。我们观察到肠道微生物群耗竭与髓样细胞比例和 SCFA（特别是乙酸盐、丁酸盐和丙酸盐）显著减少之间存在关联。MI 后 CX3CR1+单核细胞向梗死周边区的浸润也减少，提示 MI 后修复受损。因此，粪便再定植、单核细胞移植或膳食 SCFA 补充显著改善了小鼠的生理状态和存活率。MI 与肠道微生物群落的重组有关，例如乳杆菌的减少。在 MI 前用乳杆菌益生菌补充抗生素治疗的小鼠可以恢复髓样细胞比例，产生心脏保护作用，并使 SCFA 平衡向丙酸盐倾斜。