Aims Hypertension (HTN) can lead to heart and kidney damage. The gut microbiota has been linked to HTN, although it is difficult to estimate its significance due to the variety of other features known to influence HTN. In the present study, we used germ-free (GF) and colonized (COL) littermate mice to quantify the impact of microbial colonization on organ damage in HTN. Methods and results Four-week-old male GF C57BL/6J littermates were randomized to remain GF or receive microbial colonization. HTN was induced by subcutaneous infusion with angiotensin (Ang) II (1.44 mg/kg/d) and 1% NaCl in the drinking water; sham-treated mice served as control. Renal damage was exacerbated in GF mice, whereas cardiac damage was more comparable between COL and GF, suggesting that the kidney is more sensitive to microbial influence. Multivariate analysis revealed a larger effect of HTN in GF mice. Serum metabolomics demonstrated that the colonization status influences circulating metabolites relevant to HTN. Importantly, GF mice were deficient in anti-inflammatory fecal short-chain fatty acids (SCFA). Flow cytometry showed that the microbiome has an impact on the induction of anti-hypertensive myeloid-derived suppressor cells and pro-inflammatory Th17 cells in HTN. In vitro inducibility of Th17 cells was significantly higher for cells isolated from GF than conventionally raised mice. Conclusions Microbial colonization status of mice had potent effects on their phenotypic response to a hypertensive stimulus, and the kidney is a highly microbiota-susceptible target organ in HTN. The magnitude of the pathogenic response in GF mice underscores the role of the microbiome in mediating inflammation in HTN. Translation Perspective To assess the potential of microbiota-targeted interventions to prevent organ damage in hypertension, an accurate quantification of microbial influence is necessary. We provide evidence that the development of hypertensive organ damage is dependent on colonization status and suggest that a healthy microbiota provides anti-hypertensive immune and metabolic signals to the host. In the absence of normal symbiotic host-microbiome interactions, hypertensive damage to the kidney in particular is exacerbated. We suggest that hypertensive patients experiencing perturbations to the microbiota, which are common in CVD, may be at a greater risk for target-organ damage than those with a healthy microbiome.

中文翻译：

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量化肠道微生物群对炎症和高血压器官损伤的影响

目标 高血压 (HTN) 可导致心脏和肾脏损伤。肠道微生物群与高血压有关，尽管由于已知影响高血压的其他特征的多样性，很难估计其重要性。在本研究中，我们使用无菌（GF）和定植（COL）同窝小鼠来量化微生物定植对 HTN 器官损伤的影响。方法和结果 4 周大的雄性 GF C57BL/6J 同窝小鼠被随机分为保留 GF 或接受微生物定植。通过皮下注射血管紧张素（Ang）II（1.44 mg/kg/d）和饮用水中的1% NaCl诱导HTN；假处理的小鼠作为对照。GF 小鼠的肾损伤加剧，而 COL 和 GF 小鼠的心脏损伤更相似，表明肾脏对微生物的影响更敏感。多变量分析显示 HTN 对 GF 小鼠的影响更大。血清代谢组学表明定植状态影响与 HTN 相关的循环代谢物。重要的是，GF 小鼠缺乏抗炎粪便短链脂肪酸 (SCFA)。流式细胞术显示，微生物组对 HTN 中抗高血压骨髓源性抑制细胞和促炎 Th17 细胞的诱导有影响。从 GF 中分离的细胞的 Th17 细胞体外诱导能力显着高于传统饲养的小鼠。结论 小鼠的微生物定植状态对其对高血压刺激的表型反应具有重要影响，并且肾脏是高血压中微生物群高度敏感的靶器官。GF 小鼠致病反应的强度强调了微生物组在介导 HTN 炎症中的作用。为了评估以微生物群为目标的干预措施预防高血压器官损伤的潜力，有必要准确量化微生物的影响。我们提供的证据表明，高血压器官损伤的发展取决于定植状态，并表明健康的微生物群向宿主提供抗高血压免疫和代谢信号。在缺乏正常的宿主-微生物组共生相互作用的情况下，高血压对肾脏的损害尤其会加剧。我们认为，与微生物群健康的患者相比，微生物群受到干扰的高血压患者（这在心血管疾病中很常见）可能面临更大的靶器官损伤风险。