Experimental and Clinical Research Center, A Cooperation of Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Cardiovasc Res. 2023 Jun 13;119(6):1441-1452. doi: 10.1093/cvr/cvac121.
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.
4-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/day) 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 faecal 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.
The 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.
高血压（HTN）可导致心脏和肾脏损伤。肠道微生物群与 HTN 有关，尽管由于已知有多种其他特征会影响 HTN，因此难以估计其重要性。在本研究中，我们使用无菌（GF）和定植（COL）同窝仔鼠来定量评估微生物定植对 HTN 器官损伤的影响。
4 周龄雄性 GF C57BL/6J 同窝仔鼠被随机分为保持 GF 或接受微生物定植。通过皮下输注血管紧张素（Ang）II（1.44mg/kg/天）和饮用水中的 1%NaCl 诱导 HTN；假处理小鼠作为对照。GF 小鼠的肾脏损伤加重，而 COL 和 GF 之间的心脏损伤更为相似，这表明肾脏对微生物影响更为敏感。多变量分析显示 GF 小鼠的 HTN 影响更大。血清代谢组学表明定植状态会影响与 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 中抗高血压髓样来源的抑制细胞和促炎 Th17 细胞的诱导有影响。从 GF 而非常规饲养的小鼠分离的细胞的 Th17 细胞的体外可诱导性明显更高。
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强大的影响，肾脏是 HTN 中高度易受微生物影响的靶器官。GF 小鼠中致病性反应的幅度强调了微生物组在介导 HTN 中的炎症中的作用。
