BACKGROUND Tryptophan metabolism is important in blood pressure regulation. The tryptophan-indole pathway is exclusively mediated by the gut microbiota. ACE2 (angiotensin-converting enzyme 2) participates in tryptophan absorption, and a lack of ACE2 leads to changes in the gut microbiota. The gut microbiota has been recognized as a regulator of blood pressure. Furthermore, there is ample evidence for sex differences in the gut microbiota. However, it is unclear whether such sex differences impact blood pressure differentially through the tryptophan-indole pathway. METHODS To study the sex-specific mechanisms of gut microbiota-mediated tryptophan-indole pathway in hypertension, we generated a novel rat model with Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9)-targeted deletion of Ace2 in the Dahl salt-sensitive rat. Cecal microbiota transfers from donors of both sexes to female S recipients were performed. Also, Dahl salt-sensitive rats of both sexes were orally gavaged with indole to investigate blood pressure response. RESULTS The female gut microbiota and its tryptophan-indole pathway exhibited greater buffering capacity when exposed to tryptophan, due to Ace2 deficiency, and salt. In contrast, the male gut microbiota and its tryptophan-indole pathway were more vulnerable. Female rats with male cecal microbiota responded to salt with a higher blood pressure increase. Indole, a tryptophan-derived metabolite produced by gut bacteria, increased blood pressure in male but not in female rats. Moreover, salt altered host-mediated tryptophan metabolism, characterized by reduced serum serotonin of both sexes and higher levels of kynurenine derivatives in the females. CONCLUSIONS We uncovered a novel sex-specific mechanism in the gut microbiota-mediated tryptophan-indole pathway in blood pressure regulation. Salt tipped the tryptophan metabolism between the host and gut microbiota in a sex-dependent manner. Our study provides evidence for a novel concept that gut microbiota and its metabolism play sex-specific roles in the development of salt-sensitive hypertension.

中文翻译：

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盐反应性肠道微生物群会诱导性别特异性血压变化。


背景色氨酸代谢在血压调节中很重要。色氨酸-吲哚途径完全由肠道微生物群介导。ACE2（血管紧张素转换酶 2）参与色氨酸吸收，缺乏 ACE2 会导致肠道微生物群发生变化。肠道微生物群已被公认为血压的调节剂。此外，有充分的证据表明肠道微生物群存在性别差异。然而，目前尚不清楚这种性别差异是否通过色氨酸-吲哚途径对血压产生差异影响。方法 为了研究高血压中肠道微生物群介导的色氨酸-吲哚途径的性别特异性机制，我们生成了一种新的大鼠模型，该模型具有成簇的规则间隔短回文重复序列/Cas9 （成簇的规则间隔短回文重复序列相关蛋白 9） 靶向缺失 Ace2 在 Dahl 盐敏感大鼠中。进行了从两性供体到女性 S 受体的盲肠微生物群转移。此外，用吲哚口服灌胃两种性别的 Dahl 盐敏感大鼠以研究血压反应。结果 由于 Ace2 缺乏和盐，女性肠道菌群及其色氨酸-吲哚途径在暴露于色氨酸时表现出更大的缓冲能力。相比之下，雄性肠道菌群及其色氨酸-吲哚途径更脆弱。具有雄性盲肠微生物群的雌性大鼠对盐的反应更高，血压升高。吲哚是肠道细菌产生的色氨酸衍生代谢物，可升高雄性大鼠的血压，但不会增加雌性大鼠的血压。此外，盐改变了宿主介导的色氨酸代谢，其特征是两性血清血清素降低，雌性犬尿氨酸衍生物水平升高。 结论 我们在肠道菌群介导的色氨酸-吲哚途径中发现了一种新的性别特异性机制。盐以性别依赖性的方式促进了宿主和肠道微生物群之间的色氨酸代谢。我们的研究为肠道菌群及其代谢在盐敏感高血压的发展中起性别特异性作用的新概念提供了证据。