Unruptured intracranial aneurysm (UIA) is a life-threatening cerebrovascular condition. Whether changes in gut microbial composition participate in the development of UIAs remains largely unknown. We perform a case-control metagenome-wide association study in two cohorts of Chinese UIA patients and control individuals and mice that receive fecal transplants from human donors. After fecal transplantation, the UIA microbiota is sufficient to induce UIAs in mice. We identify UIA-associated gut microbial species link to changes in circulating taurine. Specifically, the abundance of Hungatella hathewayi is markedly decreased and positively correlated with the circulating taurine concentration in both humans and mice. Consistently, gavage with H. hathewayi normalizes the taurine levels in serum and protects mice against the formation and rupture of intracranial aneurysms. Taurine supplementation also reverses the progression of intracranial aneurysms. Our findings provide insights into a potential role of H. hathewayi-associated taurine depletion as a key factor in the pathogenesis of UIAs.

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Hypertensive intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease with no effective treatment. Lysyl hydroxylase 3 (LH3) is essential for collagen IV intermolecular crosslinking and stabilization. Deficiency in LH3 affects the assembly and secretion of collagen IV and basement membrane (BM) integrity of vessels. Here, we investigated whether LH3 has significant implications for disease progression and therapeutic intervention. Spontaneous hypertensive ICH of mice was induced by angiotensin II and L-NAME treatment. The adeno-associated virus was delivered into brain by stereotactic injection to knockdown or overexpress LH3. We found LH3 levels were reduced in human patients with ICH and gradually decreased in mice before ICH. LH3 knockdown increased the incidence of hypertensive ICH in mice. The incidence, number, and size of ICHs in mice were markedly reduced by LH3 overexpression. RNA-seq revealed that LH3 overexpression significantly reversed the profound alterations in gene transcriptional profiles of cerebral vessels. LH3 overexpression was sufficient to enhance BM integrity, inhibit matrix metalloproteinase activity, attenuate microglial activation and leukocyte infiltration, and reduce VSMC apoptosis before ICH. These results indicate that LH3 overexpression attenuates susceptibility to hypertensive ICH. We emphasize that LH3 modulation may serve as a viable approach for future investigations of ICH prevention.

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Plasma metabolic profiles were compared between patients with hypertension with and without left ventricular hypertrophy and significantly decreased oleic acid (OA) levels were observed in the peripheral blood of patients with hypertension with left ventricular hypertrophy. We sought to determine the effect and underlying mechanisms of OA on cardiac remodeling. In vitro studies with isolated neonatal mouse cardiomyocytes and cardiac fibroblasts revealed that OA significantly attenuated Ang II (angiotensin II)-induced cardiomyocyte growth and cardiac fibroblast collagen expression. In vivo, cardiac function, hypertrophic growth of cardiomyocytes, and fibrosis were analyzed after an Ang II (1000 ng/kg/minute) pump was implanted for 14 days. We found that OA could significantly prevent Ang II-induced cardiac remodeling in mice. RNA sequencing served as a gene expression roadmap highlighting gene expression changes in the hearts of Ang II-induced mice and OA-treated mice. The results revealed that FGF23 (fibroblast growth factor 23) expression was significantly upregulated in mouse hearts in response to Ang II infusion, which was significantly suppressed in the hearts of OA-treated mice. Furthermore, overexpression of FGF23 in the heart by injection of an AAV-9 vector aggravated Ang II-induced cardiac remodeling and impaired the protective effect of OA on cardiac remodeling. Further study found that OA could suppress Ang II-induced FGF23 expression by inhibiting the translocation of Nurr1 (nuclear receptor–related 1 protein) from the cytoplasm to the nucleus. Our findings suggest a novel role of OA in preventing Ang II-induced cardiac remodeling via suppression of FGF23 expression.