LipReg4 deletion blocks hypertension induced by gut S. aureofaciens Tü117

Streptomyces aureofaciens ( S. aureofaciens ) Tü117 and its metabolite α-lipomycin have been implicated in high-salt-induced hypertension. Previous studies showed that high-salt intake increases gut Tü117 abundance and circulating α-lipomycin levels. Mechanistically, α-lipomycin acts as a TRPV4 antagonist, impairing nitric oxide (NO)- and endothelium-derived hyperpolarizing factor (EDHF)- mediated endothelium-dependent vasodilation and thereby promoting vascular dysfunction and blood pressure (BP) elevation. However, whether hypertension is driven by Tü117 itself or specifically by α-lipomycin production remains unclear. Here, we generated a LipReg4 deletion mutant strain (ΔTü117) using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 genome editing to selectively abolish α-lipomycin biosynthesis. Deletion of LipReg4 did not markedly affect bacterial growth but completely abolished α-lipomycin production. Compared with Tü117, ΔTü117 failed to increase circulating α-lipomycin levels or induce a sustained elevation in BP. These findings identify α-lipomycin as the key metabolite mediating Tü117-induced hypertension. They further support a direct role of gut microbial metabolites in host BP regulation.