Data and code for Akebia saponin D reveals a microbial FAAH-like enzyme–oleoylglycine–HDAC7 axis in metabolic hypertension

Gut microbial regulation of host lipid-amide metabolites remains poorly understood in metabolic hypertension. Here, using Akebia saponin D (ASD) as a microbiota-modulating perturbation in high-fat diet (HFD)-fed spontaneously hypertensive rats, we investigated whether microbial remodeling contributes to blood pressure regulation through metabolite-dependent host signaling. ASD reduced blood pressure, ameliorated dyslipidemia, and attenuated vascular injury, whereas antibiotic-mediated microbiota depletion abolished or markedly weakened these protective effects. Conversely, co-housing transferred key aspects of the ASD-associated protective phenotype to untreated HFD-fed rats, supporting a microbiota-dependent mechanism. 16S rRNA gene amplicon sequencing showed that ASD induced reproducible remodeling of the HFD-disrupted gut microbial community, while integrated fecal and plasma metabolomic profiling identified oleoylglycine (OlGly) as a lipid-amide metabolite depleted by HFD feeding and restored by ASD treatment. Rather than being inferred directly from 16S rRNA gene profiles alone, a homology-guided functional screen identified Segatella copri as an OlGly-depleting bacterium encoding a fatty acid amide hydrolase (FAAH)-like enzyme. In vitro and in vivo validation demonstrated that S. copri hydrolyzed OlGly, exacerbated the metabolic hypertensive phenotype, and weakened the protective effects of either ASD or exogenous OlGly. Mechanistically, OlGly directly bound to and stabilized HDAC7, promoted its nuclear retention, and suppressed endothelial inflammatory and fibrotic signaling involving HDAC7–MEF2, NF-κB, and TGF-β pathways. These findings define a microbiota–lipid amide–host epigenetic axis in metabolic hypertension and highlight microbial FAAH-like activity as a mechanism controlling protective metabolite availability.