Indole-3-propionic acid, a metabolite of <em>Clostridium sporogenes</em>, inhibits PASMCs proliferation in PH-LHD through the Adora1-Akt-mTOR pathway

<strong>Objective: </strong>Pulmonary hypertension (PH) due to left heart diseases (PH-LHD) was the most common sub-type of PH, gut microbiota dysbiosis was involved in several sub-types of PH, but its role in PH-LHD remained elusive. <strong>Methods: </strong>SD rats were intraperitoneally injected with doxorubicin to construct a new PH-LHD model. 16S rRNA gene sequencing, non-targeted metabolomics, transcriptomics, fecal microbiota transplantation (FMT), and CRISPR-Cas9 were used to investigate the mechanism of regulating PH-LHD by gut microbiota. <strong>Results: </strong>This study established a new animal model that could simulate clinical PH-LHD disease characteristics and revealed the remarkabe changes in the gut microbiota and metabolites of PH-LHD rats, especially the significantly reduced <em>Clostridium sporogenes</em> (<em>C.sporogenes</em>) in feces and indole-3-propionic acid (IPA) in plasma. Depletion of gut microbiota with antibiotics alleviated PH-LHD, while pseudo-germ-free rats transplanted with fecal microbiota from PH-LHD rats recapitulated the disease characteristics to some degree. <em>C.sporogenes</em> increased the IPA level in vitro and in vivo, supplementation of <em>C.sporogenes</em> or IPA could inhibit the proliferation of pulmonary artery smooth muscle cells (PASMCs) and suppress PH-LHD. Mechanistically, IPA attenuated PASMCs proliferation by inhibiting the Akt-mTOR pathway via adora1, and adora1 knockout demonstrated a similar inhibitory impact on PH-LHD as observed with IPA. <strong>Conclusions:</strong> Gut microbiota dysbiosis played a promoting role in PH-LHD.<em> </em>IPA metabolized by <em>C.sporogenes</em><em> </em>could inhibit PASMCs proliferation by down-regulating the Akt-mTOR pathway through adora1, further blocking the development of PH-LHD.