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

Objective: 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.

Methods: 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.

Results: 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 Clostridium sporogenes (C.sporogenes) 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. C.sporogenes increased the IPA level in vitro and in vivo, supplementation of C.sporogenes 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.

Conclusions: Gut microbiota dysbiosis played a promoting role in PH-LHD. IPA metabolized by C.sporogenes could inhibit PASMCs proliferation by down-regulating the Akt-mTOR pathway through adora1, further blocking the development of PH-LHD.