Short-chain fatty acid-Butyrate ameliorates hypoxia-induced pulmonary hypertension in rat

Abstract Background: Gut Microbiome can produce numerous metabolites which may be absorbed into the circulation and play a critical role in the development of diseases. Our study wants to find out the roles of faecal microbiota and its metabolite in the development of pulmonary hypertension. Methods: SD rats were expose to either normoxia (Control, n=8) or chronic hypoxia (10% O 2 ) (n=16). Rats in chronic hypoxia were randomly received sodium butyrate (500 mg/kg) (n=8) or volume-matched saline (n=8) once a day. Rats in normoxia condition also received volume-matched saline once a day. RVSP and lung vascular features were assessed after 3 week’s treatment. Rats’ fecal samples were collected and analyzed by GCMS and 6S/18S Amplicon Sequencing. Activation of HIF-1α, HMGB2, TLR4, TNF-α, HDAC5 and PCNA was assessed using Western blot analysis. The effect of sodium butyrate on proliferation of pulmonary artery smooth muscle cell, induced by PDGF or hypoxia (1% O 2 ), was evaluated by CCK-8, EDU assay and wound healing assay. Results: Hypoxia significantly increased RVSP and induced a significant decrease in butyrate-producing bacteria, but a slight decrease of SCFAs without statistic difference. Administration of sodium butyrate remarkably attenuated the RVSP and improved lung vascular features. Decreased expression of HDAC5, PCNA, HIF-1α, HMGB2, TLR4, TNF-α and inhibited proliferation of PASMC were found in rats or cells with sodium butyrate. Conclusions: Decreased butyrate-producing bacteria may contribute to the development of PH, and sodium butyrate supplement can effectively attenuate hypoxia-induced PH in rats probably by inhibiting the proliferation and migration of PASMC.