Abstract Background Emerging evidence has linked gut dysbiosis to pulmonary hypertension (PH), however, the underlying mechanisms remain unclear. Objective This study aims to identify key mechanisms in the PH-associated gut microenvironment and to develop novel PH therapeutics targeting gut repair. Design The SU5416/hypoxia (SuHx)-PH rodent models were used to investigate the roles of dietary inulin, peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor GW9662 and agonist pioglitazone, and intestinal epithelial cell-specific PPARγ knockout (IEC-Pparg KO) in PH. Multi-omics analyses—including metagenomics, metabolomics, bulk RNA sequencing, and single-cell RNA sequencing (scRNA-seq)—were employed to determine the key mechanisms underlying the effects of inulin in PH. Results Hemodynamic and pathophysiological evaluations showed heterogeneous responses of SuHx rats to inulin, defining as high- (SuHx+INHigh) and low- (SuHx+INLow) responder subgroups. scRNA-seq profiling of intestinal tissues revealed an enterocyte maturation trajectory strongly correlating with the activation of PPAR signaling, particularly enriched in the mature enterocytes of SuHx+INHigh rats. Integrated microbiome-metabolome analysis uncovered conserved TMAO-producer reduction in both inulin groups, whereas significant restoration of and SCFA-producing and PPARγ-activating microbiota in SuHx+INHigh subgroup. Both GW9662 and IEC-Pparg KO abolished the inulin-induced gut, lung, and heart protection in SuHx rodent models. Synergistic PPARγ activation by inulin and pioglitazone combination therapy demonstrated enhanced therapeutic efficacy in SuHx rat model versus monotherapy, proving enhanced protection across the gut, lung, and heart. Conclusion These findings indicate that microbial-driven activation of IEC PPARγ is a key regulator mediating the therapeutic action of inulin. Targeted activation of gut PPARγ represents a novel therapeutic strategy for PH. This abstract is funded by: National Natural Science Foundation of China; National Science and Technology Innovation 2030, Major Project- Research on Cancer, Cardiovascular, Respiratory and Metabolic Diseases
Yang et al. (Fri,) studied this question.