Lactobacillus Restructures the Micro/Mycobiome to Combat Inflammation-Mediated Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

BACKGROUND: Inflammation suppresses right ventricular (RV) function in pulmonary arterial hypertension (PAH). In particular, we showed GP130 (glycoprotein-130) signaling promotes pathological microtubule remodeling and RV dysfunction in rodent PAH. Emerging data demonstrate the intestinal microbiome regulates systemic inflammation, but the impact of modulating the gut microbiome on the GP130-microtubule axis in RV failure is unknown. METHODS: Two weeks following monocrotaline injection, rats were administered daily Lactobacillus rhamnosus (4×107 colony-forming units) via oral gavage for 10 days. Next-generation metagenomics and internal transcribed spacer 2 sequencing delineated fecal bacterial and fungal compositions. SomaScan proteomics measured levels of 7596 serum proteins. RV immunoblots quantified protein abundances. Light or super resolution confocal microscopy assessed RV, lung, and jejunal morphology. Echocardiography and invasive closed-chest pressure-volume loops evaluated PAH severity and RV function. The relationship between Lactobacillus abundance and RV function was assessed in 65 patients with PAH. RESULTS: Lactobacillus administration restructured both the intestinal micro- and mycobiome. The alteration in the gut ecosystem improved intestinal health as demonstrated by increased jejunal villus length and glycocalyx thickness and diminished intestinal permeability biomarkers. Serum proteomics revealed Lactobacillus modulated systemic inflammation and decreased circulating GP130 ligands. Lactobacillus-mediated suppression of GP130 signaling blunted pathological microtubule remodeling in RV cardiomyocytes. Microtubule-associated phenotypes, including RV cardiomyocyte and nuclear hypertrophy, transverse tubule integrity, and connexin-43 localization, were all corrected with Lactobacillus. These cellular changes manifested as improved RV function despite no significant alteration in PAH severity. Finally, patients with PAH and detectable fecal Lactobacillus had superior RV function despite similar mean pulmonary arterial pressure and pulmonary vascular resistance as compared with those without detectable Lactobacillus. CONCLUSIONS: Lactobacillus supplementation restructures the gut micro/mycobiome, restores intestinal health, dampens systemic inflammation, and reduces GP130 ligands and associated RV cardiomyocyte microtubule remodeling. These data identify a novel microbiome-inflammation-microtubule axis that has therapeutic relevance for RV dysfunction.