Prisco Sasha Z, Blake Madelyn, Kazmirczak Felipe, Moon Ryan, Kremer Benjamin P, Hartweck Lynn M, Kim Minwoo, Vogel Neal, Mendelson Jenna B, Moutsoglou Daphne, Thenappan Thenappan, Prins Kurt W
Lillehei Heart Institute, Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis (S.Z.P., M.B., F.K., R.M., B.P.K., L.M.H., M.K., N.V., J.B.M., T.T., K.W.P.).
Gastroenterology Section, Minneapolis VA Health Care System, MN (D.M.).
Circ Heart Fail. 2025 Jul;18(7):e012524. doi: 10.1161/CIRCHEARTFAILURE.124.012524. Epub 2025 May 16.
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.
Two weeks following monocrotaline injection, rats were administered daily (4×10 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 abundance and RV function was assessed in 65 patients with PAH.
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 modulated systemic inflammation and decreased circulating GP130 ligands. -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 . These cellular changes manifested as improved RV function despite no significant alteration in PAH severity. Finally, patients with PAH and detectable fecal had superior RV function despite similar mean pulmonary arterial pressure and pulmonary vascular resistance as compared with those without detectable .
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.
炎症会抑制肺动脉高压（PAH）患者的右心室（RV）功能。特别是，我们发现GP130（糖蛋白130）信号传导会促进啮齿动物PAH中的病理性微管重塑和RV功能障碍。新出现的数据表明，肠道微生物群可调节全身炎症，但调节肠道微生物群对RV衰竭中GP130-微管轴的影响尚不清楚。
在注射野百合碱两周后，通过口服灌胃法每天给大鼠施用（4×10菌落形成单位），持续10天。下一代宏基因组学和内转录间隔区2测序确定了粪便细菌和真菌组成。SomaScan蛋白质组学检测了7596种血清蛋白的水平。RV免疫印迹法定量蛋白质丰度。光学或超分辨率共聚焦显微镜评估RV、肺和空肠形态。超声心动图和有创闭胸压力-容积环评估PAH严重程度和RV功能。在65例PAH患者中评估丰度与RV功能之间的关系。
施用可重构肠道微生物群和真菌群。肠道生态系统的改变改善了肠道健康，空肠绒毛长度增加、糖萼厚度增加以及肠道通透性生物标志物减少证明了这一点。血清蛋白质组学显示，调节了全身炎症并减少了循环中的GP130配体。介导的GP130信号抑制减弱了RV心肌细胞中的病理性微管重塑。微管相关表型，包括RV心肌细胞和核肥大、横管完整性和连接蛋白43定位，均通过得到纠正。尽管PAH严重程度无明显改变，但这些细胞变化表现为RV功能改善。最后，与未检测到的患者相比，检测到粪便的PAH患者尽管平均肺动脉压和肺血管阻力相似，但RV功能更好。
补充可重构肠道微生物群/真菌群，恢复肠道健康，减轻全身炎症，并减少GP130配体及相关的RV心肌细胞微管重塑。这些数据确定了一个新的微生物群-炎症-微管轴，该轴对RV功能障碍具有治疗意义。
