Altered gut microbial dynamics and the antivascular remodeling effect of carnosine in hypobaric hypoxic pulmonary hypertension rats

Abstract

Exposure to chronic hypobaric hypoxia provokes marked alterations in the gut microbiota and its metabolome, yet the functional significance of histidine-derived metabolites in hypobaric hypoxic pulmonary hypertension (PH) remains underexplored. Here, we employ 16S rDNA, metagenomic, and untargeted metabolomic sequencing to characterize longitudinal shifts in the fecal microbiota and metabolites during hypobaric hypoxic PH development in Sprague-Dawley rats. Fecal carnosine levels and the abundance of its producer, Ruminococcus bromii, both decrease significantly over 28 days of hypobaric hypoxia (P < 0.05). Spearman correlation shows that carnosine is inversely correlated with the percentage of pulmonary arteriole media thickness (MT%; r = –0.8741, P < 0.001). Therapeutic supplementation with carnosine restores systemic and pulmonary antioxidant defenses and attenuates vascular remodeling without altering right ventricular pressures. In vitro, carnosine inhibits hypoxia-induced pulmonary artery smooth muscle cell (PASMC) proliferation and migration and suppresses nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation. These findings reveal dynamic gut-lung crosstalk in hypobaric hypoxic PH and nominate carnosine as a metabolite-based intervention to mitigate hypoxia-driven pulmonary vascular remodeling.

1. Introduction

The high-altitude environment is characterized by hypobaric hypoxic conditions that profoundly impact multiple organ systems [1]. Chronic exposure to high altitude can induce hypobaric hypoxic pulmonary hypertension (PH) [2], which is classified as Group 3 pulmonary hypertension [3]. Hypobaric hypoxic PH is characterized by abnormal pulmonary vasoconstriction, vascular cell proliferation, and inflammatory infiltration, culminating in pathological remodeling of the pulmonary vasculature, which is driven by endothelial cell dysfunction and excessive proliferative migration of smooth muscle cells [4].

High-altitude exposure also perturbs gut homeostasis by altering the composition of the gut microbiota [5]. Such microbial shifts are recognized to correlate with both physiological adaptations and disease pathogenesis. Prior studies have highlighted gut microbiota dysbiosis in PH [6] and demonstrated that targeted modulation of the microbiome can influence PH progression [7]. Gut-derived metabolites, such as short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO), play important roles in PH pathophysiology, although specific microbial signatures vary according to the underlying etiology of PH [8]. Moreover, hypobaric hypoxic PH has been shown to disrupt amino acid metabolism, with notable alterations in the histidine, arginine, and ornithine metabolism pathways observed in PH [9]. Carnosine, a dipeptide product of the histidine metabolic pathway, exerts anti-inflammatory and antioxidant effects [10], protects endothelial integrity, and inhibits angiogenesis [11]. Exogenous carnosine supplementation has demonstrated efficacy in preventing atherosclerotic disease [12]. In vitro studies have revealed its antiproliferative effect on vascular smooth muscle cells [13].

Accordingly, our study aimed to characterize the dynamic alterations in the gut microbiota and metabolites during the development of hypobaric hypoxic PH, identify gut metabolites associated with pulmonary vascular remodeling, and validate the potential therapeutic role of carnosine in hypobaric hypoxic PH.