Circadian clock-gut microbiota axis in pulmonary hypertension: linking gut-lung crosstalk, immune timing and vascular remodeling.

Pulmonary hypertension (PH) is a severe disorder characterized by progressive pulmonary vascular remodeling, increased pulmonary arterial pressure, and right heart failure. Beyond local abnormalities within the pulmonary vasculature, growing evidence suggests that PH is shaped by systemic inflammation, metabolic dysregulation, gut microbiota imbalance, and disruption of host circadian organization. In this review, we examine the circadian clock-gut microbiota-gut-lung axis as a time-dependent regulatory network in PH. We focus on core clock gene dysfunction, impaired intestinal barrier integrity, altered microbial metabolites, temporal monocyte and macrophage trafficking, NLRP3 inflammasome activation, and the feedback imposed by chronic hypoxia. The evidence is not equally strong across these mechanisms. Gut dysbiosis, altered microbial metabolites, and inflammatory monocyte activation have relatively direct PH-related support, whereas bile acid rhythmicity, engineered chronobiotic bacteria, and nanoparticle-mediated butyrate delivery remain more speculative. We therefore propose a hypoxia-circadian rhythm-gut microbiota-pulmonary vascular remodeling model as a testable framework rather than a proven causal pathway. This distinction matters: the next step for the field is not simply to identify different microbes, but to determine whether gut-derived inflammatory and metabolic signals lose their timing in PH and whether this loss of timing contributes to vascular remodeling.