The Role and Mechanism of Gut Microbiota in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular disease characterized by increased pulmonary vascular resistance, pulmonary vasoconstriction, and right ventricular hypertrophy. Recent developments in genomics and metabolomics have gradually revealed the roles of the gut microbiota (GM) and its metabolites in cardiovascular diseases. Accumulating evidence reveals that the GM plays important roles in the occurrence and development of PAH. Gut microbiota dysbiosis directly increases the gut permeability, thereby facilitating pathological bacterial translocation and allowing translocation of bacterial products such as lipopolysaccharides from the gut into circulation. This process aggravates pulmonary perivascular inflammation and exacerbates PAH development through the endothelial–mesenchymal transition. Additionally, a shift in the composition of PAH also affects the gut metabolites. Changes in gut metabolites, such as decreased short-chain fatty acids, increased trimethylamine N-oxide, and elevated serotonin, contribute to pulmonary perivascular inflammation and pulmonary vascular remodeling by activating several signaling pathways. Studies of the intestinal microbiota in treating pulmonary hypertension have strengthened linkages between the GM and PAH. Probiotic therapy and fecal microbiota transplantation may supplement existing PAH treatments. In this article, we provide new insight for diagnosing, preventing and treating PAH by adding to the current knowledge of the intestinal flora mechanisms and its metabolites efficacy involved in PAH.

Partially hydrolyzed guar gum suppresses the progression of pulmonary arterial hypertension in a SU5416/hypoxia rat model

“…PHGG administration prevented PAH development in Su/Hx rats. Our previous study demonstrated that modifying the gut microbiota using antibiotics suppressed the development of pulmonary hypertension in Su/Hx rats, 17 indicating that gut dysbiosis can play a causal role in PAH development, and restoring the gut microbiota may be a new therapeutic option for PAH 3 . However, long‐term antibiotic treatment can harm patients and does not appear to be a prebiotic agent applicable in clinical situations.…”

“…The gut microbiota is an ecological community of symbiotic microorganisms that play an important role in producing vitamins and maintaining gut barrier functions and the immune system 3 . Abnormal alterations, known as gut dysbiosis, are related to the development of cardiovascular diseases 3 .…”

“…The gut microbiota is an ecological community of symbiotic microorganisms that play an important role in producing vitamins and maintaining gut barrier functions and the immune system 3 . Abnormal alterations, known as gut dysbiosis, are related to the development of cardiovascular diseases 3 . Recently, gut dysbiosis has been observed in PAH animal models 4 and patients with PAH 5 and chronic thromboembolic pulmonary hypertension 6 .…”

Targeting Iron Metabolism and Ferroptosis as Novel Therapeutic Approaches in Cardiovascular Diseases

“…Pulmonary arterial hypertension (PAH) is a vascular disease characterized by small pulmonary arteries remodeling, elevated pulmonary artery pressure and right ventricular hypertrophy [ 53 , 54 ]. PAH is a form of PH and is largely influenced by iron metabolism [ 55 ].…”

Inactivating the Uninhibited: The Tale of Activins and Inhibins in Pulmonary Arterial Hypertension

“…In systemic lupus erythematosus patients with PAH, lipopolysaccharide (LPS)-induced pyroptosis contributes to defective BMPRII (bone morphogenetic protein receptor type 2) signaling, which has a central role in PAH pathogenesis [ 13 ]. LPS is a component of the bacterial cell wall that triggers activation of toll-like receptors (TLRs), mainly TLR4, and the subsequent activation of pro-inflammatory signaling pathways, such as NF-κB, which drives inflammatory cytokine expression (e.g., IL-6), with many cytokines participating in the pulmonary vascular remodeling through perivascular inflammation [ 14 ]. An increase in serum LPS level, thought to be related to the gut dysbiosis commonly observed in PAH patients, has been noted in preclinical animal models of PAH, such as monocrotaline-treated rats, as well as in various forms of PAH, including IPAH, HPAH, PAH, and the aforementioned PAH due to SLE [ 13 , 14 , 15 ].…”