Promising dawn in the management of pulmonary hypertension: The mystery veil of gut microbiota

Abstract

The gut microbiota is a complex community of microorganisms inhabiting the intestinal tract, which plays a vital role in human health. It is intricately involved in the metabolism, and it also affects diverse physiological processes. The gut-lung axis is a bidirectional pathway between the gastrointestinal tract and the lungs. Recent research has shown that the gut microbiome plays a crucial role in immune response regulation in the lungs and the development of lung diseases. In this review, we present the interrelated factors concerning gut microbiota and the associated metabolites in pulmonary hypertension (PH), a lethal disease characterized by elevated pulmonary vascular pressure and resistance. Our research team explored the role of gut-microbiota-derived metabolites in cardiovascular diseases and established the correlation between metabolites such as putrescine, succinate, trimethylamine N-oxide (TMAO), and N, N, N-trimethyl-5-aminovaleric acid with the diseases. Furthermore, we found that specific metabolites, such as TMAO and betaine, have significant clinical value in PH, suggesting their potential as biomarkers in disease management. In detailing the interplay between the gut microbiota, their metabolites, and PH, we underscored the potential therapeutic approaches modulating this microbiota. Ultimately, we endeavor to alleviate the substantial socioeconomic burden associated with this disease. This review presents a unique exploratory analysis of the link between gut microbiota and PH, intending to propel further investigations in the gut-lung axis.

Keywords: disease management; gut microbiota; gut–lung axis; metabolites; pulmonary hypertension.

Figure 1

Presentations of the association between gut microbiota and pulmonary hypertension. With the rapid development of technologies, including metagenomic and nontargeted or targeted metabolomics, the knowledge of gut microbiota and their related metabolites is constantly growing. Dysfunctions of microorganisms are associated with cardiovascular diseases, including heart failure, hypertension, and atherosclerotic heart disease. Recently, it has been demonstrated that gut microbiota and its associated metabolites are also involved in the pathogenesis of pulmonary hypertension. In addition, pulmonary hypertension might result in the alteration of bacterial flora. Here, we provide a comprehensive landscape of gut microbiota and metabolites in pulmonary hypertension, emphasizing the interplay between microorganisms and hosts in modulating pulmonary hypertension. CVD, cardiovascular disease; SCFA, short‐chain fatty acid; TMAO, trimethylamine N‐oxide.

Figure 2

Bidirectional gut–lung axis. The gut–lung axis is the interaction between the gut and lung, which is influenced by environmental factors, gut microbiota, and metabolites. This interaction occurs through circulation, the nervous system, and other physiological processes, ultimately affecting the health of both the gut and the lungs. (1) The homology between the lungs and intestines is the structural basis for the gut‐lung axis. (2) Micro‐fold cells in muco‐associated lymphoid tissue recognize antigens and present them to dendritic cells, which migrate to lymph nodes and stimulate immune responses from T and B lymphocytes when pathogens are present. (3) Metabolites produced by gut microbiota, including TMAO and SCFAs, circulate through the blood system to facilitate bidirectional communication between the lungs and the gut, exerting distinct effects on each organ. (4) Microbial components such as lipopolysaccharides are another soluble substance that facilitate communication between the lungs and the gut via the circulatory system. (5) Dysbiosis of gut microbiota is a visible manifestation of an imbalanced lung–gut axis, and changes in the composition and functions of the gut microbiota can influence the respiratory system via a shared mucosal immune system. LPS, lipopolysaccharide; SCFA, short‐chain fatty acid; TMAO, trimethylamine N‐oxide.

Figure 3

Distinct gut microbiota profiles of PH. PH is defined as an average pressure of greater than 20 mmHg in mean pulmonary artery pressure on supine right heart catheterization at rest. Compared to controls, PAH patients exhibited significantly decreased α‐diversity, bacterial richness, and evenness. Actinobacteria and microorganisms with pro‐inflammatory properties are increased while propionate‐ and butyrate‐producing bacteria are shown the opposite situation. α‐Diversity and the bacteria with anti‐inflammatory properties are significantly reduced in patients with CTEPH. Compared to controls, TMA‐producing species were increased, and α‐diversity of gut microbiota showed the opposite trend among PH patients living in the lowland, while no difference in these gut microorganisms was identified among highlanders with PH. Gut microbiota dysbiosis, characterized by an imbalanced ratio of Firmicutes to Bacteroidetes (F/B), has been demonstrated in various animal models of PH. The changes in gut microbiota may be involved in the pathogenesis of PH. CTEPH, chronic thromboembolic pulmonary hypertension; HAPH, high‐altitude pulmonary hypertension; LPAL, left pulmonary artery ligation; MCT, monocrotaline; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; SuHx, sugen 5416‐hypoxia; TMA, trimethylamine.

Figure 4

Gut‐microbiota associated metabolites in PH. TMAO is a potential biomarker in pulmonary hypertension. In our previous cohort study, patients were strictly included, and plasma TMAO levels were measured. High TMAO levels were associated with poor prognosis of patients with pulmonary hypertension. TMAO mainly stems from choline, abundant in red meat and fish. Intestinal flora choline‐TMA lyase can break it down to produce TMA, which enters the liver through the portal vein and is then oxidized by FMOs to generate TMAO ultimately. It has been elucidated that TMAO promoted pulmonary hypertension by upregulating the production of inflammatory factors in macrophages. In addition, a decrease in TMAO level by DMB indicates a preferable effect on pulmonary hypertension, and whether DMB can be used in clinics is worth further discussion. The generation of SCFAs results from complicated interactions between diet and gut microbiota in the intestinal environment. The SCFAs exert anti‐inflammatory effects, resulting in decreased accumulation of alveolar and interstitial lung macrophages. Decreased SCFAs activated the NF‐kB pathway and inhibited the production of anti‐inflammatory factors, which might promote the development of pulmonary hypertension. Phenylacetylglutamine is associated with atherosclerotic cardiovascular disease, the development of major adverse cardiovascular events, and to increase the risk of stroke through a potentially pro‐thrombotic effect. Whether phenylacetylglutamine is involved in the pathogenesis of PH, especially in subtypes associated with thrombosis, needs to be further investigated. DMB, 3,3‐dimethyl‐1‐butanol; FMO, flavin‐containing monooxygenases; NF‐kB, nuclear factor kappa‐B; PH, pulmonary hypertension; SCFA, hort‐chain fatty acid; TMA, trimethylamine; TMAO, trimethylamine N‐oxide.

Figure 5

Future perspectives in pulmonary hypertension. Fecal and blood samples are utilized for metagenomic and metabolite exploration to discover new biomarkers in pulmonary hypertension. Effective biomarkers for assessing disease severity and prognosis will be developed and combined with traditional assessment methods, including echocardiography, right heart catheterization, and electrocardiogram, and they facilitate comprehensive assessment of disease condition. In addition to traditional treatments, increased beneficial microbiome through dietary intervention, probiotics, or fecal microbial transplantation and decreased harmful microbiome through antibiotics or targeted drugs are promising therapeutic strategies in pulmonary hypertension. Innovations powered by the rapid development of large‐scale data technologies like artificial intelligence and machine learning hold enormous potential to revolutionize our understanding of pulmonary hypertension. Leveraging these advanced technologies can facilitate the processing and application of complex big data from the gut microbiome, metabolites, clinical information, and therapeutic targets to achieve precise management of pulmonary hypertension.