Pulmonary arterial hypertension (PAH) is primarily associated with abnormal changes to the pulmonary vasculature, which eventually leads to irreversible right heart failure. Pathologists characterize endothelial dysfunction and pulmonary arterial fibrosis as the main drivers of vascular stiffening.
Over the last few years, scientists have painstakingly put together a picture of the network of pathological processes that drive abnormal pulmonary remodeling, potentially opening up new pathways to treating this disease.
“Despite recent advances in using combination drug therapy and identification of new vascular signaling pathways as targets, treatment of PAH remains a significant challenge,” Kim and colleagues wrote in Hypertension.
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One of the challenges of treating PAH is that researchers are discovering that the scope of the disease is much wider and more systemic than previously imagined. The most straightforward way to understand PAH etiology is that abnormal pulmonary remodeling makes gaseous exchange in the lungs less efficient, forcing the heart to work much harder, eventually causing failure. However, current evidence suggests that more systems may be involved.
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“Our previous studies and those of others have . . . suggested that PAH could be a systemic disease, where coordinated interactions of multiple organ systems may be involved in the initiation and establishment of PAH pathophysiology,” Sharma and colleagues wrote in European Respiratory Society Open Research.
Let’s explore this statement further. Regarding the neurological system, scientists have uncovered the role that neuroinflammation and microglia activation in autonomic brain regions play in driving PAH pathophysiology via enhanced sympathetic activity. It appears that the brain and the lungs “communicate” in PAH, consistent with studies showing that patients with PAH demonstrate increased sympathetic nervous activity. In addition, neuroinflammation can be observed in various pulmonary and hypoxic diseases.
The Role of the GI System
Just as there is a “brain-lung” axis in PAH, medical researchers believe there also exists a “gut-lung” axis in the disease.
On the surface, this may seem like an odd pairing, given the relative anatomical distance between the two organs. However, a closer look reveals that there are many striking parallels between the gut and the lungs.
“There are remarkable similarities between lung and gut in relation to infection, immunity, epithelial barrier functions and microbiomes,” Kim and colleagues wrote in Hypertension.
They offer 3 examples. First, both systems have direct contact with the external environment, meaning that toxins, smoking, and infection can influence both organs. This is why diarrhea and cough can both be symptoms of the flu.
Second, both the gut and the lungs have epithelia that serve as natural microbial barriers; incidentally, mucin plays an important role in both of them. Third, they both contain diverse microbiota.
In recent years, there has been renewed interest in the role that gut microbiota plays in overall health, driven by corporations that promote their products as being able to enhance the concentration of ”good” microbiota in the gut. However, the relationship between the gut and the lungs remains mostly enigmatic in the public’s mind.
The gut-lung axis deserves exploration because it can give us new insights into the pathophysiology of PAH and open the doors to new forms of treatment.
The Gut-Lung Axis
In the simplest of terms, scientists propose that dysbiosis and increased leakiness in the gut can cause an imbalance in the gut and plasma metabolites, triggering many of the hallmarks of PAH: inflammation, endothelial dysfunction, vascular remodeling, and cardiopulmonary dysfunctions.
Medical literature suggests that patients with PAH have distinct gut microbiome composition. Studies comparing the fecal microbiome of patients with PAH with control subjects found that patients with PAH have fecal microbiota with reduced alpha diversity, richness, and evenness.
If patients with PAH have altered gut microbiota, can that data be used to predict patients at risk of developing PAH? An algorithm was created to see if this could be done. This algorithm containing 140 individual decision trees used 30 bacterial species with the highest Gini index to predict the presence or absence of PAH. It successfully predicted the correct outcomes with 83% accuracy, higher than the 50% threshold if there was no association between gut microbiota and PAH.
Sharma and colleagues, starting with the hypothesis that gut wall pathology and alterations in gut microbial communities are associated with PAH pathophysiology, conducted a series of studies on rat models to see if this was the case.
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Their study yielded 3 important findings. The first is enhanced sympathetic nervous system activity and gut-to-brain connections in animals induced with PAH. Second, rats induced with PAH have an altered gut pathology, microbial communities, and increased gut permeability. Lastly, there was a significant difference in the bacterial genera between rat models induced with PAH and animals with systemic hypertension.
“Our data, for the first time, demonstrate that [monocrotaline]-induced PAH is associated with profound gut wall pathology,” they concluded. “This includes increased fibrosis and muscular tissue in the gut wall, stunted villi and decreased goblet cells. These changes have significant implications for host–microbiome interactions that potentially influence brain–gut–lung homeostasis.”
All this data leaves open the possibility that future therapies can target both the gut and the lungs simultaneously, potentially improving clinical outcomes. Currently, PAH therapies do not go far enough in tackling the disease in a multisystemic manner. We need to be bold enough to follow where the evidence takes us in order to come up with innovative therapies that our patients need and deserve.
References
Sharma RK, Oliveira AC, Yang T, et al. Pulmonary arterial hypertension-associated changes in gut pathology and microbiota. ERJ Open Res. 2020;6:00253-2019. doi:10.1183/23120541.00253-2019.
Kim S, Rigatto K, Gazzana MB, et al. Altered gut microbiome profile in patients with pulmonary arterial hypertension. Hypertension. 2020;75(4):1063-1071. doi:10.1161/HYPERTENSIONAHA.119.14294
Huang L, Zhang H, Liu Y, Long Y. The role of gut and airway microbiota in pulmonary arterial hypertension. Front Microbiol. 2022;13:929752. doi:10.3389/fmicb.2022.929752
