Targeting gut microbes may be strategy for PAH treatment: Study
Transplanting microbes from healthy to PAH rats reduced disease severity
People with pulmonary arterial hypertension (PAH) have abnormalities in their gut microbes that may play a role in their disease, a study reports.
Transplanting gut microbes from healthy rats into the digestive tract of a rat model of PAH led to a reduction in disease severity, suggesting that targeting gut microbes may be a viable strategy for PAH.
“This study opens up new avenues for developing innovative microbiota-based therapies” for PAH, scientists wrote in the study, “Multi-kingdom gut microbiota dysbiosis is associated with the development of pulmonary arterial hypertension,” which was published in eBioMedicine.
The human digestive system is home to trillions of bacteria and other microorganisms, known collectively as the gut microbiome. Emerging research suggests the gut microbiome plays key roles in health and human disease.
Studies have reported changes in the structure and function of gut bacteria in people with PAH, along with links between specific bacterial species and disease severity. Much remains to be understood, however, including what roles microbes other than bacteria play and if transplanting microbes from the gut can be effective in PAH.
Importance of gut microbiome
Here, scientists in China performed detailed analyses of the gut microbiome in 31 people with idiopathic PAH (that is, PAH of unknown origin) and 31 healthy controls matched by sex and age. Significant differences were seen in the gut microbiomes of people with PAH, not just with bacteria, but also other microorganisms, including fungi and archaea. Archea are single-celled organisms similar to bacteria that lack a cell nucleus, but have differences in a number of traits, such as the composition of their cell walls.
“These findings underscore the critical role of the entire [gut microbiome] in PAH,” wrote the scientists, who took fecal samples from people with PAH or rats with PAH-like disease and transplanted them into the digestive tract of healthy rats to see how these alterations in gut microbes may affect disease. Transplants from healthy rats to the PAH rat model — where PAH is induced by injecting a chemical called monocrotaline — were also performed. Transplants were given orally into the stomach over two weeks, and assessments of blood flow and heart health were done weeks later.
The rats given transplants from people with PAH or from rats modeling PAH developed increased blood pressure in the vessels that carry blood through the lungs. Other PAH-related changes indicated alterations in the function and structure of the heart’s right ventricle, which pumps oxygen-depleted blood to the lungs, and elevated pulmonary vascular resistance, or resistance to blood flow.
In a separate experiment, the researchers transplanted fecal samples from healthy rats into the digestive tract of rats with PAH-like disease. This led to reduced signs of disease, including less pressure in lung blood vessels, reversed changes in the right ventricle, and lower pulmonary vascular resistance. Other benefits included restored gut microbial composition and a shift of the blood metabolite profiles toward those of healthy rats. Metabolites are intermediate or end products of metabolism.
“[Fecal microbiota transplantation] from control rats significantly ameliorated PAH conditions in rat models, restoring [gut microbiome] composition and reversing PAH-associated changes in [blood] serum metabolite profiles,” the researchers wrote.
There were 737 genes that were differentially activated among healthy rats and those with PAH-like disease, results showed. Looking at biological pathways, the investigators found that transplanting gut microbes may ease PAH progression by reducing inflammation and structural alterations in blood vessels, and by easing blood vessel tightening in the lungs.
Finally, the researchers found that using markers from bacteria, fungi and archaea was better at diagnosing idiopathic PAH than using markers from only one of these groups. The data suggest microbiota-based therapies may be a viable treatment strategy for PAH, though the researchers said this idea must be tested in people in clinical trials.
“Our findings highlight the critical need to move beyond a bacteria-centric view of gut microbiota in PAH, underscoring the relevance of a broader microbial landscape in the prevention and treatment of PAH,” the investigators wrote.
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