Intestinal Microbiota May Potentially Serve as Therapeutic Target in PAH

A growing amount of data are pointing to intestinal microbiota playing a key role in pulmonary arterial hypertension (PAH), wrote researchers of a new paper, published in Frontiers in Cellular and Infection Microbiology. They note that targeting intestinal microbiota may have potential in complementing targeted vasodilation treatments for the condition.

With mounting evidence that modifying the gut microbiota can hinder the progression of various chronic diseases, such as metabolic diseases and cardiovascular diseases, intestinal flora has been suggested as a potential treatment target for PAH. According to the researchers, diet, antibiotics, probiotics, or fecal microbiota transplantation may be effective in this condition as various factors ranging from age to drugs can affect the microbiota.

In their paper, the researchers wrote that while there is a lack of direct data solidifying the connection between gut microbiota and PAH, gut dysbiosis generates pathophysiological changes that are similar to those of PAH. The group added that perivascular inflammatory infiltration is a key feature of pulmonary arterial lesions, suggesting that immune dysregulation leads to vascular remodeling in the disease.

“Although limited to rare human studies, convincing animal data linking gut dysbiosis to PAH have been available,” wrote the researchers.“Gut microbiota can modulate the host’s immune condition, and alterations of gut microbiota composition and the activation of inflammation support that gut dysbiosis involves in the inflammation process of PAH. Meanwhile, PAH is a complex clinical syndrome and gut dysbiosis may be a concomitant symptom of RHF or other pathogenic factors.”

Recent data coming from animal and clinical research has suggested that gut dysbiosis plays a role in the inflammatory response seen in PAH as gut microbiota helps regulate immune response through the metabolism of endotoxin, short-chain fatty acids, tryptophan, and trimethylamine/trimethylamine N-oxide. Data has also shown that gut dysbiosis disrupts the gut barrier and migrates gut microbiota into circulation and by gut microbiota.

The researchers cited a murine study in which Monocrotaline-treated rats with PAH has significantly increased intestinal fibrosis, increased muscular thickness, decreased goblet cells, and shortened villus length. In the same rats, plasma intestinal fatty acid binding protein increased by 2.3 times compared with healthy rats.

“This intriguing study firstly identified that MCT-PAH is associated with impairment of intestinal barrier function and increased intestinal permeability. All these changes significantly affect the host–microbiota interaction, which may trigger a host immune response and destroy the homeostasis of the gut-lung axis,” detailed the researchers. “Furthermore, these pathological changes may also provide a suitable growth environment for pathogenic microbiota and produce a variety of pro-inflammatory substances, consequently affecting the development of PAH. However, these data need to be validated in more patients with PAH and animal models in the future.”

In cases of patients with right heart failure, previous research has shown that intestinal morphology and permeability are altered. Several studies have pointed to specific characteristics within the intestinal microbiome of patients with HF, including decreased intestinal microbial diversity, downregulation of important microflora, and overgrowth of intestinal pathogenic bacteria. These patients may exhibit intestinal wall thickening and wall edema, as well as impaired barrier function.

Reference

Qu P, Zhu T, Tan Z, Chen S, Fang Z. Role of gut microbiota in pulmonary arterial hypertension. Front Cell Infect Microbiol. Published online May 6, 2022. doi:10.3389/fcimb.2022.812303