A Gut Feeling

Corresponding Authors

Evidence is accumulating that gastrointestinal dysbiosis may contribute to the systemic proinflammatory state that is present in infections, autoimmune diseases, and cancer.¹ Studies are ongoing testing the hypothesis that altering the microbial biome with microbiota transplant therapy (MTT) derived from donor stool may modulate this proinflammatory milieu and thus provide a novel target for treating these diseases.²

Pulmonary artery hypertension (PAH) is a condition that is characterized by extensive vascular remodeling of the small pulmonary arteries, leading to elevations in pulmonary artery pressure and vascular resistance, right ventricular hypertrophy, and ultimately, right heart failure and death. The pathogenesis of PAH is complex and likely involves several mechanisms, including genetic and environmental factors, excessive production of growth factors, and imbalances between vasoproliferative and antiproliferative mediators. Recent evidence suggests that inflammation may play a role in the pathogenesis of PAH,^3,4 even in conditions that are not typically considered to represent a systemic proinflammatory state, such as HIV infection or connective tissue diseases. In this issue of JACC: Basic to Translational Science, Moutsoglou et al⁵ explored the possibility that MTT could alter the gut microbiome in a way that would reduce the proinflammatory state in PAH and provide a novel approach to targeted PAH therapy.

The authors evaluated the effects of daily administration of encapsulated MTT for 1 week on a variety of parameters, including circulating levels of cytokines, genetic expression patterns of inflammatory mediators, immune cell subpopulations, as well as clinical parameters used to assess PAH status, including echocardiography, 6-minute walk test, B- type brain natriuretic peptide levels, and a quality of life (QoL) questionnaire. The population studied were optimally treated PAH patients with idiopathic PAH, congenital heart disease, or connective tissue diseases, and all were in WHO functional class I or II with preserved right ventricular function and exercise tolerance. Eleven subjects participated in the trial and, despite frequent minor side effects, mostly gastrointestinal, all completed the 180-day study period. Engraftment rate was low (approximately 18%) compared with studies of MTT in other conditions (over 50%), and this may have affected the exploratory results. Although no significant changes were observed in any of the parameters measured, potentially favorable directional changes in the levels of some inflammatory mediators and in the 6-minute walk and emPHAsis-10 QoL instrument were noted. The mediator profile trends were seen at the study day 30 point but were back to baseline by study day 180.

The authors achieved their primary objective by demonstrating that their study population tolerated MTT and no safety signals were seen. Although their meticulous and elegant analyses of an array of inflammatory markers and clinical parameters failed to show clear patterns of an attenuated inflammatory state or changes in clinical parameters with their treatment regimen, this is not surprising for a variety of reasons:

• 1.The sample size was small and consisted of optimally treated PAH patients who were stable and not severely impaired. Although it was wise for the authors to initiate their studies with this population because safety was the primary assessment, it is likely that more severely compromised PAH subjects would be more likely to manifest a measurable treatment response, if one was possible. Additionally, the timing of MTT may impact the effect of treatment: eg, induction therapy introduced early in the course of the disease may have a greater and more sustained effect than treatment initiated later.
• 2.Both the fixed dosing schedule and low engraftment rate could be insufficient to promote an optimal effect. The directional changes in some mediator levels at 30 days, but not 180 days, may suggest that a potentially favorable effect was present but transient. Further studies using different dosing regimens and employing techniques to optimize engraftment will clarify the impact, if any, that these design limitations had on the study results.

The trend toward improvement in the 6-minute walk test and the emPHAsis-10 QoL questionnaire are encouraging, but it should be noted that, because these study participants were unblinded to their study treatment, unblinding bias could have affected the results. Thus, although no firm conclusions regarding treatment effects can be derived from the study by Moutsoglou et al,⁵ we can be assured that their MTT protocol appeared safe and generally well-tolerated. Future studies addressing the sourcing, dosing and timing of MTT in a more heterogeneous PAH population will clarify whether the gut is a promising novel target for this life-threatening disease.

Funding Support and Author Disclosures

The author has reported that he has no relationships relevant to the contents of this paper to disclose.