High-Soluble-Fiber Diet Attenuates Hypoxia-Induced Vascular Remodeling and the Development of Hypoxic Pulmonary Hypertension

Author:

Pakhomov Nikolai V.1,Kostyunina Daria S.1ORCID,Macori Guerrino2ORCID,Dillon Eugene3,Brady Tara1,Sundaramoorthy Geetha4,Connolly Claire4ORCID,Blanco Alfonso3ORCID,Fanning Séamus2,Brennan Lorraine4,McLoughlin Paul1,Baugh John A.1ORCID

Affiliation:

1. School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland (N.V.P., D.S.K., T.B., P.M., J.A.B.).

2. School of Public Health, Physiotherapy & Sports Science, University College Dublin, Ireland (G.M., S.F.).

3. Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland (E.D., A.B.).

4. School of Agriculture and Food Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland (G.S., C.C., L.B.).

Abstract

BACKGROUND: Hypoxic pulmonary hypertension is a difficult disease to manage that is characterized by sustained elevation of pulmonary vascular resistance and pulmonary artery pressure due to vasoconstriction, perivascular inflammation, and vascular remodeling. Consumption of soluble-fiber is associated with lower systemic blood pressure, but little is known about its ability to affect the pulmonary circulation. METHODS: Mice were fed either a low- or high-soluble-fiber diet (0% or 16.9% inulin) and then exposed to hypoxia (FiO 2 , 0.10) for 21 days to induce pulmonary hypertension. The impact of diet on right ventricular systolic pressure and pulmonary vascular resistance was determined in vivo or in ex vivo isolated lungs, respectively, and correlated with alterations in the composition of the gut microbiome, plasma metabolome, pulmonary inflammatory cell phenotype, and lung proteome. RESULTS: High-soluble-fiber diet increased the abundance of short-chain fatty acid-producing bacteria, with parallel increases in plasma propionate levels, and reduced the abundance of disease-related bacterial genera such as Staphylococcus , Clostridioides , and Streptococcus in hypoxic mice with parallel decreases in plasma levels of p-cresol sulfate. High-soluble-fiber diet decreased hypoxia-induced elevations of right ventricular systolic pressure and pulmonary vascular resistance. These changes were associated with reduced proportions of interstitial macrophages, dendritic cells, and nonclassical monocytes. Whole-lung proteomics revealed proteins and molecular pathways that may explain the effect of soluble-fiber supplementation. CONCLUSIONS: This study demonstrates for the first time that a high-soluble-fiber diet attenuates hypoxia-induced pulmonary vascular remodeling and the development of pulmonary hypertension in a mouse model of hypoxic pulmonary hypertension and highlights diet-derived metabolites that may have an immuno-modulatory role in the lung.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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