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.

Bovine milk is a nutrient-dense food and a major component of the human diet. Therefore, understanding the factors that impact its composition is of great importance. Applications of metabolomics provide in-depth analysis of the metabolite composition of milk. The objective of this research was to examine the impact of lactation stage on bovine milk metabolite levels. Metabolomic analysis of bovine milk powder samples across lactation (N = 18) was performed using nuclear magnetic resonance (¹H-NMR) spectroscopy and liquid chromatography–tandem mass spectrometry (LC-MS/MS). Forty-one metabolites were identified and quantified in the ¹H-NMR spectra. Statistical analysis revealed that 17 metabolites were significantly different across lactation stages (FDR < 0.05), of which the majority had higher levels in early lactation. In total, 491 metabolites were measured using LC-MS/MS, of which 269 had significantly different levels across lactation (FDR < 0.05). Compound classes significantly affected by lactation stage included phosphatidylcholines (59%) and triglycerides (64%), of which 100% of phosphatidylcholines and 61% of triglycerides increased from early lactation onwards. Our study demonstrates significant differences in metabolites across the stages of lactation, with early-lactation milk having a distinct metabolomic profile. More research is warranted to further explore these compositional differences to inform animal feeding practice.

Fermented foods and ingredients, including furmenties derived from lactic acid bacteria (LAB) in dairy products, can modulate the immune system. Here, we describe the use of reconstituted skimmed milk powder to generate novel fermentates from Lactobacillus helveticus strains SC232, SC234, SC212, and SC210, and from Lacticaseibacillus casei strains SC209 and SC229, and demonstrate, using in vitro assays, that these fermentates can differentially modulate cytokine secretion via bone-marrow-derived dendritic cells (BMDCs) when activated with either the viral ligand loxoribine or an inflammatory stimulus, lipopolysaccharide. Specifically, we demonstrate that SC232 and SC234 increase cytokines IL-6, TNF-α, IL-12p40, IL-23, IL-27, and IL-10 and decrease IL-1β in primary bone-marrow-derived dendritic cells (BMDCs) stimulated with a viral ligand. In contrast, exposure of these cells to SC212 and SC210 resulted in increased IL-10, IL-1β, IL-23, and decreased IL-12p40 following activation of the cells with the inflammatory stimulus LPS. Interestingly, SC209 and SC229 had little or no effect on cytokine secretion by BMDCs. Overall, our data demonstrate that these novel fermentates have specific effects and can differentially enhance key immune mechanisms that are critical to viral immune responses, or can suppress responses involved in chronic inflammatory conditions, such as ulcerative colitis (UC), and Crohn’s disease (CD).

A pasture or concentrate-based dietary regime impacts a variety of factors including both ruminal health and function, and consequently milk production and quality. The objective of this study was to examine the effect of feeding differing pasture levels on the metabolite composition of bovine ruminal fluid. Ruminal fluid was obtained from rumen-cannulated spring-calving cows (N = 9, Holstein-Friesian breed, average lactation number = 5) fed one of three diets across a full lactation season. Group 1 (pasture) consumed perennial ryegrass supplemented with 5% concentrates; group 2 received a total mixed ration (TMR) diet; and group 3 received a partial mixed ration (PMR) diet which included pasture and a TMR. Samples were taken at two timepoints: morning and evening. Metabolomic analysis was performed using nuclear magnetic resonance (¹H-NMR) spectroscopy. Statistical analysis revealed significant changes across the dietary regimes in both morning and evening samples, with distinct alterations in the metabolite composition of ruminal fluid from pasture-fed cows (FDR-adjusted p-value < 0.05). Acetate and butyrate were significantly higher in samples derived from a pasture-based diet whereas sugar-related metabolites were higher in concentrate-based samples. Furthermore, a distinct diurnal impact on the metabolite profile was evident. This work lays the foundation for understanding the complex interaction between dietary regime and ruminal health.

Fermented foods and ingredients, including fermentates derived from lactic acid bacteria (LAB) in dairy products, can modulate the immune system. Here we describe the use of reconstituted skimmed milk powder to generate novel fermentates from Lactobacillus helveticus strains SC232, SC234, SC212, and SC210, and from Lacticaseibacillus casei strains SC209 and SC229, and demonstrate using in vitro assays that these fermentates can differentially modulate cytokine secretion by bone marrow derived dendritic cells (BMDCs) when activated with either the viral ligand, loxoribine, or an inflammatory stimulus, lipopolysaccharide. Specifically, we demonstrate that SC232 and SC234 increase cytokines IL-6, TNF-α, IL-12p40, IL-23, IL-27 and IL-10, and decreased IL-1β in primary bone marrow derived dendritic cell (BMDCs) stimulated with a viral ligand. In contrast exposure of these cells to SC212 and SC210 resulted in increased IL-10, IL-1β, IL-23, and decreased IL-12p40 following activation of the cells with the inflammatory stimulus LPS. Interestingly SC209 and SC229 had little or no effect on cytokine secretion by BMDCs. Overall, our data demonstrates that these novel fermentates have specific effects and can differentially enhance key immune mechanisms that are critical to viral immune responses, or can suppress responses involved in chronic inflammatory conditions, such as Ulcerative Colitis (UC), and Crohn’s disease (CD).