Abstract
Ambient particulate matter (PM) exposure is associated with atherosclerosis and inflammatory bowel disease. Ultrafine particles (UFP, dp < 0.1–0.2 μm) are redox active components of PM. We hypothesized that orally ingested UFP promoted atherogenic lipid metabolites in both the intestine and plasma via altered gut microbiota composition. Low density lipoprotein receptor-null (Ldlr−/−) mice on a high-fat diet were orally administered with vehicle control or UFP (40 μg/mouse/day) for 3 days a week. After 10 weeks, UFP ingested mice developed macrophage and neutrophil infiltration in the intestinal villi, accompanied by elevated cholesterol but reduced coprostanol levels in the cecum, as well as elevated atherogenic lysophosphatidylcholine (LPC 18:1) and lysophosphatidic acids (LPAs) in the intestine and plasma. At the phylum level, Principle Component Analysis revealed significant segregation of microbiota compositions which was validated by Beta diversity analysis. UFP-exposed mice developed increased abundance in Verrocomicrobia but decreased Actinobacteria, Cyanobacteria, and Firmicutes as well as a reduced diversity in microbiome. Spearman’s analysis negatively correlated Actinobacteria with cecal cholesterol, intestinal and plasma LPC18:1, and Firmicutes and Cyanobacteria with plasma LPC 18:1. Thus, ultrafine particles ingestion alters gut microbiota composition, accompanied by increased atherogenic lipid metabolites. These findings implicate the gut-vascular axis in a atherosclerosis model.
Highlights
Ultrafine particles (UFP, dp < 0.1–0.2 μm) are redox active components of airborne particulate matter (PM) that are enriched in transition metals and cycling organic chemicals[1,2]
The Eigen vectors and values calculated from phylum level abundance revealed that Candidatus Saccharibacteria (TM7), Cyanobacteria, Chordata, Verrucomicrobia, and Spirochaetes were significantly different in the UFP-ingested group (Fig. 1B,C)
We demonstrate that chronic oral UFP ingestion to Ldlr-null mice engendered dysbiosis, including altered microbial composition and diversity in association with increased TNF-αand atherogenic LPC 18:1 and lysophosphatidic acid (LPA) in the intestinal and plasma
Summary
Ultrafine particles (UFP, dp < 0.1–0.2 μm) are redox active components of airborne particulate matter (PM) that are enriched in transition metals and cycling organic chemicals[1,2]. In addition to inducing oxidative stress in human aortic endothelial cells[3], UFP exposure reduces anti-oxidant capacity of plasma high-density lipoprotein (HDL) and increases oxidative lipid metabolism to accelerate atherosclerosis in low-density lipoprotein (LDL) receptor-knockout (Ldlr−/−) mice[4,5]. Urban coarse particulate matter (PM10, d < 10 μm) ingested via contaminated food altered gut microbiota in IL-10-null mice, an IBD mouse model[17] For this reason, we sought to study the role of UFP ingestion on gut microbiota in Ldlr-null mice to alter lipid metabolism and atherogenic lipid metabolites. Gut microbiome-induced changes in lipid metabolism are associated with intestinal inflammation[20,23,28,29] and gut microbiota-dependent formation of dietary trimethylamine (TMA) is linked with atherosclerosis[25,30] In this context, building on our previous inhalation study in which UFP exposure promoted inflammatory responses and lipid metabolism in both the gastrointestinal and vascular systems[4,5], we hereby tested the hypothesis that oral UFP ingestion altered gut microbiota to promote intestinal and serum pro-inflammatory mediators and atherogenic lipid metabolites in Ldlr-null mice. Our findings suggest gut-vascular transmissibility via UFP-mediated changes in microbiome in a Ldlr-null mouse model of atherosclerosis
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