Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism

Abstract

Aims Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. Methods and results Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E−/− (Apoe−/−) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe−/− mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [−15.9 mg/dL (−8.1%) vs. −1.6 mg/dL (−0.5%), P = 0.016], total [−19.6 mg/dL (−7.3%) vs. −5.3 mg/dL (−1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: −18.9 mg/dL (−9.1%) vs. −0.6 mg/dL (−0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. Conclusion Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.

The promise of the gut metabolite propionate for a novel and personalized lipid-lowering treatment

“…Graphical Abstract Novel insights and open questions about the anti-atherosclerotic actions of propionate through immune-dependent regulation of intestinal cholesterol metabolism; adapted from Haghikia et al 11 The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. Unveiling the cross-talk between the gut microbiota, its metabolites, and the CV system will move us towards novel and individualized treatments able to reduce the onset and progression of ACVD.…”

“…The study by Arash Haghikia et al published in this issue of the European Heart Journal identifies a novel regulatory circuit where PA exerts immune-regulatory effects selectively in the gut to control intestinal cholesterol homeostasis and reduces the aortic atherosclerotic lesion area in the hypercholesterolaemic and atherosclerosis-prone apolipoprotein E-deleted (ApoE -/-)micefeda high-fat diet (HFD). 11 Mechanistically, PA increased Treg cell numbers, which in turn released high concentrations of interleukin (IL)-10, the major Treg cytokine, in the intestinal wall. IL-10 suppressed the expression of Niemann-Pick C1-like 1 (NPC1L1), a major transmembrane transporter responsible for intestinal cholesterol absorption.…”

Immune Mechanisms of Plaque Instability

“…These effects translated into a reduction in atherosclerotic lesion burden. In addition to the systemic effects on T-cell immunity, our group very recently identified alteration of intestinal immune system with beneficial effects on lipid metabolism in an hypercholesterolemic atherosclerotic model ( 249 ). In particular, we found an increase of intestinal CD25 + Foxp3 + T regs and elevated IL-10 levels in the intestinal microenvironment, which in turn downregulated the expression of the intestinal cholesterol transporter Niemann-Pick C1-like 1 (NPC1L1) with subsequent decrease in intestinal cholesterol absorption.…”

Inflammation in children with chronic kidney disease linked to gut dysbiosis and metabolite imbalance

“…There is a growing body of evidence about the pivotal role of SCFA in local gut homeostasis and the protection from CVD in vitro 46 and in vivo 47 . Since SCFA are known to enhance the abundance and suppressive function of Treg cells in mice 48 and humans 49 , we analyzed T cells by multi-color flow cytometry. Based on the expression of chemokine receptors 14,50 , we found a decrease of Th1-like, Th17-like and Th22-like Treg in HD patients.…”