Effects of a Vegetarian Diet on Cardiometabolic Risk Factors, Gut Microbiota, and Plasma Metabolome in Subjects With Ischemic Heart Disease: A Randomized, Crossover Study

Abstract

Background A vegetarian diet (VD) may reduce future cardiovascular risk in patients with ischemic heart disease. Methods and Results A randomized crossover study was conducted in subjects with ischemic heart disease, assigned to 4-week intervention periods of isocaloric VD and meat diet (MD) with individually designed diet plans, separated by a 4-week washout period. The primary outcome was difference in oxidized low-density lipoprotein cholesterol (LDL-C) between diets. Secondary outcomes were differences in cardiometabolic risk factors, quality of life, gut microbiota, fecal short-chain and branched-chain fatty acids, and plasma metabolome. Of 150 eligible patients, 31 (21%) agreed to participate, and 27 (87%) participants completed the study. Mean oxidized LDL-C (-2.73 U/L), total cholesterol (-5.03 mg/dL), LDL-C (-3.87 mg/dL), and body weight (-0.67 kg) were significantly lower with the VD than with the MD. Differences between VD and MD were observed in the relative abundance of several microbe genera within the families Ruminococcaceae, Lachnospiraceae, and Akkermansiaceae. Plasma metabolites, including l-carnitine, acylcarnitine metabolites, and phospholipids, differed in subjects consuming VD and MD. The effect on oxidized LDL-C in response to the VD was associated with a baseline gut microbiota composition dominated by several genera of Ruminococcaceae. Conclusions The VD in conjunction with optimal medical therapy reduced levels of oxidized LDL-C, improved cardiometabolic risk factors, and altered the relative abundance of gut microbes and plasma metabolites in patients with ischemic heart disease. Our results suggest that composition of the gut microbiota at baseline may be related to the reduction of oxidized LDL-C observed with the VD. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02942628.

Keywords: coronary artery disease; gut microbiota; plasma metabolome; randomized controlled trial; trimethylamine N-oxide; vegetarian diet.

Figure 1. Schedule of study visits and participant flow.

Figure 2. Changes in oxidized low‐density lipoprotein cholesterol (LDL‐C) and cardiometabolic risk factors according to dietary intervention.

Mean change in oxidized LDL‐C (A), total cholesterol (TC) (B), LDL‐C (C), and weight (D) before and after each intervention. Error bars indicate SEM. ΔVD vs ΔMD indicates differences in risk factors between vegetarian diet (VD) and meat diet (MD) obtained using linear mixed‐effects models adjusted for sequence of diet randomization and intervention period. *P<0.05, **P<0.01, ***P<0.001. Post, 4 weeks after the dietary intervention; Pre, baseline.

Figure 3. Gut microbiota and plasma metabolites discriminating the vegetarian and meat diets, and selected by multilevel random forest modeling.

Least‐squares means and 95% CIs of abundance of zero‐radius operational taxonomic units (A) and levels of metabolites (B) after 4‐week intervention of the vegetarian and isocaloric meat diet obtained from random forest multivariate modeling. Standardized values are presented for comparison. *Denotes microbial genera or metabolites significantly differing between meat and vegetarian diet when assessed using generalized linear mixed models. DG indicates diacylglycerol; PC, phosphatidylcholine; and PE, phosphatidylethanolamine.

Figure 4. Changes in plasma concentration of trimethylamine N‐oxide (TMAO), choline, l‐carnitine, and acetyl‐carnitine according to dietary intervention.

Boxplots (A through D) show the concentrations of the metabolites measured at baseline, after the vegetarian diet (VD) and the isocaloric meat diet (MD). Differences were assessed by paired t test. Least‐squares means and 95% CIs of levels of metabolites (E) after 4‐week intervention of VD and MD assessed by generalized linear modeling. Standardized values are presented for comparison. *P<0.05, **P<0.01, ***P<0.001. NS indicates not significant.

Figure 5. Baseline gut microbiota associated with response to diets in reduction of oxidized low‐density lipoprotein cholesterol (LDL‐C).

A, Intraindividual difference in oxidized LDL‐C between vegetarian diet (VD) and meat diet (MD) is presented. Responders were defined as participants who showed lower oxidized LDL‐C after VD than after MD. Patients who had higher oxidized LDL‐C after VD than after MD were considered as nonresponders. B, Discrimination of responders from nonresponders based on microbial genera at baseline. We applied random forest modeling on relative abundance of zero‐radius operational taxonomic units (ZOTUs) at baseline. Of 20 individuals, 17 could be successfully classified as responders or nonresponders. C, The optimal set of microbial genera for the successful classification (n=14). Relative abundance of ZOTUs for responders and nonresponders are presented. Boxes represent the interquartile range, and the line within represents the median. Whiskers denote the lowest and highest values within 1.5× interquartile range.