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Background: It is increasingly recognized that metabolic products of the intestinal microbiome may have important effects on cardiovascular disease.Methods: We studied dietary intake of precursors and plasma levels of toxic metabolic products of the intestinal microbiome in patients at extremes of carotid plaque burden, defined by residual scores (Res) in multiple regression with coronary risk factors: Protected (Res <-2, n = 83), Explained (Res -2 to 2 n = 82) and Unexplained atherosclerosis (Res >2 n = 62). Diet was assessed by a Harvard Food Frequency Questionnaire, and metabolites were measured by ultra-performance liquid chromatography (UPLC) coupled to mass spectrometry (MS). Microbiota were studied by DNA extraction from stool samples; bacteria in each sample were identified and quantitated based upon amplification and sequencing of 16S rRNA variable regions.Results: There were no significant differences in Mediterranean diet score, renal function, intake of protein, total choline, carnitine, phenylalanine or tyrosine or the fecal microbiota amongst the groups. However, plasma levels of trimethylamine n-oxide (TMAO), indoxylsulfate, p-cresylsulfate, and phenylacetylglutamine were significantly lower in Protected patients and higher in Unexplained patients (Table 1). Serum creatinine and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid ( a marker of renal function) were not different among the groups. In this small sample we did not detect differences in the fecal microbiota.Discussion: Despite no difference in dietary precursors, renal function or the fecal microbiota, patients protected from atherosclerosis had lower levels and those with unexplained atherosclerosis had higher levels of toxic metabolites of the intestinal microbiome. This suggests their intestinal microbiota are responding differently to dietary intake of precursors from those of patients with explained atherosclerosis.Conclusion: This finding raises the potential for manipulation of the intestinal microbiota function through probiotic or prebiotic intake, or replacement of intestinal bacteria, to reduce the risk of carotid atherosclerosis and stroke.