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Metabolic products of the intestinal microbiome and extremes of atherosclerosis

      Highlights

      • We identified patients at the 5% extremes of atherosclerosis, and measured metabolic products of the intestinal microbiome.
      • Patients with excess plaque (Unexplained) had higher levels of the metabolites, whereas patients with unexpectedly less plaque (Protected) had lower levels.
      • The differences were not explained by renal function or dietary intake of precursors.
      • TMAO and p-cresyl sulfate were independent predictors of carotid plaque burden.
      • New approaches to treating atherosclerosis, such as fecal repopulation or probiotics are suggested by these findings.

      Abstract

      Background and aims

      There is increasing awareness that the intestinal microbiome plays an important role in human health. We investigated its role in the burden of carotid atherosclerosis, measured by ultrasound as total plaque area.

      Methods

      Multiple regression with traditional risk factors was used to identify three phenotypes among 316/3056 patients attending vascular prevention clinics. Residual score (RES; i.e. the distance off the regression line, similar to standard deviation) was used to identify the 5% of patients with much less plaque than predicted by their risk factors (Protected, RES <−2), the 90% with about as much plaque as predicted (Explained, RES -2 to 2), and the 5% with much more plaque than predicted (Unexplained RES >2). Metabolic products of the intestinal microbiome that accumulate in renal failure – gut-derived uremic toxins (GDUT) – were assayed in plasma by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

      Results

      Plasma levels of trimethylamine n-oxide (TMAO), p-cresyl sulfate, p-cresyl glucuronide, and phenylacetylglutamine were significantly lower among patients with the Protected phenotype, and higher in those with the Unexplained phenotype, despite no significant differences in renal function or in dietary intake of nutrient precursors of GDUT. In linear multiple regression with a broad panel of risk factors, TMAO (p = 0.011) and p-cresyl sulfate (p = 0.011) were significant independent predictors of carotid plaque burden.

      Conclusions

      The intestinal microbiome appears to play an important role in atherosclerosis. These findings raise the possibility of novel approaches to treatment of atherosclerosis such as fecal transplantation and probiotics.

      Keywords

      Abbreviations:

      ADMA (asymmetric dimethylarginine), CKD (chronic kidney disease), DNA (deoxyribonucleic acid), FFQ (food frequency questionnaire), GDUT (gut-derived uremic toxins), RES (residual score in linear regression), RNA (ribonucleic acid), TMAO (trimethylamine N-oxide), TPA (total plaque area)
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