γ-Butyrobetaine is a Proatherogenic Intermediate in Gut Microbial Metabolism of L-carnitine to TMAO

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2014 Dec 3

PMID 25440057

Citations 261

Authors

Robert A Koeth

Bruce S Levison

Miranda K Culley

Jennifer A Buffa

Zeneng Wang

Jill C Gregory

Elin Org

Yuping Wu

Lin Li

Jonathan D Smith

W H Wilson Tang

Joseph A DiDonato

Aldons J Lusis

Stanley L Hazen

Affiliations

Soon will be listed here.

Abstract

L-carnitine, a nutrient in red meat, was recently reported to accelerate atherosclerosis via a metaorganismal pathway involving gut microbial trimethylamine (TMA) formation and host hepatic conversion into trimethylamine-N-oxide (TMAO). Herein, we show that following L-carnitine ingestion, γ-butyrobetaine (γBB) is produced as an intermediary metabolite by gut microbes at a site anatomically proximal to and at a rate ∼1,000-fold higher than the formation of TMA. Moreover, we show that γBB is the major gut microbial metabolite formed from dietary L-carnitine in mice, is converted into TMA and TMAO in a gut microbiota-dependent manner (like dietary L-carnitine), and accelerates atherosclerosis. Gut microbial composition and functional metabolic studies reveal that distinct taxa are associated with the production of γBB or TMA/TMAO from dietary L-carnitine. Moreover, despite their close structural similarity, chronic dietary exposure to L-carnitine or γBB promotes development of functionally distinct microbial communities optimized for the metabolism of L-carnitine or γBB, respectively.

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