Nature medicine
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Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. ⋯ Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.
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Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism, is caused by the silencing of the FMR1 gene, leading to the loss of fragile X mental retardation protein (FMRP), a synaptically expressed RNA-binding protein regulating translation. The Fmr1 knockout model recapitulates the main traits of the disease. Uncontrolled activity of metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) signaling seem crucial in the pathology of this disease. ⋯ We found that CB1R blockade in male Fmr1 knockout (Fmr1(-/y)) mice through pharmacological and genetic approaches normalized cognitive impairment, nociceptive desensitization, susceptibility to audiogenic seizures, overactivated mTOR signaling and altered spine morphology, whereas pharmacological blockade of CB2R normalized anxiolytic-like behavior. Some of these traits were also reversed by pharmacological inhibition of mTOR or mGluR5. Thus, blockade of ECS is a potential therapeutic approach to normalize specific alterations in FXS.