Abstract
L-alpha glycerylphosphorylcholine (GPC), a nutritional supplement, has been demonstrated to improve neurological function. However, a new study suggests that GPC supplementation increases incident stroke risk thus its potential adverse effects warrant further investigation. Here we show that GPC promotes atherosclerosis in hyperlipidemic Apoe−/− mice. GPC can be metabolized to trimethylamine N-oxide, a pro-atherogenic agent, suggesting a potential molecular mechanism underlying the observed atherosclerosis progression. GPC supplementation shifted the gut microbial community structure, characterized by increased abundance of Parabacteroides, Ruminococcus, and Bacteroides and decreased abundance of Akkermansia, Lactobacillus, and Roseburia, as determined by 16S rRNA gene sequencing. These data are consistent with a reduction in fecal and cecal short chain fatty acids in GPC-fed mice. Additionally, we found that GPC supplementation led to an increased relative abundance of choline trimethylamine lyase (cutC)-encoding bacteria via qPCR. Interrogation of host inflammatory signaling showed that GPC supplementation increased expression of the proinflammatory effectors CXCL13 and TIMP-1 and activated NF-κB and MAPK signaling pathways in human coronary artery endothelial cells. Finally, targeted and untargeted metabolomic analysis of murine plasma revealed additional metabolites associated with GPC supplementation and atherosclerosis. In summary, our results show GPC promotes atherosclerosis through multiple mechanisms and that caution should be applied when using GPC as a nutritional supplement.
Highlights
L-alpha glycerylphosphorylcholine (GPC) is a substrate for the synthesis of phosphatidylcholine (PC) and the neurotransmitter acetylcholine in the brain [1,2]
In order to test whether polymicrobial communities possessed the capacity to metabolize GPC to TMA, the precursor for trimethylamine N-oxide (TMAO), we incubated different murine intestinal segments with deuterium labeled GPC, GPC(trimethyl-d9) (d9-GPC), under anaerobic conditions
No d9-TMA was detected after incubation with the duodenum or jejunum, which is consistent with previous reports that TMA producing bacteria, which tend to be anaerobes, are enriched in the more distal intestine [20]
Summary
L-alpha glycerylphosphorylcholine (GPC) is a substrate for the synthesis of phosphatidylcholine (PC) and the neurotransmitter acetylcholine in the brain [1,2]. A new study from a cohort of more than 12 million human subjects indicated that the use of GPC was associated with a higher 10-year incident stroke risk in a dose-response manner [13]. Considering these recent findings, the adverse effect of GPC warrant further investigation. Given the numerous clinical studies linking TMAO levels to cardiovascular disease risks [14,20,21] and the numerous mechanistic studies linking TMAO to cardiovascular disease pathogenesis [17,22,23], in the present study, we sought to use atherosclerosis prone mice to test the following: (1) whether dietary GPC promotes atherosclerosis, (2) whether GPC can shift gut microbial community structure and the plasma metabolome, and (3) whether GPC alone can activate inflammation associated signaling pathways
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