Dysregulation of tryptophan metabolism and distortion of cell signaling after oral exposure to ethanol and Kynurenic acid.

Kynurenic acid (KYNA), an unavoidable tryptophan metabolite during fermentation is naturally blended with alcohol in all alcoholic beverages. Thus, alcohol drinking inevitably results in co-intake of KYNA. Effects of alcohol or KYNA on human health have been widely studied. However, the combined effects of both remain unknown. Here we report that alcohol and KYNA have a synergistic impact of on global gene expression, especially the gene sets related to tryptophan metabolism and cell signaling. Adult mice were exposed to alcohol (ethanol) and/or KYNA daily for a week. Transcriptomes of the brain, kidney and liver were profiled via bulk RNA sequencing. Results indicate that while KYNA alone largely promotes, and alcohol alone mostly inhibits gene expression, alcohol and KYNA co-administration has a stronger inhibition of global gene expression. Tryptophan metabolism is severely skewed towards kynurenine pathway by decreasing tryptophan hydroxylase 2 and increasing tryptophan dioxygenase. Quantification of tryptophan metabolic enzymes corroborates the transcriptional changes of these enzymes. Furthermore, the co-administration greatly enhances the GnRH signaling pathway. This research provides critical data to better understand the effects of alcohol and KYNA in mix on human health.