Effects of the L-tyrosine-derived bacterial metabolite p-cresol on colonic and peripheral cells.

Abstract

Specific families of bacteria present within the intestinal luminal content produce p-cresol from L-tyrosine. Although the hosts do not synthesize p-cresol, they can metabolize this compound within their colonic mucosa and liver leading to the production of co-metabolites including p-cresyl sulfate (p-CS) and p-cresyl glucuronide (p-CG). p-Cresol and its co-metabolites are recovered in the circulation mainly conjugated to albumin, but also in their free forms that are excreted in the urine. An increased dietary protein intake raises the amount of p-cresol recovered in the feces and urine, while fecal excretion of p-cresol is diminished by a diet containing undigestible polysaccharides. p-Cresol in excess is genotoxic for colonocytes. In addition, in these cells, this bacterial metabolite decreases mitochondrial oxygen consumption, while increasing the anion superoxide production. In chronic kidney disease (CKD), marked accumulation of p-cresol and p-CS in plasma is measured, and in renal tubular cells, p-cresol and p-CS increase oxidative stress, affect mitochondrial function, and lead to cell death, strongly suggesting that these 2 compounds act as uremic toxins that aggravate CKD progression. p-Cresol and p-CS are also suspected to play a role in the CKD-associated adverse cardiovascular events, since they affect endothelial cell proliferation and migration, decrease the capacity of endothelial wound repair, and increase the senescence of endothelial cells. Finally, the fact that concentration of p-cresol is transiently increased in young autistic children biological fluids, and that intraperitoneal injection of p-cresol in animal models induces some behavioral characteristics observed in the autism spectrum disorders (ASD), raise the view that p-cresol may possibly represent one of the components involved in ASD etiology. Further pre-clinical and clinical studies are obviously needed to determine if the lowering of p-cresol and/or p-CS circulating concentrations, by dietary and/or pharmacological means, would allow, by itself or in combination with other interventions, to improve CKD progression and associated cardiovascular outcomes, as well as some neurological outcomes in children with an early diagnosis of autism.