High cholesterol diet, oxysterols and their impact on the gut–brain axis

In a Western or Westernized diet, the abundant cholesterol is invariably associated with the presence of biochemically reactive oxysterols, the amount of which mainly depends upon the autoxidation degree of cholesterol itself, during food harvesting, production and storage. Oxysterols, in the average amount and composition detected in a highcholesterol diet, display remarkable pro-inflammatory and cytotoxic effects on the gut epithelium. Moreover, in a low micromolar range, they may change the physiological level and membrane localization of tight junctions of the intestinal epithelial barrier, which then become leaky and permeable to microbiota. This combination of toxic effects possibly exerted by dietary oxysterols likely contributes to the impairment of the microbiota–gut–brain axis, through both direct and indirect mechanisms hereby reviewed. Importantly, dietary oxysterols are absorbed like cholesterol and circulate in the bloodstream, mainly within LDLs, rendering these micelles more oxidized and dangerous. Last but not the least, dietary oxysterols may deeply interfere with correct gut–brain signalling because of the redox pathways they are hyper-regulating and sustaining. In conclusion, protective dietary measures should be adopted, including restricted consumption of cholesterol-rich food and reduction of cholesterol autoxidation in food production and storage, for instance by supplementation of food with flavonoids and/or other bioactive substances with strong anti-oxysterol properties.