A ketogenic diet substantially reshapes the human metabolome

Background Ketogenic diet (KD) has emerged as a possible countermeasure to Western Diet mediated metaflammation through immunometabolic reprogramming. To date, this has been solely attributed to the synthesis and utilization of ketone bodies. Whether additional metabolic changes contribute to these effects is currently unknown. Objective We hypothesized that the fundamental changes to nutrient consumption on a KD substantially alter the total human metabolic fingerprint. Assessing these metabolic alterations allows for the identification of commonly insinuated health risks and potential further health benefits. Design We conducted a prospective nutritional intervention study. Healthy volunteers were recruited to perform a three-week ad libitum KD. Prior to the start and at the end of the nutritional intervention serum metabolites were quantified, untargeted mass spectrometric metabolome analyses and urine analyses of the tryptophan pathway were performed. Results KD led to a marked reduction of insulin (-20%; p=0.0038) and c-peptide levels (-24%; p decreased accordingly (-16%, p=0.0247), whereas cholesterol parameters remained unchanged. Untargeted metabolomics revealed a profound shift of the human metabolism towards mitochondrial fatty acid oxidation, comprising highly elevated levels of free fatty acids and acyl-carnitines. The serum amino acid (AA) composition was rearranged with lower abundance of glucogenic AA and an increase of BCAA. Furthermore, an increase of anti-inflammatory fatty acids eicosatetraenoic acid and docosahexaenoic acid was detected. Urine analyses confirmed higher utilization of carnitines and revealed changes to the tryptophan pathway depicting a reduced quinolinic acid/ kynurenic acid ratio.