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<0.001), without compromising fasting blood glucose. Serum triglyceride concentration
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.