Shaping the human metabolome: the impact of a ketogenic diet

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In a recent study published in the Clinical Nutrition Journal, researchers explored how the human metabolic fingerprint changes with a ketogenic diet (KD).

Study: A ketogenic diet substantially reshapes the human metabolome. Image Credit: SewCreamStudio/Shutterstock.comStudy: A ketogenic diet substantially reshapes the human metabolome. Image Credit: SewCreamStudio/


Western dietary (WD) habits have showcased the promotion of chronic inflammation leading to non-communicable diseases. KDs are emerging as a novel way to regulate the immune system and counteract metaflammation caused by WD.

The positive impacts of KD have been credited only to the generation and processing of ketone bodies. The significant alteration in nutrient content during KD suggests that there may be extensive modifications in the human metabolome, which also contribute to the effect of KD on human immunity.

About the study

In the present study, researchers explored the alterations in the metabolome of healthy individuals after a KD.

A nutritional intervention study was conducted to investigate the impact of a KD on the metabolite profile of human serum.

The team obtained data from a nutritional intervention study that measured changes in messenger ribonucleic acid (mRNA) expression of Interferon-gamma (IFN-g) in T cells as the primary endpoint. The secondary endpoints involved analyzing the serum metabolite profile and urinary amino acid metabolic pathways.

The study consisted of 40 healthy participants who were over the age of 18 years. All volunteers received nutritional counseling from board-certified nutritionists and nutritional physicians at the beginning of the diet.

Volunteers followed a WD before enrolling. The KD involves limiting carbohydrate intake to 10% of daily caloric intake while increasing the proportion of fats and proteins.

Blood samples were taken before (T0) and after the KD (T1). Kinetic colorimetric assays were used to measure the concentrations of glucose and urea. Enzymatic color assays were used to measure the concentrations of triglycerides, cholesterol, and lipoproteins. Furthermore, the study utilized electrochemiluminescence immunoassays (ECLIA) to measure the concentrations of insulin, cortisol, and c-peptide.

The metabolic profile of the serum samples of healthy participants who followed a three-week ketogenic diet was assessed using untargeted metabolome analyses.

Liquid Chromatography with tandem mass spectrometry (LC-MS/MS)-based untargeted metabolomic analyses were conducted to examine the effects of a three-week ad libitum KD on serum metabolites. The calculations used Time-of-flight (TOF)-MS on human sera collected at T0 and T1.


During the three-week diet, healthy volunteers followed the KD and were able to produce ketone bodies as expected. No unintended effects or adverse events were observed. The participants experienced a slight weight loss throughout the diet, with a median reduction in body mass index (BMI) of 0.69 kg/m2, which translates to a 2.9% decrease.

Serum samples were analyzed in the laboratory before and after a three-week KD. The team found that restricting carbohydrate intake to under 30g per day resulted in a notable decrease in c-peptide and insulin levels in the blood. Throughout the study, fasting glucose concentrations were stable within the normal range.

Notably, the study found that a KD led to a significant reduction in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR).

Blood cholesterol levels were unchanged, including low-density lipoproteins (LDL), high-density lipoproteins (HDL), and non-HDL. After three weeks of KD, there was a significant reduction in triglyceride levels.

Furthermore, the serum urea concentration was increased in individuals following a KD. No significant associations were found in the correlation analysis, indicating that the changes observed were not linked to weight loss.

The study found that KD had a significant impact on serum metabolite levels. Around 95 metabolites were regulated, with 49 showing higher concentrations and 46 exhibiting lower abundance at T1.

The study participants' sera were analyzed for metabolites, revealing significant changes in the levels of several metabolites. B-hydroxybutyrate levels were significantly increased, while hexoses showed reduced serum levels. Additionally, increased fat consumption on a KD led to higher levels of unsaturated/saturated and short/medium/long chain fatty acids.

A KD also resulted in a higher abundance of linoleic and linolenic acids. At T1, elevated concentrations of eicosatetraenoic acid and docosahexaenoic acid were observed at the end of the anti-inflammatory pathway. Lower levels of platelet-activating factor, a pro-inflammatory mediator, were detected at T1.

Additionally, amino acid levels displayed intricate modifications on a KD. Also, the abundance of glucogenic amino acids such as alanine, glutamine, and proline was lower on a KD. The essential branched-chain amino acids (BCAA) isoleucine/leucine and valine concentrations were higher on a KD.


The study shows that significant changes in metabolite composition were observed after a short period of following KD, which could have beneficial effects on metabolic programming as well as immune cell fate, in addition to ketone effects.

The KD was a beneficial immunometabolic tool for both preventative and therapeutic purposes in the short and medium term.

Further research is required to determine if the long-term implementation of the KD yields comparable advantages and if incorporating short-term KDs into regular eating habits can result in sustained metabolic benefits.

Journal reference:
Bhavana Kunkalikar

Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.


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