Western dietary (WD) habits are known to cause many of today’s non-communicable diseases by promoting chronic inflammation. Recently, to counteract WD-induced metaflammation, ketogenic diets (KD) have emerged.

Given the drastic change in nutrient composition during KD, it is reasonable to hypothesize large-scale changes in the human metabolome. Furthermore, this alteration in the metabolome could also lead to changes in immunity.

A recent Clinical Nutrition study discusses alterations in the human metabolic fingerprint associated with KD.

Key findings

Even a short-term KD of three weeks fundamentally reshaped the human metabolome. In fact, the metabolic steady state adjusted rapidly towards the production and utilization of ketone bodies. This analysis also showed improved insulin and triglyceride levels and higher quantities of metabolites controlling mitochondrial protection and anti-inflammation.

The marked reduction of carbohydrates led to a reduction in both insulin and c-peptide levels, which may explain the moderate weight loss observed in the participants. It could not be confirmed whether the extent of weight loss correlated with the changes in serum metabolic parameters.

The fasting serum glucose concentration remained stable, whereas increased urea levels could be due to enhanced protein metabolism. Concentrations of alanine, glucogenic amino acid (AA) proline, and glutamine were markedly reduced, while leucine, isoleucine, and branched-chain AA (BCAA) valine showed higher abundances.

Higher fat consumption improved the serum lipid profiles of the participants. Importantly, a profound upregulation of both acylcarnitines and free fatty acids was observed.

During KD, high acylcarnitines imply a higher demand for long-chain fatty acids as substrates of β-oxidation. Using carnitine as a transport shuttle system, these substances must be transported into the mitochondrial matrix.

Linoleic acid (ω-6), linolenic acid (ω-3), docosahexaenoic acid (DHA), and eicosatetraenoic acid (ETA) levels were significantly elevated. This observed shift could contribute to the dampening of innate inflammation.

KD significantly shifted the metabolism of tryptophan towards kynurenic acid and kynurenine while attenuating the synthesis of quinolinic acid. Kynurenic acid has been shown to exert protective effects on mitochondrial respiration, while quinolinic acid is associated with mitochondrial dysfunction. Therefore, greater OXPHOS is supported by improved mitochondrial protection.

Conclusions

The current study demonstrated that even after a short period of KD, significant changes in metabolite composition could occur. These changes could have a beneficial impact on both immune cell fate and metabolic programming beyond ketone effects. No metabolic risk factors were identified.

Based on the findings, it could be concluded that KD is a useful therapeutic and preventive immunometabolic tool, at least in the short- and medium-term. However, more research is needed to determine whether KD produces similar beneficial effects in the longer term and whether short-term KD could provide lasting metabolic benefits.

Journalreference:

• Effinger, D., Hirschberger, S., Yoncheva, P., et al. (2023) A ketogenic diet substantially reshapes the human metabolome. Clinical Nutrition. doi: 10.1016/j.clnu.2023.04.027