The Biochemical Controversies of the Ketogenic Diet


Beta-hydroxybutyrate, the principal nutrient produced by our body in response to the low-carb ketogenic diet, does not offer all the benefits hitherto attributed to it by scientists... Luciano Pirola*, in collaboration with the research group of Aneta Balcerczyk**, has recently shown that this substance presents no anti-inflammatory activity and that its role in transcription remains to be elucidated.

In a context of growing public interest in the ketogenic diet, scientists are taking an increasing interest in beta-hydroxybutyrate. This diet consists of cutting out almost all carbs, especially starches, and preferring fats and proteins. The cells, usually fueled by glucose, can no longer meet their needs and so begin to use an alternative pathway to produce energy, which involves the breakdown of fatty acids.

Much is known about this pathway, which produces fatty-acid derivatives called "ketone bodies" - principally beta-hydroxybutyrate. With existing research suggesting that beta-hydroxybutyrate could offer health benefits at physiological doses, and particularly with an anti-inflammatory action, a closer look was needed.

Two molecules differing by just one atom

Pirola and his team were already working on butyrate, a molecule produced by the intestinal bacteria which differs from beta-hydroxybutyrate by just one oxygen atom. "This chemical proximity between the two molecules suggested identical activities", explains Pirola. Butyrate offers a benefit for metabolism and weight control. An activity which involves epigenetic mechanisms: butyrate inhibits an enzyme known as histone deacetylase, thereby promoting the maintenance of acetate molecules on the histones as well as facilitating the expansion of chromatin and the transcription of beneficial genes. "We decided to verify whether beta-hydroxybutyrate actually does possess anti-inflammatory activity and whether this molecule contributes to the inhibition of deacetylase histones such as butyrate".

The experiments conducted by the researchers contradict these two points. They did not find any evident anti-inflammatory effect on the human cell lines tested (endothelial cells, which line the internal blood vessel walls and are highly reactive to inflammatory phenomena). On the contrary, the effect observed is slightly pro-inflammatory. In addition, whether in the endothelial, renal or muscle cells, beta-hydroxybutyrate does not inhibit histone deacetylase. It provokes another recently-discovered epigenetic modification, known as histone beta-hydroxybutyrylation. The effects of this type of modification are as yet unknown.

"This research is a starting point. Given that we’re expecting the keto diet to increase in popularity in the coming years, we need to go further. It’s already indicated in specific situations, such as for people with epilepsy in whom it reduces seizure frequency, although we don’t have a detailed understanding of the mechanism at work. It’s also starting to be suggested in other diseases such as cancer and even diabetes. We need a better understanding of the biological link between beta-hydroxybutyrate production and the body's biochemical and metabolic responses in order to evaluate the effect and efficacy of this diet on health for the general population", concludes Pirola.



*Unit 1060 Inserm/Université Claude Bernard Lyon 1/Insa, unit 1397 Inra, CarMeN Laboratory, Nutritional adaptations, environment and diabetes team, Lyon

**University of Lodz, Poland

Source : S Chriett et al. Prominent action of butyrate over β-hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule. Scientific Reports, online edition dated January 24,2019