Ketogenic diets — extreme low-carbohydrate, high-fat regimens that have long been known to benefit epilepsy and other neurological illnesses — may work by lowering inflammation in the brain, according to new research by UC San Francisco scientists. The UCSF team has discovered a molecular key to the diet’s apparent effects, opening the door for new therapies that could reduce harmful brain inflammation following stroke and brain trauma by mimicking the beneficial effects of an extreme low-carb diet
The keto diet is focused on reducing the amount of carbohydrates as much as possible and increasing the amount of protein and fat.
Besides its weight loss-related benefits, recent studies have pointied to many other advantages. For instance, Medical News Today recently covered research suggesting that the diet may increase longevity and improve memory in old age.
However, the mechanism by which a keto diet may benefit the brain in these illnesses has been a mystery. The new research – which was led by Dr. Raymond Swanson, a professor of neurology at the University of California, San Francisco – suggests that it may do so by reducing brain inflammation.
In the new study, Dr. Swanson and team show the molecular process by which the keto diet reduces brain inflammation. The researchers also identify a key protein that, if blocked, could create the effects of a keto diet.
This means that a drug could be designed to reduce inflammation in patients who cannot follow a keto diet because of other health reasons.
The findings were published in the journal Nature Communications.
A keto state lowers brain inflammation
A keto diet changes the metabolism, or the way in which the body processes energy. In a keto diet, the body is deprived of glucose derived from carbs, so it starts using fat as an alternative source of energy.
In the new study, Dr. Swanson and his colleagues recreated this effect by using a molecule called 2-deoxyglucose (2DG).
The 2DG molecule stopped glucose from metabolizing and created a ketogenic state in rodents with brain inflammation as well as in cell cultures. Levels of inflammation were drastically reduced – almost to healthy levels – as a result.
“We were surprised by the magnitude of our findings,” said Dr. Swanson. “Inflammation is controlled by many different factors, so we were surprised to see such a large effect by manipulating this one factor. It reinforces the powerful effect of diet on inflammation.”
The restricted glucose metabolism lowered the so-called NADH/NAD+ ratio. Dr. Swanson explained to MNT what this ratio refers to, saying, “NAD+ and NADH are naturally occurring molecules in cells that are involved in energy metabolism.”
“Cells convert NAD+ to NADH, as an intermediary step in generating energy from glucose, and thus increase the NADH/NAD+ ratio,” he added.
When this ratio is lowered, the CtBP protein gets activated and attempts to turn off inflammatory genes. As Dr. Swanson told us, “CtBP is a protein that senses the NADH/NAD ratio and regulates gene expression depending on this ratio.”
So, the scientists designed a molecule that stops CtBP from being inactive. This keeps the protein in a constant “watchful” state, blocking inflammatory genes in an imitation of the ketogenic state.
Significance of the findings, future research
Speaking to MNT about the clinical implications of the study, Dr. Swanson said, “Our findings show that it is […] possible to get the anti-inflammatory effect of a ketogenic diet without actually being ketogenic.”
“[The keto] diet is difficult to follow […], especially for people who are acutely ill. Our work identifies a potential drug target that can produce the same effect as [the] ketogenic diet.”
“I think the work also increases the scientific legitimacy of the ketogenic diet/inflammation link,” he added.
Dr. Swanson went on to highlight how important it is that the research conducted by he and his team uncovered a causal mechanism rather than simply pointing to an association.
“Most scientists,” he told us, “are reluctant to accept cause-effect relationships between events in the absence of a defined mechanism. Here we have provided a biochemical mechanism by which diet affect inflammatory responses.”
Dr. Swanson also shared with us some directions for future research. “Our work was very focused on brain trauma,” he said, but “next steps will be to expand the list of pro-inflammatory conditions that can be modulated by the CtBP mechanism.”
The findings could apply to other conditions that are characterized by inflammation. In diabetes, for example, the excessive glucose produces an inflammatory response, and the new results could be used to control this dynamic.
“[The] ultimate therapeutic goal would be to generate a [drug] that can act on CtBP to mimic the anti-inflammatory effect of [the] ketogenic diet,” Dr. Swanson concluded.
“It’s a key issue in the field — how to suppress inflammation in brain after injury,” said Raymond Swanson, MD, a professor of neurology at UC San Francisco, chief of the neurology service at the San Francisco Veterans Affairs Medical Center, and senior author of the new study.
In the paper, published online September 22, 2017 in the journal Nature Communications, Swanson and his colleagues found the previously undiscovered mechanism by which a low carbohydrate diet reduces inflammation in the brain. Importantly, the team identified a pivotal protein that links the diet to inflammatory genes, which, if blocked, could mirror the anti-inflammatory effects of ketogenic diets.
“The ketogenic diet is very difficult to follow in everyday life, and particularly when the patient is very sick,” Swanson said. “The idea that we can achieve some of the benefits of a ketogenic diet by this approach is the really exciting thing here.”
The high-fat, low-carbohydrate regimen of ketogenic diets changes the way the body uses energy. In response to the shortage of carb-derived sugars such as glucose, the body begins breaking down fat into ketones and ketoacids, which it can use as alternative fuels.
In rodents, ketogenic diets — and caloric restriction, in general — are known to reduce inflammation, improve outcomes after brain injury, and even extend lifespan. These benefits are less well-established in humans, however, in part because of the difficulty in maintaining a ketogenic state.
In addition, despite evidence that ketogenic diets can modulate the inflammatory response in rodents, it has been difficult to tease out the precise molecular nuts and bolts by which these diets influence the immune system.
Intricate Molecular Waltz
In the new study, the researchers used a small molecule called 2-deoxyglucose, or 2DG, to block glucose metabolism and produce a ketogenic state in rats and controlled laboratory cell lines. The team found that 2DG could bring inflammation levels down to almost control levels.
“I was most surprised by the magnitude of this effect, because I thought ketogenic diets might help just a little bit,” Swanson said. “But when we got these big effects with 2DG, I thought wow, there’s really something here.”
The team further found that reduced glucose metabolism lowered a key barometer of energy metabolism — the NADH/NAD+ ratio — which in turn activated a protein called CtBP that acts to suppress activity of inflammatory genes.
In a clever experiment, the researchers designed a drug-like peptide molecule that blocks the ability of CtBP to enter its inactive state —essentially forcing the protein to constantly block inflammatory gene activity and mimicking the effect of a ketogenic state.
Peptides, which are small proteins, don’t work well themselves as drugs because they are unstable, expensive, and people make antibodies against them. But other molecules that act the same way as the peptide could provide ketogenic benefits without requiring extreme dietary changes, Swanson said.
The study has applications beyond brain-related inflammation. The presence of excess glucose in people with diabetes, for example, is associated with a pro-inflammatory state that often leads to atherosclerosis, the buildup of fatty plaques that can block key arteries. The new study could provide a way of interfering with the relationship between the extra glucose in patients with diabetes and this inflammatory response.