Scientists have found that both a ketogenic diet and oral supplementation with ketone bodies alleviate symptoms of multiple sclerosis, a serious autoimmune disorder, in a mouse model [1].

Keto and autoimmune diseases

In ketogenic diets, the vast majority of calories are derived from fat, some from protein, and almost none from carbohydrates. While a ketogenic diet might speed up weight loss, it has also been linked to increased cholesterol levels [2]. However, at least for some people, keto’s advantages might outweigh its drawbacks.

Ketogenetic diets are associated with reduced inflammation [3], and some studies have suggested possible benefits for people with autoimmune diseases [4]. However, the exact mechanisms are not fully understood yet. In this new study published in Cell Reports, scientists from the University of California San Francisco took a deep look at the workings of these diets in a murine model of an autoimmune disease.

Less severity and incidence

For their experiments, the researchers chose so-called experimental autoimmune encephalomyelitis (EAE) mice. These are often used as a plausible if imperfect model of human multiple sclerosis (MS) since they recapitulate many aspects of this debilitating autoimmune disease.

First, the researchers wanted to know whether keto can protect normally raised mice from EAE. Ten days after a ketogenic diet was begun, the mice were inoculated with a compound that triggers EAE. Compared to mice on a high-fat diet (75% of calories from fat, 15% from carbohydrate, and 10% from protein), mice eating a ketogenic diet (90.5% from fat, 0% from carbohydrate, and 9.5% from protein) were more resistant to the disease, with both lower incidence and much less severe symptoms. The keto-eating mice also had a more favorable immune profile.

However, when the researchers performed the same experiment in mice with depleted microbiota, the two groups barely showed any difference, demonstrating that the protective effect of a keto diet is mediated by gut bacteria.

The molecule that can replace ketogenesis

A ketogenic diet works by remodeling the body’s energy metabolism. When glucose is abundant, it is preferentially used as fuel. However, in a ketogenic environment, glucose is scarce, so the body switches to producing energy from fat using a process known as beta-oxidation. Fatty acids must be broken down into small molecules called ketone bodies, such as beta-hydroxybutyrate (βHB), which are transported across the body to be used as an alternative source of fuel.

In recent years, direct ketone supplementation via compounds such as ketone salts or esters has been tested as a way to recapitulate the benefits of ketogenic diets without the downsides. The researchers introduced a new group of mice fed the unhealthy high-fat diet supplemented with a ketone ester. This group was virtually indistinguishable from the original ketogenic diet group in terms of EAE incidence and severity.

“What was really exciting was finding that we could protect these mice from inflammatory disease just by putting them on a diet that we supplemented with these compounds,” said Peter Turnbaugh of the Benioff Center for Microbiome Medicine, a leading author on the study.

The gut connection

Interestingly, while most of the βHB production under KD happens in the liver, the beneficial effects of both keto diets and keton ester supplementation on MS seemed to be mediated by βHB production in intestinal epithelial cells. Mice genetically modified so that they could not produce βHB in the gut were not protected against MS regardless of their diet.

The researchers already knew that the gut microbiome was a crucial element, so they started hunting for bacterial species. After extensive screening, the researchers focused on Lactobacillus murinus and a metabolite it produces called indole lactic acid (ILA). ILA is known to alleviate autoimmune responses by inhibiting the production of the pro-inflammatory cytokine interleukin 17 (IL-17) by Th17, a subset of T cell strongly associated with autoimmune diseases.

Both treating MS mice with ILA and populating their guts with L. murinus alleviated the symptoms. The researchers concluded that ΒHB production specifically in the gut or oral supplementation with a ketone ester benefits ILA-producing bacteria, including L. murinus. This increases the production of ILA, which, in turn, leads to the observed anti-MS effect.

“The big question now is how much of this will translate into actual patients,” Turnbaugh said. “But I think these results provide hope for the development of a more tolerable alternative to helping those people than asking them stick to a challenging restrictive diet.”

Surprisingly, we discovered that oral delivery of a βHB-KE can mimic the protective effects of a KD. If this finding holds in humans, βHB supplementation alone could offer a viable therapeutic alternative to the full KD. The translational implications are profound, as KDs are difficult to maintain and can have negative side effects. Our identification of βHB as a key player provides a way to circumvent these barriers and provides a more general proof of concept for the ability to distill the activity of a complex diet down to a single bioactive molecule.

Literature

[1] Alexander, M., Upadhyay, V., Rock, R., Ramirez, L., Trepka, K., Puchalska, P., … Turnbaugh, P. J. (n.d.). A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity. Cell Reports.

[2] Burén, J., Ericsson, M., Damasceno, N. R. T., & Sjödin, A. (2021). A ketogenic low-carbohydrate high-fat diet increases LDL cholesterol in healthy, young, normal-weight women: a randomized controlled feeding trial. Nutrients, 13(3), 814.

[3] Pinto, A., Bonucci, A., Maggi, E., Corsi, M., & Businaro, R. (2018). Anti-oxidant and anti-inflammatory activity of ketogenic diet: new perspectives for neuroprotection in Alzheimer’s disease. Antioxidants, 7(5), 63.

[4] Brenton, J. N., Banwell, B., Bergqvist, A. C., Lehner-Gulotta, D., Gampper, L., Leytham, E., … & Goldman, M. D. (2019). Pilot study of a ketogenic diet in relapsing-remitting MS. Neurology: Neuroimmunology & Neuroinflammation, 6(4), e565.