Chewing the Fat

The identification of a key metabolic mechanism has revealed how ketogenic diets (KD) could protect against autoimmune neuroinflammation in diseases, such as multiple sclerosis. 

In a recent study, researchers at the University of California, USA, used an experimental autoimmune encephalomyelitis (EAE) mouse model to explore why mice fed a high-fat, low-carbohydrate KD exhibit significantly lower disease severity than those on a standard diet. The team also explored a high-fat diet supplemented with beta-hydroxybutyrate ketone ester (βHB-KE) because of previous work, which established the involvement of βHB in suppressing immune activation.

By limiting the intake of carbohydrates and sugars in favor of near unlimited fat consumption, the body breaks down fats rather than carbohydrates, which produces compounds called ketone bodies, such as βHB, that provide cells with energy and can affect the body’s immune system.

Specifically, βHB appears to dampen pro-inflammatory immune pathways, such as Th17 cell activation, in a microbiota-dependent manner to reduce neuroinflammation. Indeed, the researchers showed that transgenic mice genetically engineered to lack intestinal βHB production showed no reduction in disease severity, confirming the gut as a critical site for βHB’s protective action.

The study also identified Lactobacillus murinus, a gut bacterium enriched by βHB, as a key player in reducing T helper 17 (Th17) cell-mediated inflammation. The team used genome sequencing and mass spectrometry to verify L. murinus’ production of indole lactic acid (ILA). This metabolite is known to suppress Th17 cell activation, suggesting that βHB promotes neuroprotection indirectly by shaping microbial metabolites. 

“Surprisingly, we discovered that oral delivery of a βHB-KE can mimic the protective effects of a KD,” wrote the authors. βHB supplementation as a dietary intervention for managing multiple sclerosis and other autoimmune diseases could offer an alternative to strict ketogenic diets, which can be challenging for patients to sustain.