A recent study published in Cell Reports highlights the potential of a ketogenic diet (KD) to reduce the severity of autoimmune diseases by influencing interactions between the host and gut microbiome. The research suggests that dietary choices can significantly impact conditions such as rheumatoid arthritis, multiple sclerosis (MS), and inflammatory bowel disease.
The ketogenic diet is characterized by a low-carbohydrate, high-fat approach that shifts the body’s metabolism towards lipid oxidation. This metabolic transition increases levels of key metabolites, including acetoacetate and β-hydroxybutyrate (βHB), which may play a role in modulating the immune system and gut microbiota. Previous findings indicated that KDs can reduce intestinal immune activation, but the specific mechanisms involved remained unclear.
In this study, researchers fed conventionally raised (CONV-R) mice either a high-fat diet (HFD) or a ketogenic diet. After ten days, they induced experimental autoimmune encephalitis (EAE) in the mice to model autoimmune disease. The severity of the disease was evaluated using several metrics, including disease score progression and overall incidence. The results showed that mice on the ketogenic diet experienced significantly reduced disease severity compared to those on the high-fat diet.
Further analysis revealed that the KD group had lower levels of CD4+ helper T (Th) cells producing interleukin (IL)-17a and interferon (IFN)-γ in both the spleen and brain, indicating an immunomodulatory effect of the diet.
To explore these findings further, the researchers conducted similar experiments with germ-free (GF) mice. While βHB levels were elevated in KD-fed mice, there were no significant differences in disease metrics among GF mice. Interestingly, HFD-fed GF mice exhibited reduced disease symptoms, suggesting that the gut microbiota plays a crucial role in mediating the effects of the ketogenic diet.
The team then examined the effects of a βHB-containing ketone ester (KE) on mice fed HFD, KD, or HFD with KE. They found that while HFD-fed mice had higher disease scores than those on the KD, the disease incidence rates were similar between the KD and HFD-KE groups. This indicated that the presence of βHB could replicate some of the protective effects of the ketogenic diet.
To delve deeper, researchers generated transgenic mice with a selective ablation of intestinal βHB production. These mice displayed significantly higher disease scores compared to wild-type controls, even though their circulating βHB levels were comparable. When both groups were fed a KD or KD supplemented with KE, the KE supplementation raised βHB levels but did not affect the wild-type mice. However, it did reduce disease severity in the transgenic mice.
Fecal microbiota transplantation (FMT) experiments were conducted to assess the impact of the gut microbiota on disease outcomes. FMT from HFD-KE donors resulted in lower disease scores compared to HFD donors, underscoring the protective role of certain microbiota in mediating the effects of dietary interventions.
The researchers also identified specific bacteria associated with the protective effects of the KD. They established stable in vitro communities from the gut microbiota and performed sequencing to analyze microbial composition. They discovered three amplicon sequence variants (ASVs)—Parasutterella, Enterococcus, and Bacteroides—that were prevalent across different dietary groups.
Further immunological assays revealed that HFD-derived communities induced IL-17a production, while KD-derived communities did not. The study isolated a Lactobacillus strain, designated Lactobacillus murinus KD6, which was found to possess genes linked to the production of indole-3-lactate (ILA), a compound that inhibits IL-17a production.
When tested in vivo, both ILA and L. murinus KD6 administration significantly reduced disease scores and improved survival rates in mice with EAE.
Conclusion
This study uncovers a microbiome-dependent mechanism through which a ketogenic diet may protect against neurological diseases. The findings indicate that local production of βHB in the gut is essential for the diet’s protective effects. Additionally, L. murinus KD6 and ILA were both effective in mitigating disease severity, suggesting that dietary modifications can alter the immunomodulatory potential of the gut microbiota and shift host metabolism in ways that benefit autoimmune conditions.
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