WEST PALM BEACH, Florida — A comprehensive multiomics analysis of a 6-month phase 2 trial of a ketogenic diet in multiple sclerosis (MS) confirmed significant anti-inflammatory effects, aligning with mechanisms previously observed in animal models.
The findings suggest “we really can modify immune cell phenotypes with a dietary intervention,” said study investigator Michael D. Kornberg, MD, PhD, who heads a translational research laboratory focused on the pathogenesis of MS at Johns Hopkins Medicine, Baltimore.
The findings were presented on March 1 at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2025.
Strong Preclinical Evidence
A substantial body of preclinical research supports the potential for diet to influence immunologic function, demonstrating enough promise to warrant clinical testing, said Kornberg. One of the largest and longest clinical trials on this topic was published in 2022.
In that trial, which enrolled 65 patients with relapsing-remitting MS, a ketogenic diet was associated with benefit on multiple endpoints, including improvement in the Expanded Disability Status Scale score and an improvement in quality of life. A reduction in markers of inflammation was also seen, but the effects on immunoregulatory function were not then explored.
In the new analyses presented as late breaking research, Kornberg outlined changes that are consistent with reprogramming of immune cell metabolism and activity.
In the current analysis, conducted in collaboration with Wesley Godfrey, MD — a researcher in Kornberg’s lab completing his PhD — studies were performed using peripheral blood mononuclear cells (PBMCs) and plasma cells biobanked from 39 patients with MS who had participated in the phase 2 trial. The diet’s effects were assessed using samples collected at baseline and at the end of the 6-month study.
PBMCs were analyzed using flow cytometry and single-cell RNA sequencing. Plasma cell samples underwent multiplex enzyme-linked immunosorbent assay and metabolomics. The focus was on cell types and markers of myeloid and lymphoid lineages.
In myeloid cells, the ketogenic diet induced substantial changes in gene expression. While more genes were downregulated than upregulated, the most significantly downregulated were those linked to inflammatory responses. Notably, pathway alterations included a reduction in the proinflammatory cytokine interleukin (IL)-6, accompanied by an increase in IL-10.
These changes were interpreted as not just turning off myeloid cell activity but also shifting immunoregulatory expression from a type 1 to 2 response, said Kornberg.
Changes in lymphocytes included an increase in naive CD8 cells and a reduction in B-cell activity. By the end of the 6-month study, T-regulatory cells had increased, along with their suppressive activity.
Support for Further Research
Before analyzing the data, researchers predicted that the ketogenic diet would shift the balance between glycolysis and fatty acid oxidation, a change associated with anti-inflammatory effects. Indeed, gene and protein expression patterns confirmed this shift across multiple immune subsets, Kornberg reported.
“These changes were corroborated by plasma metabolomics, which demonstrated a decrease in the glycolytic products, such as lactate and pyruvate, and an increase in fatty acid oxidation intermediates, such as acetylcarnitine,” Kornberg said.
Other signs that the ketogenic diet produced fundamental immunomodulatory effects included a reduction in B-cell activation and changes in more than 70 blood metabolites, he added.
Kornberg and his co-investigators are investigating the hypothesis that lymphoid changes occur downstream of myeloid changes, based on several clues.
Although the exact mechanisms behind these changes remain unclear, Kornberg suggested that glucose restriction may play a role. He noted that glycolysis is involved in the inflammatory response of many cells.
He added that ketone bodies may have a direct impact on factors such as the NLRP3 inflammasome, which could also play a role. Additionally, a ketogenic diet may induce changes in the gut microbiome, contributing to its anti-inflammatory effects.
In the phase 2 study, from which these blood and plasma samples were biobanked, patients followed a modified Atkins diet. While not the strictest of the ketogenic diets, it was chosen for its relative tolerability, Kornberg noted. Adherence was monitored by having patients photograph urine strips that measured ketosis.
Overall, the results “provide a rationale for larger randomized studies of dietary interventions that include clinical endpoints,” said Kornberg.
Multiple Limitations
However, he acknowledged the study has multiple limitations that need to be addressed. Beyond the fact that it was a single-arm study with no control group, the analysis did not account for the potential independent effect of weight loss, which was a common occurrence.
Additional research that needs to be conducted includes investigating the effect of the ketogenic diet on the microbiome. Before and after images of brain lesions may also help evaluate whether, or how, the ketogenic diet affects MS activity in the brain.
“We also need data on the long-term safety of these diets,” Kornberg said.
Despite the favorable clinical changes observed at the end of the phase 2 trial, it remains uncertain whether the effects of the ketogenic diet are sufficient to affect clinical outcomes, even with long-term adherence, said Kornberg.
Commenting on the research, Mark S. Freedman, MD, professor of neurology, University of Ottawa, Ottawa, Ontario, Canada, noted that a lot of diets have been proposed for a lot of different diseases, but long-term adherence is often the Achilles’ heel not just for patients who might benefit but also for the clinical trials attempting to confirm that there is a meaningful clinical effect.
Freedman acknowledged that conducting a randomized trial on the ketogenic diet’s impact on MS outcomes would be extremely challenging due to adherence issues, cost, and the duration of follow-up. Although diet cannot be dismissed as a potential adjunct to MS therapy, he noted that meaningful evidence is unlikely to emerge in the near future.
Kornberg reported financial relationships with Biogen, Genentech, Janssen, Novartis, Optum Rx, and TG therapeutics. Freedman reported financial relationships with Alexion/AstraZeneca, Atara, Bayer AG, Biogen, Celestra, EMD Serono, Find Therapeutics, Hoffmann-LaRoche, Horizon, Merck, Novartis, Quanterix, Sanofi, Setpoint, and Teva.