Intermittent Calorie Restriction Alters Immune and Metabolic Markers in RRMS

New research suggests that a structured approach to intermittent calorie restriction (iCR) could actively reshape immune and metabolic pathways in patients with relapsing-remitting multiple sclerosis (RRMS). In a 12-week randomized controlled trial published in the Journal of Neurology, Neurosurgery, and Psychiatry, investigators explored how iCR influences key biomarkers, immune cell dynamics, and patient-reported outcomes.

Exploring the Impacts of iCR in RRMS

One of the most notable findings was a significant reduction in leptin, a proinflammatory adipokine implicated in T cell activation and MS pathogenesis. It was significantly reduced in the iCR group at 12 weeks compared with controls (mean difference −6.98 micrograms per deciliter; p=0.03). Although adiponectin levels did not differ significantly between the iCR and control groups at 12 weeks, levels increased from baseline within the iCR group, supporting a shift toward an anti-inflammatory adipokine profile.

While not statistically significant, iCR was associated with increased proportions of naïve CD4-positive and CD45RO-positive regulatory T cells and decreased effector memory and T helper type 1 subsets. These immunophenotypic trends coincided with significant upregulation of glycolytic (e.g., Enolase-1) and lipid metabolism enzymes (e.g., ACAD9, fatty acid synthase) in regulatory T cells, consistent with enhanced metabolic activation and a shift toward a tolerogenic phenotype.

Although between-group differences in weight and body mass index were not statistically significant, participants in the iCR group demonstrated significant within-group reductions in both measures over the 12-week period (mean weight decrease 2.66 kilograms; p<0.0001). Dual-energy X-ray absorptiometry confirmed reductions in total and trunk fat mass. Lipidomic analysis revealed significant increases in multiple phospholipid species, including phosphatidylinositols, lysophosphatidylcholines, and lysophosphatidylethanolamines, in the iCR group but not in controls. Several of these species, including LPE(18:1), were significantly correlated with improvements in fatigue scores on the Modified Fatigue Impact Scale.

Cognitive performance, assessed via the Symbol Digit Modality Test (SDMT), improved significantly within the iCR group (mean increase 6.2 points; p<0.0001), while fatigue and mental health measures showed nominal improvement. Adherence exceeded 97 percent, and no serious adverse events were reported. Mild symptoms were infrequent and self-limited.

Clinical Implications

These findings support iCR as a feasible, immunometabolically active dietary intervention in RRMS. By modulating leptin signaling, enhancing regulatory T cell metabolism, and altering lipid profiles, iCR may serve as a complementary strategy alongside disease-modifying therapies. Larger, longer-term trials are warranted to assess clinical durability, potential efficacy in progressive disease, and radiographic or neurofunctional outcomes.

Reference

Ghezzi L, Tosti V, Shi L, et al. Randomised controlled trial of intermittent calorie restriction in people with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2025;96(2):158-169. Published 2025 Jan 16.