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Randomized Controlled Trial
. 2025 Jan 16;96(2):158-169.
doi: 10.1136/jnnp-2024-333465.

Randomised controlled trial of intermittent calorie restriction in people with multiple sclerosis

Laura Ghezzi #  1   2 , Valeria Tosti #  3 , Lisa Shi  4 , Claudia Cantoni  5 , Robert Mikesell  3 , Samantha Lancia  6 , Yanjiao Zhou  7 , Kathleen Obert  3 , Courtney Dula  3 , Monokesh K Sen  4 , Anjie Ge  4 , Miguel Tolentino  3 , Bryan Bollman  3 , Anthony S Don  4 , Giuseppe Matarese  8   9 , Alessandra Colamatteo  8 , Claudia La Rocca  9 , Maria Teresa Lepore  9 , Cyrus A Raji  3   10 , Farzaneh Rahmani  10 , Gregory F Wu  3 , Robert T Naismith  3 , Luigi Fontana  11 , Anne H Cross  3 , Amber Salter #  6 , Laura Piccio #  12   4
Affiliations
Randomized Controlled Trial

Randomised controlled trial of intermittent calorie restriction in people with multiple sclerosis

Laura Ghezzi et al. J Neurol Neurosurg Psychiatry. .

Abstract

Background: Calorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) via multiple mechanisms. These include decreased leptin, a proinflammatory adipokine, but mechanistic studies in humans are lacking. Tests of daily and intermittent CR (iCR) in people with MS (pwMS) showed improvements in fatigue and well-being measures. This trial studied the effects of 12-week iCR on metabolic, immunological, and clinical outcomes in pwMS.

Method: Relapsing-remitting MS participants were randomised to iCR or a control group. Study visits were conducted at baseline, 6 and 12 weeks. The primary outcome was reduction in serum leptin levels at 12 weeks. Feasibility and safety were assessed by diet adherence and adverse events (AEs). Secondary outcomes included changes in anthropometric and body composition measures, metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate outcome differences between and within groups over time.

Results: Forty-two pwMS were randomised, 34 completed the study (17/group). Leptin serum levels at 12 weeks were significantly lower in the iCR versus the control group (mean decrease -6.98 µg/dL, 95% CI: -28.02 to 14.06; p=0.03). Adherence to iCR was 99.5% and 97.2% at 6 and 12 weeks, respectively, and no serious AEs were reported. An increase in blood CD45RO+ regulatory T-cell numbers was seen after 6 weeks of iCR. Exploratory cognitive testing demonstrated a significant improvement in the Symbol Digit Modality Test Score in the iCR group at 12 weeks.

Conclusions: iCR has the potential to benefit metabolic and immunologic profiles and is safe and feasible in pwMS.

Trial registration number: NCT03539094 .

Keywords: MULTIPLE SCLEROSIS; NEUROIMMUNOLOGY.

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Conflict of interest statement

Competing interests: LP has received research funding from the National MS Society, the NIH, the Department of Defense and Fondazione Italiana Sclerosi Multipla; she has been funded by Alector and Biogen for a project not related to the one included in this manuscript. She is one of the Editor-in-Chief of Journal of Neuroimmunology. AHC received compensation for consulting for Biogen, EMD Serono, Bristol Myers Squibb, TG Therapeutics, Octave, Genentech, Roche, Novartis, Horizon and Janssen (J&J). AHC was supported by the Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology during this study. CAR received compensation for consulting for CoreTechs.ai, Eli Lilly, Voxelwise, Neurevolution. GFW received compensation for consulting for EMD Serono, Genzyme, Novartis, Sangamo, Roche, Alumis and the US Department of Justice. He has received research grant funding from the NIH, National MS Society, Doris Duke Foundation, US Department of Veterans Affairs, Biogen, EMD Serono and Genentech. He serves on the editorial boards of Neurology: Neuroimmunology & Neuroinflammation and the Journal of Neuroimmunology. He serves on advisory boards for Progentec and Genentech. RTN has consulted for Alexion Pharmaceuticals, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, EMD Serono, Horizon Therapeutics, Novartis, TG Therapeutics. AS receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the Department of Defense Congressionally Directed Medical Research Program and is a member of the editorial board for Neurology. She serves as a consultant for Gryphon Bio and Abata Therapeutics. She is a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease (CELLO) and Methotrexate treatment of Arthritis caused by Chikungunya virus (MARCH). She holds the Kenney Marie Dixon-Pickens Distinguished Professorship in Multiple Sclerosis Research.

Figures

Figure 1
Figure 1. Overview of the study design. DEXA, dual-energy X-ray absorptiometry; MS, multiple sclerosis; OGTT, oral glucose tolerance test; PRO, patient reported outcome; CPC, complete blood count.
Figure 2
Figure 2. Consolidated Standards of Reporting Trials (CONSORT) flow diagram. iCR, intermittent calorie restriction.
Figure 3
Figure 3. Changes in adipokine and anthropometric measures in the iCR and control groups over the course of the study. (A) Leptin and high molecular weight (HMW) adiponectin serum levels at 6 and 12 weeks. (B) BMI, waist circumference and total fat measured by dual-energy X-ray absorptiometry at 6 and 12 weeks. In the graphs, for each variable, raw values (not adjusted) are reported for each participant at all timepoints. p values are adjusted for age, sex and multiple sclerosis disease-modifying therapy. The box extends from 25th to 75th percentiles. Horizontal bars are median and error bars are minimum and maximum values. BMI, body mass index; iCR, intermittent calorie restriction; ns, not significant.
Figure 4
Figure 4. Changes in T-cell subsets in the iCR and control groups over the course of the study. Absolute numbers and frequencies of (A) naïve CD4+ T cells, (B) effector memory CD4+ T cells and (C) CD45RO+ regulatory T cells at 6 and 12 weeks in the iCR and control groups. In the graphs, for each variable, raw values (not adjusted) are reported for each participant at all timepoints. The box extends from 25th to 75th percentiles. Horizontal bars are median and error bars are minimum and maximum values. iCR, intermittent calorie restriction.
Figure 5
Figure 5. LPC, LPE and PI species are affected by iCR. (A,B) Comparison of lipid levels between iCR and control groups at (A) 12 weeks and (B) baseline. Volcano plots showing effect of (C) iCR or (D) control diet on lipid levels at 12 weeks compared with baseline. p values are corrected for FDR (q<0.05). (E–G) Significant change in levels of (E) LPE(16:0), (F) LPC(22:4) and (G) PI(18:1/20:4) between baseline (closed circle) and 12 weeks (triangle) and within diet groups (q<0.05). (H) Correlation heatmap illustrating significant correlations between the 16 lipids that were significantly altered after iCR and laboratory/clinical variables that were significantly altered after iCR (*p<0.05, # indicates q<0.05). The colour scale shows the correlation coefficient (r). DG, diacylglycerol; FDR, false discovery rate; HexCer, hexosylceramide; iCR, intermittent calorie restriction; LacCer, lactosylceramide; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; PI, phosphatidylinositol; CHDLr, cholesterol to high-density lipoprotein ratio; eff: effector.
Figure 6
Figure 6. Changes in cognitive outcomes in the iCR and control groups over the course of the study. Participants randomised to the iCR group showed a significant increase in the SDMT Score between baseline and week 12. In the graphs, for each variable, raw values (not adjusted) are reported for each participant at all timepoints. P values are adjusted for age, sex and multiple sclerosis disease-modifying therapy. The box extends from the 25th to 75th percentiles. Horizontal bars are median and error bars are minimum and maximum values. iCR, intermittent calorie restriction; SDMT, Symbol Digit Modality Test.
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