Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis

Authors: FITZGERALD, KATHRYN - Johns Hopkins University School Of Medicine; BHARGAVA, PAVAN - Johns Hopkins University School Of Medicine; SMITH, MATTHEW - Johns Hopkins University School Of Medicine; VIZTHUM, DIANE - Johns Hopkins University School Of Medicine; HENRY-BARRON, BOBBIE - Johns Hopkins University School Of Medicine; CASSARD, SANDRA - Johns Hopkins University School Of Medicine; KAPOGIANNIS, DIMITRIOS - National Institute On Aging (NIA, NIH); Baer, David; Sullivan, Patrick; CALABRESI, PETER - Johns Hopkins University School Of Medicine; MOWRY, ELLEN - Johns Hopkins University School Of Medicine

Submitted to: EBioMedicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/8/2022
Publication Date: 8/1/2022
Citation: Fitzgerald, K.C., Bhargava, P., Smith, M.D., Vizthum, D., Henry-Barron, B., Cassard, S.D., Kapogiannis, D., Baer, D.J., Sullivan, P.J., Calabresi, P.A., Mowry, E.M. 2022. Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis. EBioMedicine. 82:1-13. https://doi.org/10.1016/j.ebiom.2022.104124.
DOI: https://doi.org/10.1016/j.ebiom.2022.104124

Interpretive Summary: Multiple sclerosis (MS) is an autoimmune and neurodegenerative disorder of the central nervous system. Progression of disability is currently irreversible, and prognosis is highly variable, highlighting the need for continued research regarding modifiable risk and protective factors for disease worsening. The role of diet has emerged as an important factor that may modulate MS course. Diet could potentially do so through direct modulation of the immune system, via alterations to gut bacteria, or by changes to metabolism (e.g., modification of oxidative stress or mitochondrial function). We conducted a controlled feeding study of different calorie restriction diets in 36 people with MS over 8 weeks. The control diet and different calorie restriction protocols were 1) a control diet, in which the participant received 100% of his or her calorie needs 7 days per week, 2) a daily calorie restriction diet in which the participant received 78% of his or her calorie needs 7 days per week, or 3) an intermittent calorie restriction diet in which the participant received 100% of his or her calorie needs on 5 days per week and 25% of his or her calorie needs 2 days per week. We demonstrated that calorie restricted diets are safe and effect ways to achieve weight loss in people with MS. Further, we showed that calorie restriction is associated with changes in circulating levels of several relevant lipid metabolites, including acyl carnitines and subsets of glycerophospholipids, and intermittent calorie restriction specifically is associated with a reduction in memory T cell subsets. This information will further our understanding of the long-term implications of calorie restriction in people with MS.

Technical Abstract: Intermittent fasting or calorie restriction (CR) diets may provide additional anti-inflammatory and neuroprotective advantages beyond the benefits obtained from weight loss alone. In animal models of multiple sclerosis (MS), fasting delays the onset of the disease, reduces pro-inflammatory cytokines and promotes regeneration of oligodendrocytes. However, data in humans are lacking. The objective of this study was to to assess the effects of CR diet on adipokines or immune cell subsets and to determine whether the effects are mediated by changes in the plasma metabolome. We conducted a controlled feeding study of different CR diets in 36 people with MS over 8 weeks. Energy expenditure was determined using indirect calorimetry. Patients were randomized to receive 1 of 3 diets: a daily CR diet (22% daily reduction in energy needs), an intermittent CR diet (75% reduction in calorie needs 2 days/week; 100% of daily needs 5 days/week), and a weight-stable diet (100% of daily calorie needs). Participants provided morning blood samples to obtain plasma (at baseline and weeks 4, 8) and peripheral blood mononuclear cells (PBMCs; at baseline and week 8). For individuals randomized to intermittent CR, samples at weeks 4 and 8 were collected following a 25% calorie-needs day (e.g., following a fasting day). Adipokines were measured using commercial assays. Untargeted metabolomics was performed on plasma samples at Metabolon (Durham, NC) and quantified relative abundances >500 metabolites. From PBMCs, we identified CD4+ and CD8+ T cells and identified memory subsets including effector memory (TEM: CCR7- CD45RO+), central memory (TCM: CCR7+ CD45RO+), and naïve cells (Tnaive: CCR7+ CD45RO-). We assessed within-person change in metabolite and immune cells across diets using mixed effects models. Of the 36 patients enrolled, 31 (86%) completed the trial. Over time, individuals randomized to intermittent CR had significant reductions in memory T cell subsets including CD4+CM -4.87%; 95% CI: -8.59%, -1.15%; p=0.01), CD4+CM (-3.82%; 95% CI: -7.44, -0.21; p=0.04), and CD8+EM (-6.96%; 95% CI: -11.96, -1.97; p=0.006) with concomitant increases in naïve subsets (CD4+Naïve: 5.81%; 95% CI: -0.01, 11.63%; p=0.05; CD8+Naïve: 10.11%; 95% CI: 3.30, 16.92%; p=0.006). Individuals randomized to intermittent calorie restriction also experienced significant reductions in Th1 cells (-4.26%; 95% CI: -7.11%, -1.40%; p=0.004). No notable changes in T cell subsets were observed for individuals randomized to daily CR or weight stable diets. Leptin and adiponectin did not change significantly over time in individuals randomized to CR. In those randomized to intermittent CR, larger within-person change in lysophospholipid and lysoplasmalogen metabolites were generally associated with larger reductions in memory T cell subsets and larger increases in naïve T cell subsets. In people with MS, intermittent CR diets were associated with reduction in memory T cell subsets. The observed changes may be mediated by changes in specific classes of lipid metabolites.