Table 4.

All reviewed studies investigating the effects of DR in MS. N/A: relevant data not reported; n/s: relevant data not significant; EAE: experimental autoimmune encephalomyelitis; SCH: spinal cord homogenate; PLP: proteolipid protein; MOG: myelin oligodendrocyte glycoprotein; CNS: central nervous system; BHB: beta-hydroxybutyrate; RRMS: relapsing remitting multiple sclerosis; QOL: quality of life.

1 Multiple Sclerosis Animal Studies
Model Organism (Antigen)	Age & Sex	Dietary Interventions	Clinical Findings	Immune & Biomarkers	Reference
Lewis rats, EAE (SCH)	6-weeks male	66% CR for 15 days pre-induction	↓ clinical score	↓ spleen & lymph IFN-γ	Esquifino et al. 2007 [132]
SJL mice, EAE (PLP)	5-weeks female	40% CR for 5 weeks pre-induction	↓ clinical score; ↑ survival; ↓ spinal cord inflammation, demyelination, & axon damage	↑ corticosterone & adiponectin; ↓ leptin & IL-6	Piccio et al. 2008 [133]
C57BL/6 mice, EAE (MOG)	13-weeks female	ADF for 8 weeks pre-induction, post-induction, or both	↓ incidence (ADF post)	N/A	Kafami et al. 2010 [134]
C57BL/6 mice, EAE (MOG)	10-weeks female	FMD (3 cycles) at 10% symptomatic (S), at 100% symptomatic (T), or at 2 weeks post-symptoms (C-F)	↓ clinical score (all); ↓ incidence (S); ↓ spinal cord inflammation & demyelination (T); ↑ myelin regeneration (T)	↓ blood WBC, lymphocytes, monocytes, & granulocytes; ↓ CNS CD4 & CD8 T-cells; ↑ spleen naïve:active CD4 T-cell ratio (T)	Choi et al. 2016 [136]
C57BL/6 mice, EAE (MOG)	7-weeks female	ADF for 4 weeks pre-induction	↓ clinical score; ↓ spinal cord inflammation & demyelination;	↓ lymph T-cell IL-17 & IFN-γ; ↑ corticosterone & BHB; ↑ T-regs in small intestine	Cignarella et al. 2018 [135]
C57BL/6 mice, EAE (MOG)	8 weeks-female	ADF for 4 weeks pre-induction	↓ clinical score	↓ blood & CNS inflammatory monocytes; ↓ CNS monocyte TNFα, IL-1β, CXCL2 &CXCL10	Jordan et al. 2019 [55]
C57BL/6 mice, EAE (MOG)	6-weeks female	FMD (2 cycles) at 3 weeks post-induction	↓ incidence; ↓ clinical score; ↓ spinal cord inflammation & demyelination; ↑ myelin regeneration	↓ spinal cord leukocytes & macrophages; ↓ CNS CD4 & CD8 T-cells; ↓ CNS T-cell IL-17 &↑ IFN-γ; ↑ spleen CD4 & CD11b T-cells	Bai et al. 2021 [137]
2 Multiple Sclerosis Human Studies
Patient Population	Age & Sex	Dietary Interventions	Clinical Findings	Immune & Biomarkers	Reference
Adult RRMS patients	18–68 (mean: 45) male & female	1-cycle of FMD followed by a Mediterranean diet (n = 18), KD (n = 18), or control diet (n = 12) for 6 months	↑ QOL (FMD & KD)	n/s	Choi et al. 2016 [136]
Adult RRMS patients undergoing relapse	18–60 (mean: 41) male & female	<500 kcal ADF (n = 8) or control diet (n = 8) for 15 days	n/s	↓ blood T&B cells; ↓ naïve CD4 T-cells; ↓ Leptin	Cignarella et al. 2018 [135]
Adult RRMS patients not undergoing relapse	18–50 (mean: 37) male & female	75% CR 5:2 IF (n = 11), 22% CR (n = 11), or control diet (n = 9) for 8 weeks	n/s	↓ memory T-cells and Th1 cells ↑ naïve CD4 T-cells	Fitzgerald et al. 2022 [138]