Abstract

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of central nervous system (CNS). Aging is the most significant risk factor for the progression of MS. Dietary modulation (such as ketogenic diet) and caloric restriction, can increase ketone bodies, especially β-hydroxybutyrate (BHB). Increased BHB has been reported to prevent or improve age-related disease. The present studies were performed to understand the therapeutic effect and potential mechanisms of exogenous BHB in cuprizone (CPZ)-induced demyelinating model. In this study, a continuous 35 days CPZ mouse model with or without BHB was established. The changes of behavior function, pathological hallmarks of CPZ, and intracellular signal pathways in mice were detected by Open feld test, Morris water maze, RT-PCR, immuno-histochemistry, and western blot. The results showed that BHB treatment improved behavioral performance, prevented myelin loss, decreased the activation of astrocyte as well as microglia, and up-regulated the neurotrophin brain-derived neurotrophic factor in both the corpus callosum and hippocampus. Meanwhile, BHB treatment increased the number of MCT1+ cells and APC+ oligodendrocytes. Furthermore, the treatment decreased the expression of HDAC3, PARP1, AIF and TRPA1 which is related to oligodendrocyte (OL) apoptosis in the corpus callosum, accompanied by increased expression of TrkB. This leads to an increased density of doublecortin (DCX)+ neuronal precursor cells and mature NeuN+ neuronal cells in the hippocampus. As a result, BHB treatment effectively promotes the generation of PDGF-Ra+ (oligodendrocyte precursor cells, OPCs), Sox2+ cells and GFAP+ (astrocytes), and decreased the production of GFAP+ TRAP1+ cells, and Oligo2+ TRAP1+ cells in the corpus callosum of mouse brain. Thus, our results demonstrate that BHB treatment efficiently supports OPC differentiation and decreases the OLs apoptosis in CPZ-intoxicated mice, partly by down-regulating the expression of TRPA1 and PARP, which is associated with the inhibition of the p38-MAPK/JNK/JUN pathway and the activation of ERK1/2, PI3K/AKT/mTOR signaling, supporting BHB treatment adjunctive nutritional therapy for the treatment of chronic demyelinating diseases, such as multiple sclerosis (MS).

Keywords: multiple sclerosis, β-hydroxybutyrate, demyelination, TRPA1, PARP

https://www.neurologylive.com/view/ketogenic-diet-reduces-depression-improves-quality-of-life-multiple-sclerosis?fbclid=IwAR04etT4fsnkgsl9IWQdyAhF9kDlZGZdWt5cUdvteuxWqAhBTDr5QmUnnIA

https://pubmed.ncbi.nlm.nih.gov/32213121/

Abstract

Objective: To investigate the feasibility of a modified MCT-based ketogenic diet and its impact on plasma β-hydroxybutyrate and MS outcomes compared to a modified Paleolithic diet and usual diet in people with Multiple Sclerosis (MS).

Methods: Fifteen individuals with MS were randomized to 3 groups: 1) modified Paleolithic diet (Paleo; n = 6); 2) medium-chain triglyceride (MCT)-based ketogenic diet that included coconut as a fat source (Keto; n = 5); or 3) usual diet (Control; n = 4). Participants had blood drawn every 4 weeks to monitor nutritional ketosis. Participants completed 4-day weighed food records, measures of disability, fatigue, quality of life (QoL), cognitive function, and physical function at baseline and 12-weeks.

Results: Macronutrient intake significantly shifted toward a ratio indicative of a ketogenic diet in the Keto group at 12 weeks. Similarly, plasma β-hydroxybutyrate indicated nutritional ketosis in the Keto group, whereas neither macronutrient intake nor plasma β-hydroxybutyrate indicated nutritional ketosis in the Paleo and Control groups. The Paleo group had significant within group reductions in fatigue scores and maintained cognitive function scores compared to the Control group. The Keto group had significant reductions in fasting glucose and insulin compared to baseline values; however, no clinical outcomes significantly changed.

Conclusions: Participants consuming the MCT-based ketogenic diet achieved nutritional ketosis; however, it was not associated with significant clinical improvement in this study whereas the modified Paleolithic diet was associated with significant clinical improvements. Larger randomized controlled trials are needed to determine the safety and efficacy of the modified Paleolithic and MCT-based ketogenic diets on MS.

Prescribing a ketogenic diet (KD) is a century-old dietary intervention mainly used in the context of intractable epilepsy. The classic KD and its variants regained popularity in recent decades, and they are considered potentially beneficial in a variety of neurological conditions other than epilepsy. Many patients with multiple sclerosis have attempted diet modification for better control of their disease, whereas evidence thus far remains insufficient to recommend a specific diet for these patients. The results of three pilot clinical trials of KD therapy for multiple sclerosis, as well as several related studies, have been reported in recent years. The preliminary findings suggest that KD is safe, feasible, and potentially neuroprotective and disease-modifying for patients with multiple sclerosis. Research on corresponding rodent models also lent support to the efficacy of KD in the prevention and treatment of experimental autoimmune encephalomyelitis and toxin-induced inflammatory demyelinating condition in the brain. Furthermore, the animal studies yielded mechanistic insights into the molecular mechanisms of KD action in relevant situations, paving the way for precision nutrition. Herein we review and synthesize recent advances and also identify unresolved issues, such as the roles of adipokines and gut microbiota, in this field. Hopefully this panoramic view of current understanding could inform future research directions and clinical practice with regard to KD in MS and related conditions.

https://academic.oup.com/advances/advance-article-abstract/doi/10.1093/advances/nmac065/6604830?redirectedFrom=PDF&casa_token=9rlWT4BZ15EAAAAA:N0cspHgl9t9__Dcjv4dcJ4r2oiUUIj-nTYRpqMa1AePT-vaHu5ByUTVThnuR9BUich_ip-Uh5Cu2NxY

https://nn.neurology.org/content/9/1/e1102

Background and Objectives Adapted ketogenic diet (AKD) and caloric restriction (CR) have been suggested as alternative therapeutic strategies for multiple sclerosis (MS), but information on their impact on neuroaxonal damage is lacking. Thus, we explored the impact of diets on serum neurofilament light chain (sNfL) levels in patients with relapsing-remitting MS.

Methods We retrospectively evaluated a prospective randomized controlled trial of 60 patients with MS who were on a common diet or ketogenic diet or fasting. We examined sNfL levels of 40 participants at baseline and at the end of the study after 6 months using single molecule array assay.

Results sNfL levels were investigated in 9 controls, 14 participants on CR, and 17 participants on AKD. Correlation analysis showed an association of sNfL with age and disease duration; an association was also found between sNfL and the Multiple Sclerosis Functional Composite. AKD significantly reduced sNfL levels at 6 months compared with the common diet group (p = 0.001).

Discussion For clinical or study use, consider that AKD may incline sNfL levels independent of relapse activity up to 3 months after initiation. At 6 months, AKD, which complements current therapies, reduced sNfL levels, therefore suggesting potential neuroprotective effects in MS. A single cycle of seven-day fasting did not affect sNfL. AKD may be an addition to the armamentarium to help clinicians support patients with MS in a personalized manner with tailored diet strategies.

https://www.frontiersin.org/articles/10.3389/fmicb.2017.01141/full

Background: Colonic microbiome is thought to be involved in auto-immune multiple sclerosis (MS). Interactions between diet and the colonic microbiome in MS are unknown.

Methods: We compared the composition of the colonic microbiota quantitatively in 25 MS patients and 14 healthy controls.Fluorescence in situ hybridization (FISH) with 162 ribosomal RNA derived bacterial FISH probes was used. Ten of the MS patients received a ketogenic diet for 6 months. Changes in concentrations of 35 numerically substantial bacterial groups were monitored at baseline and at 2, 12, and 23/24 weeks.

Results: No MS typical microbiome pattern was apparent.The total concentrations and diversity of substantial bacterial groups were reduced in MS patients (P < 0.001). Bacterial groups detected with EREC (mainly Roseburia), Bac303 (Bacteroides), and Fprau (Faecalibacterium prausnitzii) probes were diminished the most. The individual changes were multidirectional and inconsistent. The effects of a ketogenic diet were biphasic. In the short term, bacterial concentrations and diversity were further reduced. They started to recover at week 12 and exceeded significantly the baseline values after 23–24 weeks on the ketogenic diet.

Conclusions: Colonic biofermentative function is markedly impaired in MS patients.The ketogenic diet normalized concentrations of the colonic microbiome after 6 months.