Could diet be the new add-on DMT?

C

Barts-MS rose-tinted-odometer  ★ ★★ ★ ★

I gave my first on using diet as a potential symptomatic and disease-modifying treatment for MS and as a preventative therapeutic strategy in MS, last night.

The symptomatic part of my talk was about food coma and using diet to prevent or reduce the impact of food coma. We are still studying why pwMS are so susceptible to food coma. I suspect it is because they have less cognitive reserve and food coma may interact with other medications to make it such a problem.

The really interesting part of my talk was using caloric restriction (CR), intermittent fasting (IF) or ketogenic (K) diet as a DMT. I suspect the mode of action of all these diets is via ketosis and inducing high levels of circulating β-hydroxybutyrate one of the ketone bodies. Ketone bodies are the source of energy the body uses when we have depleted our sugar stores (glycogen) and are fasting or not absorbing sugar from the gut.

Interestingly, β-hydroxybutyrate works via the hydroxycarboxylic acid receptor 2 (HCA2), which is also known as niacin receptor 1 (NIACR1) and GPR109A. Why is this so important? This is the same receptor that fumaric acid works on. Yes, ketosis works at a cellular level in the same way that dimethyl fumarate (DMF) and diroximel fumarate work, i.e licensed MS DMTs.

Yes, CR/IF/K diet may induce a metabolic pathway that is known to be disease-modifying in MS.

There is an extensive literature, which I discovered about two years ago, showing that β-hydroxybutyrate works via NRF2 and downregulates NFKappa-B, the master inflammatory transcription factor. In other words ketosis, in particular β-hydroxybutyrate promotes programmed cell survival via the NRF2 two pathway and is also anti-inflammatory. β-hydroxybutyrate may even be better than the fumarates as a treatment for MS because it is likely to penetrate the CNS better than oral fumarates.

The corollary of the above could also explain why a processed and ultra-processed high carbohydrate diet is pro-inflammatory. Most people put it down to the pro-inflammatory signals from adipose tissue, but it could be related to the fact that carbohydrates, via insulin, inhibit ketosis and suppress β-hydroxybutyrate levels in the body.

Another nugget of information I found is that metformin also works via NRF2, but not via the HCA2 receptor. This may explain why metformin promotes rejuvenation of oligodendrocyte precursors and is being explored as a potential remyelination therapy in MS.

I have also discovered whilst reading the NRF2 literature that some statins, including simvastatin, activate NRF2. Could this be a potential mode of action of simvastatin in MS?

I didn’t have time to discuss MS prevention last night. However, we think that about 10-20% of the increase in MS incidence may be caused by childhood and adolescent obesity. This is why we are pushing for policy on sugar and a national campaign to tackle this problem.

So when I say I have declared war on sugar, I mean it in more ways than you realise.

Despite observational evidence showing that pwMS do well on CR/IF/K diets, the studies show that they are generally safe. However, we need controlled evidence before promoting these pwMS as a potential adjunctive treatment for MS. The good news is that there are ongoing studies looking into this. The one below is actually using MRI to see if a ketogenic diet has an impact on MRI activity, i.e. the inflammatory component of MS.

Are you up for biohacking your metabolism as a treatment for your MS?

Bahr et al. Ketogenic Diet and Fasting Diet as Nutritional Approaches in Multiple Sclerosis (NAMS): Protocol of a Randomized Controlled Study. Trials, 21 (1), 3 2020 Jan 2.

Background: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults that may lead to progressive disability. Since pharmacological treatments may have substantial side effects, there is a need for complementary treatment options such as specific dietary approaches. Ketone bodies that are produced during fasting diets (FDs) and ketogenic diets (KDs) are an alternative and presumably more efficient energy source for the brain. Studies on mice with experimental autoimmune encephalomyelitis showed beneficial effects of KDs and FDs on disease progression, disability, cognition and inflammatory markers. However, clinical evidence on these diets is scarce. In the clinical study protocol presented here, we investigate whether a KD and a FD are superior to a standard diet (SD) in terms of therapeutic effects and disease progression.

Methods: This study is a single-center, randomized, controlled, parallel-group study. One hundred and eleven patients with relapsing-remitting MS with current disease activity and stable immunomodulatory therapy or no disease-modifying therapy will be randomized to one of three 18-month dietary interventions: a KD with a restricted carbohydrate intake of 20-40 g/day; a FD with a 7-day fast every 6 months and 14-h daily intermittent fasting in between; and a fat-modified SD as recommended by the German Nutrition Society. The primary outcome measure is the number of new T2-weighted MRI lesions after 18 months. Secondary endpoints are safety, changes in relapse rate, disability progression, fatigue, depression, cognition, quality of life, changes of gut microbiome as well as markers of inflammation, oxidative stress and autophagy. Safety and feasibility will also be assessed.

Discussion: Preclinical data suggest that a KD and a FD may modulate immunity, reduce disease severity and promote remyelination in the mouse model of MS. However, clinical evidence is lacking. This study is the first clinical study investigating the effects of a KD and a FD on disease progression of MS.

Trial registration: ClinicalTrials.gov, NCT03508414.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

29 comments

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  • Good morning Dr. G !!
    I totally agree with the approach with the suggested diets.
    If someone has been subjected to IRT (alemtuzumab) how can we adapt the suggested diets to the treatment? Should we let the body be free of antibiotics and increase immunity to reasonable levels and only then start diets?

  • Please could you point us to a diet plan we can follow. My attempts at googling for a diet came up with so many options: 5:2, 16/8, eat-stop-eat….. and I’m not clear if intermittent fasting also means no carbs when you do eat. I want the Alemtuzumab of intermittent fasting!

    Alternatively I could go mad on sugar and develop T2 diabetes and then get on metformin + couple of trips to a gay bar might get me on HAART treatment. HAART + metformin could be a game changer.

    • As I conclude in my presentation I don’t know which of the diets to recommend. I am against caloric restriction if you are already thin and the resulting loss of muscle mass that goes with it. Intermittent fasting seems fine, but which one (16:8, 20:4, 22:2, 5:2, 3:30, etc…0? The ketogenic diet seems the easiest to do as you can eat as much fat and protein as you like.

      Until there is evidence I have no idea, which one to recommend. So let’s wait for the evidence to emerge.

      • Keto a little bit harder if you are vegetarian/pescetarian like me!

        I also thought it wasn’t recommended long term?

        As an athlete I default to cramming in the carbs (mostly whole grain but I supplement with sugary sweets), to maintain energy and performance.

        I’m really quite a big fan of carbs and I know some athletes swear by low carb high fat but I can’t imagine that working well on a vegetarian diet – and isn’t all that fat inflammatory?

  • What specific diet changes would you recommend in practical terms? I avoid sugar as much as possible already and try to eat lots of vegetables and so on, but a lot of the fasting, keto etc diets seem to be focused around weight loss, which isn’t what I want or need. I go running several times a week and have trouble putting on weight as it is, so I feel these diets won’t be possible. I think if I tried fasting alongside doing the exercise I do, I’d end up weakly shovelling Big Macs into my face at the end of every fasting period!

  • I have heard that some athletes take exogenous ketones for improved performance. So I assume that is safe. Would it make sense then to take exogenous ketones?

  • Now diets. The Drugs don’t work as the song goes. For years I kept to a healthy diet when everyone said it won’t help MS, but will be good to fight off other diseases. As you have previously posted on this blog osteoporosis is a co morbidity with MS. So is it really the answer, breaks and fractures? Personally I don’t know anyone that was obese before or after diagnosis. Surely a healthy balanced diet is the answer.

    • Re: “Personally I don’t know anyone that was obese before or after diagnosis. Surely a healthy balanced diet is the answer.”

      Childhood and adolescent obesity is only one risk factor; it is not necessary nor sufficient in relation to causing MS, but it is modifiable.

  • I find this very interesting and can give insight on the flip side. Perhaps coincidence, I’m not sure!

    I took part in a very low calorie diet which placed me into ketosis for around 5 months. I lost around 5 stone during the diet. Prior to dieting I was healthy, obese but no health issues. After the diet I’d reintroduced healthy foods and was maintaining my weight loss.

    It was at this point I began to get ill. Over the course of 14 months I’ve experienced Gait issues, balance and coordination problems, tremor, trigeminal neuralgia, Bell’s palsy, optic neuritis, sensory problems in my legs and arms.

    These haven’t all happened at once and I’ve had clear relapses and periods of remission (not full though) and currently tests are pointing towards MS or NMO (I’m waiting on the aqp4 and mog blood tests to come back).

    Like I said l, could be completely coincidental but seemed strange how it all started after I did a drastic diet. Much more research is needed on the subject.

    • Who can say really… my own MS symptoms also started after I suddenly lost 15 pounds due to a bout with anxiety. I’m trying to gain them back but it’s been a real challenge. I have always been quite a thin person, now you about can’t see me if I turn sideways! I’m definitely not doing calorie restriction but don’t eat after dinner, sort of IF-lite I guess.

  • Interesting! I was intrigued by the fumarate thing a few years ago and had my fumaric acid level tested. It was well within normal range (along with all other organic acids) Does clemastine fumarate work via the same receptor? And since ebv seems to still be the prime suspect…do ebv infected b-cells (or epithelial and other cells they infect) release something that blocks those same receptors?

    Aside from the gawd-awful misery of following a keto diet…I do feel physically better after a month or so of being keto. I can’t do it long term though. I think intermittent fasting seems a more reasonable approach.

    • Clemastine fumarate is an anticholinergic drug that is meant to promote remyelination. The amount of fumarate in the tablet is too low to have an effect it is the clemastine part of the drug that is active.

      • Thank you. Always more questions…wish I had a brain that liked minutiae more. So clemastine works via m1 muscarinic which in turn activates Nrf2? I have no idea what I’m talking about…just regurgitating info from studies. If I’m not all wrong, then aren’t they ultimately hitting the same pathway? Which inhibits macrophage activity…the same as masitinib which seems to be doing good stuff for ppms.??? Innate immune system target??

  • The b-hydroxybutyrate receptor HCA2 activates
    a neuroprotective subset of macrophages

    https://www.ncbi.nlm.nih.gov/pubmed/24845831

    Effect of intermittent vs. daily calorie restriction on changes in weight and patient-reported outcomes in people with multiple sclerosis

    https://www.ncbi.nlm.nih.gov/pubmed/29753994

    Caloric restriction enhances astrocytic coverage of synapses and synaptic plasticity in mouse
    hippocampus

    Glia 2019

    Autophagy Promotes Oligodendrocyte Survival and Function following Dysmyelination in a Long-Lived Myelin Mutant

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128639/

    Dietary Intake Regulates the Circulating
    Inflammatory Monocyte Pool

    Highlights
    d Fasting reduces the numbers of circulating monocytes in
    healthy humans and mice
    d Fasting also reduces monocyte metabolic and inflammatory
    activity
    d Hepatic energy-sensing regulates homeostatic monocyte
    numbers via CCL2 production
    d Fasting improves inflammatory diseases without
    compromising antimicrobial immunity

    https://doi.org/10.1016/j.cell.2019.07.050

    Mount Sinai Researchers Discover That Fasting Reduces Inflammation and Improves Chronic Inflammatory Diseases

    https://www.mountsinai.org/about/newsroom/2019/mount-sinai-researchers-discover-that-fasting-reduces-inflammation-and-improves-chronic-inflammatory-diseases

    Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota.

    https://www.ncbi.nlm.nih.gov/pubmed/29874567

    Intermittent fasting attenuates lipopolysaccharideinduced
    neuroinflammation and memory
    impairment

    https://www.ncbi.nlm.nih.gov/pubmed/24886300

    Obrigado

  • Interestingly, β-hydroxybutyrate works via the hydroxycarboxylic acid receptor 2 (HCA2), which is also known as niacin receptor 1 (NIACR1) and GPR109A. Why is this so important? This is the same receptor that fumaric acid works on. Yes, ketosis works at a cellular level in the same way that dimethyl fumarate (DMF) and diroximel fumarate work, i.e licensed MS DMTs.

    Thanks for explaining this so clearly.
    Great post!

  • I have been doing the keto diet for just over a year now because I was diagnosed with MS. I was diagnosed about the same time I started the diet. It makes sense to me that if the inflammatory process drives the disease, then reduce what causes inflammation I. E sugar. I do work, and lead a fairly active life, so MS has not had a big impact on my life so far. As for reducing the chance of having a relapse, I am willing to do what it takes… Within reason, and doing keto appears to work for me. I don’t really miss the sugar or the huge carbs. I do miss potatoes at times tho!! Lol

    • Re: Flushing

      I am not aware of it in the medical literature, but we tend to use KD in medication-resistant epilepsy in childhood. In other words, most neurologists don’t have much experience with therapeutic KD. However, when you do a Google search with the terms “ketogenic diet flushing” you will find a number of people complaining about this. Therefore I suspect KD causes flushing in a similar way to DMF.

    • Re lymphocyte counts

      It looks like the answer is no and hence may indicate that the level of ketosis is not sufficient to affect lymphocyte counts. Based on this I suspect KD may not be effective enough to suppress focal inflammatory activity in pwMS.

      Schreck et al. Effect of Ketogenic Diets on Leukocyte Counts in Patients With Epilepsy. Nutr Neurosci, 22 (7), 522-527 Jul 2019

      Objectives: Ketogenic diets (KDs) have long been used to treat epilepsy and are being explored in a variety of diseases. Preclinical data suggest KDs affect inflammation and cytokine release. It is unknown whether KDs affect white blood cell (WBC) counts over time. This is particularly important in clinical populations who may be immune-suppressed at baseline, such as those with cancer or autoimmune disorders.

      Methods: A retrospective review of 125 consecutive adults seen at the Adult Epilepsy Diet Center (AEDC) was conducted. Clinical data regarding compliance, laboratory data, weights, and diet records were collected. A control cohort consisted of patients evaluated at the AEDC who elected not to complete a prescribed KD.

      Results: In 52 adults on KDs, there was a small but statistically significant decrease in WBC and absolute neutrophil counts at 6 and 12 months into KD therapy. There was no effect on lymphocyte counts. This pattern was also seen in a small population of patients with gliomas (n = 10) on KDs, most (n = 8) of whom had also received chemotherapy and radiation, putting them at risk for bone marrow suppression. Across both glioma and non-glioma groups, patients with pre-existing lymphopenia did not have further worsening of their counts on the KD.

      Conclusions: In this retrospective case-control study, a small but significant decrease in total WBC and neutrophil counts was observed in patients with epilepsy treated with the KDs. These patterns are similar in patients with and without gliomas suggesting baseline immunosuppression does not worsen with KD. These findings provide data for prospective confirmatory studies.

  • Very interesting as always !! Thank you for all your work on this blog !

    I am trying 5:2 IF since your first post on biohacking last month. I am also on DMF.

    Just on question about your slide 46. You said in one of your post about diet that, for you, war against saturated fats (like in the OMS diet) was not justified. But the figure on the right of your slide 46 seems to said something else (ie strong correlation with heart desease mortality, just like sugar).

    So it’s seems important to control our saturated fat consumption (just like sugar) to lower risks of co-morbididies, isn’it ?

    About bio hacking, what do you think about the potential anti inflammatory action of Omega 3 consumption via specialized pro-resolving mediators ? (https://harvardmagazine.com/sites/default/files/inline_images/2019-MayJune/HM_Inflam_Chart.png)

    Thank you again !

    • Yes, very closely. It is very relevant to MS, other neurodegenerative disease and life in general. I subscribe to unhealthy or premature ageing being a disease. Anything that can slow down or reverse unhealthy ageing is of interest to me.

      • Nice, the thing that stuck out to me was how similar the FMD process was to various novel stem cell therapies in that it drastically reduces lymphocyte counts during the fasting period which are then replenished with fresh stem cells during the refeeding phase. There’s at least an argument that it might act as an immunotherapy as well as a general longevity diet. This is also why longer fasting might not be appropriate for many people with MS. Long term fasting has profound short term effects on the immune system which could be potentially dangerous for those on immumnosuppresives.

        When I was diagnosed with MS I decided to take the risk to do four rounds of FMD while on Tecfidera, and have been symptom free for about five years, and anecdotally it made a big difference in my symptom profile. Since I’m now pretty healthy now I decided to wait for further trials before doing another round. I think they’re doing a larger MS trial and I look forward to hearing the results.

  • This is very promising for me and others with relapsing/remitting MS. I will say I’ve done short fasts, 24 hours – 36 hours, and the next day I feel amazing! My husband had been reading about ketogenic diets and wants me to get going on that. All of this information makes me want to do it and see what it does for my relapses!

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