ketogenic diet – Prof G's MS Blog Archive

Dysbiosis

Barts-MS rose-tinted-odometer: ★★★ (a lilac rose-tinted Sunday; and why not! #C8A2C8)

Dysbiosis refers to abnormalities in the human microbiome that affect disease and life outcomes. In the context of MS, it is claimed that changes in the gut microbiome may not only increase your risk of getting MS but act as a proinflammatory signal to drive MS disease activity and reduce remyelination and recovery. The corollary is that manipulation of your microbiome with antibiotics, faecal transplantation, probiotics and diet can be used to treat MS. Do you agree?

My problem with the field of dysbiosis is how to interpret the data. Many of the hypotheses and claims being explored are plausible, but the lack of vigour and the application of causation theory in regard to some of the claims being made is worrying. More worrying is that some quacks have already jumped on the bandwagon and have started offering faecal transplants and probiotics to treat MS.

There is little doubt that the metagenome, i.e. our genomes and the genomes of the microorganisms that inhabit our bodies, is what life is. For example, without certain bacteria in our gut, we wouldn’t be able to eat certain foodstuffs. The most quoted example is the bacteria Bacteroides plebeius that allows humans to eat and breakdown seaweed; this bacteria is found more commonly in the gut of seaweed eating populations such as the Japanese.

Trying to find the gut bacterium that causes MS or increase the chances of getting MS will be like seeking a needle in ten thousand haystacks. I have been thinking about how we tackle this problem. One way may be to look at populations that had low incidence of MS and then to follow the changes in the gut microbiota longitudinally and see if something shows up in those who develop MS. The problem with this approach is the resources, the time required and the sheer size of the study required.

What is clear is that your microbiome is very plastic and can be changed relatively easily by manipulating your diet; going from a high fibre diet to a low fibre diet or from a high carbohydrate diet to a ketogenic diet changes your microbiome within days. This is very relevant to managing some diseases, for example, ketogenic diets and their presumed effect on the microbiome increases the response rate of some cancers to certain chemotherapy regimens. The question is the metabolic hacking of ketosis or the effect of the diet on the microbiome that is responsible for the treatment effect? I suspect it is both. There is also very compelling data emerging that ketogenic diets are anti-inflammatory, which in addition to their neuroprotective effects, explains why they are being studied in MS and widely adopted by segments of the MS community. Are their other diets with as a compelling scientific rationale? Not to the best of my current knowledge.

In the context of the above, you may be interested in the animal (EAE) study below which shows a small therapeutic effect of the administration of Clostridia, a bacterium that may be beneficial in MS, as a treatment in mice induced to have experimental allergic encephalomyelitis or EAE. The treatment effect is quite modest; I doubt MD would be impressed with the size of the effect. However, the authors conclude “… gut dysbiosis in MS patients could be partially rebalanced by these commensal bacteria and their immunoregulatory properties could have a beneficial effect on MS clinical course”. Really?

The question I have for you is how many of you are using probiotic supplements, diet, etc. to specifically change your microbiomes? How have you heard about these treatments and have you noticed any impact on your MS or MS-related symptoms?

Calvo-Barreiro et al. Selected Clostridia Strains from The Human Microbiota and their Metabolite, Butyrate, Improve Experimental Autoimmune Encephalomyelitis. Neurotherapeutics (2021); Published: 07 April 2021.

Gut microbiome studies in multiple sclerosis (MS) patients are unravelling some consistent but modest patterns of gut dysbiosis. Among these, a significant decrease of Clostridia cluster IV and XIVa has been reported. In the present study, we investigated the therapeutic effect of a previously selected mixture of human gut-derived 17 Clostridia strains, which belong to Clostridia clusters IV, XIVa, and XVIII, on the clinical outcome of experimental autoimmune encephalomyelitis (EAE). The observed clinical improvement was related to lower demyelination and astrocyte reactivity as well as a tendency to lower microglia reactivity/infiltrating macrophages and axonal damage in the central nervous system (CNS), and to an enhanced immunoregulatory response of regulatory T cells in the periphery. Transcriptome studies also highlighted increased antiinflammatory responses related to interferon beta in the periphery and lower immune responses in the CNS. Since Clostridia-treated mice were found to present higher levels of the immunomodulatory short-chain fatty acid (SCFA) butyrate in the serum, we studied if this clinical effect could be reproduced by butyrate administration alone. Further EAE experiments proved its preventive but slight therapeutic impact on CNS autoimmunity. Thus, this smaller therapeutic effect highlighted that the Clostridia-induced clinical effect was not exclusively related to the SCFA and could not be reproduced by butyrate administration alone. Although it is still unknown if these Clostridia strains will have the same effect on MS patients, gut dysbiosis in MS patients could be partially rebalanced by these commensal bacteria and their immunoregulatory properties could have a beneficial effect on MS clinical course.

Conflicts of Interest

Preventive Neurology

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Medium

General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

#DietSpeak: is there an ideal MS diet?

Barts-MS rose-tinted-odometer: ★★★★★

I am always being asked about what is the ideal diet for someone with MS. The simple answer is there is no ideal MS diet. What you eat is about personal choices and has to be compatible with your cultural background and your social circumstances. There is so much more to eating food than what you actually eat. I have written a piece on Medium called ‘Diet as a Philosophy’, which provides some context to this statement.

In short, my diet philosophy recommends that anyone with MS should eat socially, i.e try not to eat alone and make your meals a social occasion. To eat real food, i.e. avoid processed and ultra-processed food. To try and eat locally-produced food that is seasonal; I am aware that this easier said than done, particularly for economic reasons. Finally, it would help if you eat mindfully, in other words, think about what you are eating, why you are eating it and what impact it is having on the world.

The question about diet being an actual treatment for MS is a different question. Here I would support a ketogenic diet and intermittent fasting and I have written extensively on the science behind these diets and why I think these two diets may be disease-modifying for people with MS. At present, the evidence base for these diets working in MS remains weak and exploratory, but the good news is there are ongoing studies looking at these diets in pwMS. Despite this, the basic science on these diets from animal studies is so compelling that if I had MS I would be ketotic and fasting intermittently (5:2 or 16:8 diet).

Please note ketogenic diets and intermittent fasting are not incongruent with my diet philosophy.

I also don’t support one diet over another. The reason I don’t support a specific diet is simple; the evidence-base for anyone diet being better than another is weak and a lot of diets are not based on science. Yes, science. As scientists, we should be following the science. For example, the study below is interesting in that they flipped the question and looked at the metabolic responses to food and its influence on cardiometabolic disease. You may say what has this got to do with the central nervous system, but I believe in the aphorism ‘that what is good for the heart is good for the brain’.

What this study showed is that person-specific factors, such as gut microbiome, had a greater influence than the diet in relation to metabolism and that genetic variation only had a modest impact on the metabolic responses to food linked to cardiometabolic disease. The only metabolic output that was influenced by diet was blood glucose or sugar levels, which is dictated by carbohydrate intake and the type or quality of carbohydrates we consume.

In summary, apart from carbohydrate metabolism, it is horses for courses and personal factors (gut microbiome and genetics) which dominate how your diet impacts on your metabolism.

The good news is you can manipulate your carbohydrate metabolism; it is relatively simple. Both ketogenic diets and intermittent fasting reduce your sugar intake and blunt or flatten your blood glucose levels and the subsequent downstream insulin response, which is clearly the bad guy in driving cardiovascular risk.

Based on the above I hope you have enough information at hand for you to make an informed decision about your diet without having to ask me next time 😉

Berry et al. Human postprandial responses to food and potential for precision nutrition. Nat Med 2020 Jun;26(6):964-973. doi: 10.1038/s41591-020-0934-0. Epub 2020 Jun 11.

Metabolic responses to food influence risk of cardiometabolic disease, but large-scale high-resolution studies are lacking. We recruited n = 1,002 twins and unrelated healthy adults in the United Kingdom to the PREDICT 1 study and assessed postprandial metabolic responses in a clinical setting and at home. We observed large inter-individual variability (as measured by the population coefficient of variation (s.d./mean, %)) in postprandial responses of blood triglyceride (103%), glucose (68%) and insulin (59%) following identical meals. Person-specific factors, such as gut microbiome, had a greater influence (7.1% of variance) than did meal macronutrients (3.6%) for postprandial lipemia, but not for postprandial glycemia (6.0% and 15.4%, respectively); genetic variants had a modest impact on predictions (9.5% for glucose, 0.8% for triglyceride, 0.2% for C-peptide). Findings were independently validated in a US cohort (n = 100 people). We developed a machine-learning model that predicted both triglyceride (r = 0.47) and glycemic (r = 0.77) responses to food intake. These findings may be informative for developing personalized diet strategies. The ClinicalTrials.gov registration identifier is NCT03479866.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#T4TD: biohacking

Did you know two lifestyle options, i.e. exercise and diet, are probably the most effective add-on neuroprotective therapies for treating MS?

Exercise induces long-lasting changes in the brain, which includes upregulation of growth factors and release of endorphins, that are almost certainly neuroprotective. Similarly, diets (caloric restriction, intermittent fasting and low-carbohydrate ketogenic) stimulate metabolic pathways that are both anti-inflammatory and neuroprotective. Why would someone with MS not want to hack their metabolism to derive these benefits?

CoI: none in relation to this post

#T4TD = Thought for the Day

P.S. Please note that if you are overweight you need to lose weight first to exercise properly. Exercise, without a change in your diet, is not an effective weight-loss strategy.

Not COVID-19: obesity and MS

Are you sick and tired of hearing about COVID-19 and MS? How about something completely different; the destigmatization of obesity?

Finally, the medical community or at least a part of it are making amends for the half-century or more of treating obesity as a disorder of self-control. The joint internal consensus statement for ending the stigma of obesity is long overdue (see article and box below).

Even when I have done factual posts about childhood and adolescent obesity as a risk factor for developing MS I have been criticised by commentators for fat-shaming. I am not. All I am doing is quoting the evidence that childhood/adolescent obesity is associated with an increased risk of developing MS and may in fact be in the causal pathway that leads to developing MS.

What the consensus statement below is finally acknowledging is the irrefutable evidence that obesity is a disorder of metabolism; an endocrine disorder that leads to patients increasing the amount of energy they store as fat. Finally, the dogma that obesity is due to the excess consumption of calories and/or the reduced expenditure of calories is finally being put to rest as not being the root cause of obesity.

A simplified way of explaining the mechanisms that lead to obesity is that your metabolism gets hijacked by a hormonal imbalance that results in energy be hoarded away in your adipose tissue and it not being released for consumption by the remainder of the body. This triggers the brain to think that you are starving and sets off a behavioural response to seek more food or calories. In other words, the metabolic state associated with obesity causes hunger and the food-seeking behaviour associated with it and not the other way around.

The sad thing is that we the medical profession have known about this insight for centuries, but we decided to forget or ignore the metabolic research underpinning obesity being a metabolic disease in the 70’s and 80’s when we were hoodwinked by dodgy science and fake news. Yes, the high saturated-fat heart hypothesis of cardiovascular disease is to blame. The conspiracy underpinning the change in the dietary guidelines that have caused the global obesity pandemic has been well highlighted by investigative journalists in several extremely well-crafted exposes. The tragedy is as the population replaced saturated fat in our diets with polyunsaturated fats and carbohydrates, in particular, processed and ultra-processed carbohydrates, we created a metabolic storm that has resulted in an epidemic of obesity, diabetes, hypertension, fatty liver and the other ills associated the metabolic syndrome.

Shifting the focus sway from obesity as a result of an individual’s lack of self-discipline to it being a metabolic disease driven primarily by diet will allow us to tackle the epidemic, i.e. to flatten the curve and hopefully chop off its tail to steal a COVID-19 analogy.

The metabolic cause of obesity is rather quite simple; it is driven predominantly by raised insulin levels or hyperinsulinaemia. High blood sugar or glucose levels stimulate the pancreas to produce insulin. The insulin works to reduce blood glucose levels by signalling to the liver and muscles to make glycogen (short-term glucose storage) and to the liver and adipose tissues to make fat. Whilst insulin levels are high the adipose tissue is unable to release fat as an energy source and so the adipose tissue continues to take-up glucose to convert into fat. As glucose levels drop it triggers a counter-regulatory hormonal response that causes you to become hungry and you then seek out sugary foods. This then starts a vicious cycle that results in insulin levels being raised most of the day, instead of only being raised for a few hours after a meal. This hyperinsulinaemia eventually causes the liver and muscles to become resistant to insulin’s action, but less so in adipocytes particularly the adipocytes around the abdomen and internal organs. The latter causes the so-called centripetal and visceral obesity that is typical of insulin resistance.

The only way to break this vicious metabolic cycle is to try and lower your insulin levels as much as possible. This is why low carbohydrate or ketogenic diets work so well at correcting the metabolic syndrome (hyperinsulinaemia) and result in loss of weight. The good thing about keeping insulin levels low is that the body gets used to a new normal or steady-state glucose level that is driven by another metabolic process called gluconeogenesis (glucose from protein), which does not trigger the counter-regulatory hormonal response that makes you feel hungry. In addition, the ketones your body produce, particularly β-hydroxybutyrate, is known to suppress appetite and explains why people on ketogenic diets don’t feel the same levels of hunger as people on high carbohydrate diets.

If you have MS having high levels of circulating β-hydroxybutyrate maybe be good for your MS. β-hydroxybutyrate activates the hydroxycarboxylic acid receptor 2 (HCA2), which is also known as niacin receptor 1 (NIACR1) and GPR109A. This is the same receptor that fumaric acid works on. I suspect that ketosis works at a cellular level in the same way that dimethyl fumarate (DMF) and diroximel fumarate work, which are both licensed MS disease-modifying therapies (DMTs). By binding to the HCA2 receptor β-hydroxybutyrate stimulates a transcription factor called NRF2 and downregulates NFKappa-B the master regulator of inflammation. The NRF2 mechanism of ketosis almost certainly overlaps with what has been described in animals with intermittent fasting and the drug metformin to promote the rejuvenation of oligodendrocyte precursors, remyelination and recovery of function.

Despite criticism from dietary zealots the evidence that low-carbohydrate/ketogenic diets are bad for you is very weak. In fact, I would argue that from an evolutionary perspective man was first a low-carbohydrate species and only acquired the sophisticated carbohydrate metabolic response to fatten up for winter when fruits and grains are plentiful at the end of summer. We were never meant to metabolise carbohydrates 24/7 365 days a year. Feast and famine was the norm, which is how our primate cousins live in the wild.

Although we need controlled evidence before promoting low-carbohydrate/ketogenic diets as a treatment for MS and for MS prevention there is no reason why pwMS can’t try these dites improve their metabolic health. If I had MS I would not hesitate to hack my metabolism with either a low-carbohydrate/ketogenic diet or intermittent fasting, but not caloric restriction. The scientific case for using these former diets as an adjunct to other MS therapies is simply too compelling to ignore.

Rubino et al. Nat Med 2020 Apr;26(4):485-497.

Rubino et al. Joint International Consensus Statement for Ending Stigma of Obesity. Nat Med 2020 Apr;26(4):485-497.

People with obesity commonly face a pervasive, resilient form of social stigma. They are often subject to discrimination in the workplace as well as in educational and healthcare settings. Research indicates that weight stigma can cause physical and psychological harm, and that affected individuals are less likely to receive adequate care. For these reasons, weight stigma damages health, undermines human and social rights, and is unacceptable in modern societies. To inform healthcare professionals, policymakers, and the public about this issue, a multidisciplinary group of international experts, including representatives of scientific organizations, reviewed available evidence on the causes and harms of weight stigma and, using a modified Delphi process, developed a joint consensus statement with recommendations to eliminate weight bias. Academic institutions, professional organizations, media, public-health authorities, and governments should encourage education about weight stigma to facilitate a new public narrative about obesity, coherent with modern scientific knowledge.

CoI: multiple

#MSCOVID19: Fighting diet dogma

I did a video consultation yesterday with a patient with MS who in the event of getting COVID-19 is at very high risk of severe COVID-19. This patient has type 2 diabetes with poor glucose control, is hypertensive and is also obese (BMI of 32). I asked what their GP had done to help them lose weight. The GP had recommended exercise and believe it or not hadn’t discussed diet with them.

The idea that exercise is a primary treatment for obesity is a myth. Obesity and metabolic syndrome is an endocrine disorder due to hyperinsulinaemia (high insulin levels). The idea that can you treat obesity with exercise, and not address the hyperinsulinaemia, is a dogma that has been disproven years ago. I actually take the contrary view that you first have to start losing weight to exercise properly. If you have a BMI of 32 and you start doing unsupervised exercise you are likely to get an injury and then become less active.

The other dogma is that obesity is too many calories in and too few out; i.e. obesity is a simple imbalance of what you eat with what you expend. This dogma has also been disproven. Not all calories are made equal. Carbohydrates, in particular, processed carbohydrates with a high glycemic index are much more obesogenic compared to fats, proteins and complex carbohydrates (low glycaemic index).

I briefly explained this to this patient and referred her to Dr David Unwin’s or ‘the diet doctor’s’ website. David Unwin is one of the NHS’ heroes and deserves to be knighted to his contribution to the health of the nation. David Unwin has been treating metabolic syndrome with a low carbohydrate diet and getting over 50% of his patients with type 2 diabetics off medication; he is putting their diabetes into remission. The science behind low carbohydrate diets as a treatment for obesity, hypertension and type 2 diabetes is well-grounded; in my opinion, it’s irrefutable.

The other positive spin-off of a low carbohydrate diet, beyond weight loss, is that it is also ketogenic. Ketosis may have other health benefits for pwMS. There is very compelling data from animal models that ketosis is neuroprotective and may promote remyelination (please see my blog post ‘COULD DIET BE THE NEW ADD-ON DMT?’ from 21-Feb-2020).

So if you consider yourself of being at-risk of severe COVID-19 and you are obese and/or diabetic and/or hypertensive maybe it is the right time to try a low carbohydrate diet.

I am not saying in this post that you shouldn’t exercise. However, exercise is a powerful appetite stimulant and what happens is that if you exercise without addressing your diet you will simply end up eating more calories than you expend. You need to get your diet right first. A correct diet allows you to maximise the benefits of exercise.

If you are interested in reading more about my thoughts on diet, I would recommend reading my Medium posts ‘Diet as a Philosophy’ and ‘Evolutionary Medicine: why low-fat diets are bad for you’.

Dare I suggest that you owe it to yourself, your family and friends and the NHS to de-risk yourself from getting severe COVID-19?

CoI: multiple

Could diet be the new add-on DMT?

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

Biohacking comes of age

Barts-MS rose-tinted-odometer ★★

You know something is happening when it gets its own review article in the New England Journal of Medicine. The review article in last weeks issue covers the science and medicine around intermittent fasting (IF) and its effects on health, ageing and disease. The article even includes a few lines on IF and its potential impact on MS.

In my ‘2020 Vision’ post yesterday under #ThinkMetabolic I glibly made the comment that ‘we are our metabolism and that MS is first and foremost a metabolic disease’. I truly believe this. Let me tell you why.

MS is a complex disease due to an interaction between the environment (macro- and micro-environment) and our genomes (DNA code, epigenome or DNA modifications, and our metagenome or microbiome). Studying each component in isolation is difficult. However, the complexity comes together in the metabolome or our metabolism, i.e. in how the body and its organ systems function on a day-to-day basis. Similarly, when we treat MS we modify our metabolism. So the way to integrate all influences on the body is to study our metabolism.

The question I pose is can we hack our metabolism in a way that will improve MS outcomes? I am sure we can and one way of doing this is through diet. There is mounting evidence that caloric restriction (CR), intermittent fasting (IF) and ketogenic diets (KD) does this, which is why if I had MS I would be exploring these as potential complementary treatment options.

Common to caloric restriction (CE), intermittent fasting (IF) and ketogenic diets (KD) is a metabolic switch that triggers anti-inflammatory, neuroprotective and antiageing mechanisms. The body responds to these diets by an adaptive stress response that leads to upregulation of antioxidant defences, DNA repair, protein quality control, mitochondrial biogenesis and autophagy, and down-regulation of inflammation. Animals maintained on intermittent-fasting regimens show improved function and resistance to a broad range of stressors.

Ketosis alters cell signalling mechanisms and increases the nuclear factor erythroid 2–related factor 2 (NRF2) transcription factors, which are part of the programmed cell survival pathway. Interestingly, this pathway is the one that dimethyl fumarate works via. In fact, many of the metabolic changes that are seen with ketosis are similar to that which are seen with DMF. Similarly, metformin the antiageing diabetes drug triggers a similar metabolic switch to ketosis. Could DMF and metformin be mimicking IF or ketosis? I say yes!

Similarly, IF and KD trigger antiageing mechanisms and potentially rejuvenate senescent cells. The recent observation that CR and metformin rejuvenate senescent oligodendrocyte precursor cells and augmented remyelination in older animals suggests that these mechanisms are inter-related.

There are several dietary trials in MS exploring IF and KD as a potential DMT. Some of the preliminary results are very interesting. I suspect interesting enough for many of you to have already adopted IF or ketosis as a treatment option. So if you are wanting to hack your metabolism you may want to read the NEJM review; figure 4 from the article gives some advice on how to incorporate IF patterns into your daily life.

**Figure 4. Incorporation of Intermittent-Fasting Patterns into Health Care Practice and Lifestyles.** As a component of medical school training in disease prevention, students could learn the basics of how intermittent fasting affects metabolism and how cells and organs respond adaptively to intermittent fasting, the major indications for intermittent fasting (obesity, diabetes, cardiovascular disease, and cancers), and how to implement intermittent-fasting prescriptions to maximize long-term benefits. Physicians can incorporate intermittent-fasting prescriptions for early intervention in patients with a range of chronic conditions or at risk for such conditions, particularly those conditions associated with overeating and a sedentary lifestyle. One can envision inpatient and outpatient facilities staffed by experts in diet, nutrition, exercise, and psychology that will help patients make the transition to sustainable intermittent-fasting and exercise regimens (covered by basic health insurance policies). As an example of a specific prescription, the patient could choose either a daily time-restricted feeding regimen (an 18-hour fasting period and a 6-hour eating period) or the 5:2 intermittent-fasting regimen (fasting [i.e., an intake of 500 calories] 2 days per week), with a 4-month transition period to accomplish the goal. To facilitate adherence to the prescription, the physician’s staff should be in frequent contact with the patient during the 4-month period and should closely monitor the patient’s body weight and glucose and ketone levels (from NEJM).

If you have given CR, IF or KD a try please let us know how they make you feel. It is clear from our ‘Food Coma Survey‘ that many people with MS and food coma are already using dietary manipulation to manage their symptoms.

de Cabo & Mattson. Effects of Intermittent Fasting on Health, Aging, and Disease. N Engl J Med 2019; 381:2541-2551

Choi IY, Piccio L, Childress P, et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep 2016;15:2136-2146.

Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355).

Cignarella F, Cantoni C, Ghezzi L, et al. Intermittent fasting confers protection in CNS autoimmunity by altering the gut microbiota. Cell Metab 2018;27(6):1222.e6-1235.e6.

Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome.

Fitzgerald KC, Vizthum D, Henry-Barron B, et al. Effect of intermittent vs. daily calorie restriction on changes in weight and patient-reported outcomes in people with multiple sclerosis. Mult Scler Relat Disord 2018;23:33-39.

An intermittent fasting or calorie restriction diet has favorable effects in the mouse forms of multiple sclerosis (MS) and may provide additional anti-inflammatory and neuroprotective advantages beyond benefits obtained from weight loss alone. We conducted a pilot randomized controlled feeding study in 36 people with MS to assess safety and feasibility of different types of calorie restriction (CR) diets and assess their effects on weight and patient reported outcomes in people with MS. Patients were randomized to receive 1 of 3 diets for 8 weeks: daily CR diet (22% daily reduction in energy needs), intermittent CR diet (75% reduction in energy needs, 2 days/week; 0% reduction, 5 days/week), or a weight-stable diet (0% reduction in energy needs, 7 days/week). Of the 36 patients enrolled, 31 (86%) completed the trial; no significant adverse events occurred. Participants randomized to CR diets lost a median 3.4 kg (interquartile range [IQR]: -2.4, -4.0). Changes in weight did not differ significantly by type of CR diet, although participants randomized to daily CR tended to have greater weight loss (daily CR: -3.6 kg [IQR: -3.0, -4.1] vs. intermittent CR: -3.0 kg [IQR: -1.95, -4.1]; P = 0.15). Adherence to study diets differed significantly between intermittent CR vs. daily CR, with lesser adherence observed for intermittent CR (P = 0.002). Randomization to either CR diet was associated with significant improvements in emotional well-being/depression scores relative to control, with an average 8-week increase of 1.69 points (95% CI: 0.72, 2.66). CR diets are a safe/feasible way to achieve weight loss in people with MS and may be associated with improved emotional health.

CoI: multiple

The new black death is ageing

I say to many of patients one of the most powerful predictors of progressive, or more correctly worsening, MS is ageing. Age also predicts recovery of function; the younger you are the better you do. This study shows that ageing restricts the ability of stem cells to make oligodendrocytes to promote remyelination.

As you are aware age also predicts response, or lack or response, to DMTs. The older you are the less effective DMTs are. The list linked to ageing and poor prognosis goes on ….

I have always said ‘life is a sexually transmitted neurodegenerative disease with a 100% mortality’. This usually gets a mutated laugh until people start pondering the joke and its implications and then gradually realise that I am being serious.

Evolution never designed, and selected, the human brain and nervous system to function much past the age of 35. It is only relatively recently that life expectancy has increased dramatically with the requirement of our brains to function into ‘old age’. It is clear that when we measure cognitive function, and brain volume, it is all downhill from about 35 years of age.

Those of us who are older than 35 notice the subtle cognitive impairments that increase with age and the gradual malfunction and deterioration in our nervous systems. When last have you tried tight-rope walking? Your failing balance system is simply a reflection of the global rot that is also shredding your cognition. Fortunately, we have enough reserve to adapt and cope with the slow decline in our mental faculties. However, if we live long enough we are all likely to become demented. Dementia in this setting is simply the reduction of cognition to a point when you can’t manage socially and occupationally. To prevent the inevitable consequence of ageing is there anything we can do to optimise our brain health so our ‘brains outlive’ our ‘bodies’?

There is a lot we can do to improve brain health. However, some of the interventions may require the administration of medications in the future. For the anti-ageing revolution to happen, and be adopted by society, we need to make ageing a disease.

By defining ageing as a disease it changes everything. Firstly, it creates incentives for the pharmaceutical industry to invest in the necessary R&D to get drugs to market. If ageing is a disease healthcare providers will pay for interventions. The corollary is that if ageing is not defined as a disease, any interventions to delay or modify ageing, will be limited to lifestyle interventions. By defining ageing as a disease it will allow us to develop tools for population screening to identify people who are either healthy or in the presymptomatic phase of known neurodegenerative disease. This will then allow us to test preventive strategies to delay the onset of symptomatic disease.

If on the other hand, you have MS we already know you have a neurodegenerative disease that shreds reserve capacity and brings forward ageing mechanisms, which is why we need to manage MS as early and as effectively as possible and holistically. This is why the new treatment target is ‘to maximise brain health for the lifetime of the person with MS’.

Please be aware that ageing is a biological process and hence we can target the biology with both lifestyle interventions and drugs. For example, recent evidence suggests metformin, a diabetes drug, may reverse some of the ageing programmes. Dimethyl fumarate (DMF), a licensed MS DMT, seems to activate antiageing pathways that overlap with pathways linked to specific dietary interventions, i.e. calorie-restricted, intermittent fasting and ketogenic diets. Should all MSers be on metformin and/or DMF and/or one of these diets? We need trials to test these hypotheses. But at least there are investigators exploring the questions.

Please let me know if you find the anti-ageing hypothesis of MS compelling; it overlaps with diet, sleep, exercise and many other things that I can discuss in future blog posts.

Rivera et al. Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination. Glia. 2019 Apr 30. doi: 10.1002/glia.23624.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.

CoI: multiple

Food coma: does it affect you?

This post explains why eating may exacerbate MS-related fatigue and what you can do to counteract it.

Do you suffer from food coma or excessive sleepiness and fatigue after eating a meal?

For ‘normal people’, we call this phenomenon postprandial somnolence or the siesta syndrome. Others refer to it as the ‘food coma’. It is my anecdotal experience that people with MS, in particular, people with more advanced MS, are particularly sensitive to postprandial sleepiness and fatigue. Why?

Postprandial somnolence (PPS) is a normal state of drowsiness or lassitude following a meal. PPS is a real phenomenon and has two components: (1) a state of perceived low energy related to activation of the parasympathetic nervous system in response to expansion of the stomach and duodenum from a meal. In general, the parasympathetic system slows everything down. (2) A specific state of sleepiness, which is triggered by the hormone cholecystokinin (CCK) that is released in response to eating and changes in the firing and activation of specific brain regions. The reflexes responsible for PPS are referred to as neurohormonal modulation of sleep through the coupling of digestion and the brain. The signals from the gut to the brain travel via the vagus nerve.

My index patient is so affected by PPS that she now only eats one meal a day; her evening meal. She does this quite late so that she can crash and sleep about an hour after eating. She is a professional and needs to be functional during the day and finds if she eats anything substantial in the day she simply can’t work because of her overwhelming desire to sleep. We have tried caffeine, modafinil and amantadine to counteract PPS, but they only had a small effect in counteracting her PPS and allowing her to work productivel. Other patients reporting this have noticed some benefit from stimulants. Interestingly, my index patient, like a few others, finds carbohydrate-rich foods particularly potent at inducing ‘food coma’

Physiologists think that not all foodstuffs are made equal when it comes to causing PPS and it appears that glucose, or sugar, induced insulin is one of the drivers of this behavioural response. I suspect this why people who fast or eat very low carbohydrate or ketogenic diets describe heightened alertness and an ability to concentrate for much longer periods of time.

The reason for doing this post is to find out how common PPS is in the MS population and to give you some simple advice to counteract it. If you suffer from PPS can I suggest you review your diet and see if you identify ways to modify your eating habits and/or diets to coounteract PPS?

You could adopt the above extreme solution and only eat one meal per day. Clearly, this not for everyone and is very difficult to implement. I say this, but many of my Muslim patients report feeling so much better during Ramadan when they essentially practice this type of eating pattern.
You could reduce your meal size and cut out any carbohydrates from your daytime meals. You may find this difficult because it takes time for your metabolism to become optimised for ketosis. If any of you are interested in the science of ketosis I have written a Medium post on ketogenic and low-carbohydrate diets.
Some of my patients find micro-meals helpful, i.e. instead of large meals you eat multiple small snacks during the day.
The judicious use of stimulants. I tend to recommend caffeine, followed by modafinil and them amantadine. Please note you should probably not take stimulants later than about 3-4 pm as they have a long half-life and can cause insomnia.
Some of my patients have also reported that exercise has helped them deal with PPS. I am not sure how exercise works except by possibly lowering glucose and insulin levels and improving insulin sensitivity. The latter will reduce hyperinsulinaemia that will not only cause PPS, but is an impotant driver and component of the metabolic syndrome.

Please note that PPS will be worse if you suffer from a sleep disorder and suffer from daytime sleepiness. Most pwMS have a sleep disorder so there is little point in focusing on PPS and ignoring the elephant in the room.

If you have a few minutes to spare can you please complete this survey and let us know if you come across any other effective treatments to manage your PPS.