ketosis – 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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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.

What has my age got to do with having MS?

Barts-MS rose-tinted-odometer: ★★★ (some readers have asked for this feature to stay)

How old are you? It depends. You may be aware that there can be a disconnect between your chronological or actual age and your biological age. As ageing or senescence is a biological process driven by metabolic, genomic and environmental factors you can see how there can be a disconnect between the two. As a result, many of us in medicine are beginning to think about unhealthy or accelerated ageing as a disease process. Making ageing a disease will create incentives for pharmaceutical and nutraceutical companies to invest in ageing R&D with the hope of producing medications or dietary supplements to slow-down or reverse the effects of ageing.

Ageing is important in MS as there is emerging evidence that MS causes premature ageing of the CNS (central nervous system), which means that pwMS are more likely to experience age-related neurodegeneration sooner than they have to and this almost certainly contributes to delayed disability worsening in pwMS.

It is clear that ageing impacts one’s ability to recover from CNS damage. It has been known for some time from clinical and animal studies that remyelination and neuronal plasticity are less efficient as you get older, which is why older pwMS recover from relapses less well than younger people. The animal studies below show that there is real biology behind these observations. Oligodendrocyte (myelin-producing) progenitor cells (OPCs) isolated from the brains of neonate, young and aged female rats show an approximately 50% difference in the levels of proteins they make. Differences were noted in both myelin-associated proteins and proteins that control several metabolic pathways. This study has clinical implications and can act as a read-out for finding drugs that could be used as anti-ageing agents.

There are several interesting biological targets and drugs that already exist for targeting ageing. Metformin, a drug for treating diabetes, is one of the lead compounds going in an MS clinical trial at the moment. It is believed that its antiageing effects of performing are mediated via the so-called NRF2 or programmed cell survival pathway. Interestingly, fumarates (e.g. dimethyl fumarate) and ketogenesis also activate this pathway. Could DMF, and the other fumarates, be the panacea antiageing drug we need for tackling progressive or more advanced MS? Yes, I think so but to convince Biogen to follow the money is proving more difficult than we anticipated. We approached them recently to do a combination DMF-plus trial with another class of drug to augment DMF’s response and they said no. Pity because I think they are missing a trick and an opportunity to create new intellectual property.

Physiological ketosis from caloric restriction, intermittent fasting or low-carbohydrate diets is another way of activating the NRF2 pathway. The biology behind this is probably via β-hydroxybutyrate, a ketone body, which works via the hydroxycarboxylic acid receptor 2 (HCA2). Interestingly, this is the same receptor DMF activates.

Other anti-ageing treatments and strategies include exercise and avoiding getting comorbidities, which accelerate ageing, in particular, the metabolic syndrome (obesity, hypertension, glucose intolerance or diabetes) and smoking. The driver of the metabolic syndrome seems to be hyperinsulinaemia and the diets referred to above are all very effective in suppressing or reducing circulating insulin levels.

So in 2021 if you have MS you need to think seriously about what you can do to tackle early and accelerated ageing. Most of the things you can do now involve lifestyle changes, which are often hard to implement. My advice would be to implement the changes slowly and you may find over time that the behavioural changes you make will stick. There is a lot of evidence for this from the field of behavioural psychology.

The above advice is part of the holistic approach to the management of MS I have been pushing for several years and my adoption of the ‘marginal gains philosophy’ for managing MS.

“If we break down everything we can think of that goes into improving MS outcomes, and then improving each by 1%, we will get a large improvement in MS outcome when we put them all together.”

“Ask not what your neurologist and HCP can do for you, but what you can do yourself to optimise your own MS management and long-term MS outcome.”

de la Fuente et al. Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing. Mol Cell Proteomics. 2020 Aug;19(8):1281-1302.

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#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

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

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.