Should we all be taking metformin? As you know metformin is being tested in a remyelination therapy trial in MS; it rejuvenates senescent oligodendrocyte precursors making them more likely to make myelin.
The biology of metformin is fascinating as it also activates NRF2 the master transcription factor for programmed cell survival, which downregulates NFKappa-B the master pro-inflammatory transcription factor. I was surprised to find this paper below which shows the anti-ageing effects of metformin are not only limited to the brain but the thymus and the immune system as well.
Please note that ketogenic diets and fumarates (dimethyl fumarate and diroximel fumarate) also transactivate NRF2 and are potentially anti-ageing. It is a great pity Biogen pulled the plug on the DMF secondary progressive MS trial. I think we should revisit fumarates in progressive MS in combination with other potential agents that target mechanisms that drive smouldering MS.
The question I have is that in addition to a ketogenic diet should we all start taking metformin like so many other biohackers* are doing?
*Biohacking, also known as human augmentation or human enhancement, is do-it-yourself biology aimed at improving performance, health, and wellbeing through strategic interventions.
Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age-related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (-2.5-year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from -1.6 year/year from 0-9 month to -6.5 year/year from 9-12 month. The GrimAge predictor of human morbidity and mortality showed a 2-year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.
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.
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?
Figure from Neurotherapeutics.
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?
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.
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.
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.
