Eran Segal (Solve grantee): Personalised microbiome-based diets for blood glucose regulation

I don't keep a list of references and will have to do some more digging on the subject. It is possible @alicec can say something about this. But if the microbiome has no or only little effect on post meal glucose levels, then it invalidates the entire study presented in this thread.

 

It need not invalidate the claim that personal microbiome is a guide to which foods will give you a high glucose. People who get high glucose with ice cream might have more rapid amylase release from the pancreas and that might skew the profile of the waste products coming down to the colon and so skew the microbiome.

But I agree that if the implication is that the microbiome is somehow responsible for the glucose peaks and therefore altering the microbiome might be therapeutic, then it would invalidate such a claim.

 

My impression was that that was the claim (although other factors apart from the microbiome analysis were fed into the model) - but perhaps the claim (or the truth) is that the variation in how the various foods are processed in the body affects the microbiome, rather than the other way round.

 

I haven't had a chance yet to read up on the topic of the thread, but will for now just make a few comments on the more general question of the influence of the gut microbiome on host metabolism and things like obesity and diabetes.

There are many studies in humans showing various correlations between microbiome changes and obesity/metabolic syndrome/diabetes but while these raise suspicions they can't disentangle cause and effect or just plain coincidence.

Definitive studies have come from germ-free mice which have had different microbiota combinations transplanted. Now I know that mice aren't humans and we can't necessarily directly translate all the detail, but the mice studies do help to tease out causal links. We now need to use these results to better understand what is going on in humans.

Here is an early study which demonstrates the effect of the microbiota on energy harvest and fat storage.

Adult germ-free C57BL/6 mice were transplanted with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals. This produced a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake.

Here is a recent study which is looking at different mouse strains and their metabolic phenotype in response to a high fat/high sucrose diet.

Two strains which showed the most divergent response were selected for further studies. HF/HS feeding had no effect on any of the phenotypes measured in CAST mice, whereas it resulted in weight gain, glucose intolerance, and insulin resistance in B6 mice.

Germ free (GF) versions of each strain received faecal transplants from both the same and the other strain. B6-GF mice colonized with the CAST microbiota were less affected by chronic HF/HS feeding relative to B6-GF mice colonized with the B6 microbiota. The mice receiving the CAST microbiota secreted far less insulin in response to a glucose challenge but were still able to maintain normal blood glucose levels.

There is a lot more detail in the studies, including some insight into possible mechanisms, but I have just selected these to illustrate the quite profound effect the gut microbiota can have on host metabolism and glucose handling. The gut microbes are not simply sitting their feeding on our left-overs for their own benefit.

There have been various studies in humans correlating microbiota differences with obesity. Again we don't know which comes first, but again transplant studies in mice have shown that the microbiome plays a causal role.

Here is just one study in which the microbiota from human twin pairs discordant for obesity was transplanted into GF mice. The conclusion was:-

Increased total body and fat mass, as well as obesity-associated metabolic phenotypes were transmissible with uncultured fecal communities, and with their corresponding fecal bacterial culture collections. Co-housing mice harboring an obese twin’s microbiota (Ob) with mice containing the lean co-twin’s microbiota (Ln) prevented the development of increased body mass and obesity-associated metabolic phenotypes in Ob cagemates. (To understand this latter point you need to realise that mice eat faeces.)

I'll have a look at the thread study soon.

 

I’m still feeling queasy trying to read so haven’t read this thread properly or listened to that specific talk. I did read the research in a brainfog free window last year.

This is more how I interpreted it (but their theory locates the difference in the microbiome, though you can then alter the microbiome using their personalised diet technique).

In the information I had (possibly from the TV programme), altering diet using their method can alter microbiome results in just a week moving toward a healthier balance.

I do think it is of interest and shouldn’t be dismissed out of hand, the study involved 800 participants and IIRC was checked on 200 more. For us potentially useful as a way of levelling out blood glucose fluctuations and possibly improving microbiome balance, both of which seem problematic in ME.

Of course recognising that something interesting is going on and explaining it with accurate theory doesn’t necessarily go together, but I feel that there’s something interesting going on with this. Marketing speak is definitely something to be wary of but doesn’t mean they’re wrong, just perhaps you don’t need expensive equipment or algorithms (which is what I attempted to circumvent).

The link I have for the study is http://www.cell.com/cell/pdfExtended/S0092-8674(15)01481-6

 

@Jonathan Edwards
I agree with most you said.

But with this I am not so sure. There exist obese people who credibly say they eat less than 1000 calories a day and are indeed malnutritioned.
People with hypothyroidism will gain weight, unless they nearly fast. (I would have to eat less than 1000kcal to loose weight.)
Overtrained people tend to gain weight although they don't eat too much calories.

I don't believe that anymore. I made the experience that I loose weight while decreasing exercise. I believe there may be some connection to some overtraining effect, who knows.
I can't explain it, I only observe it. I conclude it's not only about calory count. There is something with the metabolism, too.

Example: I once had my basal metabolism measured (is that via spirometry?) and it said 1500kcal basal calories. At that time I made high intensity sports (1.5-3h per day, 7 days a week) and I ate around 1800-2000kcal per day and I had a real hard time at keeping my weight. Nobody could explain why - I was told I maybe lied with my intake. Weeelll....If anybody has another explanation...?

 

I too think that the old calories in/calories out premise is not quite as simple as it sounds. Sure we can measure calories in, but the "calories out" part is not just dependent on our exercise.

Of course, extreme calorie restriction in a long term starvation situation will ALWAYS lead to weight loss. So the general premise holds at the extremes.

But when the body senses that calorie intake is regularly restricted (eg on a diet) it is bound to start to budget carefully to avoid excess calorie expenditure. Ie the "calories out" part of the equation also drops. Meaning to sustain the weight loss on a set calorie diet, the set calories also have to drop. Which is pretty horrid - especially as you feel rubbish as things like body heating mechanisms get turned down too... so cold, hungry and a bit miserable results. Sure exercise can help light the body furnace, but it won't help those who can't exercise, and it might feel like a bit of a drag to do if the body is really trying to economise on energy expenditure!

Part of the problem I think is that our high sugar and constant snacking way of life, means that blood insulin is always high. Insulin, I understand also encourages fat storage. So the extra sugars go straight to the hips. Low blood insulin times are when we can fat burn, but if we are always snacking on sugary stuff, then the body becomes less well adapted to fat burning (fewer of those fat burning enzymes made in the cells etc.)

Appetite is also something very hard to resist. Like thirst, it is felt as a body need and hard to ignore. I think folk who put on weight can end up in a catch 22 of finding that dieting makes it harder to diet! And I suspect our gut biome doesn't help either - if those bacteria get used to their carbs they could well be releasing substances mimicking hunger hormones...

 

Just spotted this on Twitter. Fitbit trying to develop a real time blood sugar monitor. My nephew is T1 diabetic. This could be really helpful for him.
https://medcitynews.com/2017/11/fitbit-ceo-details-ambitions-diabetes-management/

 

Starting to get to the topic of this thread (rather than my previous impressions from reading their big study and doing my home version).

I’m excited that this team is now looking at ME

When I came across it last year it was on a mainstream BBC programme. It had nothing to do with ME. I just applied it because I knew that glucose stuff was odd in ME (and in particular for me, without being diabetic) and also I knew that microbiome balance is of interest to us too.

So encouraging that other people picked up on this connection.

This is the ME research they’re planning

“
Deciphering antibody reactivities against autoantigens & the microbiome in ME/CFS



A project summary as written by Dr. Segal:

Patients with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) experience a lingering fatigue that can drastically impair their social and work life. The cause(s) and exact disease mechanism(s) still remain elusive. Several directions are currently investigated, ranging from biological processes involved in energy production (e.g. metabolism and mitochondrial dysfunction) to neuroendocrinological aspects (e.g. hormone signaling).

Also, a pronounced involvement of the immune system and inflammation in ME/CFS has been proposed. Some evidence is even pointing towards autoimmunity, as ME/CFS is associated with the autoimmune diseases hypothyroidism and Sjögren’s syndrome. The immune system is crucial for the protection against pathogens such as bacteria and viruses. Yet, failure to discriminate between pathogens (non-self) and cells of the human body (self) can result in autoimmunity. Also, immune reactions against non-pathogenic (commensal or symbiotic) microorganisms can be a driving factor in autoimmune diseases (e.g. inflammatory bowel disease; Crohn’s disease). Treatment with Rituximab has elicited positive responses in the majority of ME/CFS patients in clinical trials, underlining an autoimmune aspect of ME/CFS. The monoclonal antibody Rituximab is specifically targeting the depletion of antibody producing B cells and routinely used for the treatment of lymphomas as well as autoimmune diseases (e.g. rheumatoid arthritis). The beneficial effect of Rituximab on autoimmune diseases is due to the depletion of autoantibody producing B cells. As Rituximab treatment alleviates ME/CFS in a considerable subset of patients, (auto) antibodies are believed to represent at least a contributing disease mechanism. Yet, it is currently unknown which (auto) antigens are targeted or to which extent the antibody repertoires between ME/CFS patients and healthy controls overlap.

Aside of this autoimmunological aspect, a dysbiosis of the gut microbiota in ME/CFS patients has been reported, in line with intestinal symptoms experienced by many ME/CFS patients.

In fact, humans are meta-organisms that maintain a diverse population of microorganisms on their barrier surfaces (such as the gut), collectively named the microbiota. The microbiota has co-evolved with its host over millennia and provides a range of benefits related to digestion, production of nutrients, detoxification, and protection against pathogens and regulation of the immune system. The intestinal microbiota is composed of 10 to the power of 13 to 14 microorganisms, with at least 100-times as many genes as in the human genome, termed the microbiome.

The microbiota is also engaged in a dynamic interaction with the innate and adaptive immune system, affecting different aspects of its development and function. When one or more steps in this fine “cross-talk” fail, autoimmune or auto-inflammatory diseases may occur. Despite concrete evidence pointing towards an involvement of autoimmunity and microbiota dysbiosis in ME/CFS, the exact mechanism (e.g. which antigens are recognized) and an interplay between the microbiota and immune system have not been systematically investigated yet.

Here, we propose a novel and broad approach to comprehensively study the role of antibodies against (1) autoantigens and (2) the microbiota in ME/CFS patients (compared to healthy controls). We believe that a combination of directed evolution approaches with next generation sequencing technology can serve as a powerful tool to test complex ME/CFS samples in a few simple steps. Especially, as only small amounts of patients’ blood samples are required, which can be collected in a simple and non-invasive way. In addition to gaining insights on disease mechanism(s) in ME/CFS, the identified (auto-) antigens may as well be used as potent markers for reliable diagnosis of ME/CFS.”

This appears to build on the current state of play in ME research rather than going off on a tangent.

 

I agree that it is encouraging that new groups are looking at ME. However, the project outline immediately above is disappointing. Firstly, it seems to be an exact repeat (i.e. not 'novel') of what Simon Carding and Tom Wileman have already been doing for five years in Norwich. Secondly, as an immunologist who has worked in this field all my life I would say that there is no basis for thinking that gut organisms have anything to do with autoantibodies.

The only situation where we know there is a specific immune response to an antigen in the gut and also autoantibody production is coeliac disease. And in that situation there is a T cell response to one antigen (gliadin) and a B cell autoantibody response to a completely unrelated auto antigen (tissue transglutaminase). The link between the two is a functional one, not a mimicry one. Ebringer spent years trying to prove that ankylosing spondylitis was due to a cross reactivity between Klebsiella aerogenes and HLA-B27, despite there never being any antibodies to B -27 and in the end everyone forgot about it.

 

@Inara,
I absolutely agree that exercise and thyroid status and all sorts of other things will affect how many calories you need to eat to stay the same weight. But it remains the case that, taking this into account, if you eat more calories than this you will put on weight and if you eat less you will lose weight and it does not not matter what foods you get the calories from. Once you are the right weight it may matter what foods you eat but that should to be confused with what you need to do to get down to the right weight. Nothing has changed. As far as I know the only reason for eating certain types of food rather than others if you are overweight is that some foods are more difficult not to eat too much of - like ice cream and chocolate mousse. A tiny bit of chocolate mousse is fine, but so hard to eat.

 

@Jonathan Edwards

I take it you are not impressed with this sort of research?

https://www.nature.com/nm/journal/v21/n8/full/nm.3914.html

 

But their previous research indicates individual variations in blood glucose response to the same foods, which perhaps indicates that some diets would be more effective for losing weight/health than others at an individual level. Higher blood glucose signals to the pancreas to produce more insulin, and the insulin leads to storing the excess sugar as fat.



My partner can reduce PPGR by adding fat, but this doesn’t work for me (I can do it by reducing carb quantities). This is counterintuitive to general understanding, it could be flawed research, or it could be a new insight.

Coeliac disease is actually somewhat similar to ME (gastrointestinal, brainfog, fatigue, neuro symptoms) so that’s something to consider.

My understanding is that microbiome research is expanding quickly and was previously not understood. Therefore not already having a basis isn’t a reason not to do this research. We obviously wouldn’t want loads and loads of repetition if it isn’t getting anywhere (thinking of the money wasted on CBT/GET research) but gut issues seem like something that needs a thorough investigation in ME. Even just at a symptomatic level, I rarely go a day without my quality of life being impacted by intestinal related symptoms

 

I’ve now watched the TEDX talk @Sasha shared. It just seems to be a TEDtalk style of dissemination, not unusually marketing speak (everyone who does a TED talk is effectively marketing their big idea).

They also did this animation. It won’t impress academics but it provides a simplified explanation

https://www.youtube.com/watch?v=Ryc5M3Ciytg

The most interesting part of the talk for me was showing this slide



The audience couldn’t guess correctly which diet was ‘good’ for this particular individual. It was the right hand one. The difference between personalised good and bad weeks looks something like this:

 

@Sasha BTW I like the idea of discussing research in a tone that would encourage the actual researcher to join in. I don’t mean we should be insincerely sycophantic, criticism is fine, but writing hoping that they will get involved in the discussion is probably the way to keep a good tone to it.

 

Afraid not. It is written as if by someone in the 1960s who is completely unaware of the developments of the 1990s. This problem seems now to be all pervasive. All research is copying what has been read in a review last week. Chinese whispers you might call it.

 

Because this is the internet, I always try to remember to write as though any person I'm writing about is standing right next to me!

Because essentially, they are.

 

No it does not indicate anything about losing weight, because you can only store as fat calories that are excess to what you need to use. As long as you keep the calorie intake down the body will shift the molecules around over 24hrs to give the same result. It does not matter what the post prandial glucose rise is like. It may matter if having got your weight right you still have a diabetic tendency but that is a different issue.

I agree that finding out about gut symptoms would be useful but that is not what these studies are about. We have known for decades that the gut is full of lots of different organisms. That is pretty much still what we know. Knowing the names and genomes of all the weeds in your lawn does not make a lot of difference to what you want to know about your lawn. People have been writing papers on associations between specific organisms and diseases like RA for at least thirty years. All that has changed is that they are now listing all the ones that occur in tiny amounts. The ones in tiny amounts that matter were identified long ago - typhoid, salmonella, shigella, pathogenic cloakrooms, C diff.

All these research groups seem to justify their search on the same basis of looking for molecular mimicry. Yet molecules do not mimic like that in any meaningful way - we have learnt that from our detailed understanding of antibody and T cell receptor binding.

But I have said this before, even if this is a new forum.

 

People seem to be certain types in this, so you don’t have to test every food to have an idea how it will affect you.

It isn’t just about calories. Excess glucose which isn’t required for activity gets stored as fat, yes. So our relative requirement for glucose/energy is a factor in how fat we get of course.

But if there isn’t such a thing as a universal glycemic index, instead we’re divided by types or even unique to each individual, this will influence how we store fat from the same amount of objective calories. One person’s croissant will not lead to the same amount of stored fat as another person’s croissant, because their excess glucose will be different.

It will be possible to eat so much you put on weight with a recommended personalised ‘good’ diet, but it should (according to this Israeli approach) require a lot more objective calories than if you follow your ‘bad’ diet. In their ‘good’ and ‘bad’ weeks they compare the same number of calories per meal.

 

Thinking about this a second time you are totally right in a numbers sense. If you eat nothing, you will definitely loose weight, and you will gain weight if you go over a certain limit.

(Excluding those people who claim to live on light only.)

I put in an assumption - very common - that goes with saying "more calories - more weight; less calories - less weight".

This minimal and maximal limit is highly individual. One could question that going under a certain level is unhealthy (e.g. a person would only loose weight with 800kcal). But that's not the point here.

Although I think this topic is interesting - that's why I read it - I am not for diets anymore. I listen to my body. I'm curious though about how this will develop.