We examined over 1000 super-healthy participants in China (http://msphere.asm.org/content/2/5/e00327-17). Not an easy task in any country especially when the criteria included no history of diseases! Our research team from Western University and Lawson Health Research Institute found that the microbiota of people in those aged around 100 was very similar to that of people many years younger - in other words, a decline in the microbiota is not necessarily inevitable in the healthy aged population. This raises many questions - can microbes help us age better? Is healthy aging simply reflected in our microbiota? Could we transplant 'young' microbes to ailing elderly? We are a scientific team at the Canadian Centre for Human Microbiome and Probiotic Research (https://www.Lawsonresearch.Ca/research-theme/microbiome-and-probiotics) who helped set up the Tiyani Health Sciences Centre where the samples and data for this study were collected. We have ideas on how this study might direct future studies, which we and some members of our team would love to discuss with you and answer any questions you may have.
We'll be back at 11 am ET to answer your questions, ask us anything!
Dr. Greg Gloor (http://ggloor.github.io) is a Professor of Biochemistry at Western University's Schulich School of Medicine & Dentistry who designs robust tools for the analysis of microbiome, metagenome and metatranscriptome experiments using compositional data analysis. Dr. Gloor was the corresponding author and conducted most of the analyses reported in the paper.
Dr. Gregor Reid (https://www.lawsonresearch.ca/scientist/dr-gregor-reid) has pioneered probiotic research and applications to human health around the world.
Dr. Jeremy Burton (https://www.lawsonresearch.ca/scientist/dr-jeremy-burton) is part of the Canadian Centre for Human Microbiome and Probiotics Research, holds the Miriam Burnett Chair in Urological Sciences, and is an Assistant Professor at Western University's Schulich School of Medicine & Dentistry.
Dr. Jean Macklaim is a postdoctoral researcher in Dr. Greg Gloor’s lab using computational biology and next-generation sequencing to understand the functional relationships between bacterial microbiota and their host/environment
We're here, answering your questions! https://imgur.com/gallery/ogHgU
What made you decide to look at this in China specifically rather than somewhere else?
Greg here: Several reasons for why China. First, the Chinese microbiota has been less well studied than others, especially the population we studied which was not near Hong-Kong or Beijng. So we can contribute a different population to those that have been looked at in the past. Second, we were able to collect a large number of samples in a relatively short period of time which would have been difficult in North America. Third, it would have been difficult to find enough people who would meet our very strict exclusion criteria of intergenerational health (if young) and no drug use in a Western country. As noted in the paper, we excluded about 97% of the people who wanted to participate because of these criteria. In North America countries the use of prescription and over-the-counter drugs is extremely high. So in China, we were able to collect fairly large numbers of ‘drug-free’ participants that would have been much harder to get from Canada.
What's the best explanation for the microbiomes of the healthy elderly subjects from China? Are there particular relevant features of the traditional Chinese diet, or are there other explanations?
Greg here: The best explanation I have is that the particular very elderly group we chose was healthy, active and eating well; so from that perspective the microbiota of the healthy elderly being similar to healthy active people decades younger was not surprising. However, it is a bit of a chicken and an egg situation where it is also possible that their microbiota was contributing to their good health. We do know that if your microbiota becomes less diverse, as often happens over time in North America, that you become susceptible to dysbioses and even infections such as Clostridium difficile, which obviously cause a decline in your health status. So having a healthy microbiota can be a cause and an effect of a healthy lifestyle as you age. I think the best way to put it is that a decline in your microbiota is not necessarily a fact of healthy aging.
Gregor: I like the second part of your question. It made me think of the mediterranean diet and in France the benefits of red wine. I am sure there are experts who can define a ‘traditional Chinese diet’ and whether cities like New York and Toronto with their own Chinatown produce truly traditional Chinese foods. It is hard to pin down outcomes to one factor such as food, and which components of those foods are critical. It certainly raises good questions worth investigating - sorry that sounds like a scientist cop-out but I’d rather be honest!
Did you evaluate the dietary patterns of the elderly? If so, what did you find?
Greg here. We did collect some very coarse dietary information regarding their major diet. Two limitations to this: first, the information was all self-reported; and second, the information was very high level. We asked them to tell us if they were primarily eating meat, a mixed diet, or vegetarian diet. This was done largely because the cohort was collected from the community and we were trying to maximize the number of participants. So the answer to the second question is that we really didn’t find anything of note.
Which microflora are abundant in the elderly super-healthy? What are the prospects for the rest of us to boost ours via fecal transplant or even delayed-release capsules?
Greg, I'm going to answer the first part of the question. We used an approach that measured the amount of change between groups relative to the amount of variation within the groups. This allowed us to focus on biologically-relevant differences rather than statistical ‘significance’. We did not make a big deal about the differences between groups because, by and large there were not many differences between groups that were greater than the variation within groups.
One thing we noticed was that the elderly cohort had a slightly greater relative abundance of sequences mapping to the Clostridium Sensu Strictu than did the younger members of the population, and there were some corresponding decreases in some others like Fecalibacterium and Prevotella. But, big but here, the magnitude of change for any of the was, on average modest. One of the main observations from this study was that the majority of the healthy elderly differed very little from the healthy younger members of the population.
Jeremy here: Once we have a better understanding of the microbiome there may be an opportunity to apply a fecal transplant to obtain an “ideal microbiome” However, we have to be very careful initially that we don’t transfer undesirable phenotypes with a FMT. FMT’s have been successful in treating recurrent Clostridium difficile infections, but their use for other applications where the microbiome likely plays a role is highly experimental at the moment. It has great potential though where it is thought that a significant change of the microbiome is required for health benefits.
What's your opinion on a clinical probiotic such as VSL#3 on promoting an ideal gut microbiome?
Gregor: I am not sure there is an ‘ideal’ gut microbiome or an ‘ideal’ probiotic that can promote it. The mention of VSL#3 is a good one as it implies a multi-species probiotic is worth considering. I think it may well take such a probiotic, but with strains selected to do specific functions. VSL#3’s strains were not selected for this purpose, but in the hope that the combination would have anti-inflammatory function and thus it showed promise for pouchitis. In the case of our study, we might want to consider probiotics, perhaps with prebiotics, that increase diversity. This might be through propagating species in low numbers or in adding species that to date have never been used in probiotic formulations. The latter creates regulatory headaches as species without a history of safe use would likely have to be treated as a drug, because of the antiquated regulatory system in most countries. At present, we simply don’t know the formulation that could change an ‘unhealthy’ microbiota to a ‘young and healthy one’.
What probiotics would you recommend?
Gregor: I tried to answer this above if your question is which currently available or hypothetical product should be taken to try and manipulate the microbiota to one that equates with the healthy subjects. If the question is less specific, there are two excellent sites for a first stop to select a probiotic. These are usprobioticguide.com and probioticchart.ca which were prepared by experts who reviewed the human studies associated with products on the market. Remember, by definition, a probiotic should only be called probiotic if it has been shown in human studies to confer a health benefit. Sadly, many products have not undergone such testing, and so consumers/patients/professionals providing advice, should start with those tested in humans. If companies object because their probiotic is not on the list, then they should not call their product probiotic or do the studies in humans to show benefits.
Gut Microbiota has been called the next great frontier in medical science, and I think this study proves that. What unbelievable breakthroughs do you see coming in the next 15-20 year in the field?
Gregor: I commented on this above, to some extent and agree the potential is phenomenal. I could give you blue sky personal views to answer your question, but at the end of the day there are critical factors. I think the scientists in this field can, and already are, coming up with amazing concepts. But for these to reach subjects, will require manufacturing facilities that are more flexible and innovative than currently exists (growing strict anaerobes and consortia; having smaller scale to align seasonal issues - as we reported in the Smits Science paper on the Hadza - or a larger range of products that help us move towards personalized medicine. Once produced, it needs regulatory approvals, and current regulatory agencies were set up to handle drugs and devices not living organisms, so they need to revamp drastically to get their heads around this. That will delay progress unless we find a way to insure safety but not have products fit into the keyholes currently set. Imagine we still say foods can’t treat or prevent disease! After regulatory, we need care-givers (mainly physicians) to understand this field, and if we don’t teach it to medical students, how can we expect those who are qualified to grasp it, unless they take courses and have time to read the literature. In other words, it takes a community to create and translate the breakthroughs.
What's the difference between gut microbia and other microbia?
How does it survive in my gut?
How do I get the best gut microbia if it has health benefits or How do I get rid or cure my gut microbia if it is effecting my health in a negative way?
Also, why Chinese people? Because of their diets?
And age 100? Is this to see if diets affects gut microbia by region?
If the people who were tested had no diseases, why test people with no diseases or why not have small sample groups with common diseases as a control to people who have no diseases?
Last one, did you guys try changing gut microbia on animals before this experiment?
Also, if these answers have been answered I'll take a link.
Greg here: The gut microbiota is more diverse than the microbiota in many other body sites. For example, the skin, lung or vaginal microbiota is much less diverse (contains fewer types) and even (one or a few types tend to dominate) than in the gut. There are also different species in the gut than elsewhere. The bacterial types that we sampled from stool survive in a largely oxygen-free environment and they feed on material that is relatively indigestible in the upper parts of the digestive system.
Do gut microbiota from young and old healthy Chinese share a common DNA ?
Can healthy gut microbiota be transferred to others?
Greg here, I’ll answer the first question. As far as we can tell, the old and young healthy Chinese had bacterial DNA that was indistinguishable. But, the tool that we used, 16S rRNA gene sequencing is a fairly low resolution technique and so we can’t say definitively that the exact same bacterial strains are shared between samples from people in the cohort. To to this, we would need to use a higher resolution method (such as shotgun metagenomic sequencing), but this is much more expensive, especially for a cohort of the size we reported on.
Jeremy here: yes members of the microbiome can be transferred via whole faecal microbiome transplant (FMT) or in some cases individual bacteria. However, if you transfer the bacteria using a FMT, you are almost transferring an entire ecosystem. Bacteria rely on symbiosis to survive and therefore FMT approaches are likely to lead to a longer sustained change in the recipients microbiome. FMT’s are currently used in hospitals in Canada for recurrent Clostridium difficile infections which don’t respond well to antibiotics.
Do vegetarians have healthier gut microbacteria than meat eaters do?
Jeremy here: This is likely to be true because people that eat less meat have lower risk factors for several diseases including colon cancer. The bacteria in the colon metabolize what we ingest and the metabolic byproducts can be carcinogenic. The microbiome will change its composition to reflect bacteria which have the ability to degrade the things we eat and this leads to a predisposition of certain bacterial types if we eat the same diet on a routine basis. But this is confounded since meat eaters will also ingest more carcinogenic compounds because of the diet itself.
In the paper, you propose doing a longitudinal study tracking the gut microbiome. What do you think this sort of study would add to what we already know?
Greg here: One of the problems with cross-sectional cohort studies is that it is hard to separate cause-and effect. So for example, we note in the paper that the differences between 20 year olds and 30 year olds was fairly large. But, we don’t know if that is because the two age groups had different exposures during their life, and we are looking at a survivor bias, of if the microbiota of the 20 yo group would change to resemble the 30 yo group over time. So if we re-sampled the 20 yo group in 15 years, and we saw that their gut microbiota now resembled the historical 30 yo group, then we could conclude that the difference we observed was a developmental trajectory in this population. If on the other hand, the re-sampled microbiota still looked different from all other groups, then we could conclude that there was a historical exposure effect on this age group.
Should Fecal transplantation be more widely promoted ? Should it be part of general health regimes ?
Jeremy here: Faecal transplants should be promoted where they have been shown to be safe and efficacious for certain conditions. Like any other therapy, the appropriate evaluation needs to be undertaken before wide adoptions should be undertaken. I have no doubt that this therapy may be useful for many microbiome-linked disorders. However, at present, the therapy is only routinely used in certain countries for recurrent Clostridium difficile infections, but not other applications, which are experimental. The early success of FMT for recurrent C. difficile lead to people undertaking the therapy themselves when they could not obtain the therapy medically. I don't think this should be a general health regimen because we don't know the downsides of this therapy, for example animal studies suggest that anxiety-like symptoms are transferred in mice by FMT.
Do those store-bought yogurts really work to improve your gut microbacteria?
Gregor: There are many parts to this question. Firstly, yogurt is a fermented food and is defined by having Lactobacillus delbreuckii subsp bulgaricus plus Streptococcus thermophilus. Probiotic and other strains can be added for flavour or added health benefits. These are, in my view, worth consuming and that’s why I recently advocated for a fifth item on the Canada Food Guide - meat, vegetables, grains, dairy and fermented foods. In terms of benefits, there have been multiple studies showing that fermented foods confer health benefits, albeit I hesitate to say they do this by ‘improving your gut microbiota’ as the gut microbes we have in us are not easily shifted on a permanent basis. So, ingesting these foods and dried probiotics appear to confer benefits while they pass through the intestinal tract - which is a few days but not generally longer than weeks.
If you were to live long enough in the same geographical area as the test population, eating the same food, under similar sanitary conditions and habits, how would your gut microbiota be changed?
Gregor: The Science paper (Smits et al.) we recently published looked at the Hadza which for the most part have been practicing the same diets in the same region for a very long time. It is a much more difficult question to address for other parts of the world with globalization of food. One would have to find a community in the northern hemisphere that did not have access to berries from Mexico or mangos from Rwanda in January. Sanitary conditions and habits are also difficult to examine. I was in India and my local friend ate chicken that had sat out in the sun and was heated in a wok for about 60 seconds. Had I eaten it, I would likely have been violently ill. So, immune parameters and tolerance to certain microbes play a role. These are great questions and illustrate why we need governments to take the microbiome seriously. In Canada, a centre of excellence for microbiome research was rejected, so I think we need visionary people who control funds to ‘get it’.
I’ve read that the good skin bacteria are just here to ‘squat’, essentially pushing back on potential (bacteria) invaders. Other than that, they have no real utility to the skin life cycle.
Are there bacteria like this in the gut?
Gregor: If I understand your premise, you are asking if bacteria are in the gut to perform functions that protect the host against certain diseases, rather than perform digestive functions.
I think this is certainly possible, although the intestine would still have to be a supportive environment for the bacteria to survive.
There has been a surge of kombucha drinks on the market that promote health. Do you see this as a fad? Is there a regulatory body that controls and mandates the bacterial health factors associated with these kombucha products?
Gregor: No. It represents a return to the foods that human evolved with - fermented by microbes. It is certainly building off the microbiome and probiotic scientific advances that have captured the public imagination. But, in the end it has to taste good and make you feel good. The Kombucha I’ve tasted is great! Hopefully more tasty fermented foods will come onto the market and reach children rather than them consuming sugar-rich drinks and processed foods that are clearly impacting obesity and metabolic diseases. Health Canada regulates food, but I am not aware of them mandating the companies documenting how their products work.
Jeremy: We are starting to work with fermented foods on a number of fronts including Kombucha. The cultures (bacteria) that they contain have not been well characterised in the products, so this needs to be done before we start evaluating their health properties. We need to know that the products have stable bacterial compositions, so that if we see some kind of health benefit by taking the product we and others can replicate the studies. On a personal note, I believe that most cultures have a history of fermented food consumption which is probably plays an important in human health.
Do different regions have a significant influence on people's gut bacteria? Or is it diet-based - or an equal combination of the two?
Gregor: Researchers have reported gut microbiota patterns from populations around the world. Some will certainly be diet based, but I am hesitant to put people into boxes. For example, I am not in favour of generalizing that black women, because they are black, somehow have a different risk of bacterial vaginosis, especially when the women are black Americans rather than people from a country like Kenya where they are living and are black in colour. If you want to make conclusions based upon regions of the world, you have to very carefully study the population and account for any and all compounding factors.
Thank you for conducting this amazing study in China! I noticed that over-the-counter or prescribed Chinese herbal medicine was not listed as one of the exclusion criteria. Could you please elaborate your reasoning on that? Also, from what I know, antibiotic use in agriculture and fishery is an issue in China and it's not well controlled. What do you think this may impact on their gut microbiome?
Greg here: I think that any observational study is going to have problems of this sort, especially with self-reported information. The actual question was “any medicine taken over the last 3 months” in a cohort without chronic disease and without chronic disease in the family history. So depending on the sophistication of the respondent, they may or may not have included traditional Chinese medicine when making their declaration. This is also a good reason to characterize the microbiota of a relatively large number of people. I agree that we could not control for antibiotic use in the food that the participants were taking. Antibiotic use will definitely affect the gut microbiota. I think that what we found shows that the gut microbiota was relatively stable across everyone aged over 30, whatever the background exposures were.
Gregor: I think it is outside our mandate to comment on antibiotic practices and fisheries of any country. But, the levels of pollution in the air and seas reported for China must contaminate the foods that are consumed. In general, we should be finding ways not to use antibiotics unless for fighting real infections. I believe that probiotics, even for fish, could be a viable alternative to prophylactic antibiotics.
Last question. The Chinese diet isn’t healthy: loads of salt, in most part of China, the food contains a lot of fat, little to no dairy products, little to no uncooked vegetables, very little fiber. Pretty much all dishes result from processed ingredients, and very often fried ones...
The only plus side, is that the Asian diet has very little sugars (although this is changing quite a bit), and outside of big cities, meat portions are small (fish ones are bigger). I may be wrong, but that’s my experience of Chinese cuisine, when I lived there (Beijing, Shanghai, Hong Kong).
So why would the Chinese diet be beneficial?
Gregor: We are not recommending the Chinese diet per se. We investigated if there was a correlation between the gut microbiota and health. Clearly, many of the subjects lived a long time consuming a Chinese diet. You are right in asking why such a diet maintains health given we are supposed to not consume salt, fried foods and uncooked foods, etc, but isn’t this a constant dilemma? How many connotations of foods have ‘experts’ said are healthy over the past fifty years? Breaking down what is good and what is not, is a question we would all love to answer. Plus, when people move countries, their health status sometimes changes, meaning there may be some genetic factors involved - perhaps host cells receive certain bacteria in young life and there is some sort of programming which is then altered when that person moves to a country with very different foods and maybe even different abundances of certain microbes. This will take a lot of experts in different fields to prise open.
Greg: I think it is worth remembering that we examined healthy Chinese, and that there is a survivor bias in the groups. That is one reason we asked if there were health problems in the parents and grandparents. These people were healthy given their environment, and it is certainly possible that that environment would not translate to a healthy diet here.
Do ketogenic diets affect gut bacteria?
Gregor: Short answer yes. Imagine you have trillions of bacteria sitting waiting for their next meal. For years they have been there because of the food they were given that included non-fermentable oligosaccharides that are a primary food source for the bacteria in the gut. Now, you’ve changed it dramatically, so the end result will kill off some of these organisms, and promote the growth of others.
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