We speak to two of our microbiome experts, Dr Chris Quince and Dr Falk Hildebrand, on the future of microbiome health and how the Earlham Institute is influencing the microbiome science and innovation UK landscape.
A microbiome is the community of micro-organisms living together in unique habitats; from our skin or intestines to the soil and seas.
The microbiome is an enigma to many but these invisible communities are of growing interest to scientists - the complex relationship between microbes, their hosts, and the environment are of huge importance to the state of our health and the world around us.
More and more is being discovered about the significant influence of microbiomes on human health and society. Unsung microbial heroes play a crucial role in driving forward solutions for chronic and infectious diseases, managing antimicrobial resistance, tackling future pandemics, enhancing health and wellbeing, and even improving food security.
This article forms part of our Marrying Microbes: in sickness and in health series exploring the topic of health research.
Earlier this year, we were a contributing partner to the KTN Microbiome Strategic Roadmap. The roadmap seeks to uphold the UK’s position in world-leading microbiome research and innovation by supporting emerging, enabling microbiome technology that aims to benefit academia and industry by improving public health and economic growth.
Highly diverse and dynamic, microbiome science involves a number of different technological areas to explore the data and derive new insights. Although the UK has world-leading technological expertise in these areas, more is needed on bringing the interdisciplinary research together and integrating funding to maximise its potential.
We speak to two microbiome experts, Dr Chris Quince and Dr Falk Hildebrand - research group leaders at the Earlham Institute and Quadram Institute - on the future of microbiome health and how the Earlham Institute is influencing the microbiome science and innovation UK landscape.
Chris Quince: Much of what I do relates to the gut microbiome and therapeutic diets. My collaborator in Glasgow, Dr Kostas Gerasimidis, is a nutritionist who has developed a diet for the treatment of Crohn's disease based on ordinary foods. Existing treatments for Crohn’s are quite unpleasant, but he has managed to develop a transformative solution which is a manageable diet based on meals that a catering company can deliver to your door. I am helping him understand how the impact of the diet is modulated through the microbiome; by understanding the microbiome, we can potentially improve the diets.
This allows us to also look at the microbiome pre treatment, and predict whether somebody will respond to the diet or not. With around overall 80% accuracy, it’s incredibly useful to point clinicians in the right direction to what treatment patients need - be that drugs or an alternative diet.
I think modulating the microbiome through diet is going to be a big potential industrial opportunity - improving your health by improving your microbiome. There are startups which tell you what diet will maximise the health of your microbiome from your fecal sample. Essentially, we are doing a more clinically focussed version of this, predicting optimal treatments, by extracting DNA from human faeces reconstructing the microbiome and determining the correct dietary therapy from this sample.
I think modulating the microbiome through diet is going to be a big potential industrial opportunity - improving your health by improving your microbiome.
CQ: The other area that we’re working on that can be linked to industry is anaerobic digesters for converting waste into biogas. The anaerobic digestion process uses organic matter such as animal or food waste to produce biogas and biofertiliser. This is already a major technology in Germany, where it provides 8% of electricity. Moving towards a zero carbon future in the UK, it’s potentially an important technology.
For farming, an anaerobic digester can convert slurry that would have gone into waterways, into biogas - providing heat and electricity for the farm. Copys Green Farm in North Norfolk that we are working with is doing exactly that; their dairy waste and the slurry from the cows goes into an anaerobic digester, which powers the dairy.
Inside those digesters is a whole microbiome, which is actually much more interesting than the human microbiome, in terms of the diversity of organisms and what they do. There's at least ten times as many species in an anaerobic digester, as in the human gut, with many interesting forms of methanogenesis that don't occur regularly in the human gut.
The third industry application we’re studying is Fecal Microbiota Transplantation (FMT), which is another way to modulate your microbiota. FMT administers donor fecal matter into the patient’s intestinal tract to directly change the recipient’s gut microbial composition and pass on a health benefit. I think perhaps that’s the future - in terms of knowledge transfer - how will we adjust microbiomes to be more beneficial.
Falk Hildebrand: I’m more of a microbial ecologist; trying to understand the ecosystem that microbes live in. I'm interested in understanding how to modulate any microbiome; leading from harmed or dysbiotic ecosystems to stable and resilient ones.
This is often about preserving the microbiome’s diversity or understanding how we can best manipulate the benefits an ecosystem offers. In terms of the human microbiome, it’s understanding how microbes might be inherited from our parents, and what microbes can be lost due to antibiotic treatments.
We’re also interested in the soil microbiome which is much more diverse than the human gut microbiome. You could say that this ecosystem is in general more important than the human gut microbiome, because this is driving the whole ecosphere.
For example, we previously looked at how fungi and bacteria interacted to understand how these components of the soil ecosphere are working together; which parts of the ecosystem are needed for a holistic approach towards a healthy and functioning organism.
We’re also interested in the soil microbiome which is much more diverse than the human gut microbiome. You could say that this ecosystem is in general more important than the human gut microbiome, because this is driving the whole ecosphere.
CQ: If you look at an individual, there's maybe ten times the number of genes in their microbiome as there is in the human genome. But if you were to say, to take a hundred individuals, you would find at least hundred times as many genes in the microbiome.
Each individual human doesn't add much to the human genomic diversity, but their microbiome adds a great deal to the microbiome diversity.
This is why studying the microbiome is so important because if there is this diversity, then in theory, you can modulate it. Editing our own genomic diversity is a complex practice, but adjusting your microbiome is something that's relatively easy to do so there’s that capacity for alternative species.
FH: One of my recent gut microbiome datasets had at least 42 million genes; in comparison to 30,000 in the human genome. Therefore, you see by the order of magnitude, there is much more genetic material in the microbiome, and that's just the gut microbiome; there's also the skin, mouth and other surfaces of the human body colonized by microbes.
The diversity of the microbiome is just so huge. Between two humans, the gene diversity is relatively equal, but with the microbiome alone, the comparison of genes from the species in your gut microbiome is incomparable. It's very complex, but also much more to choose from - with many more opportunities to adapt this microbiome to a new environment or new food. It’s much easier to exchange a microbe in your gut than to exchange a gene in your genome to adapt to changes.
Editing our own genomic diversity is a complex practice, but adjusting your microbiome is something that's relatively easy to do so there’s that capacity for alternative species.
Chris Quince
CQ: In translating our microbiome research to benefit academia and industry, we are developing methods that are used throughout academia; this is something that actually distinguishes the Earlham Institute from some other institutions. We're developing new algorithms and software pipelines, that are then used by a large number of people for academia and industry. In addition to our own collaborations, where we're applying those efforts relates to the finer level resolution study of the microbiome.
By reconstructing the genomes of individual strains present in the microbiota we find that even closely related strains from the same species can vary substantially in terms of the genes they possess up to 40-50% divergent, again, in a way that humans don't, or any other, eukaryotic organisms in fact.
A classic example of this is E. coli - we understand this genomic structure well now, and some strains will be extremely harmful pathogens or others are completely benign commensals, also dependent on the scenario they’re in.
FH: It’s great that Chris and I are at the same Institute, because we can really pull our resources together. I believe this model of closely related research groups pooling their expertise will become more important in the future. We, as researchers, can draw strength from our shared interests and genomics studies which means really exciting times ahead for me now here at the Quadram and Earlham.
CQ: In terms of the wider economy and public at large, there is a lot of benefit for the UK but the microbiome field doesn't have a good track record on fulfilling this potential so far. In other countries, particularly the US, perhaps less so in Europe, major pharmaceutical companies are already realising the potential of microbiome modulation as a product. This is something that works in a variety of different contexts; as well as pharmaceuticals, it's also important in agriculture, so I think it has huge potential opportunities.
FH: My research is mostly aimed at providing health benefits, fundamental science that forms the basis of industrial applications. Understanding an ecosystem comes down to identifying the main contributors and how they interact with each other, and with the environment that they are in. Our research is the foundation of any industrial application into modulation of the microbiome, be it human gut, dog oral or the lake next door.
CQ: I've just started a collaboration with IBM, working on joint methods to integrate other forms of data into the study of the microbiome and its future landscape. I think that's something where the Earlham is in a very good position through the combination of novel technologies we have, but also the computational expertise that allows us to incorporate extra sources of information beyond the sequence data we currently have.
Most microbiome studies are all about sequence data that tells you what is there and the potential it has for metagenomics. However, if you also measure things like metabolites or proteins, you can get a better sense of what they're actually doing, which is exciting explorative research.
It’s great that Chris and I are at the same Institute, because we can really pull our resources together. I believe this model of closely related research groups pooling their expertise will become more important in the future.
Falk Hildebrand
FH: I'm interested in understanding this diversity and if it is good or bad and how much this can affect our health. How much of this is passed on to the next generation - through your family and your environment.
There’s much discourse around ‘you are what you eat’ - adopting a plant-based diet and how that goes beyond helping your gut and digestive system, but actually can help with major diseases such as cancer, not to mention the beneficial psychological effects of a good diet. There's more and more studies indicating that anxiety, depression are related to microbial imbalances in our gut microbiome, even Parkinson’s and Alzheimer's disease could be.
Parkinson’s disease is an area I have extensively researched and there's proven consistent changes in these patients. This is just one small aspect of the whole picture in how the microbiota can be so influential; there are studies emerging linking gut health to helping prevent cardiac diseases, or even cancer and liver disease and how these are treated. To progress and future-proof this, we need to understand how it happens.
To put this theory into practice in the future, we can hopefully one day replace a bacterial species living in or on us, without the need for GMOs, in order to treat certain diseases. In order to do this, I imagine we will have bacterial storage banks where suitable organisms can just be picked out, optimised for a condition and the present microbiome in each patient.
FH: From what I'm working on, the soil microbiota is tricky, I believe we just don't understand enough yet. We need a picture of what’s actually going on, what could be important in these systems and what can we destroy through our intervention attempts. Even in the gut microbiome where we have already spent millions of dollars of intense research, we still often don’t understand why a bacterium is increasing or decreasing. Frankly often enough studies are not reproducible, which to me is an indication that we are still early on in the game.
CQ: Microbiome science goes beyond just correlations, the microbiome is intimately involved in a variety of diseases but we need to know more about it. An FMT procedure can be seen as very crude, where you have a sick person and a healthy person - let's try and make the microbiome that looks like the healthy person. If we do not understand the mechanism by which the microbiome is causing the disease then this treatment may not be appropriate.
Similar to antibiotics, in some cases, antibiotics are just prescribed to people who have a viral infection - it’s not fully understood and we’re throwing whatever we have at it.
It’s an interesting example because in certain contexts FMT works far better than antibiotics. So Clostridium difficile is the common example. FMT is so successful for Clostridium difficile treatment that basically any other treatment is unethical. It treats recurrence effectively in over 90% of patients, however, some typical drugs don’t work a lot of the time as we don’t really understand how the body works, and what the drug is doing. I think the paucity of our understanding of the microbiome isn’t actually a barrier, it’s relevant.
CQ: With regard to the KTN’s Microbiome Roadmap, specifically, there's some good points emphasised in the report to elevate microbiome research in the UK, such as setting up microbiome centres, and the focus on novel technologies, but the breadth of the research funded needs to be diversified and not just focused on a small number of universities.
I think much is down to correlative or causative. To design experiments in the future more towards the direction of really proving a point, rather than just finding a correlation. It’s important to test and manipulate the microbiota and prove that there is more than a correlation on your computer. If you change the microbiota, and it results in an outcome, then it's causative. For instance, there have now been successful clinical trials of probiotics, such as Akkermansia muciniphila, for the treatment of metabolic disorders and diabetes.
Hopefully there's also less intrusive techniques that can be used, such as metabolomics, that gives us a better understanding of the mechanism and one that is more plausible which results in causation. In many cases, you probably need to break research down and go back to the petri dish and classical microbiology again - even, as mentioned in the report, focusing on trying to culture microbes for health benefits.
FH: In supporting enabling and microbiome technologies, there’s a lot of opportunity at the Earlham Institute because it combines access to advanced sequencing machines, very powerful computers and the matching bioinformatics expertise. The close work with the Quadram Institute, which Chris and I are both part of, is a crucial link in this, giving access to microbiology and gut health expertise at an international level. It’s a very good research arrangement between the two leading institutes.
In supporting enabling and microbiome technologies, there’s a lot of opportunity at the Earlham Institute because it combines access to advanced sequencing machines, very powerful computers and the matching bioinformatics expertise.
Falk Hildebrand
CQ: The KTN report focuses on microbiome science adopting the ‘One Health’ approach, which I have a number of projects on, such as a key study in Pakistan where we are not exploring humans in isolation but their environment. Microbiome science naturally lends itself to that, because a lot of the organisms that we find in the human gut will also be found in the environment in various situations. Going back to E coli - this can exist in a variety of different locations, but can also exist in your gut - moving freely between the environment and the human body.
More interestingly, this same thing happens, but on a gene level. It may not even necessarily be that there's an overlap between the organisms in the environment and your gut, but an overlap in the gene content - through horizontal gene transfer (movement of genetic material other than by the (‘vertical’) transmission of DNA through reproduction) - this becomes particularly important in sanitation. The way we're dealing with the microbes and the way we’re dealing with our feces is essentially what sanitation is, impacting your degree of connectedness to your environment.
Also, antimicrobial resistance is an example of this, where there's a movement of resistance genes between pathogens in humans and commensals in the human gut, but then also into environmental organisms - and vice versa - a lot of those resistance genes came from environmental organisms in the first place.
Therefore, it’s very natural to view microbiomes in a one health perspective due to the interconnectedness of the bacteria, and more importantly their genetic content.
FH: To progress microbiome health; how we want to use the microbiome in the future is the key to this. I'm really interested in understanding the microbiome ecosystem, and especially at what resolution we can observe this. Historically, we go from a very low resolution of few species to now getting higher and higher resolutions of microbiomes that are also more comprehensive, but is that really enough?
Here, I think we still have some work ahead of us and my lab is intensely working in this direction. The microbiome and its health is an incredibly complex system to understand and exploit and is full of opportunities; and to take advantage of these, we need to disentangle this complexity to make sense out of it.
But time might play against us here: it has already been shown that Westerners’ gut microbiota diversity is significantly reduced compared to indigenous people from various regions all over the globe, but it’s really our lifestyle that seems to destroy the biodiversity in our guts. For example, people that moved from the Philippines to America lost much of their microbial diversity within two years.
For example, soil is the most diverse ecosystem we basically know of, in terms of microbes. The number of bacteria species found in healthy soil is tens of thousands, so each patch of soil has an incredible biodiversity, by far much higher than the gut microbiome. There are many microbial species and interactions in soil that have not been discovered and many which we are probably currently destroying through industrial farming practices.
