Go with the gut: Our symbiotic relationship with our intestinal bacteria

VOICEOVER
This is Up Close, the research talk show from the University of Melbourne, Australia.


ANDI HORVATH
I'm Dr Andi Horvath, thanks for joining us. Today we bring you up close, to your own microbes. There are literally trillions of microbes that live in and on our body. They include bacteria, fungi like yeasts, parasites and viruses. They outnumber our human cells 10 to one and their genes outnumber our genes one hundred fold. But humans are not just a walking talking host for a complex system of microorganisms it's in fact a critical symbiosis, we can't exist without them and they need for us for survival as well.

Microbes perform functions that our cells can't do. Like digest certain carbohydrates, but the community of microbes, known as the microbiome provide metabolites that actually affect our human genes and they regulate things like our digestive processes, our hormonal and immune systems and even our brains.

You've probably heard of the Human Genome Project, the map of all human genes. Well now it's the era of the Human Microbiome Project. Since 2012 scientists have aimed to characterise the microbes, their genes and how they connect to our health and diseases. For example, the causes of rheumatoid arthritis are kind of still unknown, but scientific evidence suggest that an out of balance microbiome might be to blame.
Microbiome issues could also be behind diabetes, obesity as well as certain cancers and mental disorders. The optimal balance of the numbers and types of microbes do matter and many bacteria keep us healthy by controlling the right human genes for healthy human functioning.

To discuss the world of the microbiome and his recent research into gut microbe chemistry is associate professor, Spencer Williams, from the School of Chemistry and the Bio21 Institute, University of Melbourne. Spencer's recent work explores the chemistry of yeast eating gut bacteria, which has provided new clues into new treatments for people suffering bowel diseases.

Welcome to Up Close Spencer.


SPENCER WILLIAMS
Good morning, Andi.


ANDI HORVATH
Spencer, orientate us. Where exactly is the human microbiome, is it mainly in our gut and how on earth does it get there?


SPENCER WILLIAMS
So the human microbiome describes a population of bacteria, a community of bacteria that live at the surfaces of our body. Any surface of the body that is exposed to the environment has bacteria inhabiting it. So the obvious surfaces would be the skin and there's certainly bacteria that live on the skin, but the more important orifices are around your eyes, your nose, and your mouth and in particular the gastrointestinal tract. The bulk of the human microbiome is found in the gastrointestinal tract.


ANDI HORVATH
So how does it get there?


SPENCER WILLIAMS
When you are born, you're sterile, you have no bacteria in your body. It's at the process of birth that you first become inoculated with bacteria. It depends upon the mode of birth, if you travel down the birth canal in a normal birth you get exposure to a wide variety of bacteria. If you have a caesarean birth you generally get exposed to a different population of bacteria.

Subsequently, particularly in your gastrointestinal tract, the nature of that population will depend on what you're fed on. So if you're breast fed the composition of human milk promotes the growth of certain bacteria, particularly bifidobacterium and if you are fed on commercial baby milk formulations they are usually dried from cow's milk, that is quite a different composition and you have different microbes that populate your gut.

When you go through weaning there are changes in the micro population and ultimately you'll be influenced both by your environment, which bacteria you may be exposed to, and the nature of the food that you eat.


ANDI HORVATH
Got you. So what else influences the species and composition of microbes? How varied is it from human to human, and are there patterns of microbes that are kind of universal?


SPENCER WILLIAMS
It's a complex answer to that question, there has been extensive sampling of the microbiome composition of a wide range of individuals. Many of which you could characterise as all being healthy individuals. Generally it's found that there's around 500 species that regularly occur. There are certainly some major species that show up often, there are the bacteroides and firmicutes that are particularly common genuses [sic] of which you have many sub-species within them.

It's been found that there are certain keystone species that, if that keystone species is present then many other bacteria species are found with it. A bit like perhaps a coral on a reef, that coral is a keystone species that can attract certain fish. There are significant changes in the composition of your microbiota that depends on what you're eating. There are groups in Japan that eat seaweed and they have particular bacteria that can confer the capacity to degrade some of the carbohydrates in seaweed. It would depend on where you live on the Earth and it would depend on your health history.

So even within that realm there's probably a wide range of different changes. So you could have a healthy person from Greece and try to compare them with a healthy person that lives in Tibet. They would both be healthy, they would have what we'd consider healthy microbiomes but the composition of those microbiomes still might change quite significantly.


ANDI HORVATH
Okay so there's some certain variation within the microbiome. Then how does the gut bacteria influence the body's complex systems, like the immune system?


SPENCER WILLIAMS
So these bacteria are intimately associated with our body and in particular the immune system is a very complex system. There are parts of our immune system that are hidden deep inside our bodies but much of our immune system is outward facing. So it's present at the surface of our bodies.

So of course it can interact with these microbes that are found in the microbiota. A variety of different mechanisms are emerging for how the microbiota may be influencing the immune system. These microbiota are bacteria and they produce metabolites that can signal through the immune system, and this signalling is sometimes critical - you mentioned it in your introduction that bacteria are often involved in symbiosis. So this signalling can be a good thing for you. But these bacteria sometimes are involved in pathogenesis and so the signalling can be bad.

The signalling pathways, for example, the important ones are found deep in the distal gut of your body. It's been found, for example that bacteroides which we'll talk a little bit about later - they provide the capacity to produce short chain fatty acids. These include things like acetic acid, propionic acid and butyric acid. Acetic acid, your listeners should of course know is present in vinegar.

It turns out when you eat vinegar as part of your diet it gets absorbed in the proximal part of your gut and it cannot penetrate deep into your distal gut. But the bacteria that live in the distal gut produce these short chain fatty acids including acetate, and it's been shown that the acetate can have a couple of functions. It can act as a food source for epithelial cells that line your gastrointestinal tract, nourishing them in what is actually a fairly nutrient poor environment because you've extracted all the goodies out early in your digestive tract. Secondly these molecules act as signalling molecules.

So, in particular a paper came out in 2013 where they demonstrated that acetate combined to a signalling protein called a G protein-coupled receptor on the surface of a subclass of T cells. These were T helper cells and it stimulates the T helper cell, and T helper cells are an important subclass of T cells that control other T cells. T cells generally are a group of cells that play a central role in how we combat infection and the status of our immune system.


ANDI HORVATH
I'm Andi Horvath and our guest today is chemist, Spencer Williams. We're talking about the human microbiome and the chemistry of gut microbes here on Up Close.

The last 50 years of western diet has meant we're eating more processed foods and consuming an array of pharmaceutical drugs. There is an increase in heart disease, diabetes, even Autism Spectrum Disorder. Spencer, surely we would see a change in the ecosystem of the gut. So is there any correlation between these particular diseases and changes in the microbiome?


SPENCER WILLIAMS
Well taking one step back there is a strong correlation between diseased humans - well the diseased human states - and the composition of your microbiota. So a big question has been is this just a correlation that's coincidental or is there a cause? A change in the composition of your microbiome somehow causing these diseases. Increasingly the answer for some of these diseases appears to be yes.

There was a lovely study done about half a decade ago where they took a rat that was genetically predisposed to becoming obese and they did a transplant of microbiome from its gut into a lean mouse and they were able to show that the lean mouse, simply by changing the nature of the microbiome in its gut, became more obese. So I think that's a really nice clear example where the composition of the microbiome has a big effect on what we consider a very complex problem like obesity.

There's many other examples that are becoming identified and the particular one that I have an interest in is Crohn's disease. Crohn's disease is an autoimmune disease that's poorly understood but it leads to poor bowel function, usually diarrhoea, regular passage, often many trips to the toilet every hour, let alone many trips to the toilet every day. So it's a severe debilitating disease that has a profound effect on those suffering from it.

Crohn's disease is often caused by a bacterium Clostridium difficile, so the basis of that disease is fairly clear in many cases that it's Clostridium difficile that's causing the problem. People with Crohn's diseases often have more of that bug, people that don't have Crohn's disease either have none of that bug or only a little bit of it.


ANDI HORVATH
We'll come back to Crohn's disease Spencer because this is the area of your research, but I have a burning question. That is, how does the microbiome respond to foods like artificial sweeteners? The body has never encountered these molecules before, how does it cope?


SPENCER WILLIAMS
There was a study on the use of artificial sweeteners just recently. Artificial sweeteners are an interesting thing that's become common in our diets since the 1970s. An interesting point about artificial sweeteners is that it doesn't seem to have an impact on the amount of sugar that we eat. We seem to have an insatiable appetite for sweetened foods, even if we take artificial sweeteners we still tend to consume significant amounts of normal sweeteners like sucrose.

But this recent study looked at the effect on animals that were fed diets containing artificial sweeteners. So things like aspartame and saccharin, which I guess is now banned, and sucralose and related artificial sweeteners. They showed that rats and mice fed these artificial sweeteners induced metabolic syndromes, a metabolic syndrome encompasses a wide variety of different conditions that include obesity and Type 2 diabetes. It appears from this study that consumption of these artificial molecules that are present in artificial sweeteners was one of the causes for the induction of metabolic syndrome.

So the outcome of this study was that these artificial sweeteners correlated to an increase in obesity and diabetes, this was done in animals so whether or not this transfers into humans is an open question but it's something that definitely needs additional study.


ANDI HORVATH
And this begs the question, can we actually cure diseases by managing the human microbiome? Can we create good environments like the sort of prebiotic approach? Or can we actually replace the bugs as a sort of probiotic approach?


SPENCER WILLIAMS
There are two ways that you can conceive of manipulating your microbiome. One is simply to inoculate somebody with what we think are good bacteria and perhaps hope they will displace the bad bacteria or perhaps give them a course of antibiotics to kill off the bad bacteria and hope to repopulate with good bacteria. That's what you'd call a probiotic approach and we kind of use these approaches already through consumption of yoghurts and the like but I think there's a good chance that we could expand this sort of approach to include a wider range of bacteria and perhaps even genetically engineered bacteria that have the capacity to produce molecules that we're now learning are good for health.

A second approach is to change our diet. Do certain bugs prefer certain food sources in things that we eat and might other bugs prefer other food sources in the things that we eat, and by changing our diet or having certain additives, might we promote the growth of one bacteria, hopefully a beneficial bacteria, in preference to a bacteria that causes disease.

I'll give one example of, again another recent study that came out right at the start of this year in 2015. In this study, dealing with Clostridium difficile which as I mentioned is one of the causes of Crohn's disease, they ask the question why does Crohn's disease populate the gut and is it displacing some other bacterium, and if you could identify which other bacterium it's displacing maybe you could super colonise an infected person with this other bacterium that should have been there in the first place. What this lovely study published in Nature demonstrated was there was another variety of Clostridium that is not pathogenic but has the ability to super colonise and displace Clostridium difficile. So it's actually a bacteriotherapy that you would use to manipulate the microbiome and alleviate the symptoms of Crohn's disease.


ANDI HORVATH
So in fact you are what you eat?


SPENCER WILLIAMS
Oh I think that's exactly the case and it's becoming more and more apparent that our diet and the bugs that live in our gut have profound effects on our health.


ANDI HORVATH
I'm Andi Horvath and you're listening to Up Close. In this episode we're talking about our microbiome with chemist Spencer Williams.

Now humans have been eating fermented food and drink, including beer and bread, for the last 7000 years. This has led to the evolution of bacteria eating yeast from the fermented foods. The bacteria, known at Bt may possibly hold the key to strengthening the immune system in humans and treat various bowel disorders like Crohn's disease. Spencer, lower us in. How does yeast eating bacteria operate in our digestive system?


SPENCER WILLIAMS
Well there are a couple of answers to that question, the question is, for a start, where did they come from? So humans domesticate other organisms to act in our service, obviously cattle and sheep are one example but we've also domesticated microorganisms and it's estimated around 7000 years ago that we domesticated yeast and it's become a common part of our diet. You mentioned of course in fermented food, so things that we eat like bread and particularly bottle fermented ales, also soy sauce.

We regularly eat small amount of fungus as part of our diet. So I guess it's not unexpected that our gut may have adapted to this change in our diet. This recent study that we published in Nature in 2015 demonstrated that there are special bacteria that exist in our guts that provide the capacity to break down cell wall components of yeast in our diet. As I mentioned, humans have done a lot of domestication of different organisms and in fact this flows through in to other animal species.

So we went looking for where this bacteria can be found and can it be found in other organisms. In fact the only other place we were able to locate this bacteria were in pigs and they were located in a piggery adjacent to a brewery. Of course a brewery, one of the by-products of a brewery is spent brewer's grain. So this is grain that's been fermented with yeast and it's an industrial by-product that you then feed to pigs and of course now these pigs have a history of consuming domesticated yeast and those pigs as well also had bacteria in the guts - that had the same capacity that we thought was uniquely in humans, well in fact it has spilled over to one animal species that we were able to identify.


ANDI HORVATH
Technically how does this yeast eating bacteria operate in our digestive system and connect it with Crohn's disease?


SPENCER WILLIAMS
This bacteria lives in our distal gut, so deep in our digestive system. When we consume foods, early in our digestive system we break down certain polysaccharides, so things like starch and sucrose, they get broken down and we use them as food. Other polysaccharides which include things like dietary fibre and in this case includes the cell wall of the yeast, pass through our gastrointestinal tract and reach our distal gut. It's there where the bacteria lives and it uses the cell wall components of the yeast as a type of food.

Now what our work has shown is that the bacterium has a really complex machinery of enzymes that are found on the surface of the bacteria that can trim these very complex structures in the yeast cell wall, then import them into what's called the periplasmic space, so a space between the outer wall and the inner wall, where they are then degraded down to individual monosaccharides, so just single sugars that are directly useable for energy.

You mentioned in your opening that these bacteria are involved in a symbiosis and in fact this bacteria produces those short chain fatty acids that I mentioned before. So upon digesting the yeast cell wall and in fact other polysaccharides, they produce a wide range of short chain fatty acids which are then released and that nourishes our cell wall.

One of the interesting components of our study was sometimes Bacteroides thetaiotaomicron, acts as a keystone species and other bacteria can live around it. But in particular with this component of the yeast cell wall it has a selfish mechanism, it takes it up exclusively and does not release anything out. So this idea of a particular food source that can only be utilised by a particular bacterial strain may have uses in biotechnology and possibly in treating human health.

So how does this relate to Crohn's disease? It's a fairly complex story but let's slowly work through the issues. So the direct correlation is perhaps not there but there's lots of interesting connections. Patients with Crohn's disease often have a marker antibody that they produce called the ASCA antibody. What ASCA stands for is the Anti-Saccharomyces cerevisiae antibody and Saccharomyces cerevisiae is yeast. So people with severe Crohn's disease often have an anti-body that's against yeast.

What does this antibody recognise specifically within yeast? Well it recognises the same structures that we've shown that this organism, Bacteroides thetaiotaomicron has the capacity to degrade. So if you try to think about what might Bt provide, it might provide the ability to degrade this carbohydrate in the cell wall of the yeast so that it cannot be recognised by the immune system and it may not give rise to autoimmunity.

If that would be the case then one might think that people with Crohn's disease might have less of this bug which might lead to them having more yeast in their gut and that might lead to these autoimmune responses and people that are healthy that don't have Crohn's disease might have more of this bug and consequently they have less yeast cell wall because it's all been consumed. Indeed that seems to be the case.


ANDI HORVATH
Spencer, Bt has now been granted orphan drug status by the Federal Drug Administration and it's going to be used for paediatric Crohn's disease. What does that exactly mean and what does that entail?


SPENCER WILLIAMS
Paediatric Crohn's disease of course refers to Crohn's disease affecting infants. So if you imagine how debilitating it is for adults it's particularly debilitating for children. So Bt has been granted orphan drug status because there are no other treatments. So this is a debilitating disease that there are really no options to treat these children. So this company is investigating the use of Bt as a bacteriotherapy to restore a normal microbiome composition and hopefully overcome the problems of Crohn's disease.


ANDI HORVATH
So why are some people sensitive to yeast and could these people possibly use Bt?


SPENCER WILLIAMS
I think there're a broad range of reasons why people are sensitive to yeast and it's got a lot of interindividual variability so it's probably not well understood, and I wonder whether or not people will ever understand it particularly well. But this case of Crohn's disease I think it's emerging that there is a stronger link. People are consuming yeast, if it's not degraded in their bowel, you're generating an immune response against it and somehow that's causing a change in your immune status and that causes the symptoms of Crohn's disease.
If indeed that is the case then a bacteria that has the ability to degrade the yeast cell wall and not produce the so-called epitopes, the parts of the yeast cell wall that are recognised by the immune system could be a way of treating these people or allowing them to manage their symptoms.


ANDI HORVATH
So Spencer, where does this work with yeast and Bt lead to?


SPENCER WILLIAMS
Well one direction that we think could be useful, I mentioned before that the amount of Bt in your gut seems to correlate with positive health, although you have to be careful, there are other studies that show that if you have too much Bt in your gut that can also lead to other problems.

So when we're thinking about prebiotic strategies, is it possible to feed yeast deliberately to somebody to encourage the growth of Bt? Now in fact yeast is easily genetically manipulated and the particular cell wall structure that we're dealing with here, the mannan, there are many mutants available that have all sorts of different structure and we showed that some of these mutants have better effects on growth than others.

What I wonder is, whether genetically engineered forms of yeast that produce certain cell wall structures might be able to be added to our diet and whether they might encourage the growth of helpful beneficial populations of Bt in our gut.


ANDI HORVATH
So does Bt have the potential for other uses as well?


SPENCER WILLIAMS
It's a genetically tractable organism and it's possible to genetically engineer it to produce drugs. So if we were then to have a person who's in need of a regular dose of a drug to keep them healthy, perhaps we could inoculate them with a genetically engineered form of Bt that could then populate their gut and we could be certain that that bacteria would keep living in that gut by ensuring that they eat a particular form of yeast that we now know acts through a selfish mechanism. And a nice part of that idea could be, we could then remove the yeast from the diet and clear out the bacterial strain from their gut when they no longer need that drug.


ANDI HORVATH
There appears to be a lot of scientific references to glycans and polysaccharides, which I know are your favourite molecules. But when it comes to gut microbes, can you explain to us why are these important molecules?


SPENCER WILLIAMS
I think they should everybody's favourite molecules because you regularly consume these things. So we've all heard of carbohydrates, well in fact carbohydrates is a very general term and we can break carbohydrates up into two groups. Those that we can digest which includes things like starch and sucrose, and those that we can't digest which can include something like wood, cellulose and soluble dietary fibre like Beta-1 3-d glucan that you find in oats.

So it turns out that many of the bugs in our gut survive on what we consider non-digestible carbohydrates, this would make sense. Of course in our gut we consume the digestible ones and that provides us with energy, what are these bacteria going to live on? Well they have the capacity to degrade so called non-digestible carbohydrates and so this is their major food source.

In fact it's not quite as simple as that. As I mentioned before there's a symbiosis that when these bugs degrade these non-digestible carbohydrates they release short chain fatty acids which we use as food and it's been estimated that we derive around 10 per cent of our caloric intake from bugs digesting so called indigestible carbohydrates and supplying them to us as part of that symbiosis.

You also mentioned in your introduction that there are many more genes encoded by the bacteria that live in our gut than we have genes encoded ourselves so in fact these bacteria have a rich capacity to degrade almost every single carbohydrate that you could imagine that is in your diet and convert them into a beneficial food source. Humans are omnivores, we change what we eat every day, between meals. So these bacteria, particularly in humans, have evolved this capacity to be generalist, so called glycan generalist and break down lots of different types of carbohydrates depending on your whim of today, whether you're going to have a sandwich or muesli.


ANDI HORVATH
If that doesn't make you eat more fibre and drink more yoghurt, nothing will. Associate professor Spencer Williams, chemist at the Bio21 Institute, School of Chemistry, University of Melbourne, thank you for being our guest on Up Close today.


SPENCER WILLIAMS
Thanks for having me Andi.


ANDI HORVATH
Relevant links, a full transcript and more info on this episode can be found on our website. Up Close is a production of the University of Melbourne, Australia. This episode was recorded on the 29th of January, 2015. Producer was Eric van Bemmel. Audio engineering by Gavin Nebauer.  Up Close was created by Eric van Bemmel and Kelvin Param. I'm Doctor Andi Horvath, cheers.


VOICEOVER
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