Understanding microbial interactions, histopathology and the importance of the colonic microbiome

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Published: 21 Sep 2017
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Dr Alex Swidsinski - Charité Universitätsmedizin Berlin, Berlin, Germany

Dr Alex Swidsinski talks with ecancer at Microbiome in Cancer and Beyond 2017 meeting about the role of polymicrobials in our health, in particular in the colonic microbiome.

He explains the importance of understanding the histopathology, location and types of microbe in order to determine whether they are important. He emphasises the necessity to research more than just the composition of a microbiome, but the relationships and functionality of the microbes within.

He moves on to discuss the potential benefits of the colon as an organ, and how we can mimic the unique properties of its microbiome. It comes with risks, an unbalanced colon microbiome can lead to cancer, and parallel issues within the world of biotechnology. In order to do this, he reiterates the importance to understand the microbiome fully, with the entire chain of relationships starting from the underpinning biology.

I was talking about polymicrobials and their role in the intestine and in health, in cancer, in multiple sclerosis and IBS, many other diseases. Actually the most important part is that we do know a lot about microbials and polymicrobials and not just from now but from 1648 as Leeuwenhoek had looked between his teeth, looked under a microscope and saw that there are a lot of bacteria there. He was so delighted he saw that we are not alone in this world and everybody saw it [??  0:48] both microscopes and looked at what is happening there. Two hundred years gone but nothing happened for a simple reason – bacteria were everywhere. If you left your soup on the table there were bacteria there. If you had a wound there were bacteria there. So everybody saw the bacteria, I imagine, [??  1:10] so we can’t do anything. Even Lister wrote in 1848 that the surgeon had to have a specific smell, he didn’t call it bacteria but it was actually anerobes, if we can recollect that now. The surgeon, if he lost his knife on the earth he took it and started to cut further for the simple reason – if there are no bacteria there there will be bacteria there so why should I do anything. So it was first Pasteur who showed that bacteria are not [?? 1:48], that they need specific conditions and that we can investigate one bacterium by one, showing what can they do, how can they harm and what can they do. Everything else was gone.

So from that time point the infection disease started and everybody knew the pathogen should be in healthy, it should not be in diseased and if you transfer it it should cause a disease. So that was the paradigm and it’s changed a lot. We have eradicated all infections which we thought to be infections. But there’s just one point of the story since all infections that we do know using Pasteur’s method are mono-infections with just one infection but how many polymicrobial infections do we know? Actually a lot, but what do we know about them? We can say appendicitis is polymicrobial. What do we do? We make surgery. It’s IBD, it’s Crohn’s disease, it’s bacterial vaginosis and probably most autoimmune diseases are likewise polymicrobial diseases where a community is important where some kind of band of bacteria which are cooperating and which are working and behaving absolutely differently than a single bacterium and a single culture. So investigating them would be important to see what happens since until now we are just living in 1864, we’ve made no progress through them, just by mono-infections.

But the problem is how can we make progress just knowing what is there? What is there is not actually important, it’s important where it is. So, for example, mycelium meningitis is a germ which causes meningitis. Meningitis is a very severe disease but actually it’s normal for your mouth, in 30% of healthy people it’s living there. So is it pathogenic? Sure, but not if it is in your mouth, if it is in your meningea. So it is quite important to show where bacteria are, what they are doing, how they are cooperating with each other. But in a moment if we look what all are saying about is just there are a lot and we are just trying to correlate what we find in composition and [?? 4:14] some diseases. Are they good, are they bad? I don’t think that there’s a good way to get to a decision about the real pathogenic role of these bacteria. We have to show where they are, what they are doing, with what they are cooperating and not just sequencing and saying yes, they are there or they are not. We do know that there are a lot. Thus, most presentations are saying, ‘We have investigated that. We have investigated thus and we have meta, nano, micro and so on,’ and at the end so what? ‘We will investigate it further.’ But they’re not coming to the end. Actually what do we want? We want to find the pathogenesis - how bacteria, groups of bacteria, are cooperating with each other and what they are doing. Until we do it, until we care about problems of our patients and problems of our health and not just making basic science, there is something there, we will have no progress.

How can we conclude whether the presence of a pathogen is important?

The locations are actually you use molecular genetic methods to say where it is but you take a sample which is a biopsy, so it is intracellular, it is intramucous, it is on the cell, it is outside the cell, so you actually don’t know what you are investigating. So without looking at what is the functional anatomy, where is the bacterium or specific bug at a specific point, if you have no histopathology of it you don’t understand what is happening. There is a mycelium in your mouth, so is it bad, is it good? It’s nothing. But if it is in meningea it is something. There is fusobacterium nucleatum in your mouth, is it something? No, it is absolutely normal there. But if it has a specific histopathology in your appendix it’s very important. As long as we just take probes or samples based on the microscopic view, a sample with a biopsy, a cut of histology, and making a very specific analysis with sequencing, what do we know? There is something somewhere there and everything else is just a noise of names. Mucosa associated, it’s a biopsy, it’s not mucosa associated, mucosa associated faecal and so on.

What positives can we draw from the composition of the colonic microbiome?

What I started my talk with is about asking the doctors what is actually the colon for and most didn’t know what for. So you know the heart is for bringing blood further, your muscle is for moving your body, your head is for moving your thoughts, your kidney for removing your gifts from the body but what is the colon for? What is the positive of it? What we know, it is a reason for cancer, for IBD for Crohn’s disease, colitis, for diarrhoea, for constipation, for [?? 7:27] but what is the positive of it? What can we call positive of it? For heart we can say it makes blood, it has pressure and so on. For thoughts we can say there’s some kind of sociology, but what we can say for colon? Stool frequency? Stool smell? Stool form? Is it really worth something positive? So nobody knew. But actually the answer is quite clear – it is a highly sophisticated organ which we are not still growing to understand. You see, the future of civilisation is bound on biotechnology. We are getting [?? 8:05], we are getting biologicals which are very, very precious. We are getting insulin all with molecular genetic methods. The most important tool of it is it’s a bioreactor. So a bioreactor is where we are getting all this mass of substances to go. I am sure that in the future we will get all with it and everything else. It is just a question of time.

But evolution developed a bioreactor much earlier than we started our experiments with molecular genetics and it is much more efficient. If you look at the efficiency of our bioreactor we can reach concentrations of 1010 for short periods of time. The colon reaches concentrations of 1030 for years. Our bioreactor, which we are working with for the producing of biologicals, are working with one bacterium, if we get three bacteria we never know what happens in two hours. The colon is working with at least 5,000 different bacterial groups and other micro-organisms and is stable over years if it is working correctly. So the question is not what is in it, how can we look how it works, what it works and what it does. If we look not just in composition but at criteria the most interesting and important criterion, for example high concentration, each kind of species has bacterial groups which have to be there and probably they are important for bio-fermentation. For human beings there are just three groups. All other bacteria are individuals so we can steer over these bacteria the biological input of our bioreactor and the benefits are enormous. So what we have to look at is how these aims are reached – is it concentration, is it how they are distributed through the colon reactor, how stable they are over time, how can they be influenced? And how can we be protecting against this?

Are there any risks to this?

Direct, similar with a nuclear reactor. Everything is good as long as it is there and it is well protected but everything is bad as soon as it comes out, like Fukushima. If it comes out nothing is good and if it comes out it makes cancer. So you can start arguing what is before cancer, bacteria, what is primary, what is secondary, but let us take as an example Fukushima. You have a tsunami, that’s the first. You have then failures of administration, failures of management which takes days before they start chilling the reactor. Then you have an outburst, you have a lot of sequences and many people will die of cancer just from that. So nucleotides are not primary, surely, but is a tsunami a reason for cancer? Surely not. Is failure of administration a reason for cancer? Surely not. Nucleotides, and each of them is quite specific and has a quite specific effect on cells, on organs which causes specific cancer regions. So it’s like a bioreactor, as soon as your protective mechanisms are perfect, as soon as known bacteria has a contact with your epithelial services, everything goes good. But in case you take emulsifiers, for example, or you take [?? 11:58] or your mucocilia [?] is disturbed bacteria come in contact with your epithelial cells, a process starts which is germ related. So they are carcinogenic since bacteria, E.coli with [?? 12:15] and so on, they will be very meaningful, not less meaningful than carcinogenesis caused by nucleotides from Fukushima.

How should we assess problems that arise concerning the colonic microbiome?

We have to investigate each of them and we should start not with there is a bacterium there, we should start to follow the whole chain from tsunami to disturbance to getting out and what can we do, how can we protect and so on. It is the same. Just having an instrument I can sequence, so if I sequence I can find it is correlating or it is not correlating. Correlation doesn’t mean much, we need to understand what is behind it. So at the moment the microbiome is something like astrology, you see how ancient people looked at the sun, looked at the stars and they found quite quickly that some pictures of stars are correlating with the weather, with changing [?? 13:28], with a lot of things. So if these correlations are so important for such massive things they would be important also for your habits, they would be important for your life. So astrology came. We do know that they have no importance for this, they are just markers of what is happening in the universe, but there are a lot of people who gave money just for describing how the stars are moving and what an impact they have on something else. That’s not the question. We have to find out what is behind so we should start moving from I have a bacterium somewhere and it is something and it is correlating with something else, but how does this correlation come true?