A long time ago I was working on signalling pathways, so all the wires that connect cells and absorb signals and transmit them inside. I was working on epithelial cells of the gut and we were thinking let’s put this cytokine and see what happens to the cells. Then for some reason neglected to think that the cells live in a sea of microbes and here I was looking at cytokines, these small molecules. Then it occurred to me that I should look at the microbes as a modifier of epithelial cell function so that’s how it came about. We had a technology that allows you to study a mouse in germ free conditions, so without any bugs, that makes perfect sense, and to look at without bugs, with bugs, what will be the response and then try to layer down this response with manipulation of microbes. So that was how it works.
Which different microbiomes could contribute to carcinogenesis?
We don’t know that much about that so we’re still sequencing. We know for sure that there are changes, so some members’ membership decreases in cancer and other members increase. We try to understand the function and the consequences of this. So there are different signatures, some are associated with loss of short-chain fatty acid producing bacteria that are the good ones; others are the bad ones that will produce different toxins like hydrogen sulphide or genotoxins that hit your DNA and damage your genome which is not a good thing and often leads to cancer. So there are groups of bacteria that have function in terms of producing toxic metabolites or genotoxins and other bacteria that produce protective and it’s all about the balance of these. If you lose the good one and gain the bad one then the consequences could be cancer. But we don’t have a clear understanding of who is doing what, that if you have that you have cancer. We don’t have that knowledge yet.
Might disruptions in microbiota be solely due to infection, or age-related immune senescence?
Many things disrupt the microbiome but most of the microbiome is very resilient so it’s not because you’re going to eat sushi that your day that your microbiome is going to change. If you move to Japan then after a year, yes, you may have a change. But it’s really resilient until you get an infection and the infection, the change, is often associated with the treatment. If you give antibiotics to someone who has a salmonella infection it’s not only the salmonella changing, it’s the antibiotics that you want to give rid of the salmonella so they will wipe out a lot of bacteria. Although they’re all like, ‘It’s a gram-negative antibiotic,’ you will hit a lot of microbes. So that change. But the genome, our genetic makeup, also counts for some balance of the microbes. So if you have a specific defect in an innate response you may have a different microbiome than another one. But I don’t think we should be too much focussing on the taxonomy of microbes as opposed to their function. Because you and me have very different microbiomes yet we share a lot of function, very similar function, because they overlap. So even though we have different microbiomes it’s not a big deal; when it’s in the disease state that’s something else. Infection, medication, some medications, have a profound effect on microbes and a lifestyle that could be at the extreme of the healthy lifestyle could have consequences on the microbiome.
Can this damage be repaired?
We don’t know the plasticity, how much the changes will be causing disease. There may be some plasticity that you change your microbiome but you’re not entering the danger zone yet and maybe you need a little bit more yoghurt, some probiotics. It’s not clear, some of these probiotics don’t colonise, they’re just passengers. They’re going to come and flush out so you have to take it all the time. But you want to avoid the stressor, so if the stressor is inflammation, you have GI problems and you could be put into remission, prolonged remission, your microbiome probably will recover because it is not under stress. The same for as soon as the infection is gone and the antibiotic is removed you will bounce back to some sort of normalcy. It’s just a prolonged stress on the microbiome that may be difficult and it’s not coming back unless you give something. But we don’t know what to give you. If I give you the latest probiotics that Nestlé is selling, it doesn’t mean that you’re going to restore your microbiome, you just put more of a different biome that is supposed to be good. So all these questions are extremely important; we don’t have a precise answer to it but intuitively we’ll think if I have bad microbes I need something to replenish it and I will take these good bugs. In theory it sounds great, in practice we have no idea if it works. Because if I take a picture of your microbiome here you look like that, in the disease state look at this. If I give you probiotics A, B or C now you’re going to go back to this. No-one has this knowledge.
Is it possible to keep a record of a microbiome from an early age?
Absolutely. There are companies out there; uBiome will offer you a little bit like a DNA footprint, they will get your microbiome so you will see a map and you just don’t know what it means. It’s a [?? 6:35] assembly of microbes and they will say ‘You’re here and the rest of the people are here.’ Oh my god, that’s not good. It means nothing, right? But you just have a snapshot of what you are. The most important is what happens when you have a disease state, how does it look like now? Is there anything that could be done about it? But this knowledge will need multiple time point collections and no-one’s going to do that. ‘I don’t feel very good, let’s check my microbiome. Go to the doctor and let me see my microbiome now. Is it worse than the picture that I had when I was sixteen and healthy?’ We don’t know that.
Maybe in the future. Age is a confounding factor on changing the microbiome. As you age you lose diversity and you lose members and we’re not quite sure if that microbiome is defective as opposed to sixteen years old. We know the extremes of age, 0-2 and above 75, the microbiome is very different. In the early stage it’s very formative, building up, varied diet, the very dynamic assembly, then after that it’s pretty stable. It’s pretty stable throughout your life until the end where you start losing members and is that associated with aging problems, related problems, that we see? Now we don’t know but that’s fascinating and that’s why we need to keep investing effort in microbiome relationships with many diseases. Cancer is certainly something that is of a great interest to many institutes.