But a healthy gut doesn’t just reduce the risk of cancer, it has wide-ranging benefits. “We have to think of the gut as this big sensory organ which has lots of lovely bacteria in it,” says Dr James Kinross, a consultant colorectal surgeon at Imperial College London. “That bacteria interacts with your environment, which then in turn communicates with your immune system.” Ray was readmitted to St Mary’s critically unwell and was soon diagnosed with Clostridium difficile (C diff) infection (officially, this bacteria has now been renamed Clostridiodes). A “hospital-acquired infection”, this disease is a complication of 20th-century medicine and an unintended consequence of Alexander Fleming’s discovery of penicillin, the first effective mass-produced antibiotic, in 1928. It is a global problem that afflicts 500,000 people in the United States each year and it kills 29,000 of them. It’s also becoming clear that samples from some donors are much more effective than those from others. These are known as “super donors” and their faeces seems to contain a magical ingredient that makes it particularly effective. But we don’t understand why this happens, or whose poo will be most effective. Spector’s 30-year-long study of 15,000 twins, TwinsUK, and his PREDICT studies have shown that even genetically identical people respond to the same foods very differently (our microbiomes are so variable that twins share only 30% of the same gut microbes). By feeding participants the same meals on different days, he was able to show that responses to the same meals also vary hugely between individuals, influenced by both the microbiome and genetics. This matters, says the ZOE team, because our response to food is linked to our risk of heart disease, type 2 diabetes and obesity, but also because it blows apart the tired and useless mantra “calories in, calories out”, which doesn’t make sense in a world where two people’s blood glucose levels can be hugely different after eating the same slice of cake.

I first understood what the microbiome was when I started my Ph.D. in 2005 and it became obvious to me that this has to be an important part in the story of human health and happiness. These microbes are there for a reason, they're not there by accident. This is an evolutionary partnership, and if we're getting more cancer or chronic disease in the gut, they have to be part of the story. Microbes have been used as therapy and cancer treatment for hundreds of years—but they've been ignored by mainstream science. I knew the gut microbiome was important to our health and I wanted to focus my future career on understanding how.

Nicholson JK, Holmes E, Kinross JM, Darzi AW, Takats Z, Lindon JC: Metabolic phenotyping in clinical and surgical environments. Nature 2012, 491(7424):384-392. We compared these diets to those in Sub-Saharan Africa where rural communities have very high-fiber, plant-based diets. They eat meat very rarely, and when they do, it is very lean. They exercise a lot and live in social communities, where they farm together, cook together and share plates of food. So, they exchange and share microbes through lots of different routes. As a result, they have a much more diverse and resilient population of gut micro-organisms than we do. Yet it is only now, as we are beginning to discover the microbiome's enormous potential, that we are realising it is in grave danger, being irrevocably destroyed through the globalisation of our diets, the war on bugs and the industrialised world. Ideally, we need to nurture our gut microbiome from birth. I think that this is so important, that it should be a given human right. One of the ways to do this is for women to breastfeed if they can and for children to have all their vaccinations—that way, they're much less likely to need antibiotics. When used correctly, antibiotics save lives, but overuse causes more harm than good. We also need our children to play outside with other children and to have a diverse diet that is high in fiber and low in saturated fats. Everything we’re doing now is scratching the surface,” says Spector. “We are maybe 10% of the way there, because every week, we’re discovering something new. Humans want an easy answer [to improve our gut health], but you shouldn’t take anyone seriously who doesn’t say it’s complicated,” he says. “There’s a massive industry that needs a simple message to sell its products. They want to say all you’ve got to do is eat this bar, this yoghurt or this protein drink.”

The molecular toolbox of the gut microbiome is vast and incompletely mapped. In a human population, we definitely don’t know in a lot of detail how the microbiome influences these drugs. What we are yet to determine is the complex network between these drugs on chemotherapy efficacy or toxicity. They have got a very broad series of mechanisms of action so they might influence translocation, immune function, metabolism, enzymatic degradation or they might have some form of other indirect effect that we don’t yet quite understand so this is definitely an area that warrants further research. However, this is a very exciting concept as it means we now have a vast new set of targets we can utilise for cancer therapy.

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How would this understanding of the host-chemotherapeutic microbiota axis help us to formulate cancer treatment therapies in the future? We're trying to engineer the microbiome to improve cancer therapy. I've got a really great Ph.D. student looking at how bacteria might reduce the adverse side-effects of chemotherapy. The chemotherapy agents we use are toxic to all cells, not just cancer cells. We want to see if the microbiome may have a role in protecting normal cells. His research interests include how the gut microbiome causes colorectal (bowel) cancer, how we can influence it to improve our health and the use of artificial intelligence for real-time decision support in the operating theatre. Dr Kinross’ is also an active researcher with interests spanning three NIHR BRC themes- Digestive Diseases, Surgery and Cancer and Infection and AMR. He is performing clinical research at Imperial College London and at the Royal Marsden Hospital. The aim is to develop novel biomarkers for the early detection of bowel cancer, and to develop novel therapies for its treatment based on a deeper understanding of how the microbiota that reside in the gut influence tumour biology and the response of cancer to treatment. We all know from epidemiological studies what a healthy diet for the gut looks like. The microbiome is the critical mediator that determines whether our diet is going to be good or bad for us and therefore this poses the question whether we can engineer the microbiome so that we can get the very best out of the diet we’re consuming. Or could we possibly supplement with secondary metabolites that may have some benefit?

Kinross J. How surgeons will use data to inform intra-operative decision making. Intelligent Health. London, September 2020. I was keen to bring together all the work going on in microbiome science, because it creates such a compelling argument for taking it seriously. It's not just about the gut: it's about the human microbiome.

Advancing microbiome research

My general hypothesis is that we are experiencing a fundamental change in the type, number and function of micro-organisms that live within us in the developed world. That has happened over a very short timeframe and the reason for that is not just about diet and food. It's also about our rapidly changing environment, which we call the exposome, (particularly urbanized environments) and the fact that we are now taking lots of medicines, especially antibiotics. Clearly diet is a major driver too and in America and Europe, we now eat a kind of globalized, processed, white, gloopy diet which is very low in plant-based fibers and very high in animal fats and refined sugars. Imperial is partnering with biotechnology company EnteroBiotix on research into the potential of therapies based on the gut bacterial community. The last decade has seen an upsurge of interest in the gut microbiome – the community of trillions of bacteria, fungi, and other microorganisms that live in the digestive tract – and its importance for human health. “Instead of viewing bugs as bad, we’re embracing them as being part of a symbiosis – a fundamental part of making us healthy and happy,” says Dr James McIlroy, EnteroBiotix founder and CEO. Dr Ben Mullish and Professor Julian Marchesi (left and centre) show Dr James McIlroy of EnteroBiotix around the lab at St Mary's Hospital. Dr Kinross advises eating around 30g of fibre a day. “Fibre is broken down by bugs in your gut. We don’t metabolise fibre, the bugs do that on our behalf. This helps grow those molecular goodies, that promote health. Fibre also absorbs toxins in the gut.” Eat more fibre Most of us eat only half the recommended 30g a day. But start slowly – our guts don’t like rapid change