Dark Matter: The New Science of the Microbiome

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Dr Ben Mullish, a clinical scientist at Imperial College London, was running a trial of FMT in patients with C diff infections. Ray was so unwell that Dr Mullish offered him the treatment. Heather understood that there are good and bad bugs and advised her husband to go ahead with it, but Ray was not having it. The idea of taking another human’s faeces was just too much for him, and he refused. Three days later, however, he had deteriorated so much that there was no other choice. Ray consented to the trial. An Imperial surgeon specialising in the gut microbiome has published a new book to explain why it is important for our health. Dr James Kinross is a consultant surgeon at Imperial College Healthcare NHS Trust and senior lecturer in colorectal surgery in the Department of Surgery & Cancer at Imperial College London. 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. It then followed that for elective surgery at least, we could pre-emptively engineer the microbiome to improve surgical outcomes. We initially looked to see if galacto-oligosaccharides could in some way optimise the growth of mucosal commensal bacteria and prevent the metabolic and inflammatory complications of intestinal ischemia, but that turned out to be more difficult than anticipated. In times of critical illness, giving these sorts of complex sugars can have unexpected outcomes and sometimes it can make matters worse. But that was my original PhD, my work has now evolved into a number of different avenues including disease prevention, improving perioperative outcomes, engineering the microbiome to improve outcomes for chronic diseases and lastly biomarker discovery.

Kinross J. How surgeons will use data to inform intra-operative decision making. Intelligent Health. London, September 2020. 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. Though there’s still much about our microbiome we don’t understand, Dr Kinross highlights how learning about our microbiome has the potential to prevent illness, to shape how we think, how we feel and even who we choose as a partner. This is a really nuanced and difficult thing to talk about, because of course, sometimes we have to take medicines,” says Dr Kinross. “I don’t want people to think that if your GP recommends antibiotics you shouldn’t take them.”Holmes E, Kinross J, Gibson GR, Burcelin R, Jia W, Pettersson S, Nicholson JK: Therapeutic modulation of microbiota-host metabolic interactions. Science translational medicine 2012, 4(137):137rv136. 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. If you want to learn more about what’s going on in your gut, the first step is to turn your poo blue. How long it takes for a muffin dyed with blue food colouring to pass through your system is a measure of your gut health: the median is 28.7 hours; longer transit times suggest your gut isn’t as healthy as it could be. We are only now beginning to understand the importance of the gut microbiome: could this be the start of a golden age for gut-health science? The company produces capsules that contain diverse ecosystems of microbiota obtained from healthy and rigorously screened donors, which provide a compositionally consistent, safer and non-invasive alternative to current methods for transferring microbiota from donors to patients. If you look through literature, there are a couple of recurring candidates for causation with Fusobacterium nucleatum being at the top of the list. These bugs seem to be strongly associated with cancer and have some sort of mechanism that explains why they may or may not initiate cancer. The problem with these bugs is that they are invariably found in the general population and probably around 20 – 25% of patients demonstrate high abundance of Fusobacterium nucleatum. The association is therefore not that clear, and it is not yet established if they are ‘driver’ bugs. We hypothesise therefore that the driver species are probably replaced by the evolving mucosal and luminal ecology of the gut, and by the time the cancer has formed (this is the point at which most studies study cancer) they are replaced with ‘passenger’ organisms. Increasingly, the data is showing that it’s likely that it is the genotype of the cancer that determines the passenger mucosal microbiome signature that we see.

Can you tell us about your career path, and how you got to your current position as Senior Lecturer in Colorectal Surgery and Consultant Surgeon? We're trying to engineer the microbiome to improve cancer therapy. I've got a really great PhD 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. Minimally invasive Component Separation Technique (CST) repair for complex abdominal hernia with meshThis study – the Microbiota Transplant Prior to Allogeneic Stem Cell Transplantation (MAST) study – is being run by a multidisciplinary team that includes haematologists ( Dr Jiri Pavlu and Dr Andrew Innes), microbiology and infectious disease experts ( Dr Frances Davies and Dr Rohma Ghani), along with digestive diseases and microbiome experts (Dr Benjamin Mullish and Professor Julian Marchesi). Evidence also suggests that our gut microbiota affects the efficacy of anticancer therapy. Can you elaborate on this? Polyphenols are a naturally occurring antioxidant that helps produce good bacteria in the stomach. It also helps reduce inflammation in the gut. This magic chemical can be found in blueberries and vegetables such as aubergine, tomatoes, white potatoes and peppers. “It occurs in a lot of nightshade vegetables, so we have a lot of that,” he says. 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. Dr Kinross is a Reader in Colorectal Surgery and a Consultant Surgeon at Imperial College London. His clinical interest is in robotic surgery and minimally invasive surgery for colorectal cancer. He performs translational research in the fields of early colorectal cancer detection and prevention and in surgical technology transfer.

His book, "Dark Matter," looks at the role of micro-organisms—harmful and helpful—in our bodies and the impact on our health of their imbalance in our system and in the world around us.

I first understood what the microbiome was when I started my PhD 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. What role does diet play in the gut microbiome?

The scale of the task is huge: there is 1.5kg of bacteria in our guts.’ Illustration: Lisa Sheehan/The Observer I first understood what the microbiome was when I started my PhD 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. One condition for which IMT has proven safe and effective is recurrent C. difficile infection (rCDI), a bacterial infection of the gastrointestinal tract that can sometimes lead to multi-organ failure and death. Even though antibiotics are an effective therapy for CDI, there is a risk of the antibiotics not working, or of patients having further recurrence of the condition once the antibiotics are finished, according to Dr Benjamin Mullish, a clinician and lecturer in Imperial’s Department of Metabolism, Digestion and Reproduction. If you want to get rid of C. difficile infection, a more effective strategy is to restore the composition and function of your gut microbiome to how it was before you became ill. Dr Benjamin Mullish Department of Metabolism, Digestion and Reproduction The final frontier for gut microbiome exploration is its relationship with our brains, something the new fields of nutritional psychiatry and psychobiotics are digging into. We already know the gut has its own nervous system, the enteric nervous system, and contains 100m neurons. We also know the gut-brain axis, via the vagus nerve, shoots neurotransmitters produced within the gut around the body and to the brain, which is why Cryan’s lab has studied the impact of particular bacteria on sleep and how certain types of fibre can improve complex cognitive processes. 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.In this ground-breaking book, surgeon and expert on the microbiome, James Kinross, takes us on a guided tour of our extraordinary inner universe, showing how our relationship with microbes may hold the key to why we are increasingly succumbing to diseases and conditions such as cancer, Alzheimer's, autoimmune conditions and allergies. He highlights how hyperglobalization and our addiction to antibiotics has transformed our internal ecosystems and why this matters so much to our future health and happiness. The early data already generated so far by Imperial is very exciting,” he adds. “It is helping to build a strong case for microbiome enhancement. The Imperial team is a discovery engine and EnteroBiotix can help translate that into a commercial product that benefits patients around the world.” 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. Kinross specialises in the detection of colon cancer and benign conditions of the gut. In his 18-year career, he has researched gut microbiome extensively and is the author of Dark Matter: The New Science of the Microbiome. He has learned that “lifestyle is overwhelmingly important for the gut”.