James Kinross Sun 11 Jun 2023 09.00 EDT
As a nation, we British are obsessed with our gut function, largely because it has never been unhealthier. I spend large parts of my working day talking to patients about their bowel habits, and many of them want to talk about little else. There is also a deeper, more fundamental fascination with the digestive system; the colon is a national source of comedy that has kept us going through every crisis since the beginning of time.
“Shit” is a crucial and ubiquitous word that serves as a noun, a verb and an adjective, propping up the entire English language. This wondrous word is both a profanity and a term used to denote an item of high quality, and it is liberally sprinkled into the daily chatter of our lives.
The sense of revulsion we feel when we’re faced with human excrement (or even just the thought of it) is, in part, a response to the way it looks and smells. But that revulsion is also a psychological reflex, ingrained by potty training and social stigma. This aversion is an important safety mechanism: handwashing and sewer systems prevent the spread of diseases that have killed millions.
But what if I told you that faeces was not toxic waste and that it contained the secret to human health? Would you eat it, if your life depended on it? What if it was rebranded as a faecal microbiota transplant (FMT) or, more accurately, a faecal milkshake given through a tube that passes through the nose into the stomach? You could even take it in the form of a capsule – or “crapsule” – if you wanted.
To help persuade you that this might not be such a terrible idea, I’ll tell you the tale of a patient. Raymond had driven the No 7 bus between Oxford Circus and East Acton from the age of 20 until taking early retirement in his mid-40s after learning he had genetic heart problems. He gave up his job on his doctor’s orders. Like you and me, and everyone else on the planet, Ray was a host to several trillion microbes that lived in and on his body. From our first breath to our last, and even beyond, microbes are our ever-present companions. While they take up residence in any number of places in our bodies, they’re especially keen on – and abundant in – the various cavities and niches found in our gut.
The “gut microbiome” is the name we have used to describe not only the wildly diverse collection of microbes that live there, but also what happens when they interact with each other and with our bodies. In other words, it’s an ecosystem made up of trillions of microbial life forms going about their business inside us, as we go about ours.
In the last two decades, scientists have started to leverage the new science of the microbiome to transform how we conceive of human health. Throughout his life Ray’s gut microbiome had changed with him. But as time passed, his genes and his gut microbiome began to do battle, causing multiple chronic diseases. Eventually, Ray developed a type of leukaemia that left him profoundly frail.
‘The scale of the task is huge: there is 1.5kg of bacteria in our guts.’ Illustration: Lisa Sheehan/The Observer
Ray and his wife, Heather, navigated his various health issues together until the day pneumonia struck. He was admitted to St Mary’s Hospital in Paddington, London, where he was treated with intravenous antibiotics. Without the drugs he would have died. He was discharged within the week. However, it was at this point that a terrible antibiotic firestorm started in his gut. Imagine the worst-possible diarrhoea, incapacitating nausea, plus severe cramping pain in your abdomen, depriving you of sleep. Now imagine that you are frail. Your heart is working at 40% of its normal function and your lungs are full of fluid. You can’t breathe. Arthritis means you can’t get to the loo in time. You are cold, clammy and profoundly dehydrated, but can’t drink enough to satisfy your thirst. You are soiled, but too close to death to care.
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.
C diff debilitates its host organism – the human being – by generating toxins that destroy the lining of the gut. The particular strain of C diff in Raymond’s gut had engaged in an aggressive campaign of molecular warfare. His personal gut-microbe collection was gone. His intestine was failing and he was dying. He was treated with yet more antibiotics. This seems counterintuitive, but it is in accordance with best practice. But C diff has a trick up its sleeve, which is to produce antibiotic-resistant spores that wait to germinate, biding their time. Raymond was given an antibiotic drug called vancomycin. Many patients will respond to vancomycin, but about a quarter will relapse. And in those who do, 45% will have a second relapse. These are the patients who typically benefit from FMT, or the “good shit”.
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.
The logistics of preparing an FMT should not be underestimated. Faecal donors have to be found – harder than you might think. Most of us are squeamish about pooing in pots, and we struggle to do it on demand. Some studies use friends and families, others use members of staff, volunteers or “pooled” samples taken from lots of donors mixed together.
The complexity and demand for faecal transplants have spawned an entire industry, and FMT can now be purchased frozen from biobanks. As with an organ donation, donors have to be carefully screened to make sure they don’t harbour transmittable diseases or parasites. Potential stool donors undergo a rigorous screening questionnaire, medical interview and examination, followed by blood- and stool-testing.
It may be like turning a computer on and off again – it’s a complete reset of the gut’s immunology software
Then there are the practicalities. Fresh samples must ideally be acquired within a short time from delivery, diluted with sterile saline, stirred, strained and then poured into a sterile bottle. Dr Mullish’s job can at times be less than glamorous. Once the faecal cocktail was mixed (shaken, not stirred), the transplant was administered to Ray during a colonoscopy. This procedure involves a flexible telescope that is passed into the colon through the bottom, and the bowel is gently coated in the soothing balm of microbes, which are passed through the colonoscope using a syringe.
While an FMT might be a new idea to many of us today, the medical practice of faecal transplant is ancient, and it has been drunk as “yellow soup” since the 4th century AD for the treatment of infective diarrhoea. In 1958 an innovative surgeon, Dr Ben Eiseman, administered faecal enemas to his patients in Denver, Colorado, with severe and recurrent C diff infections. It was remarkably effective, but like all important medical discoveries, this intervention was largely ignored at the time of its first report.
More than half a century later, the Dutch gastro- enterologist Josbert Keller and his team at the Amsterdam Medical Centre randomised patients with recurrent C diff into three groups. The first group received vancomycin, a wash-out of the colon using a strong laxative, and a faecal transplant. The second had vancomycin and the colonic wash-out, and the third just received vancomycin. The FMT group did so much better than the other two groups that the study had to be stopped early, as it was deemed unethical to continue.
The race to discover how FMT works is now on. We do know it restores the metabolism of bile (a digestive fluid made in the liver and stored in the gall bladder), which is co-metabolised by bacteria, and this in turn blocks the germination of C diff and controls the infectious disease. It is also probable that a process of “bioremediation” occurs, in which the donor micro organisms consume and break down toxins that exist in the recipient’s gut. However, there are trillions of organisms producing an infinite number of bioactive molecules, and each disease has a discrete microbiome. Therefore, it may really be a bit like turning a computer on and off again; it’s a complete reset of the gut’s immunology software.
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.
Regardless, FMT is now being investigated with varying degrees of success in hundreds of trials across the globe. These include trials for inflammatory bowel disease, irritable bowel syndrome, obesity, acute malnutrition, diabetes, arthritis, hepatic encephalopathy (decline in brain function with severe liver disease), liver transplants, skin cancer, autoimmune diseases, Alzheimer’s, neurodevelopmental conditions, bipolar disorder, hair loss, depression, neurodegenerative diseases and recurrent urinary tract infections, to name but a few.
Some of these studies are extremely encouraging and offer treatments where few effective medical therapies exist. For example, FMT appears to be a promising treatment for irritable bowel syndrome and a recent study suggests that its benefit can last for many years: 125 patients were randomly assigned to receive either 30g or 60g of faeces from the same donor or a placebo transplant containing their own faeces. Researchers not only found that the FMT improved the symptoms, but there was a lasting benefit three years after it was given.
Unlike C diff, where there is a dramatic and acute clinical change caused by a defined pathogen, the impact of FMT is less clear in chronic disease states, where it hasn’t yet been proven that bacteria are the cause, or where we haven’t defined exactly how the disease develops. As a result, at the time of writing in the UK and the US, recurrent C diff is the only clinical condition for which regulatory bodies have approved the use of FMT. The bottom line (pun firmly intended) is that we don’t understand how FMT works or its long-term risks well enough to start using it more widely in clinical practice. Nevertheless, because word of its incredible potential is spreading, there’s a worrying growth in online enthusiasts offering back-street FMT “cures”. I hope it goes without saying: please don’t try this at home.
Ray’s response to his FMT treatment was just like that in the reported literature. Within three days of receiving the microbiota transplant he was out of bed. Heather described it as a miracle. If I’ve spent longer than is entirely comfortable talking about faeces, that’s because FMT is a starting point for understanding the importance of the gut microbiome to human health. The extraordinary benefit of FMT in some patients has opened the clinical world to the idea that our microbes may have an important role in the causation and treatment of diseases where their involvement runs contrary to medical science.
The scale of the task is immense. The bacteria in the gut alone weigh close to 1.5 kg, they’re made up of about 100,000,000,000,000 bacterial cells (that’s 100 trillion) – equivalent in number to the total number of cells that make up the human body – and they speak millions of different molecular languages. Another major challenge in studying the microbiome is its physical distribution. The micro- biome is dispersed across our bodies in different niches, each with varying total abundances of microbes. Being clear about our anatomical definitions is important.
We are only just beginning to map all of the microbial life in the vast ecosystem inside our bodies – and to understand how it connects us to the world around us. In this backward world, shit has become a therapy, used to replenish our delicate internal ecosystems, which are being lost as quickly as they are being discovered. Even with the impressive advances in biology, metagenomics and bio-informatics (computational biology), we might not be able to count and name all of the beneficial microorganisms that live inside us before they die out, mutate or evolve into something very different.
We are deciphering the molecular language of the human microbiome, one of the great challenges of modern medicine, and faecal transplantation is a critical and fascinating tool that is being used to unlock these secrets.
The human microbiome represents the most important new therapeutic target that we have for treating the greatest threats to human life in the 21st century and for preventing future pandemics of pathogens. This was not only important for Ray – it is critical for all of us: without a stable and diverse microbiome, we may well lose our minds. Behind all this is a simple message: microbes are not the enemy.
Leave a Reply