Tuesday 21 January 2020

14 minutes read time

The Gut

Good shit

The new frontier of medical science is closer than you think – much closer. It lies within us, in the bacteria and viruses of the gut, and in the mysterious efficacy of faecal transplants

By James Kinross

Modern medicine has gone to shit. Yes, hospital waiting times are too long, healthcare is too expensive and there are not enough nurses. But medical science has turned to waste in a more literal sense. Because actual human waste may hold the key to the world’s most pressing health challenges.

Revulsion from human excrement is in part our response to the way it looks and smells. The persistent brown stain is caused by stercobilinogen (a byproduct of the gut bacterial metabolism of haemoglobin) and the stink is caused by intestinal fermentation (no explanation needed). It is also a psychological reflex, ingrained by potty training and social stigma. This aversion is an important safety mechanism; hand-washing and sewer systems prevent the spread of diseases that have killed millions. This is bad shit.

But what if faeces is not just a toxic waste product to be flushed away into a porcelain chamber? What if it is a medicine? Would you eat a shit sandwich if your life depended on it?

There is precedent for this behaviour from the animal kingdom where coprophagia – eating shit – is widely practised because it confers a survival benefit. Some species of the mighty tortoise get their essential minerals necessary for shell development by eating droppings. Maternal panda bears feed their offspring faeces to pass them bacteria that help them metabolise cellulose, the molecule that provides the nutritional value from bamboo. Hippos, elephants, dogs, koalas and insects do it, so this scatological horror has some benefit. But there is also a rapidly growing body of science that is providing us with new insight into how the gut works and this suggests that the molecular contents of faeces are really important for human health too. This is good shit.

So how would you feel if that sandwich was rebranded as a faecal microbiota transplant (FMT), made up of a newly discovered organ called the “gut microbiome”?

Poo bear: Young pandas eat faeces to help them process bamboo

In 2009, just 694 papers were published that year on the microbiome and searchable on pubmed.gov. In 2019, there were 14,575, which is a 2,100 per cent rise in a decade. Many of these papers were association studies, some of which I published. By comparison, Facebook had 158 million users in 2009, it now has 2.4 billion. Even that is only a 1,600 per cent rise.

So what is the subject of this surge in interest? The gut microbiome is all the genetic code of all the bacteria, yeasts, viruses and even parasites that live within your bowel. All these living organisms are connected to each other and they work in concert like a giant metabolic engine. So your shit is not just waste but a soup of interacting bug genomes – i.e. genetic codes – that constantly communicate with you and all of your organs. In other words, it is really important for your health, and maybe even someone else’s. It is also potentially the key to unlocking the next revolution in modern medicine.

One way the power of the gut microbiome can be harnessed is through an FMT – if not a shit sandwich, then essentially a shit milkshake – and if you believe the hype, FMT is a wonder treatment that can treat cancer, diabetes, eczema, and even make you look younger. So is the gut microbiome the most important scientific re-discovery in modern medicine? Or is this all just – ahem – bullshit? The answer is complicated and best illustrated with a story.

Raymond had driven the Number 7 bus between Oxford Circus to East Acton until he retired in his mid-40s. He had heart problems which he was told were genetic. His brother had died suddenly of a heart attack and Ray was told he needed a heart bypass.

Throughout his life, Ray’s gut microbiome had changed with him. As a child it helped his brain develop, it educated his immune system, and it sustained and nourished him into adulthood. After he retired, he learned to tinker with computers and, as he did so and time passed, his genes and his gut microbiome began to do battle, causing multiple chronic diseases. His doctor prescribed an ever-longer list of medicines. Eventually he developed a type of leukaemia that left him profoundly frail. Ray had to rely on his wife, Heather, a nurse at Great Ormond Street, for care.

Then pneumonia struck. Ray became seriously unwell, had difficulty breathing and was admitted to hospital. He was admitted to St Mary’s Hospital in Paddington (now part of Imperial College London). This place is important in this story because it is here that penicillin was first discovered by Sir Alexander Fleming in 1928. Fleming’s work, developed by Ernst Chain, Howard Florey and the often-forgotten Margaret Jennings saved hundreds of millions of lives. And, without that work, Raymond would have died there and then, in the chaos and noise of an acute admission ward at St. Mary’s, surrounded by monitors, alarms and bright lights, with his arms full of drips.

Thanks to Fleming, Ray lived; but with great antibiotic power comes great antibiotic resistance. It is worth pausing here to note that the current global antibiotic multi-drug resistance crisis was entirely predicted. In Fleming’s Nobel oration he stated:

The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under dose himself, exposing his microbes to non-lethal quantities of the drug making them resistant”.

But Fleming did not predict what would happen to Ray and nor did he predict the global impact of the industrialisation of his discovery. After a week of intravenous antibiotics Ray was discharged, and then a terrible antibiotic firestorm started in his gut.

Imagine the worst diarrhoea: opening your bowels more than ten times a day, incapacitating nausea, severe cramping pain in your abdomen depriving you of sleep. Now imagine you are frail and your heart is working at 40 per cent 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 and filthy, but too close to death to care.

Three days after he had returned home, Ray’s son called an ambulance. Ray was readmitted to St Mary’s critically unwell and was soon diagnosed with Clostridioides difficile infection (also known as C. diff or CDI). This disease is a “hospital acquired infection”, a complication of twentieth-century medicine and an unintended consequence of Fleming’s discovery. It is a global problem that afflicts 500,000 people in the United States each year and kills 29,000 of them. It typically afflicts the elderly or those with multiple medical problems and a vulnerable immune system. Ray was a sitting duck.

The idea that there are good and bad bugs is an oversimplification of the gut microbiome. All bacteria have the potential to cause harm under the right circumstances. Think of C. diff as a radicalised sleeper cell that waits dormant in the gut for its instructions from its antibiotic masters. In Ray’s case, the antibiotic treatment destroyed the indigenous bacterial community and, by releasing the hand brake, triggered an intestinal C diff insurgency that escalated into systemic organ failure.

Bugging out: C. diff bacteria in a stool sample

Clostridioides difficile debilitates its host organism – or, to put it more humanely, the patient – through the generation of two toxins (enterotoxin A and cytotoxin B) that cause inflammation and the destruction of the lining of the gut. Inspection of the gut with a flexible camera that is passed into the bowel reveals an apocalyptic scene; massive destruction of the colonic architecture which is left raw and bleeding. The particular strain of C. diff in Raymond’s gut had engaged in an aggressive campaign of molecular warfare. His personal gut microbe collection, carefully and uniquely developed since his birth and fuelled during lunches on the Number 7 bus, was gone. His intestine was failing. He was dying.

The doctors at St Mary’s quickly diagnosed his condition by looking for the toxins that C. diff makes in his faeces and he was treated with yet more antibiotics. This seems counter-intuitive, but it is in accordance with best practice. Bacteria don’t just roll over and die, though. C. diff has a trick up its sleeve, which is to produce antibiotic-resistant spores that wait and then germinate when the time is right to trigger another disease. Raymond was given an antibiotic drug called Vancomycin, designed to target the C diff. Many patients will respond to Vancomycin, but about one quarter will relapse. And, in those that do, 45 per cent will have a second relapse.

These are the patients that typically benefit from FMT – the shit sandwich.

Dr Ben Mullish, a clinical scientist at Imperial, was running a trial of FMT in patients with C. diff infections. Ray was so unwell, he offered him the treatment. Heather understood that “there are good and bad bugs” and advised her husband that he should try the treatment, but he was not having it. The idea of ingesting another human’s faeces was just too much for him, and he refused. Three days later, when he had deteriorated further despite the Vancomycin, there was no other choice. Ben gained Ray’s consent for the trial, and set to work on preparing the transplant.

The logistics of preparing an FMT should not be underestimated. Faecal donors have to be found and this is 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, some use members of staff, volunteers or “pooled” samples taken from lots of donors mixed together. The complexity and demand for faecal transplants has spawned an entire industry, and FMT can now be purchased frozen from biobanks and in capsules (or to be more precise “crapsules”). But, just as with any organ donation, donors have to be carefully screened to make sure that they do not harbour diseases or parasites that could be transferred to the patient. Potential stool donors therefore undergo a rigorous screening questionnaire, medical interview and examination, followed by blood and stool testing.

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 in a sterile bottle. Ben’s job is not an easy or glamorous one.

The medical practice of faecal transplant is ancient and it has been drunk as “yellow soup” since the 4th Century for the treatment of infective diarrhoea. In 1958, a highly innovative surgeon, Dr Ben Eiseman, administered faecal enemas to his patients in Denver, Colorado, who had severe recurrent C. diff infections. It was remarkably effective, but like all really important medical discoveries this intervention was largely ignored at the time of its first report.

More than half a century later, Josbert Keller’s team at the Amsterdam Medical Centre randomised patients with recurrent C. diff into three groups. The first received Vancomycin, with a wash-out of the colon using a strong laxative and a faecal transplant. The second had Vancomycin with the wash-out alone. And the third just received Vancomycin. The FMT group did so much better, the study had to be stopped early as it was deemed unethical to continue. 93 per cent of patients having FMT got better, compared to just 31 per cent with the Vancomyin alone or 23 per cent with the Vancomycin and wash-out.

Ray’s response was just like that in the reported literature. Within three days of treatment he was out of bed. Heather described it as a miracle.

So how does FMT work? No one is precisely sure. Firstly, there is a lot of disagreement in the clinical community because of the very significant variation in the way that FMT trials are performed. Second, the mechanism by which FMT works remains poorly defined.

And, third, not all donors behave in the same way and some are much more effective than others. These FMTs are known as “super donors” and their faeces seems to contain a specific combination of bacteria or bacterial functions that are particularly effective: the gut’s microbial make-up is highly variable between individuals.

Nonetheless, FMT is now being investigated with varying success in 268 trials listed on clinicaltrials.gov. These include such varied conditions as inflammatory bowel disease, irritable bowel syndrome, obesity, acute malnutrition, diabetes, arthritis, hepatic encephalopathy, liver transplant, melanoma, Sjögren’s syndrome, Alzheimer’s, autism, bipolar disorder, alopecia, amyotrophic lateral sclerosis, and recurrent urinary tract infections.

Each of these diseases is caused by different mechanisms and in some cases the causes are not known. To make matters worse, the way that the FMT has its beneficial effect will also be different in each condition. And so, unlike C. diff where there is a dramatic and acute clinical change caused by a defined pathogen, the impact of FMT is much less clear. As a result, recurrent C.diff remains the only clinical condition that regulatory bodies such as the Food and Drug Administration (FDA) in the US and the National Institute for Health and Care Excellence (NICE) in the UK have approved FMT for clinical use.

What is less talked about in FMT are the not-so-beneficial side effects. There are some rare reports of serious harm, such as reflux of faeces into the lungs, causing pneumonia. In June 2019, the FDA announced an alert after two immunocompromised adults who received an FMT developed a multi-drug resistant Escherichia coli (E. coli), leading to the death of one of the patients. But, in general, FMT is well tolerated, and most patients will only get a bit of stomach upset.

Infectious personalities: E. coli bacteria are a normal component of the gut, but some strains can cause terrible illnesses

The impact of Ray’s FMT on his future leukaemia treatment is not known. Nor is its impact on his ability to safely metabolise his long list of medicines. FMT was the choice between life and death, so survival made these risks worth taking for him. But for patients engaging in trials for more chronic health conditions, where the benefit of FMT is less clear, this risk-benefit equation remains harder to quantify.

The bottom line (pun intended) is that we simply don’t understand the long-term risks of FMT.

For many patients suffering from chronic inflammatory diseases who have been failed by traditional medicine, the gut microbiome represents the missing link. The lack of scientific detail means it can be conveniently combined with anecdotal observations and associations to meet any requirement. Quite often these patients or their carers are vulnerable and will try anything to get better. This makes the rapid growth in online enthusiasts and backstreet FMT practitioners worrying. FMT should only be given in the context of a trial.

It seems ridiculous to say this, but please don’t watch a YouTube video and do this at home, and never eat a literal shit sandwich.

The most important reason why we can’t perform FMT perfectly is because we don’t yet have a complete blueprint for the gut microbiome. In fact, FMT really just represents a starting point for understanding the importance of the gut microbiome to human health. It has been used by scientists for decades as an experimental discovery tool, but as a clinical therapy it is relatively blunt.

The microbiome is definitely not bullshit. It represents the most compelling new target for drug discovery in modern times. Our understanding of it is moving rapidly, perhaps faster than our understanding of the brain or the nervous system. Doctors have always looked into humans from both ends. These days, the bowel is more intriguing than ever, host to a world of secrets that help us understand how our brains tick and our bodies operate, that could unlock why we get sick and how to get better.

We are just beginning to make use of good shit. To make this shit really work, though, we have to understand the molecular complexity of the gut. Let’s go down there.

Raymond has still not had a recurrence of his C. diff.


Author: James Kinross

Editors: James Harding, Keith Blackmore, Peter Hoskin

Illustrations and design: Jay Prynne

Graphics: Michael Kowalski and Chris Newell

Cartoons: David Haldane

Additional research: Imogen Harper

Picture editor: Joe Mee

Special thanks: Professor Julian Marchesi, Julie McDonald, Ben Mullish

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