Tuesday 21 January 2020

15 minutes read time

The Gut


Your body is having a climate crisis of its own. Decades of external change have wreaked havoc on our internal ecosystems

By James Kinross

I want you to act as you would in a crisis. I want you to act as if our house is on fire. Because it is.

Greta Thunberg, 2019

Global warming and climate change is not only external. It is internal – happening in you and me – now. The same fires sweeping across Australia have figuratively rampaged through our diverse ecosystems for 150 years. The consequences for our health are significant.

Advances in medicine over this same time have been immense. We can treat and in some cases completely eradicate pathogens that previously killed millions. Parallel improvements in social care, a global diet and living standards have caused infant mortality to fall and our lives to last longer. But a longer life does not necessarily mean a healthier one, and a new epidemic of chronic diseases has slowly crept up on us.

This is best illustrated in our elderly populations, who carry the burden of cardiovascular disease, cancers, neurological decline and immobility. But consider this: 70 per cent of millennials will be overweight or obese by the age 35 to 45. Almost 10 per cent of the entire NHS budget (£3 billion) is now spent on treating diabetes. Then there are the rising rates of allergy, asthma, inflammatory bowel disease and mental health disorders. A millennial has a risk of bowel cancer four times that of someone born in the Sixties, and it is not the only cancer type we are seeing rising in incidence in this age group. The gut is at the epicentre of it all.

It’s hot outside. And inside too

Pollution doesn’t just influence oceanic ecosystems, it influences yours. The industrial processes that produce the carbon dioxide and which drive up the planet’s temperatures also manufacture the products, foods and drugs that we consume. Cities are fundamentally changing the nature of human interaction and of bacterial transfer between relatives, and they are changing the way rural communities live. The aeroplanes that churn out fossil fuels into the upper reaches of our atmosphere also transfer pathogens in their human passengers all over the world and, in turn, are fundamentally redrawing the infectious diseases map.

As a direct result of the monumental shifts in the fabric of our society over a very short period, the human microbiome has changed faster than at any other rate in history. Possibly irreparably. The change is so rapid, there are now global projects attempting to biobank the human microbiome so we can have some idea of what the hell was supposed to be there after we have completely destroyed it. But some environmental pollutants have been more damaging to the human microbiome than others.

Change is in the air and on the runway

The importance of antibiotics to the medical revolution cannot be underestimated. They are a cornerstone of modern medicine and we literally live longer because of them. In the United States, the rate of mortality due to infectious diseases was about 580 deaths per 100,000 of population; one third of all deaths in the year 1900 were due to infectious diseases, and the top three causes were all infections. In 1998, only pneumonia and influenza made the top 10, and mortality due to infectious disease had fallen spectacularly to 34 deaths per 100,000 population.

This is good for mankind. But it presents two big problems.

The first is antibiotic resistance. In the United States, the Centre for Disease Control and Prevention (CDC) reported that, each year, emergency departments hand out almost almost seven million antibiotic prescriptions to children. In the developing world, the World Health Organisation (WHO) reports, in a recent prospective study of eight countries, that children under two received an average antibiotic use of 4.9 courses per year. And let’s not forget its use in farming where antibiotics were used widely prophylactically and as growth promoters in some parts of the world. It is predicted that, as it stands, meat demand will almost double by 2050, which will not only have further consequences for gut health but exacerbate our dependence on antibiotics.

A course of antibiotics helps fight tuberculosis in India

And then there is industry. In Patancheru, near Hyderabad in India, one particular facility treated wastewater from 90 drug manufacturers every day and tipped the waste into the local stream. As a result, the concentration in the treated wastewater of an antibiotic called Ciprofloxacin would have been strong enough to treat 44,000 people. Antibiotics are in your food and your water. They are everywhere.

As a result of this orgy of prescribing and misuse, more than two million infections are now caused by antibiotic-resistant organisms in the US each year, resulting in 50,000 deaths. According to the UK government, it is now official: we are in the post-antibiotic era.

The second problem is that, after 70 years of blissful prescribing, we are beginning to understand that this has caused dramatic global perturbations in the human microbiome and unexpected deleterious consequences for our health. The most critical time point for antibiotics influence on chronic disease risk may be in early life.

The human microbiome remains relatively stable but evolves slowly in each of us during our lifetimes along a unique trajectory.  It is assembled at birth and it undergoes continuous refinement until about the age of three, although this varies a little between individuals. After this age it essentially has all of the same core functions as an adult microbiome. Therefore, it is logical that disruption of this critical process of microbiome construction may have dramatic implications for the development of the immune system and solid organs (in particular, the brain), gut function and chronic disease risk.

In short, if we want to engineer the microbiome to prevent chronic disease we have to do so in those very first years of life.

The gut microbiome is thought to undergo development in four overlapping phases. The first is dispersal, where the gut is seeded. Then comes a period of selection, where bacteria must compete and live or die in the baby’s gut as they adjust to the immune environment. The gut ecosystem then enters a phase known as “drift”, during which the gut is exposed to random ecological events that influence diversity (which varies between us all). Finally, a period of diversification occurs, and that is influenced by many environmental factors. There is a saying in pregnancy that mums are eating for two. This is not true. They are  eating for trillions.

Breast milk is both a source of bugs that disperse into the gut, but in many infants it is also the primary nutrient source for both baby and bacteria. Breast milk commonly harbours Bifidobacterium, Lactobacillus, Staphylococcus and Streptococcus species. It also contains energy in the form of fat; short-chain fatty acids; vitamins and oligosaccharides. But evolution is clever, and breast milk also contains antimicrobial elements that modify the gut microbiome and filter out harmful bugs in the developing baby’s gut.

Engineering the gut microbiome requires an early start

Similarities in gut bacteria between babies and mothers tend to increase over the first years of life, but then decrease. As babies become autonomous, they play and put everything they can in their mouths. But they also come into contact with their father, their siblings, their pets and other children. Nursery is essentially a very expensive petri dish. So it’s not just antibiotics that are important, it’s also how we choose to parent.

My daughter was diagnosed with pneumonia aged five months. When she was in the high dependency unit she received antibiotics. They saved her life. If your child gets a bacterial pathogen that makes him or her unwell, give them antibiotics. Don’t feel guilty. Yes, antibiotics if given at the right (or wrong) moment early in life will disrupt a child’s microbiome assembly. But they are literally everywhere and, even if you choose not to use them in a clinical context, your children have already been exposed. In most children, any medical use will have a transient impact on the gut microbiome and they will recover without any lasting impact. The problem comes when we use them inappropriately at a population level, and when we use them because it’s easier to prescribe them than not.

You may not agree with her, but Greta Thunberg is an astonishing young person. She suffers from Asperger’s, which means she is on the autism spectrum. She refers to this as her superpower and there is a small chance that her amazing abilities could yet save the planet. But she may be more personally affected by global warming than is commonly understood. This is because there is a theory that the human microbiome climate crisis perturbs neurological development in early life.

Greta Thunburg with her mother Malena Ernman, an opera singer

By the age of two the brain is 75 per cent of its adult size. By the age of ten a child’s brain represents five to ten per cent of body mass; it consumes twice the glucose and one-and-a-half times the oxygen per gram of tissue compared with an adult’s brain; and it accounts for up to 50 per cent of the total basal metabolic rate of the body. That is a lot of energy.

The brain and the gut develop together. First, the gut produces much of the energy required for this massive and rapid brain growth. You can’t sustain a growing brain with the wrong bugs. But gut microbiota may also disrupt various aspects of brain metabolism, or interfere with the formation and function of specific neural circuits indirectly. This is because the gut signals to the developing brain through a two-way language of small molecules that reach it via the vagus nerve. This nerve runs directly from the gut to the brain, or via the blood, and has led to significant speculation about the role played by the gut in the development of neuropsychiatric disorders and autism. It is highly contentious.

Autism Spectrum Disorder (ASD) refers to a range of conditions characterised by some degree of impaired social behaviour, communication and language, and a narrow range of interests and activities that are both unique to the individual and carried out repetitively.

There is a huge amount of work across multiple scientific fields attempting to define why children develop autism, and the gut is just one hypothesis. But there are points worth noting. Many children will first develop symptoms by the age of three, just as the gut microbiome reaches its final stages of assembly. Moreover, many children with ASD develop gastrointestinal symptoms. Bear in mind that children in the developed world and those from high-socioeconomic-status families are more likely to be affected (they have less exposure to environmental bacteria that educate the immune system). Studies that have looked at the gut microbiome of children with autism have found the faecal microbiome to be different to that of children without ASD. The implication is that disruption of the gut microbiome as it assembles in early life may adversely influence brain development. But, remember, these are only association studies, typically performed in small numbers of children. So this remains a theory.

However, it is not just the developing brain that could be influenced by the gut microbiome. Parkinson’s and Alzheimer’s are also linked to abnormal microbiome functions and their ability to produce proteins which we now know can reach the brain. For example, Alzheimer’s is caused by the deposition of a protein called amyloid. It has recently been observed that bacteria produce this in the gut and this can, in turn, travel to the brain via the vagus nerve. If nothing else, it is intuitive that an increasingly long life of gut microbiome-immune interactions drives the development of chronic neurological decline as it also influences the risk of cardiovascular disease or cancer. However, defining the microbiome’s role in this is challenging because you need really well designed, very large and expensive studies that track populations over a lifetime.

The most important lesson here is that the real gift of the gut microbiome is not in disease treatment but in disease prevention.

In 2009, Martin Blaser and Stanley Falkow published their “disappearing microbiota” hypothesis. They made a compelling argument that the equilibrium of the human microbiome (not just the gut) should be “a major pillar of our biological stability and health”.

They observed that the environmental impact on the human microbiome is unprecedented and correlates with the epidemic of new, modern diseases. Their essential argument was that we are no longer able to share bacteria directly through our social interaction. The hygiene (or “oral-gut”) hypothesis states that we stopped playing in the dirt. Without this, and the bacteria that came with it, our children’s immune systems could not develop. Therefore, asthma and allergy became more prominent. Geoff Gordon’s work on obesity showed that the diversity of our gut has declined and evolved to become adept at harvesting energy from a narrow westernised diet, and this in turn drives the obesity epidemic.

It’s time to get our hands dirty once again

The potential consequence of this environmental catastrophe of the gut is not that we will be left living like germ-free mice, locked in sterile environments unable to interact in the world for fear of pathogens. Bacteria will be here long after homo sapiens is a historical footnote. Some will disappear and the critical biological functions they managed on our behalf will be left unregulated or they will be at the mercy of parasites and amensalistic bacteria. The survivors will share their genes, mutate and evolve at an increasing rate as they attempt to escape global persecution. They will move from a mutualistic microbiome towards something that is hostile; the epidemic of chronic disease will intensify and we won’t have the antibiotics to deal with them.

The solution is not just look back and try to recreate a Neanderthal’s microbiome; it would be unable to sustain itself in a 21st-century environment. The solution may look something more like the theory of “herd immunity”, which states that a vaccine will only work if enough of the population actually takes it up. It is why not vaccinating your kids is so dangerous. You don’t just put your children at risk, you put every child at risk. (In other words: vaccinate your kids.) As a species, we need “gut ecological immunity”. This requires a health strategy based on a “systems” understanding of our health that integrates the microbiome.

Like climate change, it is hard – but not impossible – for all of us to make a big enough positive difference to our systems biology over a lifetime if the microbiome is not programmed correctly at the outset. Because we do not have ecological immunity, millennials can follow conventional medical doctrine and still be obese or get cancer. Many children are simply set on a metabolic trajectory which they have no control over; it could be malnutrition or obesity depending on whether they are born in, say, Sub-Saharan Africa or London. In adulthood, those same children remain trapped in a rut of health policy failure from which there is no escape.

We need to be able to engineer the microbiome so that its assembly, stability and functions act as a form of chronic health vaccination. We need legislation and a society that supports it. We have to do something; our guts are so unhealthy that some people’s only option is to have a faecal transplant. This has to be wrong.

All photographs Getty Images

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