The gut is not just a food-processing tube
If skin is more than wrapping, the gut is more than plumbing.
The human gastrointestinal tract contains an enormous immune system.
That makes sense when you consider its job.
The intestinal surface has to tolerate food and enormous communities of harmless or beneficial microorganisms while remaining capable of responding to genuine pathogens.
It is an extraordinary border-control operation.
Every meal introduces foreign proteins.
Most are tolerated.
That tolerance is actively maintained through networks of immune cells, signalling molecules and interactions with the intestinal environment.
Among the cells involved are regulatory T cells, often shortened to Tregs.
You can think of regulatory T cells as part of the immune system's braking and diplomatic machinery.
Where some immune responses shout:
Attack.
regulatory mechanisms can help say:
Stand down. This is harmless.
Developing and maintaining that balance appears to be fundamental to food tolerance.
And the microorganisms living in the gut may help shape it.
You are an ecosystem
The human body contains vast communities of bacteria, viruses, fungi and other microorganisms.
Collectively, these communities are known as the microbiota.
Their collective genetic material and, in looser everyday usage, the ecosystem itself are often discussed under the term microbiome.
The gut microbiome helps digest components of food, produces biologically active substances and interacts constantly with the immune system.
This has led researchers to ask an obvious question:
Could differences in gut microbes influence whether food tolerance or food allergy develops?
Evidence increasingly suggests that the microbiome is involved in immune development and allergic disease.
Studies have found differences in microbial communities associated with food allergy, and experiments in animals have demonstrated that particular microbial environments can influence allergic responses.
Certain gut bacteria produce short-chain fatty acids, including butyrate, when they ferment dietary fibre. These substances can affect the intestinal barrier and immune regulation.
The possibility is fascinating:
Diet feeds microbes.
Microbes produce molecules.
Those molecules influence immune cells.
Immune cells influence tolerance.
A meal may therefore affect the immune system not only through the food proteins it contains, but through the ecological system living inside the person eating it.
But don't buy a "food allergy microbiome cure" just yet
The microbiome is one of the most exciting areas in medicine.
It is also one of the easiest areas to oversell.
Finding that people with food allergy have different gut bacteria does not tell us whether:
the microbial difference caused the allergy;
the allergy caused the microbial difference;
dietary avoidance changed the microbiome;
medication changed it;
or another factor influenced both.
This is the classic problem of correlation versus causation.
Researchers are investigating probiotics, prebiotics, bacterial metabolites and other microbiome-directed approaches.
Some may eventually become important in allergy prevention or treatment.
But we are nowhere near the point where a commercial microbiome test can reliably analyse someone's stool and prescribe a personalised collection of supplements that has been proven to cure their mustard allergy.
An exciting field of research and a clinically proven treatment are not the same thing.
What about antibiotics?
Antibiotics can profoundly alter microbial communities.
That has made antibiotic exposure another subject of allergy research.
Observational studies have reported associations between early-life antibiotic use and subsequent allergic disease, including food allergy in some datasets.
But interpreting this is difficult.
Children receiving antibiotics may differ from children who do not in numerous ways.
The infections themselves may matter.
Healthcare use may differ.
Family characteristics may differ.
And antibiotic class, timing and number of courses may all be relevant.
This is not an argument against antibiotics when they are medically necessary.
It is another reminder that the developing immune system exists within an ecological context.
Changing that context may have consequences we are still learning to understand.
The "hygiene hypothesis": useful idea, terrible slogan
Most people have encountered some version of this claim:
Children get allergies because modern homes are too clean.
This is usually attributed to the hygiene hypothesis.
The original scientific idea was much subtler.
In 1989, epidemiologist David Strachan observed that hay fever appeared less common in children from larger families and proposed that infections transmitted by older siblings might influence allergic disease.
Over subsequent decades, the hypothesis evolved considerably.
Research began examining microbial diversity, farm environments, animals, parasites, gut bacteria and immune maturation.
The modern picture is not:
Dirt is good. Cleaning is bad.
And it certainly isn't:
Stop washing your hands so your child won't develop allergies.
Good hygiene prevents infectious disease.
Handwashing, safe food handling, sanitation and vaccination have saved enormous numbers of lives.
The more interesting idea is that the modern immune system may encounter a different microbial environment from the one in which human immune regulation evolved.
That is a much more sophisticated proposition.
The "old friends" idea
One development of the hygiene hypothesis is sometimes called the old friends hypothesis.
The idea is that humans evolved alongside particular microorganisms and environmental exposures that helped train and regulate the immune system.
Modern urban living may reduce some of those long-standing interactions.
Again, this isn't a prescription for deliberate infection.
It is an attempt to understand why growing up on a traditional farm, exposure to diverse environmental microbes and certain early-life circumstances have repeatedly been associated with different rates of allergic disease.
Farm studies are particularly intriguing.
Children raised in some traditional farming environments have shown lower rates of asthma and allergic sensitisation.
But "farm exposure" bundles together many things:
animals;
microbial diversity;
unprocessed farm milk in some populations;
dust;
outdoor exposure;
family size;
diet;
and lifestyle.
Scientists then have to disentangle which components actually matter.
Nature rarely conducts clean experiments for us.
Pollution may push in the opposite direction
At the same time that some beneficial microbial exposures may have declined, other environmental exposures have increased.
Air pollution is one candidate.
Particulate matter, traffic-related pollutants and other environmental contaminants can affect respiratory and epithelial barriers and influence inflammation.
Climate change can also alter pollen seasons — changing when plants release pollen, how long seasons last and potentially the quantity or allergenicity of pollen people encounter.
For mustard allergy, that becomes especially interesting because of the pollen cross-reactivity discussed earlier.
Mugwort pollen doesn't simply exist in an immunology textbook.
It grows in a changing environment.
Allergic disease sits at the intersection of human biology and the world humans have built around themselves.
The barrier hypothesis goes beyond skin
A broader modern idea sometimes described as the epithelial barrier hypothesis proposes that damage to the body's barrier surfaces may contribute to the rise in allergic and inflammatory diseases.
The relevant barriers include skin, respiratory epithelium and the gastrointestinal tract.
Pollutants, detergents, chemicals, diet, microbes and other environmental factors are being investigated for their potential effects on these barriers.
If barrier integrity is compromised, substances from the environment can interact differently with the immune system.
The idea is appealing because it can potentially connect eczema, asthma, rhinitis and food allergy within a broader biological framework.
But, again, a framework is not the same as a fully proven single explanation.
The rise of allergic disease probably does not have one villain.
The atopic march: allergy can change its costume as a child grows
Doctors have long observed a pattern known as the atopic march.
A child may develop eczema early in life.
Food allergy can appear.
Later, allergic rhinitis and asthma may emerge.
The word "march" makes this sound like an inevitable procession.
It isn't.
Not every child with eczema develops food allergy.
Not every child with food allergy develops asthma.
Some children develop the conditions in a different order.
Some develop only one.
Modern researchers increasingly view the atopic march as a collection of related trajectories rather than one fixed sequence.
Nevertheless, severe early eczema is an important marker of increased food-allergy risk.
And this returns us to the skin barrier.
Sometimes what looks like the first allergic disease may also be part of the environment in which the next one develops.