Microbe tenants help your immune system

Obesity isn’t the only condition linked to imbalanced gut microflora. A host of autoimmune and inflammatory conditions – inflammatory bowel disease, coeliac disease, multiple sclerosis, rheumatoid arthritis and lupus – are also associated with changes to gut microbial ecosystems.

(Indeed, obesity is often described as an inflammatory condition for the widespread immune reaction that accompanies excess weight.) 

Connecting the dots between altered gut microbes and disease is a lively area of research. Scientists are working on the ‘chicken or egg’ problem: does disrupting the gut microflora cause the disease, or does having the disease lead to changes in gut microflora?

In many cases, it is likely that a complex interplay between genetics and environmental triggers – including the microbes in our guts – is involved.

One clue seems to lie with the gut’s role as a barrier. The surface of our intestinal tract is larger than a tennis court. This is great for facilitating nutrient absorption. But the flipside is a gargantuan barrier that our immune system needs to defend.

There’s now compelling evidence that breaching this barrier – a condition known as ‘leaky gut’ – allows bacterial toxins including fragments of bacterial cell wall (lipopolysaccharide) and tail proteins (flagellin) into our bloodstream, triggering inflammation in tissues far removed from the intestine.

The types of microbes living in our gut can influence how leaky it is. Increasingly, research is showing that just as in obesity, inflammatory conditions could be more a case of protective microbes being wiped out than damaging microbes taking over.

Several groups of related beneficial bacteria called the ‘clostridial clusters’ seem to be particularly important. (These are not be confused with their distant relative, the extremely harmful diarrhoea-causing Clostridium difficile.)

Members of these groups are specialist fibre fermenters, pumping out those beneficial short chain fatty acids, which help to keep our gut intact by strengthening the molecular bonds between intestinal cells.

Without short chain fatty acids, the gut becomes leaky and the immune system pumps out damaging pro-inflammatory signals. But with them, the gut is kept intact and inflammation is quelled by specialised immune cells that multiply in their presence.

The clostridial clusters are in a prime location for immune-microbe chatter. They hunker down in the thick mucous that lines the gut, stimulating its production and even feeding off it.

When the mucous layer thins out – perhaps due to a loss of these beneficial microbes – toxins and other microbes that are normally kept at a distance are able to gain access to and cross the delicate gut lining, causing inflammation.

In 2014, scientists at Keio University in Tokyo found that killing clostridial clusters with antibiotics makes mice more susceptible to bowel inflammation. Conversely, supplementing mice with these microbes prevents or even reverses inflammation. The same year, researchers at the University of Chicago discovered that wiping them out made mice more likely to develop peanut allergy.

In one mouse study, transferring a single member of the clostridial clusters found to be lacking in people with inflammatory bowel disease – Faecalibacterium prausnitzii – protected mice from induced gut inflammation.

It’s not yet known whether having fewer clostridia causes inflammatory bowel disease, or whether it simply accompanies and exacerbates the condition. It is also unclear whether a clostridial cocktail could work in people.

Studies of other probiotic cocktails have seen improvements in some cases of bowel inflammation but not others, suggesting that we haven’t yet hit on a magic formula that will work for everyone.

The same is true for multiple sclerosis, rheumatoid arthritis and lupus. Changes in gut microbes have been found in all of these autoimmune conditions, but studies in mice – and to a lesser extent, people – are yet to clearly identify which microbes are important for keeping the condition at bay, and which microbes exacerbate the condition.

Neither probiotics (microbial supplements), nor prebiotics (microbial food supplements) have seen consistent benefits for these conditions.

But it’s become clear that the microbes we are exposed to and colonised by as young children play an outsized role in our future immune health.

Numerous studies support what has been dubbed the ‘hygiene hypothesis’. Children who grow up in less industrialised settings or on farms, or have older (microbe-sharing) siblings, are less likely to develop hayfever and allergies than their more germ-free counterparts. 

Although the hygiene hypothesis initially focused on childhood infections as the key ingredient in a healthy immune system, it is now understood that exposure to our ‘good’ microbes underpins the relationship.

Mice raised germ-free fail to develop normal immune systems, with entire components of their immune arsenal missing or underdeveloped.

And children born via caesarean section are more prone to asthma and allergies, presumably because they are missing some key players necessary for immune development.

In cancer, too, our microbial companions have a say. At least three species of bacteria have been shown to increase colon tumours in cancer-prone mice. These strains may also play a role in colorectal cancers in people, but research needs to shore up this link.

Gut microbes can also turbo-charge cancer immunotherapies – drugs that ramp up our immune system to fight cancer.

In 2015, researchers at the University of Chicago found that fast-growing tumours in mice can be slowed simply by spiking food with beneficial bugs. When combined with an immune-boosting drug, tumour growth was brought to a standstill.

In another 2015 study, by researchers in France, antibiotics effectively removed all benefits of the immunotherapy drug. 

This research could help to answer the perplexing question of why immune-boosting drugs only work in some people.

Microbial communities outside of our gut are also important when it comes to immune regulation.

Psoriasis, atopic dermatitis and eczema have been linked to imbalances in the skin microbiota, and the composition of a woman’s vaginal microbiota has been found to influence how susceptible she is to HIV infection.

But turning these findings into meaningful treatments or preventative measures needs more investigation.