microbes
We are not alone. Our bodies are teeming metropolises of microscopic life - and the microbes that call us home influence everything from bowel to brain.

Over the past decade, technological advances in the lab have allowed us to take a census of our microbial entourage - known as the microbiota - like never before. Instead of seeing only the small fraction of microbes from our skin or poo that blossom on a petri dish, we can now blend, extract and read the genetic essence - the DNA - of all microbes, called the microbiome, to get a better idea of who's there.

The picture that has emerged is one of staggering complexity. From nostrils to armpits, wisdom teeth to bowels, lungs to vaginas, unique communities of bacteria, fungi, viruses and parasites have got us covered.

"Every single surface of our body is colonised with microbes," says Laura Cox, a biologist at the Brigham & Women's Hospital and Harvard Medical School in Boston in the US.

Bacteria alone are as numerous as the cells of our own body. The genes they harbour dwarf our own genetic endowment more than a hundred times over. Together, we work in concert in what some consider a 'super-organism' - with our existence as reliant on theirs as theirs is on us.


Comment: Gardening your microbiome: Self as superorganism


Gut microbes synthesise vitamins, while those on our skin earn their keep by eating dead cells and transforming oils into natural moisturiser. And microbes everywhere play a role in keeping harmful pathogens at bay.

On the other side of the ledger, a mother's milk contains some nutrients useless to her baby, but essential for the early microbial colonisers of her baby's gut.

The assemblages of species inhabiting each bodily niche represent complex ecosystems that have evolved with us over millennia. The microbes lurking on the doorknob of the public toilet might give us the heebie-jeebies. But those that take up residence on or in us aren't usually picked up from the environment. They are passed down from generation to generation, and have been for millions of years.

Families of gut microbes living in both us and other apes diverged from a common ancestor some 15 million years ago.

And bacterial strains from Africa and America diverged 1.7 million years ago, around the time early humans made their first forays out of Africa. If you wanted to, you could trace the history of human migrations around the globe using our microbiome.

Our microbes continue to evolve with us, and in response to our modern lifestyles. People living in industrialised societies have less diverse microbial communities than people in places such as Malawi.

Microbiome composition ebbs and flows depending on the food we supply and the various chemicals and drugs we send their way. Not surprisingly, the fluctuations in our microbial residents have clear implications for our health - from immune responses to how we think and act.

Next we'll explore how gut microbes tinker with our metabolism.

How bugs in your gut can make you fat (or thin)

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© JOSE LUIS PELAEZ INC / GETTY IMAGESWhile there's no doubt calorific intake does affect weight gain or loss, we shouldn't underestimate the power of our microbiota.
By far the majority of our companion microbes, weighing an impressive 1.5 kilograms and containing more than 1,000 species, reside in our gut, mostly in the large intestine.

As soon as a baby is born - and perhaps even before - microbes move in. Many are seeded from bacteria in the mother's birth canal if it's a vaginal birth or from her skin if it's a caesarean birth.

An infant's milky diet fosters a unique set of gut microbes. The infant microbiome gradually changes until, by the time a toddler is three years old, it has morphed into a more diverse ecosystem that is indistinguishable from an adult's.

Gut communities differ from one person to the next, and are heavily influenced by the food we eat. They are also rapid responders to dietary change, re-configuring for a new diet in just a day or two.

Gut microbes do more than just scavenge from the food we eat. They also harvest energy and synthesise essential nutrients, such as certain B vitamins and folate, for us. Indeed, pregnancy sways a mother's gut ecosystem towards one that harvests more calories per bite.

Mice raised to be germ-free are skinnier than their germy counterparts, even when they eat more; with no microbes at all, they can't extract as many calories from their food.

There's now compelling evidence that tinkering with microbes living in the depths of our bowels could be contributing to our expanding waistlines. Scientists are still figuring out what microbiota changes are most detrimental and how such changes cause weight gain.

Some of the earliest evidence that gut bugs affect weight gain came from farm animals. Since the 1940s, farmers have fattened livestock by feeding them low doses of antibiotics - enough to affect their gut microbiota but not enough to be therapeutic.

Humans, it turns out, aren't immune to this effect. Taking repeated courses of antibiotics during infancy increases the risk of becoming overweight, at least in childhood, which is a good predictor of obesity in adulthood. The first six months of life are particularly critical. And boys seem to be more susceptible than girls, though why is a mystery.

And why infancy is such a crucial time isn't fully understood either. One suggestion is that it coincides with the time our body decides how many fat-storing adipose cells to lay down to accommodate calories.

It's not just antibiotics that can make a baby's microbiota fattening. Birth by caesarean section and being fed formula instead of breast milk also seem to tip the scales towards greater childhood weight gain.

In many cases, antibiotics, caesarean delivery and baby formula can't be avoided. And an untreated infection or undernourishment can be far more harmful than a potential increase in the risk of being chubbier as a toddler.

Another thing to remember is that even with microbiota disruptions as a child, it's not a foregone conclusion you'll end up obese, says Laura Cox, a biologist at the Brigham & Women's Hospital and Harvard Medical School in Boston in the US who has studied the antibiotic-obesity connection: "The risk of being overweight from microbiota disruption [in early life] is not as big as other risk factors, such as certain genetic factors or eating certain diets or never exercising."

The situation in adults is murkier.

Scientists are still getting a handle on how disruptive antibiotics - and other chemicals and food additives we encounter daily - might be. Our gut communities tend to bounce back after a dose of antibiotics, but Western gut microbiota are generally less diverse - and perhaps less resilient to disruption - than those of people living more traditional lives. And there's enormous individual variation.

Mice demonstrate the power of gut microbes to influence weight gain between individuals. In 2006, a research group from Washington University in St Louis took poo from obese mice and transplanted it into the gut of skinny, germ-free mice, which promptly became obese.

It didn't matter whether the original obese mice were fat from too much healthy chow or from eating a high-fat 'Western' diet. Excess calories seemed to be the key factor turning their microbiota into an obesity-causing (or 'obesogenic') community.

A single case report from 2015 suggests the same applies to human-to-human poo transplants. A woman who received poo from her overweight daughter to treat severe diarrhoea became obese in the months following the procedure.

So, what makes a microbial ecosystem obesogenic?

According to Cox, there doesn't seem to be any 'bad' microbes that take over in an obese gut community. But along with an overall loss of diversity in the ecosystem, a handful of microbes consistently become less common.

Other studies have focused not just on who's there, but what they collectively do.

A hallmark of an obesogenic microbiota is a change in the types and amounts of short chain fatty acids microbes pump out after fermenting dietary fibre (and to a lesser extent, protein).

Short chain fatty acids provide up to 10% of calories absorbed when consuming a Western-style diet - and probably more in extremely high-fibre, plant-based diets. But they also act as signalling molecules, dialling up satiety messages in our brain, slowing food movement through our gut and boosting fat cell production.

How do we keep good microbes happy? Unfortunately, cultivating protective microbes with dietary supplements called prebiotics has seen mixed results. When mice are fed a low-fibre diet, their microbial ecosystem becomes less diverse. Simply re-adding fibre to their diet doesn't fix the problem - once an organism is lost, it may be lost for good. And over generations, the problem is compounded - mothers can't seed their offspring with gut bacteria they no longer have.

Similarly, in obese women given the fermentable fibre inulin - to boost short chain fatty acid production - weight loss was only modest. And the best responders already harboured particular clusters of beneficial bacteria that could blossom with the added nutrient.

Probiotics - consuming live bacteria to replenishing the gut with microbes that have been lost or are limited in number - has been touted as a possible solution. But scientists are yet to identify microbes that reliably work to reduce weight gain, and many strains of so-called 'good bacteria' that are available in commercial probiotic concoctions don't stick around to become long-term members of the gut community.

The more drastic approach of replacing the entire ecosystem with a poo transplant hasn't fared much better. In 2012, researchers in the Netherlands transplanted poo from lean donors to people showing early signs of developing type 2 diabetes, a metabolic disorder that frequently accompanies obesity.

Although metabolism improved in the immediate aftermath of the transplant, microbes and metabolism reverted to an unhealthy state within six months.

The lesson seems to be that the best way to foster a healthy, diverse gut community is to feed it right from the get-go - with foods high in fibre, low in fat and not overloaded with calories.


Comment: Understanding the importance of microbes: How gut bacteria plays a crucial role in weight management

Microbe tenants help - and hinder - 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.

Mood, mind and memory: can gut bacteria meddle with the brain?

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© RICHARD WAREHAM FOTOGRAFIE / GETTY IMAGESLinks between the microbiota and psychological disorders such as depression and anxiety have, for the most part, only been shown in rodents.
The microbes in your gut may be tiny, but their influence appears to extend as far as the brain, affecting mental health, stress levels, memory and cognitive abilities. Yet many of the most compelling results illustrating the microbiota-gut-brain axis, as it has become known, have only been seen in animals.

The potential for gut microbes to affect mood is probably best illustrated by an experiment conducted at McMaster University in Canada. Mice devoid of a microbiota were effectively given 'personality make-overs' via poo transplants. Timid mice became more brazen, and once daring mice retreated into shyness, taking on the anxiety profiles of their donors.

Human-to-rodent poo transplants also work. When researchers at University College Cork in Ireland fed rats poo from people with depression, the rats became depressed and anxious.

In humans, a handful of studies link changes in the gut microbial ecosystem to our mental health. Anxiety levels in patients with inflammatory bowel disease, for instance, track with the level of disruption to their gut microbial communities. Altered gut microbes, as well as gastrointestinal symptoms - such as constipation, diarrhoea and inflammation - are also common in autism spectrum disorders.

Scientists are still nutting out the possible mechanisms behind these long-ranging effects, and have found several possible communication channels between the gut and brain.

The first is via neurotransmitters - chemicals that relay messages between nerve cells. Many of these chemical messengers are made by the brain and other neural tissue. But some, including serotonin (and its precursor tryptophan), norepinephrine and dopamine are also synthesised by gut microbes.

When the University College Cork team treated mice with the probioticLactobacillus rhamnosus, they saw levels of a lock-and-key partner of one neurotransmitter - GABA - rise in some brain areas and drop in others. The mice were also less depressed, less anxious and less prone to stress.

But whether tinkering with the gut ecosystem in humans translates into changes in neurotransmitter signalling in the brain - much less the behaviours they affect - is still largely a mystery.

Another communication highway between gut and brain is the vagus nerve. The vagus nerve connects the base of the brain (the brainstem) to the gut - as well as the heart and lungs - and controls a bunch of unconscious tasks, such as regulating heart rate, squeezing food through the gastrointestinal tract, and sweating. It also relays stress response signals back to the brain.

Research in mice suggests that when the vagus nerve is severed, a crucial line of communication between gut and brain is taken down. In the study of mice fed the probiotic Lactobacillus rhamnosus, the beneficial effects of the bacteria - lower levels anxiety, depression and stress - disappeared when the vagus nerve was cut. But it's still a mystery how the vagus nerve works to relay messages from the gut to the brain.

The leaky gut phenomenon also makes an appearance in the microbiota-gut-brain axis. When there are fewer beneficial microbes to spit out short chain fatty acids, the lining of the intestine - usually firmly glued together and protected by a thick layer of mucous - becomes permeable to bacteria and other by-products of digestion that wouldn't normally leave the confines of the gut.

This leakage can ramp up inflammatory signals around the body, including in the brain, and could be one source of the chronic, low-level inflammation seen in people with depression.

A leaky blood brain barrier may also be part of the picture. The short chain fatty acids that help to maintain the gut barrier play a similar role maintaining the highly selective membrane that protects the brain from bits and pieces in the bloodstream.

Germ-free mice have a leakier blood brain barrier than conventional mice. But a Swedish team at the Karolinska Institute found that when fed poo from conventionally raised mice, or a selection of microbes known to churn out short chain fatty acids, the blood brain barrier becomes less leaky.

Fast food diets have been linked to leaky gut and depressive symptoms. Unsurprisingly, diets rich in fruits, vegetables and fish tend to decrease depressive symptoms.

These dietary studies raise the question of whether behaviours seen in mice - and perhaps in humans, too - could be the result of what's happening in the gut, rather than just the brain. They also beg the question of whether rectifying disturbances in the gut ecosystem could improve symptoms.

In mice, the evidence is promising but mixed. Bacteroides fragilis - a microbe known to protect against gut inflammation - plugged the leaky gut, restored microbiota to normal and reduced autistic-like behaviours in mice with an experimental form of autism, even those fully grown.

But a study of a different mouse model of autism using a different beneficial microbe found that adding back the depleted microbe could restore some, but not all, of the behavioural deficits.

There are hopeful signs that probiotic microbes could alleviate depression. Bacteroides infantis and Lactobacillus rhamnosus decrease depressive symptoms in rodents, and a French team showed that a Lactobacillus helveticus/ Bifidobacterium longumcocktail does the same in non-depressed human volunteers.

It is enticing to think probiotic supplements to treat psychological disorders - dubbed "psychobiotics" - could one day hit the shelves. But much more work needs to be done - especially in populations of people with mental health disorders - before this happens.


Comment: Mind-Gut Connection: Why Intestinal Bacteria May Have Important Effects on Your Brain