Saturday, 3 September 2016

[1] "Microbe City"


When Jop de Vrieze met the bacteria that call him home, he set out to learn how to keep them happy and himself healthy

THERE they are: my microbes. I feel like someone who's just been introduced to a group of lost relatives. Staring through a microscope, I see a cluster of Staphylococcusepidermidis bacteria sitting together in a Petri dish. They look like a bunch of grapes. Until yesterday, they were living in my armpit.

I had set out on a quest to learn about my microbiome and how it affects my health. It soon made me think of myself quite differently. Looking down that microscope, I no longer felt like an individual – I was the mayor of my own microbe metropolis.

There are many trillions of microbial organisms living in and on our bodies, outnumbering our own cells 3 to 1. We have battled them for years, with antibiotics and disinfectants. But as we get to know them better, a lot turn out to be our allies. "It's like we've been breaking down our house and only started appreciating it when we've already destroyed it to a great extent," says Margaret McFall-Ngai at the University of Wisconsin-Madison. "It's a complete wake-up call."
It wasn't just my own cells I had to look after, but the multitudes that call me home – from the downtown districts in my gut to the suburban sprawl of my skin. Bad management could get me into trouble. Imbalances in microbial flora have been linked to many conditions, from inflammatory bowel disease and type 2 diabetes to cancer, heart disease and depression. Upset the good guys and I risk letting a bad crowd move in. So how do I keep them happy?


The gut is the powerhouse of my microbial world. Vast numbers of bacteria live in my intestines, feeding on my leftovers. They help break down undigested food, contributing about 10 per cent of my energy and producing a variety of molecules that have an effect on my metabolism, immune system and even brain. Faecalibacterium prausnitzii, for example, plays a role in regulating sugar uptake, and having too few has been linked to Crohn's disease. Then there's Bacteroides fragilis, which keeps my immune system on its toes, and the lactic acid bacteria that help me handle stress by producing appropriate neurotransmitters.

A healthy immune system creates the right environment to attract species like these, while keeping others out. "The microbiota shape the immune system and the immune system shapes the microbiota," says Martin Blaser at New York University. "It's a two-way system."
If they eat what I eat, how does my diet affect them? To get a rough idea, Willem de Vos at Wageningen University in the Netherlands helped me set up a small experiment. For four weeks, I followed four consecutive diets. The first week I ate as I normally would – a little bit of everything. In the second week I ate a vegetarian diet and in the third week I ate meat and starch but no fruit or vegetables. In week four I returned to my regular diet but ate probiotic yogurt with every meal. At the end of each week, I took a stool sample to de Vos and his team, who analysed the fragments of microbial DNA it contained.

The dietary changes shifted my gut microbiome quite a bit – as a recent study showed, diet can alter microbiome make-up in just a few days. My microbes took a hit when I changed my normal diet. But the most interesting shift came when I gave up fruit and vegetables. During my meaty week, populations of certain species that reduce inflammation dropped, including Clostridium and Prevotella species. At the same time, other populations bloomed to take their place. For example, the number of Bacteroides went up (see diagram). Bacteroides are typical of Western diets that are high in animal protein and saturated fat and some studies have linked having too many of them to obesity.

Eating fruit and veg doesn't just keep different gut populations in balance, though. Bacteria also process plant fibres into short-chain fatty acids, which regulate several processes in the body and keep the gut barrier healthy. A weak gut barrier can allow harmful bacterial products to enter the body, with potentially dangerous results. For example, metabolic endotoxemia – a disruption of the metabolism that can lead to conditions such as type 2 diabetes – may be triggered by changes in gut flora. As for probiotic yogurts, after a week they had little effect on my relative population numbers. My lesson? Keep eating my greens, but don't worry too much about the rest.


Nothing hits gut populations like antibiotics. These drugs don't just kill pathogens, they also wipe out most of the microbiome. The disruption can cause severe diarrhoea or even chronic inflammatory bowel disease. Even a relatively mild upset can have long-term consequences, like irritable bowel syndrome.

Taking probiotics alongside antibiotics can help. The lactic acid bacteria in probiotics don't replace all the eradicated species, but they can outcompete or kill opportunistic pathogens advancing to take their place. They can also help digest lactose, give the immune system a boost and strengthen the gut barrier.

The trouble with probiotics is that their strength varies. Populations of the commonly used types, Lactobacillus and Bifidobacterium, are weakened during the culturing and production process. They also take up temporary residence only, not settling in the gut for long. A second generation of probiotics is on its way, but they are more difficult to produce and haven't yet been approved for sale.

In the meantime, there's the DIY approach. One Dutch scientist told me in confidence that she stores two tubes of her children's faeces in her freezer – just in case. She hasn't used them yet, but came close after her children took a course of antibiotics. She thinks most people will have similar tubes stored in their freezers in a couple of years. Using your own stool is healthier than a faecal transplant, in which you take a sample from a healthy volunteer, she says. "These microbes are used to your body and your body is to them." It's a conviction born from her particular expertise. Personally, I'm not yet persuaded to clear a space between the ice cream and frozen peas.


What about the bacteria living in my mouth? I spat in a cup to find out. As in the gut, the balance of bacteria in the mouth also depends on our eating habits. A healthy mouth should contain a wide range of species. But an unhealthy mouth can be dominated by just a few different types of bacteria. "The microbes in healthy mouths are a lot more alike than those in unhealthy mouths," says Wim Crielaard at the University of Amsterdam in the Netherlands.

Some bacteria, like Streptococcus mutans, produce acids by breaking down sugars. Others, like Porphyromonas gingivalis, trigger inflammation. Too many of either can cause trouble. Acids break down tooth enamel, increasing the risk of cavities, and inflammation can lead to gum disease. Inflamed gums also let bacteria like S. mutans enter the bloodstream when we brush our teeth. Once there, it's only a short hop to colonising our joints, where they can cause rheumatoid arthritis, or our heart, where they can cause infective endocarditis, a life-threatening inflammation of the heart-lining.

In a healthy mouth, both of these species are present but are counterbalanced by others like Streptococcus sanguinis, which competes with S. mutans. Though no species alone would be beneficial, together they keep each other in check. Your saliva also neutralises acids and kills inflammatory species by producing antimicrobial peptides that target certain bacteria. So chewing sugar-free gum can help by stimulating saliva production. Some brands also contain xylitol, a kind of fake sugar, which is taken up by acid-producing bacteria like S. mutans but not digested. It builds up inside these bacteria, disrupting their metabolism.

When Crielaard gave me my result, I was happy to find that my inflammatory species were low. But the balance between acid producers and neutralisers was shifted in the wrong direction, raising my risk of getting cavities. "It's not a sin to eat or drink sweet and sour products," says Crielaard. "But when the frequency of acid attacks is too high – more than seven times a day – your saliva and neutralising species can't keep up." I made a mental note not to snack too often.


It was time to learn about the needs of my skin microbes. For four days, I skipped my shower and instead took a daily swab from my armpit, cheek, back and foot. From these swabs, Dries Budding at the Free University in Amsterdam identified hundreds of species, including typical skin dwellers such as Staphylococcus epidermidis, but also Streptococcus parasanguinis – more usually at home in a healthy mouth – and potential pathogens such as Staphylococcus aureus, Klebsiella pneumoniae and Haemophilus influenzae. And over the four days the diversity increased.

That makes it sound like skipping showers is unhealthy. On the contrary. In fact, some researchers think that by washing our skin on a daily basis we could be scrubbing off a natural shield. The harmless bacteria on our skin help form a physical barrier against microbes that are potentially harmful, says Elizabeth Grice at the University of Pennsylvania in Philadelphia. "They protect us, educate the immune system, modulate the immune and inflammatory response and don't allow pathogenic or opportunistic bacteria."

Harmless bacteria also prime immune cells to respond to their pathogenic cousins, as well as raising the alarm to immune cells when a pathogen arrives by triggering immune-signal pathways. For example, one recent study showed that immunity to the protozoan parasite Leishmania major requires the presence of S. epidermidis.

I faced a dilemma. Did I want the best for my microbes or the people around me? Unwashed, I risked social exclusion. In the end I made a compromise: I now wash every other day and haven't yet lost any friends.


We are born sterile. But from the moment we leave the womb, bacteria begin colonising our skin and setting up home in our gut. Just a millilitre of stool from a 1-month-old baby contains a trillion microbes. Right from the start, bacteria influence our development by shaping our immune system and producing hormones that guide the growth of our brain.

The make-up of our early microbe populations seems to depend on how and where we are born. Infants that pass through the vaginal canal during birth pick up bacteria from the mucus of the vagina. But babies born by caesarean section will be exposed to different bacteria, picking up their first microbes from the skin of other people and the environment.

One-month-old babies born by C-section have been found to have fewer friendly bacteria and more harmful ones in their guts, like the diarrhoea-causing Clostridium difficile. Formula-fed babies were found to have greater numbers of C. difficile and E. Coli. C-section babies are also more likely to develop a range of conditions, including asthma, type 1 diabetes and obesity. But whether this is due to a different microbiome or other confounding factors such as maternal obesity or premature birth isn't yet clear (PLoS One, vol 9, p e87896).

Still, a growing number of parents are choosing to supply vaginal bacteria by hand, including microbiome pioneer Rob Knight at the University of Colorado in Boulder. Using a sterile swab, he and his wife gave his newborn daughter an oral dose of microbes from her mother's birth canal shortly after she was born by C-section. Studies to look at what difference this might make are under way.


Graham Rook of University College London has proposed a theory he calls the old friends hypothesis. Over our long symbiotic history, he says, microbes and humans co-evolved. We incorporate them into our physiology, and they regulate our immune system.
Thanks to our modern lifestyles, though, we may have exiled several old friends and, worse, welcomed new enemies. Large urban communities and intensive farming have allowed harmful microbes to flourish and spread. A recent study showed that a modern office has a characteristic microbiome and buildings with natural ventilation contain different microbes to air-conditioned ones.

Rook believes it all matters. For example, city-dwellers living next to a park have been found to be healthier than less lucky neighbours just streets away. "Some psychological explanations have been proposed," he says. "But I wouldn't be surprised if the microbes turn out to make the difference."

So how should I win back my old friends? "It's not a matter of living a dirty life," says Rook. "In a modern environment, this would confront us with our new enemies." But simply stroking a cat or dog might help. Pet owners share skin bacteria with their animals that could be beneficial. Living with pets also seems to reduce asthma risk among young children, probably by boosting populations of gut microbes such as Lactobacillus johnsonii, which is thought to protect against allergies.

But my old friends may not be your old friends, as backpackers often discover: different human populations around the world tend to have established relationships with slightly different strains of bacteria. In Colombia, for example, most people have Helicobacter pylori in their stomach, which may protect against allergies. In some Colombians, though, the bacteria can also cause stomach ulcers and cancer. It turns out that the mountain strains of H. pylori were brought to Colombia by Europeans and the immune systems of the indigenous people at higher altitudes hadn't learned to cope with it.

On my quest, I learned a lot about what makes me who I am. If you, too, are urban and omnivorous, chances are we aren't dissimilar. But, of course, it's complex. We are only beginning to uncover the subtle relationship between us and our tiny inhabitants.

Questions of cause and correlation remain knotty. "Scientists should not run to conclusions about the microbiome," says Jonathan Eisen at the University of California, Davis, who thinks the microbiome will emerge alongside genetics, lifestyle and our environment as a major factor influencing our health. "When Darwin entered an island, he first catalogued all the species and only then started studying them," he says.


This article appeared in print under the headline "Mayor of Microbe Metropolis"
Jop de Vrieze is a science writer based in the Netherlands. His book Allemaal Beestjes ("Our Tiny Creatures and Us") is published in Dutch (Maven Publishing, 2014)