THE average human is more microbe than mammal, a veritable super-organism comprising 10 times as many microbial cells as human cells. The total number of microbial genes in the human body is thought to outnumber human genes by up to 1000 to 1. Read this article out loud, and long before you reach the end you will have released 10,000 bacteria-laden droplets into the air. With so many microscopic hangers-on you can afford to shed a few. But you would be in big trouble without any at all. In fact, you wouldn’t be human, a paradox that scientists are trying hard to get their heads around.
The only time in our lives when we are microbe-free is the nine months we spend in the womb. Then, bam!, we are thrust into the world of germs. For most of us, the first microbes we encounter will be those in our mother’s birth canal, respiratory tract and skin. Only some of these gain a foothold in the newborn, but once the hardiest have staked their claim the favourable conditions they set up open the door for successive waves of migrants, streaming in from other people, animals, the home, in fact anything the baby encounters that is not sterile. Within the first few years of life, healthy infants acquire stable microbial communities in all but a few parts of their bodies, such as the brain, kidneys, blood and lungs. Then microbes and host happily co-exist for the rest of their lives.
Our resident communities are not mere passengers, though. We depend on them for survival. Indigenous or “normal” microbes – which include viruses, fungi, protozoans and bacteria – provide us with a vital shield against more unpleasant, disease-causing bugs in the environment. In a stable, established community, every possible niche is filled, so pathogens must compete with the incumbent bugs to gain a foothold. What’s more, without our normal microbes we could not perform many of our bodily functions. Yet, disturb the natural harmony, and our seemingly benign bugs can make us sick – sometimes fatally so. Which is why scientists are so curious to know exactly what is in there, and how our microbial inhabitants interact with each other and with us.
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Until recently, our knowledge has been limited, not least because it was only possible to identify those microbes that could be cultivated in the lab – a mere 1 to 2 per cent of the full quota. As a result, we have a distorted or rudimentary view of the microbial inhabitants of some parts of the body. Much attention has focused on methicillin-resistant Staphylococcus aureus (MRSA), for example – the notorious superbug that can take up residence in the upper respiratory tract. However, very few studies exist on the other bugs that are up your nose, let alone further along the respiratory tract, where there are several different environments, each harbouring different microbes. We are pretty ignorant about the eye, too. And when it comes to the female urethra, forget it: most of what we know dates back to the 1970s and primarily relates to women’s high susceptibility to urinary tract infections.
Still, recent years have seen an explosion of knowledge about the microbial inhabitants of some parts of our bodies, made possible by the new tools of molecular biology. In particular, microbiologists can analyse the genomes of entire microbial communities by chopping up all their DNA into little bits, rapidly sequencing these fragments and then fitting the pieces together as if re-creating the pictures from a muddled-up multitude of jigsaw puzzles. Now this whole area, known as metagenomics, is poised to take off. In May, the US National Institutes of Health approved a five-year plan to investigate the human microbiome – the entire microbial content of the human body. The next few years will bring a massive leap in our understanding, but already smaller-scale metagenomics projects, investigating the microbes of the gut and mouth, for example, are beginning to throw up some intriguing insights.
The most striking revelation is the sheer diversity of our microbial inhabitants (see “Skin“). At a given anatomical site, the core of the community seems not to vary much across all humans – regardless of climate, diet, age or lifestyle. These bugs have evolved with us over millennia, passing from generation to generation. At the fringes, however, there is flux, with the make-up of the microbiome constantly shifting in response to environmental conditions. As a result, scientists are coming round to the idea that there is a continuum between our internal microbes and those inhabiting the outside world. With this change in thinking comes the realisation that it might be possible to manipulate the human microbiome to improve our health. Probiotic yogurt containing live bacteria is just the start; future prospects include caries-busting bacteria and perhaps even microbes to help you lose weight (see “Gut“).
Another idea now emerging is that your unique microbial fingerprint provides a historical record that can be used to pinpoint the origin of your ancient ancestors (see “Mouth“). What’s more, since the overall composition of the human microbiome traces our species’ long co-evolution with its microbes, it reflects changes in the way we have lived over millennia. From the beginning of the 20th century, and most notably since the introduction of antibiotics after the second world war, our microbiome has been changing faster than ever before. Whether this will ultimately be good or bad for human health, only a better understanding of the human microbiome will tell (see “The price of progress”).
“Your unique microbial fingerprint provides a historical record, which can be used to trace your ancestry”
“Obesity could be linked to an increased ability to absorb calories, thanks to the ratio of gut microbes”
Skin
Your skin comprises six or seven different habitats, from the humid spaces between your toes to the dry outer ear. No wonder it is a veritable “zoo” of microbes, says Martin Blaser of the New York University School of Medicine. In February, Blaser, Zhan Gao and colleagues published probably the most thorough survey of the skin ever conducted. Even so, it only looked at one small patch of forearm ().
The team found an impressive 240 species on six healthy volunteers, using a technique called 16S rDNA sequencing, which identifies different microbes based on comparisons of the gene that codes for a portion of the ribosome – an ancient component of cells. Since then, the researchers have increased their sample to 12 people and counted 360 species. They also discovered that no two individuals have the same microbial complement, and it even changes over time for each person – but they all share a bacterial core or scaffold. “There are certain genera or species that we think are common in everyone, that represent the major populations on the skin,” says Blaser. “Then there are a lot of transients, tourists or minor populations that could bloom into a major population depending on environmental circumstances.”
Given that skin is the boundary between you and the outside world, it is hardly surprising that its microbial community is so variable. The balance is extremely sensitive to environmental fluctuations, changing each time you have a shower or even use a new brand of soap. Such differences are there right from the start, with babies delivered by Caesarean section having a different profile of microbes on their skin to those born naturally and therefore exposed to the microbes in their mother’s birth canal. We don’t know whether these differences are long-lasting, only that by six weeks the complement of microbes living on the skin of infants resembles that found on adults – with all the variability that entails.
Although a huge variety of microbes can live on your skin without doing you any harm, they are not always benign. Skin bacteria can cause serious infections if they get into your blood, as they sometimes do via hospital catheters, says Mike Wilson, a microbiologist at the Eastman Dental Institute, part of University College London, and author of Microbial Inhabitants of Humans. Some regular skin-dwellers also do damage in situ, causing a multitude of skin complaints, from athlete’s foot and impetigo to dandruff. None is quite so prevalent as Propionibacterium acnes, an anaerobic bacterium that lurks in oxygen-poor glands and pores and causes acne, the most common skin disease. This particular microbe also offers a salutary lesson to anyone wanting to manipulate the skin’s microbial community.
For more than three decades, acne has been treated with antibiotics. In 2002, researchers at the University of Leeds, UK, found that over the previous decade there had been almost a doubling of the number of patients whose strains of P. acnes were resistant to each of the antibiotics used to treat acne (). Worse still, says Wilson, other skin microbes are acquiring antibiotic resistance. “Recent research has shown that the throats of individuals with acne who are treated with [the antibiotics] tetracyclines become colonised by tetracycline-resistant Streptococcus pyogenes, a pathogen which is responsible for a wide range of life-threatening diseases,” he says. Tetracycline-resistant bacteria have even been found in the gut and on the skin of relatives of acne sufferers undergoing treatment.
Gut
The rapid flow of partly digested food through your small intestine makes it a poor home for microbes, since the bugs are constantly being washed through. In the colon, however, things slow down and microbial concentrations soar. Thousands of different types of microbe inhabit the gut, an estimated kilogram’s worth in the average adult. Without them we would not be able to digest certain foods, metabolise drugs, detoxify noxious compounds or make essential vitamins.
There are two main phyla of bacteria in the colon, the Bacteroidetes and the Firmicutes, as well as Archaea (evolutionarily ancient, single-celled organisms that consume hydrogen and generate methane). It has long been known that gut microflora changes with age, diet and other factors. For example, there is a significant difference in the ratio of microbial groups between breastfed and bottle-fed babies. “In breastfed babies the community is qualitatively less pathogenic,” says Wilson. Although gut microbes in infants all converge towards a more adult profile by the age of 2, any pathogen is potentially more dangerous before this time because the baby’s immune system is still developing. “So breast is best from the point of view of the indigenous microbiota,” says Wilson.
However, it took metagenomics to reveal some truly startling links between gut microflora and human health. In 2005, researchers at the French National Institute for Agricultural Research (INRA) at Jouy-en-Josas, near Paris, led an international consortium in launching the Human Gut Metagenome Initiative. In one of the first studies of its kind, published in 2006, Joel Doré and colleagues at INRA show that the diversity of Firmicutes is significantly reduced in people with Crohn’s disease, a type of inflammatory bowel disease, compared to the communities found in the gut of healthy controls ().
In the same year, Jeffrey Gordon and colleagues at the Washington University School of Medicine in St Louis, Missouri, also used metagenomics to reveal that obese people have a higher ratio of Firmicutes to Bacteroidetes than lean ones, raising the intriguing possibility that obesity could be linked to an increased ability to absorb nutrients from the gut, thanks to the ratio of resident microbes.
Moreover, when obese individuals were placed on a low-calorie diet, the proportion of Bacteroidetes in their guts increased, bringing their gut microbial profile more into line with that of lean people. The researchers noted that because species across both groups were affected, there was no obvious microbial target for an anti-obesity drug. In another study published last month, however, (), the same group identified a possible candidate for therapeutic intervention.
Methanobrevibacter smithii, the dominant Archaean in the gut, is important for the efficient digestion of polysaccharides – complex sugars, ubiquitous in nature, that provide us with a major source of energy but cannot be degraded by human enzymes. Genetically obese mice have more M. smithii in their gut than their lean litter-mates, and when Gordon transplanted those communities into mice with sterile guts, he found that they put on more weight than similarly sterile mice given gut microflora from lean mice.
The team has now sequenced the genome of M. smithii as a first step towards manipulating numbers of the bacterium in the gut, and perhaps towards tackling the obesity epidemic.
Mouth
If we are not using our mouths to chew or swallow food, we’re talking, gargling or brushing our teeth. Even so, some bugs do manage to hang on in there. For the most part they do no harm, but under certain circumstances they can cause problems.
The worst of these is the gum disease periodontitis, the most prevalent chronic infectious disease in humans. It begins when normally benign mouth bacteria are allowed to accumulate, forming a sticky layer of plaque at the interface between teeth and gums. This creates an environment in which anaerobic bacteria can thrive, producing enzymes that degrade the surrounding tissues, triggering an inflammatory response and eventually eroding the alveolar bone in which the teeth are embedded. “If you’re over 30,” says Wilson, “you are more likely to lose teeth because of periodontitis than caries.” Caries, or cavities, have received more airtime, though. You get them when Streptococcus mutans, a component of plaque, ferments sugary foods to produce lactic acid. This not only erodes the tooth’s enamel surface, it also allows S. mutans to proliferate. “The bug starts outgrowing the other bugs, many of which can’t survive in low pH,” says Wilson.
Caries could soon be a thing of the past, though. Jeffrey Hillman of the University of Florida College of Dentistry in Gainesville has come up with an ingenious strategy for preventing them. It involves a genetically modified strain of S. mutans that also thrives on sugars but, instead of producing lactic acid, secretes an antibiotic that kills all other strains of the bacterium. The treatment, which is now being tested for safety in clinical trials, aims to provide lifelong protection with just a single, 5-minute application. Hillman has now set up a company called Oragenics to sell the idea.
Page Caufield of the New York University College of Dentistry and colleagues are also studying S. mutans, but with a completely different aim. Almost all humans are infected with the bacterium, and once a particular strain is in place, no naturally evolved rival can oust it. Exploiting the fact that S. mutans is almost exclusively transmitted from mother to child, the researchers have used it to trace human evolution back to the earliest migrations out of Africa. The various strains that travelled with the different branches of the human diaspora have co-evolved with them over millennia, so Caufield’s team used DNA markers to differentiate between strains, and then traced their evolution back to an original African population (see Diagram). The trail follows an important exodus to Asia, and branching off this, a bunch of very closely related strains that co-evolved with Caucasians.FIG-mg26171301.jpg
Caufield suspects Caucasians might have been founded by a splinter group of Asians who retraced their footsteps back to Europe. “Because there was virtually no variation in the Caucasian strains of S. mutans, we speculated that that particular group of humans originated from a very small founder population,” he says. “The strains strongly resemble one of the Asian strains, suggesting a relationship.”
While analysing our microbes to trace our ancestry, Caufield has made another potentially important discovery: differences in the genetic make-up of S. mutans strains could give rise to different degrees of virulence, meaning that some ethnic groups may be more susceptible to dental caries than others. He now intends to follow this up.
There is little doubt that as researchers start to decode the entire human microbiome, projects such as Caufield’s will get a huge boost. The next few years look set to see an explosion in our understanding about the tiny inhabitants that make us who we are.
The price of progress
The conquistadors brought flu to the South American Indians. Medieval urbanisation made it easier for Yersinia pestis to travel, and hence for the Black Death to lay waste to Europe’s population. There is nothing new about the idea that human advances lead to changes in our ecology, which in turn bring us into contact with new diseases. But can progress also lead to damaging changes in our internal ecology, to the communities of microbes that live within us?
Martin Blaser from the New York University School of Medicine thinks they can. “Many people are worried about changes in the macro-ecology of the world leading to global warming. I’m concerned that there might be parallel changes in the micro-ecology of humans that are the result of our rapid rate of change of human life, and that these have consequences for health and disease.”
He holds up Helicobacter pylori as an example. This bacterium is transmitted from mother to child, or between siblings, and has infected the majority of us for most of human history. When present, it is the dominant microbe in the stomach and plays a role in causing peptic ulcers and stomach cancer. Over the past century, however, better hygiene and an explosion in antibiotic use – not only in humans but also in the farm animals we eat – have meant that the incidence of H. pylori has dropped off rapidly. Blaser’s research suggests that fewer than 1 in 10 American children now have it (). That may sound like unmitigated good news, but he believes that you cannot remove the dominant microbe in a community without consequences.
Blaser points out that while ulcers and stomach cancer are on the decline, rates of oesophageal disease, asthma, eczema and allergic rhinitis are increasing. Over the past decade his group and others have shown an inverse correlation between the disappearance of H. pylori and the emergence of these diseases. Whether there is a physiological mechanism underlying the link is less clear, but Blaser points out that people infected with H. pylori develop a system of lymph vessels called a lymphoid compartment that secretes immune cells in their stomach. “It is my speculation that the lymphoid compartment is involved not just in local immunity, but in a generalised regulation of immunity in the body, and that people who do not have it have a lowered threshold to allergic sensitisations,” he says.
With the decline of H. pylori we may have traded one set of diseases for another. That is not necessarily bad, but the consequences of other changes in our microbial inhabitants could be more damaging. “As a biologist,” says Blaser, “I’m worried about upsetting long-term relationships. Nature abhors a vacuum, and perhaps the next H. pylori won’t be as benign as this one.”
