Our bodies’ best buddies
Elisabeth M Bik, Stanford University
Note: this article was written for the September 2014 issue of the San Francisco Medical Society magazine.
Antony van Leeuwenhoek probably could not believe his eyes. It was 1683, and the Dutch scientist had put some tooth scrapings from his own mouth under the primitive microscope that he had built himself. He had used similar microscopes to look at algae and ciliates in lake water, but now he wanted to study a different type of sample. He decided to not clean his mouth for a couple of days, and to use the material growing between his teeth for a new experiment. He must have been very excited when he looked through the lens and saw hundreds of tiny creatures wiggling and moving. “I then most always saw, with great wonder, that in the said matter there were many very little living animalcules, very prettily a-moving”, he wrote to the Royal Society of London. 
That observation made van Leeuwenhoek the first human to study and describe bacteria – the beginning of microbiology. Most of the famous pioneers in that field focused on the causative agents of infectious diseases, such as Robert Koch’s research on anthrax, cholera, and tuberculosis, and Louis Pasteur’s work on developing vaccines for anthrax and rabies. The devastating effects of bacterial and viral diseases on humans throughout history lead to the belief that most microorganisms are detrimental for our health. Even nowadays, disturbing headlines about flesh-eating bacteria or deadly microbes present on dollar bills or lurking in your kitchen sink makes some people think that the only good germ is a dead germ.
Fortunately, most bacteria are not harmful, and many of them are our closest friends. As van Leeuwenhoek discovered, human bodies are home to trillions of microbes. An often used but not very well founded quote states that our bodies have ten times more microbial cells than human cells, or, in other words, that we are only ten percent human. Luckily, the microbes are much smaller than human cells, and there is plenty of room for them. Most of these microbes are bacteria, with archaea and yeasts present in lower numbers. Humans are not the only hosts of large microbial communities. Nearly all living organisms, from microscopically small nematodes to elephants, from microalgae to Sequoia trees, both animals and plants are associated with microbes that play important roles in their physiology.
Who they are: Composition of the human microbiome
The microbes associated with our bodies are pretty much everywhere: on our skin, between our teeth, in our saliva and stomachs, but the largest group of them is housed inside our large intestine. There are hundreds to thousands of different bacterial species within a single person. Together, we call these conglomerates of microbes the human microbiome, or microbiota.
New molecular techniques have allowed scientists to look at millions of microbial DNA molecules from a single sample, such as stool or an oral swab. Because many bacterial species are hard to grow in the lab, these DNA-based methods have provided a more unbiased view of the human microbiome composition than culturing. Surprisingly, Escherichia coli, previously thought to be the most abundant inhabitant of our intestinal tract because it grows easily on culture plates, was found to constitute only 0.1% of the distal gut flora. Instead, molecular studies showed that the majority of bacteria in the human gut belongs to the Firmicutes and Bacteroidetes groups, which are much harder to recover by culture. 
Every body site harbors a distinct microbial community.  Characterized by different physiological properties, each body habitat will appeal to a different set of bacterial species, similar to how plant communities vary between different climate zones, altitude, or soil types. Not only do the human-associated microbial conglomerates differ between anatomical sites, they also differ between individuals. That makes as unique from the inside as we are from the outside!
How they got there: It all starts at birth
The assembly of a newborn’s individual microbiome takes mostly place in the first three years of life, starting with the simple communities obtained in the delivery room, gradually increasing in complexity, until the conglomerates resemble an adult-like microbiome. Although low amounts of bacteria have been found in placentas, the main colonization of an infant’s body starts during birth, and delivery mode plays a pivotal role in this process. Minutes after birth, vaginally born infants’ skin contains Lactobacillus and Prevotella species very similar to the species found in their mother’s vagina. Instead, infants born via Cesarean section carry a more skin-like flora that does not match the skin microbiomes of their mothers, but might have derived from other people present in the delivery room. The microbiome differences between these infant groups last for many months, and C-section delivered children appear to have a higher risk for asthma, atopic diseases, and obesity later in life. 
What they do: Functions of the human microbiome
Not only have scientists investigated who our bacterial inhabitants are, we have also learned about what they can do. Together, the human gut microbiome contains 150 times more genes than our own genome, therefore supplementing our own functional capacity with an enormous additional potential. 
An important function of the gut microbiome is the digestion of complex carbohydrates in our food for which we lack the enzymes. The presence of a gut microbiome allows a mammalian host to break down these starches and fibers and to extract more energy out of the diet. Germ-free mice, born and raised in sterile incubators, need to eat 30% more food to remain the same body weight than mice with a conventional microbiome. In addition, the gut microbiome is involved in an ever-increasing list of other functions, such as lipid metabolism, blood glucose levels, release and response to hormones, vitamin synthesis, and the correct development of anatomical structures and the immune system. 
Microbiome and obesity
About 35 percent of American adults are obese, and sedentary lifestyle and poor food choices are obvious causes. But, given the important roles that our gut microbes play in food digestion and fat metabolism, could they be involved in obesity as well? Studies from the laboratory of Jeffrey Gordon have shown that obesity is indeed partly determined by the composition of our microbiome. Although the precise role of the microbiome in obesity is yet unclear, obese humans have less bacterial species in their stool than lean people. Working with human pairs of twins discordant for obesity, Gordon’s group showed that stool from an obese human twin could transfer obesity to mice, while mice that received stool from the lean human twin stayed thin. 
Collateral damage of antibiotics
The human-associated microbiome is relatively stable over time in the absence of travel, diet changes, or diseases.  However, a single course of antibiotics can have a dramatic impact on its composition. Most antibiotics are designed to kill broad groups of bacteria and cannot distinguish between the pathogenic bacteria causing a sore throat or skin infection, and the beneficial microbes in our guts. Each time we take a course of antibiotics to treat an infection, we are also killing parts of our microbiome. The gut communities usually bounce back, but it can take weeks or even months to go back to their starting point. In some cases, the intestinal microbiota never completely recovers from this perturbation, and particular groups might be permanently lost. 
Antibiotic use can also lead to antibiotic-associated diarrhea. This is often caused by a toxin-producing bacterium called Clostridium difficile, which is normally present at very low abundance in the human gut where it’s competing with many other bacteria for space and food. It is less sensitive to antibiotics than most beneficial gut microbes, and can take advantage of the open space left by antibiotics. The overgrowth of C. difficile can lead to persistent and hard-to-treat diarrhea, and C. difficile infection is now the leading cause of hospital-acquired infections. 
Low exposure to germs
Despite an increasing awareness that some microbes might be good for us, many people try to avoid contact with germs. We eat nearly sterile food, put paper on the toilet seat, disinfect toothbrushes with UV light, and clean grocery carts and exercise equipment with germ-killing wipes. In addition, we wash our skin with antibacterial soaps, and decimate our gut bacteria when we take antibiotics for a suspected infection.
While many infectious diseases have rapidly declined in the past decades, many other diseases such as allergies, inflammatory bowel diseases, asthma, celiac disease, diabetes, and obesity are on the rise. In his recent book “Missing Microbes”, Martin Blaser links their increase to the overuse of antibiotics, which has not only contributed to an increasing number of antibiotic-resistant strains, but which is also detrimental to our microbiome.  At the age of 3 years, the average US child has already received 3-6 doses of antibiotics, exactly during the time that their microbiome is developing. 
Since our microbiome is involved in many processes in our bodies including educating and balancing our immune system, the increased use of antibiotics and reduced exposure to bacteria early in life might be related to the increase in diseases of the immune system and obesity.
A healthier view of microbes
Obviously, we do not want to return to the Dark Ages where infectious diseases could kill half of a continent’s population. We should support vaccination, treat life-threatening infections with antibiotics, and wash our hands with regular soap. But knowing how important a healthy and diverse microbiome is for our health, we should embrace the thought that low amounts of bacterial exposure might be good. Maybe we should not disinfect children’s school desks or buy antibacterial soap, and take antibiotics only when it’s absolutely necessary. Maybe we should be eating more live bacteria by consuming fermented food and yogurts with probiotics, and let the kids play in that dirty sandbox.
Even grosser treatment options are emerging. Stool transplants, in which a patients’ own microbiota is killed and replaced with the gut microbes of a healthy donor, have been successfully used to treat patients with recurrent C. difficile diarrhea . People have even suggested that we should smear babies born via C-section with rectal and vaginal samples from their mom, immediately after birth.
But realizing that we have to take care of our internal microbes is already a start. Microbiome research is a very hot research topic and an exciting field to work in, and scientists expect to find many more roles that these little buddies play in our health.
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