What we don’t know is what all this means for each individual. We notice pretty quickly when we have ingested diarrhea-causing bacteria. But what do we notice of the work carried out by the many millions, billions, trillions of tiny creatures inside us every day? Does the precise nature of the creatures that colonize us make a difference? Skewed proportions of the different bacteria in our gut have been detected in those suffering from obesity, malnutrition, nervous diseases, depression, and chronic digestive problems. In other words, when something is wrong with our microbiome, something goes wrong with us.
One person might have stronger nerves than another because she has a better stock of vitamin B–producing bacteria. Another person might be able to deal easily with bit of bread mold eaten by mistake. Yet another might have a tendency to gain weight because the “chubby” bacteria in his gut feed him a bit too willingly. Science is just beginning to understand that each of us is an entire ecosystem. Microbiome research is still young, complete with wobbly milk teeth and short pants.
Bacteria population density in the different regions of the gut.
When scientists still knew very little about bacteria, they classified them as plants. This explains terms like gut flora, which is not scientifically accurate, but it is appropriately descriptive. A bit like plants, different bacteria have different characteristics concerning their habitat, nutrition, or level of toxicity. The scientifically correct terms are microbiota (which means “little life”) and microbiome, to refer to our collection of microbes and their genes.
In general, it is accurate to say that the number of bacteria is smaller in the upper sections of the digestive tract, while a very, very large number reside in the lower parts, such as the large intestine and the rectum. Some bacteria prefer the small intestine; others live exclusively in the colon. There are great fans of the appendix, well-behaved homebodies that stick to the mucus membrane, and rather cheekier chaps that nestle up close to the cells of our gut.
It is not always easy to get to know our gut microbes personally. They don’t like to be removed from their own world. When scientists try to grow them in the lab to observe them, they simply refuse to cooperate. Skin bacteria merrily gobble up the lab food and grow into little microbe mountains—gut bacteria don’t. More than half the bacteria that grow in our digestive tract are just too well adapted to living there to be able to survive outside the gut. Our gut is their world. It keeps them warm, moist, protected from oxygen, and supplied with pretasted food.
Only ten years ago, many scientists would probably have maintained that there is a stable stock of gut bacteria that is more or less common to every human being. For example, when they spread feces on a culture medium, they always found E. coli bacteria. It was as simple as that. Today, we have machines that can scan tiny amounts of feces molecule by molecule. This reveals the genetic remains of billions of bacteria. We now know that E. coli make up less than 1 percent of the population in the gut. Our gastrointestinal tract is home to more than a thousand different species of bacteria—plus minority populations of viruses and yeasts, as well as fungi and various other single-celled organisms.
You might think our immune system would pounce on this multitude of settlers. Defending the body from foreign invasions is high on the immune system’s to-do list. Sometimes it even wages war on tiny pollen grains that accidently get sucked into our nostrils. Hay fever sufferers know the signs: a streaming nose and itchy eyes. So, how do the bacteria sidestep the immune system and stage a bacterial Woodstock inside our bodies?
The Immune System and Our Bacteria
WE FACE POTENTIAL death every day. We could get cancer, get eaten away by bacteria, or get infected with a deadly virus. And several times a day, our lives are saved. Strangely mutated cells are destroyed, fungal spores are eliminated, bacteria are peppered with holes, and viruses are sliced in two. This agreeable service is provided by our immune system, with its many little cells. Its workforce includes experts at spotting foreign bodies, contract killers, hatters, and mediators. They all work hand in hand, and together they are a pretty top team.
The vast majority of our immune system (about 80 percent) is located in the gut. And with good reason. This is where the main stage at the bacterial Woodstock is situated, and any immune system worth its salt must be there or be square. The bacteria are confined to a fenced-off area—the mucus membrane of the gut—preventing them from getting too dangerously close to the cells of the gut wall. The immune system can play with the cells without ever posing a danger to the body. This allows our defender cells to get acquainted with many previously unknown species.
If, sometime later and elsewhere in the body, an immune cell encounters a now-familiar bacterium, it can react to it much more quickly. The immune system has to be extremely careful in the gut, suppressing its defensive instincts and allowing the many bacteria there to live in peace. But, at the same time, it must also recognize dangerous elements in the crowd and weed them out. If we decided to say “Hi” to each of our gut bacteria individually, we might just manage it in around 3 million years. Our immune system not only says, “Hi,” it also says, “You’re okay,” or “I’d prefer to see you dead.”
Also, strange as it may sound, the immune system must be able to distinguish between bacterial cells and the body’s own human cells. That is easier said than done. Some bacteria have structures on their surface that bear a close resemblance to those on the surface of our own cells. This is the reason why, for example, scarlet fever should be treated immediately with antibiotics. If it is not treated quickly, the immune system can begin to mistake the cells of the joints or other organs for the bacteria that cause scarlet fever and attack them. It might suddenly think our knee is a nasty sore-throat germ hiding out in our leg. It happens rarely—but it does happen.
Scientists have observed a similar effect in patients with juvenile diabetes. Also called diabetes mellitus type 1, this condition results from the autoimmune destruction of the cells that produce insulin. One possible cause is a breakdown of communication with the bacteria of the gut. It may be that they are failing to train the immune system properly or the immune system is somehow getting the message wrong.
The body actually has a very rigorous set of measures designed to guard against such communication breakdowns and cases of mistaken identity. Before an immune cell is allowed to enter the bloodstream, it has to complete the toughest boot camp of any cells. Among other things, it must cover a vast distance while being constantly confronted with various structures of the body. If our little immune cell encounters something it cannot clearly identify as belonging to the body or coming from outside, it stops and prods at it a little. That is a fatal error: this cell will never graduate to the bloodstream.
In this way, immune cells with a tendency to attack the body’s own tissue are weeded out before they leave boot camp. In their training center in the gut, they learn to be tolerant of foreign bodies, or rather, they learn to be better prepared for an encounter with them. This system works rather well and usually without untoward incidents.
There is one lesson that is particularly tricky to learn: what to do about foreign bodies that aren’t actually bacteria but remind the immune system of them? Red blood cells, for example, have very bacteria-like proteins on their surface. Our immune system would attack our own blood if it had not learned in boot camp that the blood is a no-go area. If our blood cells have the blood-group marker A on their surface, we have no problem receiving transfusions of blood from donors with the same blood group. The reasons for needing a transfusion can be diverse, from a motorbike accident to heavy blood loss during childbirth.
However, we cannot receive blood from donors whose blood cells have a different blood-group marker on their surface. It would immediately remind our immune system of bacteria, and since the immune system knows that bacteria have no business being in the bloodstream, it would consider the donated blood cells an enemy and cause the cells to form clumps. If it weren’t fo
r this combat readiness—learned through training by our gut bacteria—there would be no blood groups and any donor could give blood to any recipient. For newborn babies, who do not yet have many bacteria in their guts, this is indeed the case. They can theoretically receive transfusions of blood from any group without any incompatibility effects. (As a precaution, hospitals give babies blood from the mother’s blood group, since antibodies from the mother can find their way into the baby’s bloodstream.) As soon as babies begin to develop a rudimentary immune system and gut flora, they can only tolerate blood from their own group.
If antibodies match with foreign blood cells, the cells will form clumps. Blood group B has antibodies against blood group A.
Blood-group development is just one of many immunological phenomena caused by bacteria. There are probably many more waiting to be discovered. Much of what bacteria do tends to be fine tuning. Each kind of bacteria has its own way of affecting the immune system. Some species have been observed to make our immune system more tolerant, for example, by causing more peace-loving, mediatory immune cells to be produced, or by affecting our cells in a similar way to cortisone and other anti-inflammatory drugs. That results in a milder, less belligerent immune system. This is probably a clever move on the part of these tiny creatures, since it increases their chances of being tolerated in the gut.
The fact that the small intestines of young vertebrates (including humans) have been found to contain bacteria that provoke the immune system leaves room for speculation. Could it be the case that these provocateurs help keep the bacteria population in the small intestine down? That would make the small intestine an area of low bacteria tolerance, giving it some peace and quiet for a while. The provocateurs themselves do not hang out in the mucus membrane like good little bacteria, but dock firmly onto the villi of the small intestine. A similar preference is shown by pathogens such as harmful versions of E. coli. When they want to colonize the small intestine, but find their favorite places occupied by such provocateurs, they have no choice but to leave.
This effect is known as colonization resistance. The majority of the microbes in our gut protect us simply by occupying spaces that would otherwise be free for harmful bacteria to colonize. Incidentally, the provocateurs of the small intestine belong to that group of characters that refuse to be cultivated outside the gut. How can we be sure that they are not actually harming us? Well, we can’t. It is possible that they do harm some people by overstimulating the immune system. Many questions remain to be answered.
Some of those questions might be answered with the help of a group of germ-free mice in a New York laboratory. They are the cleanest creatures in the world: they come into the world via sterile cesarean births, they live in antiseptic cages, and they eat steam-sterilized food. Disinfected animals like these could never exist in nature. Anyone working with these mice must take the utmost care, since even unfiltered air teems with flying germs. The mice allow researchers to watch what happens to an immune system that has nothing to do. What goes on in a gut with no microbes? How does an untrained immune system react to pathogens? What differences are so obvious they can be seen by the naked eye?
Anyone who has ever had anything to do with such animals will tell you—germ-free mice are weird. They are often hyperactive and exhibit an un-mouse-like lack of caution. They eat more than their germ-colonized peers and take longer to digest their food. They have hugely enlarged appendixes, shriveled digestive tracts with few villi and blood vessels, and a reduced number of immune cells. They are easy prey for even relatively harmless pathogens.
Feeding them with cocktails of bacteria taken from other mice produces astonishing results. If they are given bacteria from mice with type 2 diabetes, they soon begin to develop problems metabolizing sugar. If bacteria from obese humans are fed to germ-free mice, the mice are more likely to gain weight than if they receive bacteria from people in the normal weight range. Scientists can also administer a single species of bacteria to observe its effect on the mice. Some bacteria, acting alone, can reverse the effects of the sterile environment—cranking up the immune system, shrinking the mice’s swollen appendixes down to normal size, and normalizing their eating behavior. Other lone bacteria have no effect whatsoever. Yet others take effect only in cooperation with colleagues from other bacteria families.
Studies using these mice have advanced our knowledge quite considerably. We now have good reason to speculate that, just as the macroscopic world we live in influences us, we are also influenced by the microscopic world that lives in us. This is all the more interesting when we realize that each person’s inner world is unique to him or her.
The Development of the Gut Flora
AS UNBORN BABIES, we live in an environment that is normally completely germ-free—the womb. For nine months, we have no contact with the outside world except through our mother. Our food is predigested, our oxygen is prebreathed. Our mother’s lungs and gut filter everything before it reaches us. We eat and breathe through her blood, which is kept free of germs by her immune system. We are sheathed in an amniotic sac and encased in a muscly uterus that is corked with a thick plug like a big earthenware jug. All this means not a single parasite, virus, bacterium, or fungus—and certainly no other person—can touch us. We are more sterile than an operating table flooded with disinfectant.
This situation is unusual. Never again in our lives will we be so protected and so isolated. If we were designed to remain germ-free once we leave the womb, we would be very different creatures. But that is not the case, so all living things of any size have at least one other living thing that helps them in some way and is allowed to live on or in them in return. This explains why our cells are constructed in such a way that bacteria can easily dock with structures on their surface, and it explains why certain bacteria have coevolved with us over many millennia.
As soon as there is any breach in the protective amniotic sac, colonization begins. While 100 percent of the cells that make us up when we start life are human cells, we are soon colonized by so many microorganisms that only 10 percent of our cells are human, with microbes accounting for the remaining 90 percent. We cannot see this, because our human cells are so much larger than those of our new lodgers. Before we look into our mother’s eyes for the first time, the creatures that live in her body cavities have already looked into ours. The first ones we meet are her protective vaginal flora—an army that defends a very important territory. One way it does this is by producing acids that drive away other bacteria and keep the way cleaner and cleaner the closer they are to the womb.
Unlike the flora in our nostrils, which can be made up of around nine hundred different kinds of bacteria, the criteria for life in the birth canal are much stricter. This sorting process leaves women with a useful coating of bacteria, which wraps itself protectively around the sterile body of the baby as it emerges. About half these bacteria are from one genus: Lactobacillus. Their favorite pastime is producing lactic acid. This means the only residents that can set up home in the birth canal are those that pass the acid test.
With a routine birth, all we have to do as babies is decide which way to face as we come out. There are two attractive possibilities: toward the back or toward the front. During birth we are exposed to all sorts of skin contact before we are wrapped up in something soft by another person, who is usually wearing latex gloves.
By now, the founding fathers of our first microbial colonies are already in us and on us. These are mainly our mother’s vaginal and gut flora, mixed with a few skin-dwelling germs and possibly a few others from the hospital’s repertoire. This is a very good mixture to start with. The acid army protects us from harmful invaders, while other bacteria are already starting to train the immune system, and the first, indigestible components of our mother’s milk are broken down for us by helpful microbes.
Some of these bacteria take less than twenty minutes to spawn the next generation. What takes us twenty years or more happens in a fraction of the t
ime—a fraction as tiny as the colonists themselves. While our first gut bacterium watches its great-great-great-great grandchild swim by, we have spent just two hours in the arms of our proud new parents.
Despite this rapid population growth, it will be about three years before the gut flora develops to the right level and then stabilizes. Prior to that, our gut is the scene of dramatic power struggles and great bacterial battles. Some folks who find their way into our mouth spread rapidly throughout the gut, only to disappear again just as quickly. Others will remain with us for the rest of our lives. The composition of our gut colony depends partly on our own actions: we might lick our mother’s skin, gnaw on a chair leg, and give the car window or the neighbor’s dog the occasional sloppy kiss. Anything that finds its way into our mouth in the process could soon be building its empire in the world of our gut. Whether it will continue to prevail will remain to be seen. And whether its intentions are good or bad will also remain to be seen. So, we could say we gather our own fate with our mouth. Stool samples can show what comes out the other end. It’s a game with many unknowns.
We receive some help creating this collection—mainly from our mother. No matter how many sloppy kisses we give to the car window, if we are allowed to kiss and cuddle with our mother regularly, we will be protected by her microbes. Breast-feeding also promotes particular members of our gut flora—breast-milk-loving Bifidobacteria, for example. Colonizing the gut so early, these bacteria are instrumental in the development of later bodily functions, such as those of the immune system or the metabolic system. Children with insufficient Bifidobacteria in their gut in their first year have an increased risk of obesity in later life compared with infants with large populations.
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