Bacteria

The bacteria that live on and in the human body far outnumber the body itself, both in numbers of cells and in numbers of genes. Now scientists are wondering: Are we in charge, or are symbiotic bacteria?
Biologists used to think of the human body as an island of biology, entirely capable of regulating its internal workings. Our bodies secrete digestive enzymes to digest food, synthesize nutrients and maintain body tissues and organs; You can sense your own signals, like hunger and fullness; Immune cells recognize dangerous microbes (pathogens) and attack them without harming their own tissues.
But over the past decade or so, researchers have discovered that the human body is not a self-contained island. It’s more like a complex ecosystem, a huge society. Trillions of bacteria and other microbes live in our bodies. They live on our skin, our genitals, our mouth, and especially our intestines. In fact, human cells are not the most numerous cells in the body; symbiotic bacteria outnumber human cells by 10 to 1. The bacterial community, made up of microbial cells and the genes they contain, is not harmful to our health, but good for us, helping the body digest, grow and defend itself.
It’s amazing how little bacteria can have such an impact. Biologists have studied some of the most abundant bacteria in the human body. More recently, they have looked at other bacteria. These studies can help us better understand how our bodies function. It also helps us understand why some diseases, such as obesity and autoimmune diseases, are on the rise.
You can’t see me

When people think of microbes in the body, they usually think of germs. In fact, for a long time, researchers focused only on the bad bugs and ignored the good ones. Sarkis K. Mazmanian, a biologist at the California Institute of Technology, thinks we’ve got it wrong. “Our eyes are mesmerized by our narcissism. We think we have all the functions we need to stay healthy. These good bacteria are not in our body but they are an integral part of our body.”
From a very young age, we have a microbiome in our body, but of course, these bacteria are not born with us. Each person gradually forms their own symbiotic bacterial community as they interact with their surroundings. As a rule, there are no bacteria in the womb, so a fetus at the start of life is a truly sterile individual. But when a newborn passes through the birth canal, the mother’s symbiotic bacteria transfer to the baby and start reproducing. With contact with parents, grandparents, siblings, friends, sheets, blankets, and pets, babies accumulate more bacteria, and by late infancy, we have built up the most complex microbial community on the planet.
About five years ago, scientists began studying this microbial ecosystem. They had a problem — gut bacteria were so used to living in colonies and without oxygen that individual bacteria simply couldn’t survive in an open petri dish. Now the conundrum has been solved. Instead of studying individual bacteria, the researchers studied their genes — the structure of the strands of DNA and RNA. Because DNA and RNA can be studied in conventional aerobic environments, scientists can take samples of bacteria from people and then extract genetic material from the samples for experimental analysis.
Each symbiotic bacterium has its own identity card, the 16S ribosomal RNA gene, which is different in each bacterium. The gene encodes specific RNA molecules in the ribosome, the machine in cells that makes proteins. By sequencing these genes, scientists are trying to create a manual for human bacteria. In this way, we can know which bacteria we have in our bodies and how they differ from others.
The next step is to analyze other genes in the bacterial community to figure out which bacteria are active in the body and what functions they have. The work is also complicated. Not only are the bacteria numerous, but their genes get mixed up during the extraction process. It is difficult to identify which species a gene belongs to. Identifying whether a bacterial gene is active or not is relatively easy. Fortunately, in the last decade, more powerful computers and super-fast gene sequencers have made it possible, if not impossible, to sort and analyze bacteria in ways that were previously impossible.
Two teams of scientists in the United States and Europe are using the new technique to tally bacterial genes in the human body. In early 2010, a European team published its tally of the number of bacterial genes in the human digestive system — 3.3 million genes (from more than 1,000 species), nearly 150 times the number in humans (who have 20,000 to 25,000 genes).
In studying the bacterial community in humans, there have been many surprising discoveries — for example, you will rarely find two people with identical bacterial communities, even identical twins. The Human Genome Project has confirmed that DNA is 99.9% the same in all people. Variations in bacterial genes, it seems, have a far greater impact on individual human fate, health and behaviour than our own genes do. The types and numbers of bacteria vary widely from person to person, but for most people the genes that play a key role in good bacteria are pretty much the same, even though they come from different strains. In addition, even the most beneficial bacteria can cause serious diseases if they thrive in the wrong places. For example, when bacteria get into the bloodstream, they can cause sepsis. It gets into the network of tissues between the abdominal organs and causes peritonitis.
Lurking comrade in arms

The benefits of bacteria were first discovered decades ago through studies of digestion in animals’ guts and the synthesis of vitamins. In the 1980s, researchers discovered that vitamin B12 helps the body’s cells produce energy, synthesize DNA and make fatty acids, but the enzymes that make vitamin B12 must be made by bacteria. Scientists have known for years that bacteria in the gut can break down certain hard-to-digest and absorb components of food, but it’s only recently that they’ve discovered an interesting detail: There are two other types of bacteria in the body’s symbiotic bacterial community that affect digestion and appetite.
Bacteroidetes multiformis, which probably takes its name from the Greek sorority or fraternity, is the best carbohydrate-degrading bacteria, capable of breaking down the large carbohydrates found in many plant-based foods into glucose and other small, easily digestible sugars. There are no genes in the body that make enzymes that degrade carbohydrates, but genes in Bacteroides multiformis make more than 260 enzymes that digest plant ingredients, helping the body efficiently extract nutrients from foods such as oranges, apples, potatoes and wheat germs.
In experiments with mice, the researchers found that Bacteroidetes multiforme can interact with their hosts to provide them with nutrients. The mice were raised in a completely sterile environment (they were free of any bacteria) and then exposed to Bacteroidetes multiform. In 2005, researchers at Washington University in St. Louis found that Bacteroidetes multiform survived by eating polysaccharide molecules, or complex carbohydrates. Bacteroides multiform ferments these nutrients to produce short-chain fatty acids (their excrement) that feed the mice. In this way, the bacteria get calories from carbohydrates that would otherwise be indigestible, such as the dietary fiber found in oatmeal. The researchers also found that to gain the same weight, mice that did not carry Bacteroidetes multiform needed to eat 30 percent more than mice that carried the bacteria.

The search for symbiotic bacteria has also brought a pathogen, Helicobacter pylori, back to fame. In the 1980s, Australian doctors Barry Marshall and Robin Wallen discovered that H. pylori, one of the few bacteria that thrive in the acidic environment of the stomach, was the cause of stomach ulcers. Until now, the continued use of nonsteroidal anti-inflammatory drugs (such as aspirin) had been thought to be a common cause of stomach ulcers, so the discovery of bacteria causing stomach ulcers quickly made headlines at the time. Since then, the use of antibiotics to treat stomach ulcers has become a standard clinical treatment. Soon, the incidence of ulcers caused by h. pylori dropped by more than 50 percent.
But Martin Blazer, a professor of internal medicine and microbiology at New York University, says it’s not that simple. Professor Blazer has been studying H. pylori for 25 years. “Like everyone else, I thought H. pylori was just a pathogen, but after a few years, I realized that it was actually a good bacterium that lived in symbiosis with the human body.” In 1998, Blazer and colleagues found that H. pylori is good for most people, regulating stomach acid levels to create an environment suitable for both it and its host. For example, helicobacter pylori thrives when the stomach produces too much acid, and the cagA gene in the bacterium starts producing a protein that causes the stomach to make less of it. In susceptible people, however, cagA has the undesirable side effect of aggravating ulcers caused by h. pylori.
Ten years later, Blazer published another study showing that H. pylori not only regulates stomach acid production, but also has other effects. Scientists have long known that the stomach produces two hormones linked to appetite: ghrelin, which tells the brain that the body needs to eat, and leptin, which tells the stomach that it is full and no longer needs to eat. “When you wake up in the morning, you’re hungry, and that’s because your ghrelin levels are high,” Says Blazer. “This hormone tells you that you need to eat. Ghrelin levels drop after breakfast.” Scientists call this physiological process “postprandial reduction.”
In a study published last year, Dr. Blazer and his colleagues compared ghrelin levels before and after meals in two groups of subjects: one with H. pylori and the other without. The results were clear: People with H. pylori had lower ghrelin levels after meals; People without H. pylori do not have this ability, suggesting that h. pylori regulates levels of ghrelin, or appetite. Unfortunately, the exact mechanism is still largely a mystery. In a study of 92 veterans, those who had taken antibiotics to destroy the bacterium h. pylori gained weight more quickly than their uninfected counterparts. This may be because their ghrelin levels do not drop at the right time, causing them to feel hungry longer and eat more.

Eighty percent of older Americans carry the acid-resistant bacterium Helicobacter pylori. Today, fewer than 6 percent of American children test positive for H. pylori. “This generation of children is growing up without h. pylori regulating ghrelin,” Says Breezer. And because these children are often given high doses of antibiotics, their microbial makeup has changed dramatically. For example, most American doctors treat children with antibiotics for otitis media. Blazer suspects that the increased use of antibiotics by teenagers, which alters the composition of bacteria in their gut, may be driving the rise in childhood obesity. He believes that within the bacterial community, different bacteria affect the body’s fat, muscle and bone stem cells separately. Giving teenagers antibiotics destroys certain bacteria, interferes with normal physiological signaling, and eventually leads to an excess of fat cells.
With the demise of H. pylori and other bacteria, more high-calorie foods and less manual labor, could the microbiome be tipped off, triggering a global obesity epidemic? “We don’t know how much the microbiome affects obesity,” Blazer said. But I’m willing to bet that the impact of bacteria on humans is anything but trivial.”
According to Blazer, the widespread use of antibiotics is not the only culprit that destroys the body’s bacterial community. Changes in the ecology of human society since the beginning of the last century have also had an impact. Over the past few decades, the number of pregnant women giving birth by cesarean section has increased dramatically, preventing some important strains from passing through the mother’s birth canal to the baby (in the United States, more than 30 percent of births are by cesarean section; In China, nearly two-thirds of urban women opt for cesarean sections). What’s more, modern families are small and have fewer siblings, meaning there are fewer ways for bacteria to pass on to young children. And while drinking water purification projects have saved millions of people from diseases caused by unsanitary drinking water, they have also reduced our exposure to symbiotic bacteria. It is clear that more and more people are being born and raised in a shrinking microbial world.
An integral

In the study of Bacteroidetes Multiformis and H. pylori, complex answers emerge to even the most basic questions. Like, what are these bacteria doing in the body? If we look further, how does the body act on these foreign cells? Then the problem becomes more complicated. It is well known that the body’s immune system differentiates between its own cells (the self) and external cells (foreign bodies) that have different genes, and automatically rejects the latter. It seems that our body’s biological defense system should be actively engaged in war against the vast number of symbiotic bacteria. Why don’t the immune cells in the gut do the same? This has been one of the great mysteries of immunology.
Scientists have found clues that point to a very novel idea: over 200,000 years of evolution, bacterial communities and immune cells in the human body have reached a peaceful coexistence, or equilibrium. Over the past hundred million years, the immune system has evolved to be neither too aggressive (attacking its own people) nor too relaxed (letting go of enemies). For example, T cells play an important role in recognizing and fighting back against invading pathogens, as well as triggering a range of inflammatory responses (swelling, redness, fever, etc.). However, after producing a large number of T cells, the body soon produces regulatory T cells, which counteract the effects of pro-inflammatory T cells and reduce inflammation.
Normally, regulatory T cells are quick to kick in before pro-inflammatory T cells can take over. “The problem is that the things these pro-inflammatory T cells do to defend themselves against foreign enemies, like releasing toxic compounds, can damage our own tissues,” says Marzmanian of the California Institute of Technology. Fortunately, regulatory T cells produce a protein that inhibits pro-inflammatory T cells. Eventually, inflammation is reduced and the immune system no longer attacks the body’s own cells and tissues. Once a balance is struck between aggressive pro-inflammatory T cells and peaceful regulatory T cells, the body remains in good health.

For years, researchers thought that this homeostatic system was entirely created by the immune system. But Mazmanian and his colleagues found that whether an immune system is healthy and mature depends on whether good bacteria are constantly working against it. This fact proves once again that we are not masters of our own destiny. “The notion that bacteria can make our immune system work better may be a counterintuitive one,” Says Marzmanian, “but it’s becoming clear that the driving force behind the immune system is symbiotic bacteria.”
Marzmanian and his team at Caltech found that most people — 70 to 80 percent — have a bacterium called Bacteroides fragilis in their bodies. The bacteria release anti-inflammatory substances that help keep the immune system in balance. They studied germ-free mice with a defective immune system, whose regulatory T cells were impaired. When the researchers injected bacteroides fragilis into mice, the rodents’ immune systems returned to normal, restoring a balance between pro-inflammatory and anti-inflammatory T cells.
What’s the mechanism? In the early 1990s, researchers studied several sugar molecules that stretch out on the surface of Bacteroidetes fragilis and found they were responsible. In 2005, Marzmanian and colleagues showed that one of these molecules, called polysaccharide A, promotes the maturation of the immune system. Soon after, they found that polysaccharide A signals the immune system to make more regulatory T cells, which in turn tell the pro-inflammatory T cells not to attack bacteroidetes fragilis. Conversely, bacteroides fragilis, which lacks polysaccharide A, cannot survive in the intestinal mucosa because immune cells attack the bacteria as pathogens.
In 2011, Marzmanian and colleagues published a paper in the journal Science detailing the molecular reactions involved in these effects, the first to illuminate symbiosis between microbes and mammals. “Bacteroides fraginis is very good for us, helping us to compensate for our own DNA,” Dr. Mazmanian said. “A lot of times, it’s dictating to our immune system, manipulating it.” But, unlike many pathogens, this manipulation doesn’t suppress or weaken the performance of our immune system. Instead, it helps it function. Other bacteria in our bodies may have a similar effect on the immune system. “This is just the first example,” he cautioned. There will no doubt be more examples to come.”
Unfortunately, bacteroides fragilis, like H. pylori, is facing extinction because of changes in people’s lifestyles. “So-called social development has completely changed our connection to the microbial world in a very short period of time,” Marzmanian said. “In trying to insulate ourselves from pathogens, we’ve also disconnected ourselves from beneficial microbes. We mean well, but we will pay a heavy price for it.”
In the case of Bacteroides fragilis, the cost may be an autoimmune disorder. Without polysaccharide A to signal the immune system to produce more regulatory T cells, those aggressive T cells will attack anything they come in contact with, including the body’s own tissue. Mazmanian believes the decline in beneficial bacteria is linked to a seven-to-eight-fold increase in immune system diseases in recent years, such as Crohn’s disease, type 1 diabetes and multiple sclerosis. “There are both internal and external causes of these diseases,” Dr. Mazmanian said. “I believe the external cause is the symbiotic bacterial community, and changes in that community are affecting our immune system.” Changes in the way we live lead to changes in the microbial community that reduce bacteroides fragile and other anti-inflammatory microbes, leading to regulatory T cell dysplasia. For those who are genetically susceptible, the changes can lead to immune disorders and other illnesses.
Of course, that’s just one possibility. Studies at this stage can only show that a decrease in the number of symbiotic bacteria is associated with an increased incidence of immune diseases. But it’s hard to tell which is the cause and which is the effect. Take obesity, for example. On the one hand, the decline in the number of bacteria that are inherent in the body has led to a sharp rise in the incidence of autoimmune diseases and obesity. On the other hand, these diseases also make the internal environment inhospitable to symbiotic microbes. Mazmanian believes the former is the main contradiction, with changes in the bacterial community in the gut leading to increased rates of immune diseases. But “it’s up to scientists to go further and do studies to prove cause and effect and clarify the mechanisms behind it,” Marzmanian said. “That’s our responsibility and our job.”