From boiling thermal hot springs to deep beneath the Antarctic ice, microorganisms can be found almost everywhere on earth in great quantities. Microorganisms (or microbes, as they are also called) are small organisms. Most are so small that they cannot be seen without a microscope.

Most microorganisms are harmless to humans and, in fact, many are helpful. They play fundamental roles in ecosystems everywhere on earth, forming the backbone of many food webs. People use them to make biofuels, medicines, and even foods. Without microbes, there would be no bread, cheese, or beer. Our bodies are filled with microbes, and our skin alone is home to trillions of them. Some of them we can’t live without; others cause diseases that can make us sick or even kill us.

Although much more is known today about microbial life than ever before, the vast majority of this invisible world remains unexplored. Microbiologists continue to identify new ways that microbes benefit and threaten humans.

Did you know that your body contains many more microbes (including bacteria and viruses) than human cells? And, even though some microbes can cause dangerous infections, you can't live without others? Viral and bacterial genomes might be small, but they are packed with information and some surprises about evolution and human health.

When you think of bacteria or viruses, what comes to mind? If you've been sick recently, you might not have good thoughts about them.

In 2018, infections from the influenza virus have been particularly rough. A big difference between 2018 and 15 years ago when the Human Genome Project was completed, is that genomics is now used routinely to track influenza virus infections, in real time, as the virus spreads across the country. These data are used to help design the vaccine used for our annual "flu shot." Even so, just one mutation in the virus's genome can make a big difference in the severity of someone's infection. Beyond influenza, the most advanced genomics technologies are being used to track infections caused by the Ebola and Zika viruses as they spread and mutate.

You may have also heard of situations where the overuse of antibiotics in both the medical and agricultural fields has contributed to bacteria becoming resistant to antibiotics, because with more exposure, bacteria that spontaneously develop resistance survive and reproduce more in this new environment, spreading this trait to the next generation. Now that we can track various microbes' genome sequences very accurately, we can see that antibiotic resistance most often happens when bacteria trade their DNA back and forth transferring the resistance trait. DNA sequencing of many, many bacterial species has now shown us that there has been rampant transfer of genes throughout history from early species of bacteria to those in existence today. These findings should make people think about the overuse of antibiotics in our world, since in the most extreme cases of infection with antibiotic-resistant bacteria can lead to serious illness and even death.

Microbes Make You Who You Are

Besides the microbes that make you ill, there are also "good" microbes. We contain multitudes of microbes (bacteria, yeast, and viruses), called our "microbiome." We would not be able to properly digest food without them living in our gut, or to have a working immune system without regular exposure to these microbes. However, things can also go wrong with your gut microbiome, such as when infection with the bacterium H. pylori leads to ulcers - this discovery led to the Nobel Prize in 2005. But, for the most part, our gut bacteria are huge helpers; they even train our own immune systems on what is "good" and what is "bad" in the microbial world. In another story related to our microbiome, we acquire millions of microbes from our mother at birth, including ones that live in our throats and quickly spread to keep out other, more harmful species. Genome sequencing has shown us how diverse our microbial communities are, and we will learn even more as the NIH's Human Microbiome Project finishes its work in 2018.

We Can Engineer New Microbes

Now that we have learned so much about microbial genomics, what else can we do? The field of synthetic biology has emerged directly from advances in DNA sequencing technologies, allowing for the design and construction of new biological systems. Teams from around the world are manipulating microbial genomes for applications in energy production and medicine. There is even the International Genetically Engineered Machine Competition (or iGEM) in which thousands of students compete each year to build new systems using standard parts called BioBricks. In 2016, a winning high school team from Taiwan constructed a new strain of E. coli, a famous bacterium that lives in your gut, that can detect levels of poisonous metals in Chinese medicines.

Most people today, even those who know very little about microbiology, are familiar with the concept of microbes, or “germs,” and their role in human health. Schoolchildren learn about bacteria, viruses, and other microorganisms, and many even view specimens under a microscope. But a few hundred years ago, before the invention of the microscope, the existence of many types of microbes was impossible to prove. By definition, microorganisms, or microbes, are very small organisms; many types of microbes are too small to see without a microscope, although some parasites and fungi are visible to the naked eye.

Humans have been living with—and using—microorganisms for much longer than they have been able to see them. Historical evidence suggests that humans have had some notion of microbial life since prehistoric times and have used that knowledge to develop foods as well as prevent and treat disease. In this section, we will explore some of the historical applications of microbiology as well as the early beginnings of microbiology as a science.

Fermented Foods and Beverages

People across the world have enjoyed fermented foods and beverages like beer, wine, bread, yogurt, cheese, and pickled vegetables for all of recorded history. Discoveries from several archeological sites suggest that even prehistoric people took advantage of fermentation to preserve and enhance the taste of food. Archaeologists studying pottery jars from a Neolithic village in China found that people were making a fermented beverage from rice, honey, and fruit as early as 7000 BC.

Production of these foods and beverages requires microbial fermentation, a process that uses bacteria, mold, or yeast to convert sugars (carbohydrates) to alcohol, gases, and organic acids (Figure 1.3). While it is likely that people first learned about fermentation by accident—perhaps by drinking old milk that had curdled or old grape juice that had fermented—they later learned to harness the power of fermentation to make products like bread, cheese, and wine.

The Iceman Treateth

Prehistoric humans had a very limited understanding of the causes of disease, and various cultures developed different beliefs and explanations. While many believed that illness was punishment for angering the gods or was simply the result of fate, archaeological evidence suggests that prehistoric people attempted to treat illnesses and infections. One example of this is Ötzi the Iceman, a 5300-year-old mummy found frozen in the ice of the Ötzal Alps on the Austrian-Italian border in 1991. Because Ötzi was so well preserved by the ice, researchers discovered that he was infected with the eggs of the parasite Trichuris trichiura, which may have caused him to have abdominal pain and anemia. Researchers also found evidence of Borrelia burgdorferi, a bacterium that causes Lyme disease. Some researchers think Ötzi may have been trying to treat his infections with the woody fruit of the Fomitopsis betulinus fungus, which was discovered tied to his belongings. This fungus has both laxative and antibiotic properties. Ötzi was also covered in tattoos that were made by cutting incisions into his skin, filling them with herbs, and then burning the herbs. There is speculation that this may have been another attempt to treat his health ailments.

Early Notions of Disease, Contagion, and Containment

Several ancient civilizations appear to have had some understanding that disease could be transmitted by things they could not see. This is especially evident in historical attempts to contain the spread of disease. For example, the Bible refers to the practice of quarantining people with leprosy and other diseases, suggesting that people understood that diseases could be communicable. Ironically, while leprosy is communicable, it is also a disease that progresses slowly. This means that people were likely quarantined after they had already spread the disease to others.

The ancient Greeks attributed disease to bad air, mal’aria, which they called “miasmatic odors.” They developed hygiene practices that built on this idea. The Romans also believed in the miasma hypothesis and created a complex sanitation infrastructure to deal with sewage. In Rome, they built aqueducts, which brought fresh water into the city, and a giant sewer, the Cloaca Maxima, which carried waste away and into the river Tiber (Figure 1.4). Some researchers believe that this infrastructure helped protect the Romans from epidemics of waterborne illnesses.

Even before the invention of the microscope, some doctors, philosophers, and scientists made great strides in understanding the invisible forces—what we now know as microbes—that can cause infection, disease, and death.

The Greek physician Hippocrates (460–370 BC) is considered the “father of Western medicine” (Figure 1.5). Unlike many of his ancestors and contemporaries, he dismissed the idea that disease was caused by supernatural forces. Instead, he posited that diseases had natural causes from within patients or their environments. Hippocrates and his heirs are believed to have written the Hippocratic Corpus, a collection of texts that make up some of the oldest surviving medical books. Hippocrates is also often credited as the author of the Hippocratic Oath, taken by new physicians to pledge their dedication to diagnosing and treating patients without causing harm.

While Hippocrates is considered the father of Western medicine, the Greek philosopher and historian Thucydides (460–395 BC) is considered the father of scientific history because he advocated for evidence-based analysis of cause-and-effect reasoning (Figure 1.5). Among his most important contributions are his observations regarding the Athenian plague that killed one-third of the population of Athens between 430 and 410 BC. Having survived the epidemic himself, Thucydides made the important observation that survivors did not get re-infected with the disease, even when taking care of actively sick people. This observation shows an early understanding of the concept of immunity.

Marcus Terentius Varro (116–27 BC) was a prolific Roman writer who was one of the first people to propose the concept that things we cannot see (what we now call microorganisms) can cause disease (Figure 1.5). In Res Rusticae (On Farming), published in 36 BC, he said that “precautions must also be taken in neighborhood swamps
. . . because certain minute creatures [animalia minuta] grow there which cannot be seen by the eye, which float in the air and enter the body through the mouth and nose and there cause serious diseases.”

The Birth of Microbiology

While the ancients may have suspected the existence of invisible “minute creatures,” it wasn’t until the invention of the microscope that their existence was definitively confirmed. While it is unclear who exactly invented the microscope, a Dutch cloth merchant named Antonie van Leeuwenhoek (1632–1723) was the first to develop a lens powerful enough to view microbes. In 1675, using a simple but powerful microscope, Leeuwenhoek was able to observe single-celled organisms, which he described as “animalcules” or “wee little beasties,” swimming in a drop of rain water. From his drawings of these little organisms, we now know he was looking at bacteria and protists.

Nearly 200 years after van Leeuwenhoek got his first glimpse of microbes, the “Golden Age of Microbiology” spawned a host of new discoveries between 1857 and 1914. Two famous microbiologists, Louis Pasteur and Robert Koch, were especially active in advancing our understanding of the unseen world of microbes (Figure 1.6). Pasteur, a French chemist, showed that individual microbial strains had unique properties and demonstrated that fermentation is caused by microorganisms. He also invented pasteurization, a process used to kill microorganisms responsible for spoilage, and developed vaccines for the treatment of diseases, including rabies, in animals and humans. Koch, a German physician, was the first to demonstrate the connection between a single, isolated microbe and a known human disease. For example, he discovered the bacteria that cause anthrax (Bacillus anthracis), cholera (Vibrio cholera), and tuberculosis (Mycobacterium tuberculosis). We will discuss these famous microbiologists, and others, in later chapters.

As microbiology has developed, it has allowed the broader discipline of biology to grow and flourish in previously unimagined ways. Much of what we know about human cells comes from our understanding of microbes, and many of the tools we use today to study cells and their genetics derive from work with microbes.

Did you know that you are never really alone? That is, that you spend every moment in the company of microorganisms in and on your body?

The human body carries an amazing 100 trillion microorganisms - ten times number of actual human cells. Most of these microbes reside in the large intestine; smaller numbers reside in and on other parts of the body. Collectively, they are referred to as the microbiota.

A healthy colon microbiota functions much like an organ of the body. It converts undigestable components of foods into forms that can be absorbed in the colon. In this way, it renders available from dietary fiber energy that the individual could not otherwise use. The fatty acids it produces also signal the immune cells of the colon and prevent growth of harmful bacteria.

The colon microbiota is thought to have a significant role in the utilization of food energy by converting dietary fiber to fatty acids. Research has indicated that this may account for as much as 10% of daily energy absorbed. Thus, factors that affect the nature and function of the microbiota may also affect the utilization of food energy. In fact, the microbiota of obese appear to glean food energy more efficiently than those of lean individuals.

An individual first acquires microbiota from the mother during birth. The nature of the microbiota observed in the first year of life has been associated with the risk of developing obesity later in life. Therefore, the health of the gut microbiota may be an important consideration in a weight management program.

Research has shown that what you eat affects your gut microbiota. Dietary sources of soluble fiber, collectively referred to as prebiotics, stimulate the growth of a healthy microbiota and increase resistance to harmful bacteria. Prebiotic carbohydrates are found in whole grains and many vegetables - beans, peas, lentils, asparagus, garlic, leeks, onions, artichokes. By following the US Dietary Guidelines for Americans (4 1/2 - 6 1/2 cups of vegetables and fruits, 6 - 10 ounces of grains containing about 50% whole grains) one should expect to get at least 21 - 38 grams of prebiotic carbohydrates each day.

A healthy diet is good for you in a way you may not have thought - by also being good for your healthful gut microbiota.

Microscopic bugs called microbes can be found in your eyes, mouth, gut, skin, and everywhere else. But don’t be alarmed. Most of your microbes are useful. They help you digest food. They prevent dangerous infections in your organs. And so much more. They’re vital for your health.

This collection of microbes in your body includes bacteria, fungi, and viruses. Together, it’s called the human microbiome.

“The microbiome is just as important as the brain, liver, kidney, or heart,” says Dr. Eugene Chang, who studies gut microbes at the University of Chicago.

Scientists have cataloged the types of microbes that live in the human body. They’ve found that changes in your body’s bugs are linked with many health problems. These include diabetes, obesity, inflammatory bowel diseases (IBD), and cancer. They can also cause skin disorders and tooth decay.

Certain things can harm the helpful microbes in your body. These include using antibiotics inappropriately or eating an unhealthy diet. Now, studies are starting to uncover ways to use microbes to improve your health.

Restoring Balance

One of the big jobs for our helpful microbes is to take up space. They live in places in the body that might otherwise be filled by harmful microbes that can cause disease, says Dr. Yasmine Belkaid, an immune system expert at NIH. “This is one way your microbiome prevents infection,” she says.

Your immune system normally attacks microbes that get into the body. But people grow up with their microbiome, Belkaid says. Many microbes are acquired from your mother at birth. So your immune system recognizes them as friendly and doesn’t attack them.

If these helpful microbes aren’t thriving, harmful ones can move in. But studies have shown that helpful microbes can be restored.

For example, people with a skin condition called eczema often have changes in their skin microbes. NIH researchers tested spraying a type of bacteria onto the skin of people with eczema. They found that it improved symptoms, including itching and rashes.

Your gut hosts lots of microbes. These can be thrown out of balance by many things, including antibiotics and diet. That can make room for harmful ones to grow.

One especially dangerous microbe is a type of bacteria that can grow in the intestines called Clostridioides difficile.C. difficile can cause fatal diarrhea, especially in older adults. It’s often resistant to treatment.

Researchers have developed a type of treatment for C. difficile infection called fecal microbial transplant. A patient is given microbes from the large intestine of a healthy person. This is done by transferring stool (poop) via tubes or pills.

Researchers don’t yet know exactly which of the microbes are needed for a healthy gut microbiome. So for now, they transfer the entire microbiome.

“Fecal transplants are a full-spectrum treatment. We’re just trying to change things wholesale,” says Dr. Gary Wu, a gut-health expert at the University of Pennsylvania.

Wu is part of a nationwide team that’s tracking the use of fecal transplants for C. difficile. In a nationwide study, they found that about nine out of 10 people who received fecal transplants were cured of C. difficile. “It works marvelously well for treating this infection,” Wu says.

The team continues to track people who have had fecal transplants. They want to learn more about its long-term safety.

Researchers are also testing this treatment for other conditions. These include IBD and other conditions that cause gut inflammation .

Wu says scientists are working on more targeted treatments to repair or replace a damaged gut microbiome. Different collections of microbes grown in the lab may eventually be tailored to treat different gut diseases. “That’s going to be the next generation of treatments,” he says.

Microbes and Obesity

Microbes in the gut do much more than just take up space, says Chang. “Gut microbes help regulate our metabolism—the digestion, absorption, and use of nutrients,” he explains.

His research team and others study proteins that gut bacteria release into the bloodstream. “These tell us how much we eat, when to eat, and what to eat,” he says.

This communication between our cells and our microbes seems to play a role in obesity. Chang and others have shown this in mice. They transplanted gut microbes from mice fed a high-fat diet into lean mice without any microbes. The lean mice then processed dietary fat differently and gained weight.

It’s not yet understood exactly how microbes help control metabolism. “But if we figure out how, that could be a game changer in preventing diet-induced obesity,” Chang says.

Keep Your Microbes Healthy

Researchers have started testing whether altering microbes can impact other areas of health.

Belkaid and her team found that changing the gut microbiome may improve how well a certain cancer treatment works. They’re also doing studies in mice to see if changing a female’s microbiome during pregnancy can boost her offspring’s immune system.

For now, what can you do daily to keep your helpful microbes healthy? “Diet is the major driver that shapes a person’s microbiome,” Chang says. Fortunately, your microbes respond quickly to changes in diet.

The dietary fiber found in plants is especially good for your gut bugs, says Belkaid. “One of the best things we can do for our microbes is to eat a healthy and diverse diet, and make sure it’s rich in fiber,” she explains.

Some types of foods may harm our microbiome, Belkaid adds. “These include foods high in carbohydrates, rich in sugar, or with too many artificial components,” she explains. “These can enrich for microbes that are bad for your health.”

“The microbiome is an extraordinary ally. It’s a healthy partner in helping the body function,” Belkaid says. See the Wise Choices box for other tips to help keep this partner healthy.

Protect Your Body’s Microbes

• Take antibiotics exactly as prescribed. Antibiotics are life-saving medicines. But they can also disrupt the healthy balance of microbes in your body.
• Eat a diet high in fiber. Fiber is found in plants, including fruits, vegetables, and whole grains.
• Limit foods that can hurt your gut microbes. These include sugar and fatty or highly processed foods.
• Wash your hands when preparing food, before eating, or after handling pets or garbage. Learn more about handwashing (CDC).
• Use hand sanitizer when you can’t use soap and water. Be sure it contains at least 60% alcohol. But washing with soap and water cleans more effectively.
• Avoid antibacterial soaps and other products. These have little or no health benefit. But they can harm the protective microbes on your skin.
• Be wary of “probiotics.” These products can be food or supplements. They may claim to restore a healthy microbe mix, but many have not been properly studied. Learn more about probiotics.