Scientists at Penn State are at the forefront of microbiome research. Growing understanding of these microscopic organisms is changing the way we treat diseases, grow crops, and create everyday products.
New high-throughput sequencing technologies uncover a world of interacting microorganisms.
Your body teems with them–100 trillion microbes in your gut, lungs, mouth, and skin. Your home swarms with them–in toilets and sinks, on tables and chairs, in the carpet, and on your dog. Even the ground on which you stand abounds with countless bacteria, fungi, protozoa, algae, and viruses–all microscopic, all part of a community of organisms interacting with one another and the environment. These communities and the environments with which they interact are known as “microbiomes,” and our growing understanding of them is changing the way we treat diseases, grow crops, and create everyday products.
It’s changing how we view nature.
Scientists at Penn State and in the College of Agricultural Sciences are at the forefront of research on microbiomes. They are probing human and animal guts to learn how microorganisms influence health, and they are exploring the soils to uncover how microbes benefit crops. Through this work the scientists are gaining an appreciation for the complexity of microbial life on Earth. And they’re also exploring the potential benefits and challenges these creatures present.
The human journey into the realm of the microscopic began in 1657, when Antoni van Leeuwenhoek, a draper living in Delft, Holland, revealed that he had discovered, by looking through his self-created simple microscope, tiny “animalcules” living in lake water.
In a letter to the newly formed Royal Society of London, van Leeuwenhoek wrote that these animalcules were “so small, in my sight, that I judged that even if 100 of these very wee animals lay stretched out one against another, they could not reach the length of a grain of coarse sand.. . ’twas wonderful to see.”
Van Leeuwenhoek’s discovery of microorganisms constituted an unprecedented shift in human understanding of the natural world. All of a sudden, life on Earth became at once considerably more complex and exceedingly marvelous. And yet, more than 350 years later, we remain in the dark about who many of these creatures are and what they are doing.
“Depending on who you talk to, we may not know anything about 99 percent of the microorganisms in the environment,” says Carolee Bull, professor and head of the Department of Plant Pathology and Environmental Microbiology. But, she adds, much like the shift that occurred after van Leeuwenhoek discovered microbes, a modern-day scientific revolution promises to reveal the identities and activities of the communities of microorganisms that so greatly impact our lives.
This time, the tool making it all possible is high-throughput sequencing–also known as next-generation sequencing. First available in the year 2000 and only widely used since the last decade, the technology can determine the order of nucleotides–the As, Ts, Gs, and Cs–for hundreds of thousands of DNA molecules from myriad species concurrently. The technology makes it possible to learn the identities of every species present in a small sample of, for example, pond water. Simple DNA sequencing, on the other hand, is much more limited in its abilities.
“The concept of microbiomes isn’t particularly new,” says Bull. “But with high-throughput sequencing, the black box of microbiology is finally being illuminated,” says Bull. “It’s showing us that microbes don’t work alone in a vacuum. Instead, they are part of a community in which the environment, other organisms, and microbes influence and respond to each other.”
Protecting Water Quality and Restoring Soils
Soil microbiome is a complicated study subject. A teaspoon of soil likely contains a billion individual bacterial cells, perhaps 500,000 fungal fragments, thousands of protozoa, and who knows how many viruses, says Mary Ann Bruns, associate professor of ecosystem science and management. And of the bacteria alone, she adds, there may exist 10,000 to 20,000 different species.
Bruns is using high-throughput sequencing, among other tools, to tease apart this “DNA soup,” as she calls it, that is contained within soil. Her research on nitrogen-cycling microbes at the field scale fits into the bigger picture of reducing nutrient transport to coastal dead zones. “Overall, half of the nitrogen in fertilizer that’s applied to crops is not taken up by the crops,” she says. “Instead it leaches to the groundwater or runs off in sediment. Much of that nitrogen eventually makes its way into the Gulf of Mexico and the Chesapeake Bay, where it upsets ecosystems. I’m interested in how we can stop this process at the source, how we can make our nitrogen application and management methods less wasteful.”
The key, she says, lies in finding nitrogen-conserving plant-soil microbial communities because they are responsible for much of the nutrient cycling in the soil. For example, microbes convert ammonium to nitrate, which is the most easily lost form of nitrogen. “Certain microbes are responsible for many of the biochemical reactions in soil that result in poor efficiency,” says Bruns. “In traditional agriculture, we have countered this problem of nitrogen loss by adding an insurance amount. It’s cheaper and easier to add more rather than try to figure out how to prevent losses in the first place.”
The good news is that while some microbes promote the loss of nitrogen from soil, other species are capable of fixing nitrogen from the atmosphere and keeping it in place. Using high-throughput sequencing, Bruns and one of her graduate students characterized a mixture of two closely related strains of cyanobacteria and several species of nonphotosynthetic bacteria that form biofilms quickly on soils to reduce erosion and runoff. This “consortium,” she says, could be added to agricultural soil to fix carbon and nitrogen and help nutrients stay in place, thus reducing the need for additional applications of nitrogen and protecting downstream environments from nitrogen pollution.
The environment of the human gut comprises tens of trillions of individual microorganisms, collectively weighing nearly 4.5 pounds. Many of these microbes are implicated in reducing the risk of cancer, depression, obesity, and even autism. In fact, “good” bacteria are becoming so popular for their positive health effects that the newly emerging probiotic industry netted more than $35 billion in profits in 2015. But some species are linked to problems.
Consider obesity. In the United States alone, 34 percent of adults and 15 to 20 percent of children and adolescents are obese. In recent years, researchers and clinicians have been turning to the gut microbiome to try to better understand this problem. Fecal matter is 50 percent bacteria. Microorganisms must be playing an important metabolic role.
Andrew Patterson, associate professor of veterinary and biomedical sciences, has learned a great deal about how bacteria influence obesity and the metabolic diseases associated with obesity, namely type II diabetes and non-alcoholic fatty liver disease. For instance, in his studies, he has noticed that mice given tempol, a drug typically used to protect cells against radiation damage, weigh significantly less than mice not given the drug. To investigate further, he and his team designed an experiment in which they fed mice a high-fat diet and gave them the drug tempol. They found that these mice gained significantly less weight than mice that were fed a high-fat diet but were not given tempol.
Patterson determined that the tempol was likely reducing the amounts of Lactobacillus and Clostridium bacteria in the mice guts. And when these bacteria decreased, a specific bile acid–known as tauro-beta muricholic acid–increased. “For some reason the bacteria metabolize bile acids either as a protective mechanism, or as a way of scavenging off nutrients for growth,” he says.
Secreted from the liver into the intestine, bile acids are responsible for digesting dietary fats and oils. “If you have a disorder in these types of processes then you have a really hard time digesting fat,” says Patterson.
To determine what was going on between the Lactobacillus and bile acids, Patterson turned to metabolomics–the study of the chemical fingerprints that are left behind after cellular processes take place. He learned that when the bile acid tauro-beta muricholic acid increases, it turns off the farnesoid X receptor (FXR), which is responsible for regulating the metabolism of bile acids, fats, and glucose in the body. “FXR is there to say, ‘Hey, there’s enough bile acid in the intestine, shut off synthesis in the liver, or there’s not enough bile acid so synthesis needs to be turned on,'” says Patterson.
The revelation about FXR’s involvement led Patterson and his colleagues at the Hershey Medical Center and the National Cancer Institute to design their own anti-obesity drug that specifically targets FXR. In less than two years, they created a pill, modeled after tauro-beta muricholic acid but made from glycine-beta muricholic acid, that caused mice to gain significantly less weight and have less insulin resistance when fed a high-fat diet than mice in the untreated control group.
Patterson received a RAIN grant from the college to help commercialize his product. He also formed a company, called Heliome Biotech, Inc., to commercialize the drug, along with any others that may arise. But Patterson cautions that although his drug has the potential to help patients, it isn’t a cure-all. “I don’t think this is going to be the magic pill that allows you to eat a tub of ice cream every day and not see any metabolic problems later in life,” he says. “You have to adopt a healthy lifestyle as well.”
Indeed, microbiome research is an open book with the potential to transform our lives. “We know now that microbiomes are driving more than we ever thought,” says Bull. “There is a wealth of information that we have only just begun to tap.”