• Research

    Discovery’s Edge: Rise of the Microbiome

As a species, we have a love-hate relationship with microbes. For centuries, we didn’t even know they existed. Then came the microscope and Louis Pasteur’s germ theory, and suddenly we could see that microorganisms were the cause of deathly diseases like bubonic plague, smallpox, and tuberculosis. The knowledge launched a war against microbes, resulting in new ways to treat and prevent infections that have doubled our lifespans.

But it wasn’t until recently that we realized that there are some microorganisms we can’t live without. Our bodies carry more than 100 trillion bacteria on our skin and in our mouths, noses, genitalia, and guts. These bacterial communities, collectively known as the human microbiome, can synthesize vitamins, bolster our immune systems, help us digest our food, and even boost our brain function.

Today, researchers at the Mayo Clinic’s Microbiome Program are using genetic sequencing and other technologies to become better acquainted with our bacteria and ourselves. Thus far, they have discovered the human microbiome does much more for us — both good and bad — than we ever imagined.

Surgeon Heidi Nelson, M.D., heads Mayo Clinic's Microbiome Program
Surgeon Heidi Nelson, M.D., heads Mayo Clinic's Microbiome Program

“The human microbiome is one of the most exciting scientific frontiers I’ve seen come along in a long time,” said Heidi Nelson, M.D., director of the Microbiome Program at the Center for Individualized Medicine. “It is amazing to understand what we have not understood for all these years — that our health depends on our relationship with the bugs that live in and around us.”

Go with your gut

Just as it might be hard to comprehend a time when we didn’t recognize germs as carriers of death and disease, it is also difficult to fathom how we missed the thriving microbial communities living (literally) right under our noses. Single-celled microbes coat practically every surface of the human body, outnumbering human cells by ten to one. Altogether, the members of the human microbiome weigh roughly three pounds, about as much as the liver or brain.

These microbes are as inherent to us as our own genetic signatures or our own human cells, says Purna C. Kashyap, M.B.B.S., a gastroenterologist at Mayo Clinic in Rochester, Minn.. “We can’t really separate the two,” says Dr. Kashyap. “These microbes were here before we were, and they are here to stay. The more we understand about them, the better it will be for us.”

Gastroenterologist Purna Kashyap, M.B.B.S., says the gut is much like a brain.
Gastroenterologist Purna Kashyap, M.B.B.S., says the gut is much like a brain.

Dr. Kashyap studies gastrointestinal disorders like irritable bowel syndrome (IBS), a condition that affects as many as 20 percent of Americans. Patients with IBS can experience painful bouts of cramping and diarrhea, or bloating and constipation. No one knows the cause, though some studies have suggested the nerves in the gut are more sensitive in people with IBS. “The gut really has a mind of its own,” says Dr. Kashyap. “It has a separate nervous system that is potentially even more complex than the brain.”

Among other things, these nerves keep food moving from one end of the digestive tract to the other.

Fecal transplants

A few years ago, Dr. Kashyap began to investigate how gut bacteria influence gastrointestinal movement. In one approach, he and his team transplanted human gut microorganisms into mice that lacked any microbes of their own. They discovered that the microbial makeup of these “humanized mice” dictated how quickly food moved through their bodies. In addition, Dr. Kashyap found that droppings from these germ-laden mice had higher levels of the neurotransmitter serotonin than mice that were germ-free.

Serotonin is best known as a feel-good chemical, but only a small part of the body’s serotonin is synthesized in the brain. The rest of this neurotransmitter is made in the gastrointestinal tract, where it affects motility and sensation (hence, that “gut feeling”). Dr. Kashyap showed that the microbiome generates specific metabolites — like butyrate and acetate — that tell the gut to up its production of serotonin. Now, he is trying to figure out if the bacterial communities produce their own neurotransmitters that have similar effects on gut physiology.

“Serotonin dysfunction has been implicated in human diseases like IBS for a long time,” says Dr. Kashyap. “The drugs used to treat it have typically targeted serotonin receptors, but they have had such severe side effects that they are no longer in use. Bacteria that enhance serotonin production could provide an appealing alternative for the treatment of gut-related disorders.”

Because bacteria control so many aspects of gut health, Dr. Kashyap began to wonder if changes in the microbiome could make the gut more inviting to pathogens like Clostridium difficile, often called C. difficile or C. diff. Infections with this dangerous bacteria kill 14,000 Americans a year. Dr. Kashyap has developed an entire research program devoted to studying the different microbiomes of patients with and without C. difficile colitis.

He and his colleagues treat the disease by transplanting fecal matter from healthy donors into the digestive tract of patients. While the approach works 90 percent of the time, it is not very appealing and is hard to standardize. Therefore, Dr. Kashyap is using genomic sequencing to take a bacterial census of the gut before and after fecal transplant. Once he knows which microbes are necessary to make a healthy microbiome, he may be able to generate the ingredients in the laboratory, eliminating the need for stool donations.

The world’s most complex ecosystem

Though the microbiome is often thought of as a forgotten organ, it is not an organ or even an organism, but rather an entire ecosystem that is more diverse and complex than any tropical rainforest. The gut microbiome is home to over a thousand different species of bacteria, each with their own personalities: some are predators, some are prey, some coexist peacefully, and some fight for power.

Nicholas Chia, Ph.D., studies the impact of the microbiome on colon cancer.
Nicholas Chia, Ph.D., studies the impact of the microbiome on colon cancer.

Nicholas Chia, Ph.D., a systems biologist at Mayo Clinic in Rochester, believes the key to understanding the environmental basis of disease may be hidden within this tiny ecosystem. After all, members of the microbial community serve as the body’s first point of contact with the outside world. Practically everything we do — running on the treadmill, popping antibiotics, eating a cheeseburger — shows up in our microbiome. Depending on the environmental input, our gut microbes might turnover completely, or they might churn out chemicals that can predispose us to cancer.

Over the last decade, researchers have published study after study showing a link between the microbiome and colorectal cancer. Many of the studies have looked at the development of colon cancer in humanized mice, whereas others have compared gut bacteria from people with and without the disease. What these studies have been missing, Dr. Chia says, is a search for the uniting factor that pushes all of these different bacterial species to cause cancer.

“What the data shows is there are different cancer signatures, or different microbial species that cause cancer in different patients,” says Dr. Chia. “Getting rid of those microbes is going to be like playing whack-a-mole, you knock down one, then the next one and the next one. Instead, we need to study the chemistry of these microbes — getting a handle on the genotoxic byproducts they secrete — so we know what kind of actions to go after to stop cancer.”

Diet, the microbiome and colon cancer

Dr. Chia is particularly interested in identifying microbial metabolites that could explain the impact of diet on the development of colon cancer. In his laboratory, he creates computer models that treat each bacterial strain as if it were a production line in a biochemical factory. Dr. Chia plugs in a typical microbial diet — a soupy mixture of sugars, amino acids, and fats — and then calculates the expected output, based on each microbe’s chemical structure.

For example, he found certain gut bacteria spring into action when there is an excess of protons in the gut, which happens after an acid-producing meal like a steak dinner. Sulfate-reducing bacteria take these protons and use them to produce hydrogen sulfide, a potent carcinogen that also gives intestinal gas its telltale rotten egg odor. Methanogens have the opposite effect, creating methane gas to protect the intestinal lining from damage.

At the moment Dr. Chia is still perfecting his mechanistic models on the computer, but eventually he would like to test his findings in humanized mice. He is also gathering samples from colon cancer patients who are undergoing bowel resections at Mayo Clinic, which will give him real-world data that he can combine with his models to draw connections between microbial metabolism and cancer.

“If we can understand the mechanisms behind colorectal cancer, then we can prevent it,” says Dr. Chia. “I think the answer could be as easy as a diet. Just like efforts to prevent cardiovascular disease have focused on eliminating saturated fats and sodium, we may find diets that can strengthen our microbiomes to keep us from developing cancer.”

Such an approach could potentially address a wide range of health issues that are associated with the microbiome. The list continues to grow, and now includes IBS, cancer, coronary artery disease, gastric ulcers, obesity, rheumatoid arthritis, asthma and allergies, autism, mood disorders, and cavities.

“Over the next ten years, I think we will develop a much greater understanding of the interplay between our genes, our environment, and our microbiome,” says Dr. Nelson, the Microbiome Program director. “Using this knowledge, we can develop a robust translational machine to get ahead of infectious diseases and also find new solutions for disorders like cancer that we didn’t realize had microbial underpinnings.”

— Marla Vacek Broadfoot

February 2016