Mining the microbiome

Ten-to-one. Cell for cell, they’ve got us outnumbered. And as a group, they have 100 times more genes than we do. Fortunately, these microbes that share our corporeal space are usually on our side.

Known collectively as the microbiome, the microbial species that flourish along our mucosal surfaces—the linings of our intestines, mouth and nose, for example—and in and on our skin, live in community with us. We give them safe harbor and food; they perform tasks useful to us, such as digesting nutrients and warding off harmful pathogens.

Our understanding of these teeming populations of microbes has taken off in the last decade, says Seth Bordenstein, Ph.D., a Vanderbilt biologist who studies the role of microbes in animal evolution and health.

“We have gone from the microbiome being a fringe discipline to one of the most important fields in all life sciences,” he says. “The importance of the microbiome cannot be overstated.”

Together, the genes of our microbial friends and our own genes form a “hologenome”—the total set of genes of an animal—and because the microbiome has so many more genes than we do, “it wields a vast genetic influence on our fitness,” explains Bordenstein, associate professor of Biological Sciences and Pathology, Microbiology and Immunology.

“When these genomes are in harmony, all is good. But when the human and microbial genomes get out of balance, that’s when we see inflammation and disease.”

 

Microbiome-disease links

Our gastrointestinal tract is home to 99 percent of the microbial mass in our bodies. The gut microbiome—comprised of bacteria, fungi, archaea and viruses—has the greatest impact on our overall metabolism, and it is the best studied of our various microbial communities.

“We are starting to understand that manipulation of the microbiota (the particular species of microbes) can profoundly affect disease states,” says Richard Peek, M.D., Mina Cobb Wallace Professor of Immunology at Vanderbilt.

Peek cites a series of studies conducted by Jeffrey Gordon, M.D., and his colleagues at Washington University in St. Louis, demonstrating that the microbiota differ in obese and lean human beings and mice—and that the phenotypes linked to a particular microbiota can be “transferred” between animals. Gordon’s team showed that colonization of germ-free mice—mice raised to have no microbes living on or in them—with “obese” microbiota caused a greater increase in body fat than colonization with “lean” microbiota.

Increasing numbers of studies also are linking the gut microbiome to cancer.

Studies showing that germ-free animals and animals treated with antibiotics develop fewer spontaneous, genetically-induced or carcinogen-induced tumors suggest that the microbiome plays a tumor-promoting role. Other studies have demonstrated differences in the gut microbiota of patients with colorectal cancer versus those without cancer, for example, and have linked certain strains of bacteria to pre-malignant and malignant lesions in the colon.

Even Helicobacter pylori, a bacterium that increases the risk of gastric cancer, may be relying on changes in the microbiome to exert its deadly effects, Peek says.

A clinical trial of antibiotic treatment in a population at high risk of gastric cancer found a significant reduction in the development of new cancers of the stomach 15 years later in patients who had received antibiotics. But half of the patients who had been treated were still infected with H. pylori, Peek says, suggesting that the antibiotics may have reduced the development of gastric cancer by altering other bacteria in the gastrointestinal tract.

Another study found that mice with a normal gut microbiome develop gastric cancer at a much more rapid pace after H. pylori infection, compared to germ-free mice.

“These findings suggest there are other bacteria in the GI tract that collaborate with H. pylori to augment the progression to gastric cancer,” Peek says.

 

Cancer prevention strategies

“Many pieces of data from independent researchers all point in the same direction—that the microbiota in both the colon and stomach are exerting important effects on the development of cancer,” Peek says. “Still, we need more in-depth studies in which we can manipulate the microbiota in animal models to establish how changes in this population are causing disease.”

Investigators are moving in that direction.

Researchers at the University of Michigan recently demonstrated a causal role for the gut microbiome in a mouse model of inflammation-associated colorectal cancer. They found that the microbiome changed during tumor development and that antibiotics reduced the number and size of tumors. Transfer of the tumor-associated microbiome to germ-free mice accelerated inflammation-associated colon cancer growth in these animals.

Studies like this one, which demonstrated changes in specific microbes that accelerate tumor growth—enrichment of Bacteroides, Odoribacter and Akkermansia and decreases in Prevotellaceae and Porphyromonadaceae—are what’s needed to develop interventions that target the microbiome to prevent cancer growth.

Such interventions could attempt to change the types of microbes in the gut using dietary manipulations such as prebiotics (nutrients that promote the growth of certain microbes) and probiotics (microorganisms themselves), or using personalized antibiotics to selectively eliminate harmful microbial species.

Interventions might also include genetically engineered bacteria that produce helpful compounds. Sean Davies, Ph.D., assistant professor of Pharmacology at Vanderbilt, recently reported that bacteria engineered to produce a therapeutic compound reduced obesity in mice.

Peek points out that manipulation of the microbiota might also be beneficial for enhancing the metabolism of cancer therapies that depend on certain microorganisms in the gut.

“There’s almost a limitless possibility regarding the microbiome and health and disease, but right now the most important thing is to establish cause-and-effect,” Peek says. “Our advanced technologies make it easy to gather a lot of information, but we need the heft and breadth of cutting-edge bioinformatics and mechanistic studies to really understand what it all means.”

“Until proven otherwise, targeting the microbiome for cancer prevention is a strategy worth delving into,” Bordenstein adds. “I am deeply fascinated to see where the basic and applied microbiome sciences will take us in the next decade. The frontier is ahead of us.”