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By Erik Ness

Jim Steele used to be one of the skeptics. He’d be at a conference, listening to early research on the health benefits of probiotics. Steele scoffed at the small experiments. “We would literally try not to laugh in the audience, but we’d laugh pretty hard when we went out that night,” he admits.

But slowly the punch lines gave way to revelation. Steele, a professor in CALS’ Department of Food Science, conducts research on lactic acid bacteria, with a focus on Lactobacillus species. They’re important for human gut health, critical for the production of cheese and yogurts, and are the most common probiotic genus. He knew how incredibly useful they were, but still watched with a humbling disbelief as the data on the health potential of these microbes kept getting broader, deeper and more intriguing.

Our microbiota—what we call the totality of our bacterial companions—is ridiculously complex. Each human harbors a wildly diverse ecosystem of bacteria, both in the gut and elsewhere on the body. They have us completely outnumbered: where the typical body may contain a trillion human cells, your microbial complement is 10 trillion. They have 100 times more genes than you, a catalog of life potential called the microbiome. (The terms “microbiome” and “microbiota” are often used interchangeably in the popular press.)

While our initial, germaphobic impulse may be to freak out, most of these bacterial companions are friendly, even essential. On the most basic level they aid digestion. But they also train our immune system, regulate metabolism, and manufacture vital substances such as neurotransmitters. All of these things happen primarily in the gut. “In many ways the gut microbiota functions like an organ,” says Steele. “It’s extraordinarily important for human health,” with as much as 30 percent of the small molecules in the blood being of microbial origin.

Early research has suggested possible microbiota links to protecting against gastric cancers, asthma, numerous GI disorders, autoimmune disease, metabolic syndrome, depression and anxiety. And the pace of discovery seems to be accelerating; these headlines broke in just a few months last spring:
• Mouse studies suggested that the microbe Akkersmania muciniphila may be a critical factor in obesity;
• Kwashiorkor, a form of severe malnutrition that causes distended bellies in children, was linked to a stagnant microbiota;
• Risk of developing Type 2 diabetes was linked to an altered gut microbiota.

The catch: For all the alluring promise of microbes for human health—and it’s now clear they’re critically important—we have almost no idea how this complex system works.

The human gastrointestinal (GI) tract is a classic black box containing hundreds or thousands of species of bacteria (how many depends on how you define a species). There are viruses, fungi and protozoans. Add to that each person’s distinct DNA and their unique geographic, dietary and medical history—each of which can have short- and long-term effects on microbiota. This on-board ecosystem is as unique as your DNA.

Beyond these singularities, the action is microscopic and often molecular, and even depends on location in the GI tract. Most microbiota studies are done with fecal material. “Is that very informative of what’s going on in the ileum?” asks Steele, referring to the final section of the small intestine, which is thought to be the primary site where immunomodulation occurs. “From an ecosystem perspective, fecal material is many miles away from the ileum. Is it really reflective of the ileum community?”

Developing the tools to unlock this black box begins with simply accepting the idea that these bacteria—germs!—are part of us. It’s a fundamental shift in how we think about health, which has evolved for centuries around the prism of disease development, or pathogenesis. For centuries we had no idea that microorganisms caused plague, cholera, and dozens of other debilitating diseases.

“Because we couldn’t know who they are and what they’re doing, we focused on pathogenesis,” explains Margaret McFall-Ngai, a professor in the Department of Medical Microbiology & Immunology at the UW–Madison School of Medicine and Public Health. Once we knew that bacteria existed and developed the germ theory, modern medicine grew by leaps and bounds. “Pathogenesis has had such a profound effect on human history,” she notes.

Except that’s not how the world normally works. McFall-Ngai studies mutualism, where microbes and their host organisms scratch each other’s backs. For the last 25 years, she and colleague Ned Ruby have been untangling the elegant relationship between the Hawaiian bobtail squid and its luminescent bacterial symbiont Vibrio fischeri. She argues that these collaborative relationships are far more important than we realize—that instead of viewing the world through the framework of disease, biology needs to be understood through the prism of beneficial microbes.

“I think we are in a revolution,” McFall-Ngai says. She recently was lead author—Ruby was one of 25 others—of a major PNAS review. They argued that new technologies have “revealed a bacterial world astonishing in its ubiquity and diversity” and that the resulting relationships in symbiosis and in larger ecosystems are “fundamentally altering” our biological understanding. “All biologists will be challenged to broaden their appreciation of these interactions and to include investigations of the relationships between and among bacteria and their animal partners as we seek a better understanding of the natural world,” the authors state.

This is the beginning section of a larger story called “Microbes & Human Health,” which was originally published in the Fall 2013 issue of Grow magazine. Please read the full story here to learn about specific microbiome-related research projects at the UW-Madison.