The Big Potential of the Very Small
By Katie Courage
For more than 150 years, most known microbes were our avowed enemies. No longer. In just the past decade, science has upended our understanding of these microscopic organisms that reside almost everywhere. Thanks to rapid technological advances, we now know that bacteria, archaea, and fungi are frequently friend, not foe. This new view of their environments and ecologies, known as microbiomes, enables us to enlist them as collaborators in everything from battling antibiotic resistance to preventing cancer.
Leading the charge is Colorado State University’s Microbiome Network, a group of more than 30 researchers from a wide range of disciplines who are tackling this rapidly evolving field. And the College of Veterinary Medicine and Biomedical Sciences is setting the pace for dynamic new collaborations that are changing how we think about everything from dairy farms to infant feeding.
Microbiome Network co-coordinator Zaid Abdo, an associate professor in the Department of Microbiology, Immunology, and Pathology, says microbiome research reminds us that we are all connected.
“From the farm where you produce your food to whoever is going to eat it, microbes play an essential role,” he says. “It’s a holistic – and necessary – way of looking at things. And now we have the tools to finally look at this bigger picture.”
A tour through a typical farm will reveal only a fraction of the resident organisms. “It’s not only the animals or the crops,” Abdo says. “It’s also the gut microbes of the animals and the microbes in the soil that help the plants.”
These actors were long hidden from view. But now, Abdo notes, “we are developing new ways of looking at these microbes. We can use that information to improve production on the farm – whether that’s for cows or wheat.”
Under the soil’s surface, for example, microbes are busy in important roles, such as recycling nutrients and defending plants against pathogens. But for generations, we have been working at cross-purposes with them. “Soil disturbances caused by farming practices can stress microbial community structures,” says Abdo, whose work on soil microbiomes has ranged from hot springs and glaciers to Colorado potato fields. “And then the food web within that soil is no longer going to effectively work to replenish nutrients.”
Microbes impact nutrient availability – and thus growth – in animals as well. Farmers and ranchers have known for decades that using antibiotics to alter the microbe profile of animal guts can accelerate growth, but there is now a strong push to reduce the use of antibiotics in agriculture. So scientists are finding ways to get creative and enlist microbes to do this nutrient-conversion work – without antibiotics. Early research is creating directions for a new path forward that will mean fewer drugs – and more helpful bugs – on the nation’s farms.
Good microbes are often the best defense against bad ones. “We know that diverse microbiomes are linked to healthier organisms – whether that’s livestock animals or the people who care for them,” says Sheryl Magzamen, an associate professor of epidemiology in the Department of Environmental and Radiological Health Sciences.
Magzamen, Abdo, professors Stephen Reynolds and Craig McConnel, doctoral student Chloe Stenkamp-Strahm, and other collaborators have been peering into animal guts (which means a lot of manure sampling) to see how these different microbial profiles correlate with better defenses against pathogens. “We know that certain activities, such as administering antibiotics, can shift the microbiome to be less diverse and allow for certain pathogenic bacteria to proliferate,” Magzamen says.
They found that the profile of cows’ intestinal microbes impacted the spread of pathogenic E. coli O157 – results they published in the Journal of Applied Microbiology. This research has set the stage for new work to see how gut microbes might be manipulated to “mitigate O157 dissemination, protecting the human food chain,” they wrote.
Much of the push to reduce antibiotic use on farms has come from the worrisome spread of antibiotic-resistant bacteria. Resistant microbes can survive antibiotic treatment, which leads to worsening infections in animals – and in humans. The rapid spread of these infections is due to the ability of bacteria to easily transfer genes – such as those that can help a bacterium survive antibiotic treatment – between one another, a process known as horizontal gene transfer.
To help researchers all over the world dive into this complicated field, college scientists, including Steven Lakin, a Ph.D. candidate in the Department of Microbiology, Immunology, and Pathology, and nine other CSU researchers created MEGARes, a robust database of antibiotic-resistant genes available for anyone to search. So far, “it has helped more than 100 international research teams study how these ‘superbugs’ come to be and how we might prevent them from getting into the food supply and the ecosystem in general,” Lakin says.
The healthy human body hosts trillions of microbial organisms, which impact our immune and nervous systems. Scientists are now finding connections between the human microbiome and everything from our earliest health to late-stage cancer.
As on the farm, antibiotics have altered our own microbiomes. CSU researchers are also studying another way we influence our microbial communities: diet. In particular, foods that are high in certain kinds of fiber have positive impacts on our health – via our microbes – over the course of our entire lives.
Dietary fiber might even impact the quality of breast milk, according to Elizabeth Ryan, associate professor of environmental and radiological health sciences. “Mother’s breast milk composition is important to understand in the context of diet,” Ryan explains. “How the infant microbiome processes the complexity of components of the breast milk and weaning foods is really important early in life for the maturation of the microbiome.”
Ryan and her CSU collaborators have examined fiber intake and microbiome composition during the weaning stage of humans and bovine calves. “These early-life environmental exposures and the microbial compounds produced from them have an influence on the developing immune system, growth, brain function, sleep cycles, and more,” she says.
Regardless of age, dietary fiber plays an important role in modulating the microbiome for better health. Ryan’s work has focused on whole grains and legumes. These staple foods cannot only shift the inhabitants of the gut microbiome but can also change its function by altering what chemicals the microbes are producing. “I am continually excited about expanding these applications from chronic disease and colon cancer prevention,” she says. “We see similarities and common themes in microbial metabolic structures after rice bran feeding to mice, pigs, chickens, dogs, and humans – even in the presence of different microbiomes.”
Ryan and researchers from the Department of Clinical Sciences are also examining the changes in dog microbiomes after canine cancer treatments at the Robert H. and Mary G. Flint Animal Cancer Center – and how diet during treatment might help the microbiome do its best work. “Our studies of healthy companion animal microbiomes have shown similar patterns following dietary changes to those we see in people,” Ryan says. Mouse studies often fall short because rodents are kept in such controlled conditions, she notes. “But by working with humans and companion animals, our diet impacts on microbiomes are being evaluated with real-world exposures and lifestyle conditions.”
And the work is just beginning. “Throughout our lifespan, our bodies have an enormous capacity to receive, respond to, and reject environmental exposures,” Ryan says. “I am fascinated to understand how our host microbiome works with the immune system to protect health and prevent disease.”
Microbe research began in the tradition of the old biological sciences: Collect (or, in this case, culture), categorize, catalog. But with so many new species and strains of microbes, the old method – which might have worked well enough for plants and animals – has simply become impractical and not all that impactful.
Now, thanks to rapid advances in sequencing technologies, Lakin and others can skip these nomenclatorial formalities and get right down to figuring out what some of these microbes are doing. As his Ph.D. adviser, Abdo explains, “now you don’t have to know a microbe’s name to figure out part of its function.”
For Lakin, the draw of microbiome research was never in the individual organisms anyway, but in the complexity of their interactions. “While I could have worked for a major social media company doing similar research – studying how individuals and networks interact – I am also a veterinarian and want to use what I learn to prevent disease and to better understand the world we live in,” he says.
Lakin is tackling this by developing efficient software to better read data from microbiome analyses. For such small organisms, microbes are generating massive amounts of data that need to be analyzed. This summer, Lakin plans to visit one of the world’s fastest supercomputers, at Oak Ridge National Laboratory, to run programs he has been developing as part of his doctoral research. “Using this software, we hope to understand more about the vast number and diversity of microbes that live on Earth.”
The potential of microbiome research is expanding faster than any single field can track, which is thrilling – but also presents its own challenges. “Understanding something as complex as a microbiome requires combining perspectives from many disciplines,” Abdo and more than two dozen other renowned microbiome researchers wrote in Nature Microbiology in 2019. “Advancing microbiome research so that it can fulfill its translational potential and be harnessed to improve ecosystem and human health will require the ‘horizontal transfer’ of knowledge, expertise, and ideas.” To help accomplish this, the CSU Microbiome Network is among about two dozen academic centers that have self-assembled to create the national Microbiome Centers Consortium.
And CSU is poised to take a leadership role in this field. The University hosts an annual Front Range Microbiome Symposium. The academic meeting, which draws top-level scientists from across the country, is organized in part by CSU’s dedicated Graduate Researchers Across Microbiomes group. The University also continues to expand the broader Microbiome Network through internal funding and strategic hires and to foster connections within the larger One Health initiative. “Connection to CSU’s Microbiome Network allows fantastic opportunities for discovery, collaboration, and translation,” Magzamen says.
Fortunately, the subject seems to be infectious, winning over senior scientists and eager undergrads alike. Part of the reason for this, says Abdo, is that beyond the incredible potential to make outsized changes in the world by working with these small organisms, “it’s just fun to have interactions where you’re in a continuous learning environment. It stretches you to think in new ways, from different perspectives, and that’s exciting.”
Katie Courage is an independent journalist and author, most recently of Cultured: How Ancient Foods Can Feed Our Microbiome (Avery/Penguin Random House, 2019).
Modeling Microbial Ecology with Controlled Chaos
On any given day in Angela Bosco-Lauth’s lab, there might be a rainstorm, a wind event, or a long, hot day in Thailand.
In collaboration with faculty and students in the College of Agricultural Sciences and the Walter Scott, Jr. College of Engineering, Bosco-Lauth, an assistant professor in the Department of Biomedical Sciences, developed highly controlled “bioboxes” in which to study microbes in simulated macro environments.
Recently, her bioboxes were simulating rice paddies in Thailand. Each high-containment biobox looked about the same to the naked eye, with matching UV-light exposure, warmth, and humidity cultivating rice plants. But inside each box under the soil, the microbial environment was very different. Some housed the bacterium Burkholderia thailandensis, which is closely related to the human and animal pathogen Burkholderia pseudomallei. Some of those bioboxes also contained a naturally occurring microbe known as Pandoraea pnomenusa, which appears to outcompete the pathogen. Bosco-Lauth and her colleagues are watching the microbial war play out in real time to see if these helpful microbes can vanquish the bad ones. If so, harnessing the microbes’ capabilities could provide a way for farmers to avoid using more pesticides and simultaneously reduce the human and animal disease burden.
“The bioboxes provide a way to study complex interactions in a controlled setting where we can manipulate the inputs (temperature, humidity, wind, and so on) and identify how environmental changes can alter the system microbially,” she says. “This is a way to simulate what’s happening in the real world and can help identify relationships between the microbiome and the broader environment.”
“Our goal is to get as close as we can to simulating reality,” Bosco-Lauth says. “Usually, you have either a very sterile lab experiment or very messy fieldwork – and nothing that bridges that gap. We’re trying to make a messy lab experiment.” These messy-but-controlled experiments are already elucidating how we can harness the powers of microbes to boost productivity, health, and sustainability.