Scientific research takes guts – at least it does at the University of Colorado School of Medicine where the Ost Lab investigates microbes that live in the intestinal microbiota.
“I am fascinated by the commensal microbes that live on us and live in us,” says Kyla Ost, PhD, assistant professor of immunology and microbiology. “They really challenge the perception that many of us grew up thinking about, which is that microbes and germs are bad. But we have this community of microbes that do incredibly important things, like helping us digest our food, shape our immune system, and even impact how our brain functions.”
Some members of this microbial community, however, can have a dark side.
“These microbes live in almost everybody and for the most part they are what we call ‘peaceful colonizers,’ but in certain cases — like in the case of inflammatory bowel disease or people who are immunocompromised, for example — certain members of this community can cause really significant disease.”
Ost and her lab staff of two post-doctoral fellows, two PhD graduate students, and four undergraduate interns, zero in on these microbes, the ones that can become bad actors, because they contribute to inflammatory diseases when they aren’t kept in check.
Learning how and why that occurs is the foundation to better understanding the diverse dynamic of the gut microbiota and designing strategies to prevent some microbes from becoming pathogenic and negatively impacting health.
A focus on fungi
In many ways, the gut microbiome is its own ecosystem. There are bacteria — lots of bacteria — archaea, viruses, and fungi all cohabitating and maintaining the body’s overall health.
Fungi have become the main interest of the Ost Lab for their vital role in gut health and immune health and because they can sometimes go from existing in a non-pathogenic state to wrecking inflammatory havoc.
One example of this is Candida albicans (C. albicans), a fungus that stimulates immune response. It shapeshifts when it turns to the dark side.
When harmless, C. albicans are typically a round balloon shape, but when they turn long, sort of like a sword, they also become pathogenic. As much as 80% of the population live with C. albicans in the intestines, and while these microbes mostly keep that balloon shape, the sword-like C. albicans can be troublesome when the fungi bloom out of control of the immune system and invade the walls of the intestines. This can cause illness such as Chron’s disease and ulcerative colitis, both forms of chronic inflammatory bowel disease.
Ost and her team are diving deep into what causes that change and asking vital questions that could lead to discoveries that may prevent or treat inflammatory bowel diseases.
“What are the interactions in our gut that maintain these microbes as a nonpathogenic commensal? It's important to understand how they're constrained to these nonpathogenic states for us to understand how to then restore them to a nonpathogenic state in patients who are at risk,” Ost says.
Immune response keeping balance
Understanding C. albicans also requires understanding the immune system’s response to the community of microbes living and working in the gut.
“Our immune system is sort of like a military within our body that targets and tries to kill or protect us from invading pathogens, but in the gut that gets complicated,” Ost explains.
“We have this microbial community that lives with us always, so there must be a balanced response from targeting and eliminating pathogens but also allowing microbes to live in the gut. It's almost as if it's constant communication between the immune system and the microbiota within the gut to limit pathogenesis while also being able to maintain colonization,” she says.
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Communication between the gut and immune system has become the source of many questions for the Ost Lab. One key immune interaction the researchers are currently focused on is the role of intestinal antibodies in preventing the fungi from causing disease. Ost previously discovered that IgA antibodies in the gut selectively target molecules that are almost exclusively on the pathogenic C. albicans and facilitates the suppression so that it trains the Candida to primarily colonize the gut as the nonpathogenic type of C. albicans, the balloon-shaped version of the fungi.
“Here was an example where this antibody response isn’t targeting and clearing a microbe, but actually changing the biology of the microbes such that it's less pathogenic, somewhat constraining it,” Ost says. “Since starting my lab, we have found that for other fungal species that come commonly colonize the gut, they are also targeted and regulated by that by IgA, but it's really dependent on the strain of fungus, and we're trying to now figure out why certain strains of fungi can stimulate this IgA response, and certain strains don't.”
The researchers suspect it's correlated with a strain’s pathogenic potential. Strains of fungi that are more adhesive and have increased capacity to escape the gut and cause disseminated infection are the ones that are stimulating an IgA response during normal colonization of the gut.
The gut’s great unknowns
Researchers like Ost who are investigating the gut microbiota and its connection to health still have a lot to learn.
“We don’t truly grasp all the important things that the microbiota is doing for us. But it's also important to remember that a number of these important commensal microbes can be pathogenic, and we know this because many of the deadliest infections in our country driving many deaths are from these organisms that are called ‘all opportunistic pathogens,’” Ost says.
“These are pathogens that are not generally thought of to infect and harm people who have healthy immune systems but are a huge problem in people who have compromised immunity or other health or other medical vulnerabilities, and we really don't understand why.”
By understanding gut microbes and immune responses, researchers can begin thinking about how to prevent infection and disease. In the realm of Ost’s work, one option could be using vaccines to target and control microbes.
“Many of these microbes also have beneficial roles. By blocking the ‘dark side’ behaviors that some of these microbes, we can help make sure we maintain them as commensals,” Ost says. “Using vaccination against these fungi to prevent against infection and limit their damage they can cause during chronic intestinal inflammation is just one potential avenue. There are a ton of therapeutic and translational avenues that you can take from the discoveries that that we make in understanding how these fungi are controlled.”
