Tiny Bacteria, Lifelong Impact
October 17, 2020
Every day, University of Virginia researchers are learning more about how the microbiota in our gut – the trillions of bacteria that perform essential functions in the human digestive tract – affect everything from our brain development to our battles with cancer.
The connections are myriad and often surprising. A mother’s gut microbiome could affect her baby’s developing brain or her post-partum mental health, for example; or an unhealthy gut could contribute to depression or metastatic breast cancer.
UVA researchers are making these discoveries and many more. A new University-wide initiative launched in the spring, the Trans-University Microbiome Initiative, or TUMI (pronounced “tummy”), will provide critical resources for their work, from specialized germ-free labs to grow and study microbes to advanced computer networks that can handle the huge amounts of data needed to identify, track and study so many bacteria.
It’s the latest step in a long line of UVA research studying connections between gut microbes and disease. That legacy includes a shocking discovery by neuroscience professor Jonathan Kipnis, who in 2016 found previously unknown vessels directly connecting the brain to the immune system. It also includes three Nobel Prize winners. Dr. Barry Marshall, a UVA School of Medicine researcher and faculty member from 1986 to ’96, won the Nobel Prize in Medicine in 2005, and Dr. Alfred Gilman and Dr. Ferid Murad, both members of the UVA Department of Pharmacology in the 1970s, won the Nobel Prize in Physiology or Medicine in 1994 and 1998, respectively, for research that changed our understanding of gastrointestinal diseases and disorders.
“UVA has a very proud history when it comes to understanding how microbes in the gut cause disease,” said Dr. Sean Moore, chief of the Division of Pediatric Gastroenterology, Nutrition & Hepatology. “There is a wonderful environment here for people who study gut microbes, and there are so many researchers on Grounds doing high-quality microbiome research. This new initiative will help bring their work to the next level.”
Moore co-directs TUMI with Dr. William Petri, Wade Hampton Frost Professor of Medicine and Chief of the Division of Infectious Diseases and International Health. Microbiologist Casandra Hoffman serves as the initiative’s senior research program manager.
Learn more about what they and their colleagues have discovered so far about how gut bacteria can affect each stage of life.
From Birth On
can Affect Babies’ Health
A mother’s microbiome can affect her children even before birth, as ongoing UVA research projects have shown.
Risk Of Neurodevelopmental Disorders
In 2018, neuroscientist John Lukens and his colleagues in UVA’s Center for Brain Immunology and Glia published research connecting a mother’s microbiome during pregnancy to her child’s risk of developing of autism spectrum disorders.
“The microbiome can shape the developing brain in multiple ways,” Lukens said at the time. “The microbiome is really important to the calibration of how the offspring’s immune system is going to respond to an infection, injury or stress.”
An unhealthy microbiome can make unborn children susceptible to neurodevelopmental disorders, the researchers said. Now that the link has been established, they are searching for specific ways to modify the microbiome, which can be changed fairly easily through diet, probiotic supplements or fecal transplant procedures.
“The next big step would be to identify features of the microbiome in pregnant mothers that correlate with autism risk,” Lukens said. “I think the really important thing is to figure out what kinds of things can be used to modulate the microbiome as effectively and safely as we can.”
In related research, Kevin Pelphrey is planning further clinical trials to study how inflammation in the microbiome could lead to developmental disabilities in young children, and working with UVA pediatrician Dr. Karen Fairchild on some studies in the NICU. Pelphrey, one of the nation’s leading autism researchers, is the Harrison-Wood Jefferson Scholars Foundation Professor of Neurology and works with UVA’s Brain Institute.
He is part of a group of UVA researchers, including Moore, Petri, and many others, working to secure National Institutes of Health funding for a UVA center focused on understanding linkages between the microbiome, inflammation and brain development in infants.
Mothers’ And Babies’ Physical And Mental Health
After meeting as first-year Ph.D. students, Caitlin Dreisbach and Caroline Kelsey were awarded a UVA School of Data Science Presidential Fellowship to study how mothers’ microbiomes might influence babies’ physical and mental health. The project turned into both of their dissertations, Dreisbach focusing on maternal health and obesity and Kelsey focused on infant brain development. Both researchers found interesting connections linking the microbes in the gastrointestinal tract to longer-term maternal and child outcomes.
“At least in the prenatal stage, it appears that obesity influences regulation in the microbiome, although that can be impacted by antibiotics,” said Dreisbach, who also worked as a labor and delivery nurse at UVA and is now a postdoctoral researcher at Columbia University. “Entering pregnancy at a healthy weight appears to have a protective effect, actually decreasing factors like inflammation.”
“Already within the first few weeks of life we are seeing a connection between gut microbiome diversity and infant brain and behavior,” said Kelsey, who worked as a graduate student in the UVA Baby Lab and is now a postdoctoral researcher at Boston Children’s Hospital. Kelsey, Dreisbach and a team of researchers at UVA and the NIH continue to follow up with these infants in hopes of learning about the long-term associations between the gut and the brain.
Complications In The Nicu
Also in the NICU, Moore and his team are studying babies who have developed complications after receiving intravenous nutrition, including a condition called parenteral nutrition-associated cholestasis that can lead to serious liver problems. In one example, one twin infant developed a liver injury after receiving IV nutrition, while the second twin did not.
“The microbiome of twins who did and did not get that complication was clearly different [and healthier] in a way that was actionable,” Moore said.
Childhood Nutrition And Immunity
Carrie Cowardin, who returned to UVA as a faculty member this summer after earning her bachelor’s degree and Ph.D. here, is studying how gut bacteria shape immune development in the first 1,000 days of life, and the problems that can come from undernutrition during that critical stage.
Her postdoctoral research included studying samples from the gut microbiota of both healthy and malnourished children. She found that those samples, when implanted in mice, resulted in significant differences in growth.
“One of the things we found is that the development of certain immune cells, called lymphocytes, is altered in animals with malnourished microbiota. This is interesting because we know that malnourished children often have poor responses to certain vaccines and may be more susceptible to infectious diseases,” said Cowardin, now an assistant professor in the Department of Pediatrics. Lymphocytes play an important role in the human immune system and help respond to vaccines and protect against infections.
“We think that some of the changes we saw are the result of different microbiota compositions, and that the microbiome could impact really important factors for these children, such as resistance to infections, vaccine responses as well as linear growth,” Cowardin said. “Our goal is to eventually design probiotics or immunotherapeutics to help restore that growth and immune function in malnourished children.”
from Cancer To Depression
In adults, researchers have found numerous connections between imbalances in the microbiome and serious health risks.
Metastatic Breast Cancer
Melanie Rutkowski, a research faculty member in UVA’s Department of Microbiology, Immunology and Cancer Biology, found that an unhealthy, inflamed gut can cause breast cancer to become much more invasive and spread more quickly. She and her team documented how disrupting the microbiome of mice essentially primed hormone receptor-positive breast cancer to spread by increasing inflammation within the precancerous breast tissue. Her team is working to understand how certain immune cells, triggered by an unhealthy gut, within precancerous breast tissue influence breast tumor invasion and metastatic spread.
“Some of the cells that we have identified are not typically associated with normal mammary tissue and in the presence of a tumor appear to enhance tumor metastasis,” she said. “Our hope is that we can utilize currently available drugs intended to block the function of these particular cells as a means of preventing metastatic breast cancer.”
The research also addresses a larger question: why women with similar diagnoses and treatments can have drastically different outcomes.
“Our findings have the potential to address a larger question within the field, which is why some women, despite being diagnosed and treated at similar stages, develop metastatic disease, while others do not,” Rutkowski said.
Rutkowski is also considering how her results can shed light on health care disparities. One study she cited, the TailoRx study, showed that African American women diagnosed with hormone receptor-positive HER2-negative breast cancer had approximately a 40% increased risk of developing metastatic disease, and a more than 50% risk of dying, higher than that of white women.
“The authors of this study could find no differences in the treatment either group received, suggesting that differences in outcome are driven by an underlying biological basis,” she said. “Perhaps what we are finding could help explain some of these differences.”
Researcher Alban Gaultier and his team were able to reverse depression symptoms in mice by feeding them lactobacillus, a probiotic bacterium found in live-culture yogurt. This suggests that a lack of lactobacillus can contribute to the onset of depression symptoms, and that altering the microbiome might help doctors treat depression with few harmful side effects.
“Mental health is a major issue in medicine, and it is estimated between 5% to 8% of the U.S. population is suffering from major depressive disorders, probably linked to accumulating stress from our modern lifestyle,” Gaultier said. “When you look at current treatments for mental health, some work, but some are not very effective or even harmful. When we started, we asked if we could find a better way to impact mental health, and the promise of the microbiome is that you can adapt your diet or otherwise alter gut bacteria and perhaps have a low-impact way to fix health issues.”
Gaultier and his team are in the midst of follow-up studies. One day, he envisions a future where doctors can utilize specific diet-and-bacteria combinations much as they do prescription drugs.
“As we fully figure out what the microbiome does, we will be able to prescribe a diet to make it more efficient, or complete it with bacteria,” he said. “That is a big hope, and I think it will happen, giving us better options than many drugs with a lot of side effects.”
treating The Microbiome
Colleagues across Grounds are hard at work on bringing such a future to life, using complex computer modeling and lab work to predict how different microorganisms could affect the microbiome and human health.
Mapping The Microbiome
Because there are quite literally trillions of bacteria in our microbiome, identifying each one and figuring out how it interacts with others is no small task. That’s why researchers like Jason Papin and Greg Medlock have turned to big data.
Papin, a professor of biomedical engineering, and Medlock, an assistant professor of pediatrics and co-director of data science for TUMI, are combining computer modeling with laboratory research to map and predict how microorganisms interact and what effect they have. With computer simulations, they are answering questions like, “What molecules are being produced by particular bacteria? Which bacteria then use those molecules? What are the ultimate effects on different bacteria?”
The ultimate goal is to allow scientists to see how increasing or decreasing a particular type of bacteria might affect a patient, leading to possibly engineering different treatments or cures.
custom Probiotic Blends
Medlock is also using a competitive grant from the Bill and Melinda Gates Foundation to develop a process for producing different gut microbes and custom blending them to battle disease. Medlock has developed computer algorithms identifying ideal growing conditions for different microbes and how they interact, allowing scientists to grow microbes with speed and efficiency and, ultimately, create targeted probiotic blends.
“Probiotics in yogurt, for example, are marketed for very general health benefits. This new generation of probiotics are much more complex and targeted, with the goal being to replicate the complexity of bacteria in our gut,” Medlock said. “The long-term goal is, if you are trying to prevent a disease caused by a particular pathogen, to design a bacterial environment to fight that pathogen.”
understanding The Effects Of Antibiotics
Petri, one of TUMI’s co-directors, has studied how antibiotics affect the microbiome, particularly focusing on Clostridioides difficile infections, which can cause life-threatening gastrointestinal symptoms. UVA has a clinic that specializes in treating patients with recurring C. difficile infections and has pioneered innovative treatment methods, including fecal transplant.
Petri and his team have shown that overuse of antibiotics can reduce the variety of microbes in the gut, and interfere with the immune system’s ability to fight off infections. This can be very harmful to patients. In one study, focused on children in Bangladesh, Petri and his team found that children with more severe gut infections had less diversity in their microbiome, suggesting that early, frequent antibiotic treatment (common for children in developing countries) had done more to harm than to help.
“I think the take-home is that this is another important reason not to use antibiotics unless they are clearly needed,” Petri said at the time. “Unwise use of antibiotics not only increases the risk of multi-drug resistant bacteria and the risk of C. difficile infection, but also impairs white blood cell function.”
Ready For What Is Next
Petri, who has devoted his career to studying gut microbes and their effect on human health, is thrilled to see TUMI come to fruition, supported by researchers and faculty in many different departments and schools – especially the new School of Data Science – and funded in part by UVA’s Strategic Investment Fund.
“The microbiome cuts across so many different areas in medical science, and this is a huge opportunity to help UVA be even more competitive in this crucial area,” he said. “We know that changes in microbiota are associated with autism, obesity, depression, malnutrition and more, but those are just associations until you can prove it. TUMI is giving us the ability to do that.”