LOUISVILLE, Ky. - Nathan Schmidt, Ph.D., has published research showing that microbes in the gut of mice can affect the severity of illness suffered from infection with Plasmodium, the parasite that causes malaria. To pursue this research further, Schmidt, assistant professor in the Department of Microbiology and Immunology in the University of Louisville School of Medicine, has received a five-year research grant of $2.6 million from the National Institute of Allergy and Infectious Diseases, one of the National Institutes of Health. In his new research, Schmidt intends to determine which microbes are responsible for protecting against illness and to learn more about the mechanism behind that protection.
"Now we are hoping to determine which bacteria or metabolites are interacting to determine the severity or lack of severity of illness in the individual," Schmidt said. "If we can identify the bacteria, it raises hope that we can target those mechanisms to prevent severity of the disease, thereby reducing illness and death from malaria in sub-Saharan Africa."
Globally, malaria afflicts more than 200 million people and causes more than 400,000 deaths each year, with 90 percent of cases occurring in sub-Saharan Africa. However, many more individuals are infected with the Plasmodium parasite but do not become seriously ill. Schmidt's research aims to learn more about why some people become seriously ill while others do not.
In 2016, Schmidt published research in Proceedings of the National Academy of Sciences (PNAS) revealing that mice having one community of microbiota colonizing their gut were less susceptible to severe infection from Plasmodium than mice with a different community of microbiota. In this research, Schmidt showed that when the microbiota from the mice experiencing low or high levels of illness were transplanted to mice that previously had no microbiota (germ-free mice), the transplanted mice had similar levels of disease following infection as the low and high donor controls, respectively. These results demonstrate that it was the gut microbiota causing differences in disease severity. In another series of experiments, he treated mice with antibiotics followed by doses of Lactobacillus and Bifidobacteria in lab-cultured yogurt. The parasite burden in the susceptible mice decreased dramatically and symptoms of illness were reduced in the mice treated with the yogurt.
Schmidt believes the antibiotic allowed the Lactobacillus and Bifidobacteria introduced in the yogurt to colonize the gut, thereby controlling the Plasmodium population.
"Enteric bacteria provide a competitive environment for other bacteria to grow and survive in. Treatment of mice with antibiotics provided an opportunity for the Lactobacillus and Bifidobacteria to grow and provide protection against severe malaria. Alternatively, it is possible the Lactobacillus prevented recovery of bacteria that cause severe malaria," Schmidt said.
Schmidt hopes to further isolate which bacteria are responsible for protecting the host from illness and tease apart the mechanisms by which they influence Plasmodium populations and immune response. This should allow collaboration with other researchers to test those effects in humans.
"Nathan's current findings and the proposed studies will enhance our understanding of how microbiota may modulate host immunity to malaria, which could explain why some individuals develop severe disease while others suffer milder symptoms. This is an understudied area with many opportunities," said Nejat Egilmez, Ph.D., chair of the Department of Microbiology and Immunology.
Schmidt is one of a growing number of researchers investigating links between gut microbiota and disease across the UofL Health Sciences Center campus.
"The role of commensal microbiota in host physiology and health is a highly active, cutting-edge area of research amounting to a new paradigm in medicine," Egilmez said. "In addition to Nathan, several of our faculty, including Drs. Michele Kosiewicz, Krishna Jala and Hari Bodduluri, have ongoing projects exploring the link between host microbiota and diseases such as autoimmune disorders, infectious disease and cancer. The new award will create opportunities for future collaborations not only amongst these individuals but also with others in the department who study the more basic processes underlying host immunity and microbial pathogenesis."