The Iowa State University Office of the Vice President for Research (OVPR) has awarded $150,000 in 2023 Presidential Interdisciplinary Research Seed Grant program (PIRS) funding to support university scholars focused on exploring novel approaches to a trio of human health challenges.

Established in 2017, the PIRS program is administered by the OVPR and supported with funds from the Office of the President and an endowment from the Mary G. Miller estate. The annual award is given to support faculty members pursuing initiatives that are innovative, high-risk, and high reward with an interdisciplinary focus and strong potential for external funding. Three teams were recently selected to receive $50,000 each in 2023 PIRS funding, to be used over the course of two years. Professor of veterinary microbiology and preventive medicine and W. Eugene Lloyd Chair in toxicology Mark Lyte and assistant professor of food science and human nutrition Peter Clark will use funding to investigate how probiotics influence gut health, inflammatory disease and human behavior. Professor of animal science Aileen Keating will lead a collaboration with University of Iowa to determine how environmental contaminants impair female reproduction. And affiliate assistant professor of biochemistry, biophysics and molecular biology Muslum Ilgu, in conjunction with a research team, plans to fight antimicrobial resistance by developing new approaches for sensitizing bacteria to antibiotics.

“Our office is delighted to provide PIRS program support for the innovative research of Doctors Lyte, Clark, Keating, and Ilgu,” said Vice President for Research Peter Dorhout. “The bold and novel approaches each of these researchers and their teams offer the hope of forging new frontiers in human health that could ultimately benefit countless individuals around the globe.”

Probiotics as a Dopamine Delivery System

Numerous studies have found that critical human immune system functions originate in the gut and are moderated by the activity of dopamine, a chemical released in the brain that is responsible for feelings of satisfaction and motivation, as well as the ability of nerve cells to communicate with each other. When present in healthy amounts, dopamine serves as an anti-inflammatory support in the digestive tract. Conversely, low levels of dopamine contribute to increased gut inflammation, which has been linked to a number of chronic health conditions, including Crohn’s disease, ulcerative colitis, and irritable bowel syndrome (IBS). Because biological danger signals from intestinal inflammation are communicated across the entire nervous system through what is called the “gut-brain axis,” the inflammatory process can spread to the brain, resulting in short-term memory and attention deficits, anxiety, and depression. Experienced long-term, inflammation stemming from the gut that spreads to the brain has been hypothesized to result in a significantly increased risk of developing an age-related neurodegenerative disorder — such as Alzheimer’s disease or Parkinson’s disease — later in life.

Although the presence of healthy amounts of dopamine have been found to protect against health conditions stemming from the gut, to date, the delivery of consistent levels of dopamine to tissue sites where inflammation may develop has not been executed successfully. Lyte and Clark, whose project is titled “A Novel Use for Supplementation with the Probiotic E. faecium in the Treatment of Gut- Brain-Axis Inflammation,” believe that the key to safely delivering dopamine to the human digestive track lies in probiotics. Through their PIRS project, the duo will experiment with the Enterococcus faecium probiotic, which was discovered in Lyte’s lab to efficiently convert the amino acid L-dopa to dopamine, to test if probiotics can be utilized to increase dopamine levels in the human gut and control the inflammatory state. Currently, no clinical trials using probiotic-based dopamine compounds to treat chronic inflammatory conditions exist, making Lyte and Clark’s study the first of its kind.

“If this initiative is as successful as hypothesized, what we might end up with is a well-tolerated natural treatment to reduce inflammatory disorders within the intestines that can also benefit inflammatory disorders within the brain,” Clark said. “Many of these health conditions do not currently have a form of treatment available, so having a novel treatment approach that can better human health, from intestinal difficulties and cognitive function to mental health and neurodegenerative disorders, could have a pretty broad sweeping benefit.”

The first half of Lyte and Clark’s project will focus on the connection between alcohol misuse and inflammatory conditions within the gut. Alcohol use disorder and gastrointestinal diseases are often comorbid, as chronic alcohol use has been found to cause intestinal inflammation. According to Clark, chronic intestinal inflammation as a result of long-term alcohol misuse may contribute to augmented levels of brain inflammation that can produce mental health and memory disturbances, as well as increase the risk for developing neurodegenerative diseases later in life. The study will evaluate if daily doses of dopamine-producing probiotics could reduce inflammation across the gut-brain-axis using a rodent model of chronic alcohol misuse.

During the project’s second year, the same process will be used to investigate the impact of dopamine delivery on inflammatory intestinal disease and associated brain inflammation using a rodent model of ulcerative colitis.

“There are significant medical implications if we can use probiotics mechanistically, design them to do a specific function – and in this case a neurochemical function – that can affect a human host in a consistent, reproducible manner,” Lyte said. “We would have the opportunity to convince the medical community of the utility of probiotics in a way that could not have been done before.”

Uncovering Environmental Impacts on Infertility

Per- and poly-fluoroalkyl substances (PFAS), considered to be “forever chemicals,” are environmental pollutants that stay in human bodies and the environment for years. They can be found in consumer products ranging from microwaveable popcorn to non-stick cookware, and they do not break down over time. With the help of a newly formed partnership between Iowa State and the University of Iowa’s Center for Advanced Reproductive Care and Environmental Health Sciences Research Center, Keating will explore the role these forever chemicals may play in infertility and reproductive difficulties, specifically in women and female swine.

Through her PIRS project, titled “Forever Infertile? Investigating Ovarian Impacts of Perfluorooctanoic Acid Exposure,” Keating and her collaborators will determine the ovarian impacts of exposure to consistent environmental pollutants on pigs, as a link has already been found between contaminants and reproduction ability in mice and swine production is a major industry in the state of Iowa. They will also search for, and if found, quantify PFAS chemicals in samples of human ovarian follicle fluid provided by the University of Iowa Department of Obstetrics and Gynecology Division of Reproductive Endocrinology and Infertility Database and Tissue Bank.

Currently, levels of PFAS exposure found in midwestern women is unknown, but according to Keating, the Iowa Department of Natural Resources has recently found PFAS in waterways across the state. Detectable levels of contaminants above newly issued safety advisory levels have already been found in Ames, Des Moines, Tama, Davenport, and Keokuk. Oral ingestion is a common way for PFAS exposure to occur, indicating that both women and livestock can be exposed to chemicals harmful to reproduction just by drinking water or consuming livestock feed or plants grown with contaminated water.

On June 15, 2022, the U.S. White House released a statement regarding the need for strategies to combat PFAS pollution, bringing Keating’s PIRS project into alignment with national human health and environmental priorities.

“Environmental effects on female reproduction are not often considered by the general community, but impaired female reproduction can be a consequence, and is an economic and welfare issue for many women and female production animals,” Keating said. “The goal of this project is to increase our understanding of a major environmental risk to the swine industry and design strategies to overcome this exposure. Determining the risk of midwestern women to PFAS chemicals will add to understanding exposures that are experienced in this part of the United States and pave the way forward for other investigations dedicated to improving human fertility and the animal agriculture industry in Iowa.”

Targeting the “Gates” of Harmful Bacteria

Antimicrobial resistance (AMR) is one of the greatest challenges currently facing human health, as bacteria, fungi, and viruses that cause serious illnesses become more adept at evading existing drugs. In 2015, the U.S. government declared a strategic national action plan to strengthen efforts to prevent, detect, and control illness and death related to infections caused by antibiotic-resistant bacteria. Within the realm of AMR, the food-borne Campylobacter species of bacteria — which is responsible for up to 500 million cases of diarrhea each year and is the leading cause of bacterial gastroenteritis — is especially problematic, as many existing antibiotics are ineffective in combating it.

Although there is a high need for new antibiotics, few have come to the market, driving the need for the development of alternate, novel ways to make existing antibiotics a better treatment approach to common AMR bacterial species. Through Ilgu’s PIRS project, “ATAC (Aptamers for Theranostic Applications against Campylobacter),” he and a team of researchers from both Iowa State and the University of Tennessee intend to develop a specific type of nucleic acid molecules, known as “nucleic acid aptamers,” that would sensitize multi-drug resistant Campylobacter bacteria to available antibiotics.

According to Ilgu, antimicrobial-resistant organisms utilize membrane proteins as gates that can recognize drugs at the molecular level, preventing relevant drug therapies from ever reaching the part of the bacteria necessary to be impactful. Instead, the so-called gates bind to and remove the drugs, allowing the bacteria to survive even in the presence of antibiotics. The proposed novel aptamers would possess the ability to interact with a specific surface protein of the Campylobacter bacteria and keep the gates closed, making the bacteria more susceptible to drugs and decreasing the amount of antibiotics needed to kill harmful organisms.

“Antimicrobial resistance is a global problem that continues to grow in both human and animal health systems,” Ilgu said. “AMR results in extra spending of billions of dollars each year. Finding solutions to antimicrobial resistance will be economically beneficial to the whole of society and help save lives. Through this PIRS collaboration, I feel that we will have a collection of groundbreaking results as a team.”

 The Presidential Interdisciplinary Research Seed Grant Program (PIRS) is open to full-time, tenured/tenure-eligible, and term faculty with the rank of assistant professor, assistant teaching professor, clinical assistant professor, and adjunct assistant professor, or higher ranking faculty from any discipline. PIRS supports the initial development of innovative research, with up to $50,000 in funding designated for selected teams to pursue high-risk, high-reward projects over a two-year period. The awards are designed to support projects that help researchers from different disciplines collaborate on groundbreaking research, including collecting data, organizing workshops, and building partnerships with other organizations.