The five-year grant from the National Institutes of Health (NIH) is an extension of a��Center of Biomedical Research Excellence (COBRE) grant awarded in 2018��to study the connection between those microorganisms — such as bacteria, yeasts, fungi, viruses and protozoans — and disease. The work could lead to discoveries in, among others, Alzheimer’s disease, heart disease, diabetes, periodontitis and colorectal cancer.

The grant will support research by three faculty members focused on microorganisms in the mouth, GI tract and the blood-brain barrier, said Richard Lamont, principal investigator for the grant and chair of School of Dentistry Department of Oral Immunology and Infectious Diseases.

“Collectively, these three projects provide innovative approaches to an increased understanding of the host-microbe interface as it defines health and disease and these advances will establish the basis for new therapeutic approaches,” Lamont said.

The School of Medicine’s Department of Microbiology & Immunology also is involved in the COBRE research, including interim chair Haribabu Bodduluri, the center’s co-director.

“An essential feature of these awards is the support of shared resources for development of new research areas,”��said Bodduluri.��“In the past few months since the renewal, we were awarded supplemental funding to the COBRE that enhances the research core facilities and initiates a novel��‘Team Science’��project.”

Gerry Bradley, interim university provost, said the NIH grant allows UofL to further the COBRE’s groundbreaking research, development of new innovations and training the next generation of scientists.

“This huge commitment from the government reinforces that UofL is one of the top dental schools in the United States in terms of the value of research work conducted here and research funding dollars,” he said.

The original COBRE grant allowed UofL to establish an interdisciplinary research program to study associations linking microbiome with inflammation and disease. The grant provides junior research faculty with seed funding to build potential for independent research funding. The first five faculty researchers involved are successfully continuing their research with other financial support.

“As a top-tier research institution, UofL works to expand understanding and find solutions to important problems,” said Kevin Gardner, executive vice president for research and innovation. “The work of Drs. Lamont and Bodduluri, along with their��team, for example, could lead to life-changing therapies, treatments and more that could dramatically improve the lives of people living with numerous conditions.”

Kevin Sokoloski, assistant professor in the Department of Microbiology & Immunology and participant in UofL’s initial COBRE grant, said the program helped his research by connecting him with a robust scientific community focused on inflammation and pathogenesis.

“Our ongoing involvement in the COBRE program has accelerated our success and continues to enhance our scientific mission,” Sokoloski said.

The newly funded researchers are:

• Fata Moradali,��(Oral Immunology and Infectious Diseases), who will address periodontitis, a common condition driven by a synergistically virulent bacterial community that triggers destructive inflammatory responses in the periodontal, or gum tissues.
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• James Collins,��(Microbiology & Immunology), who will investigate the GI tract pathogen��C. difficile, an evolving organism whose ability to cause disease can be enhanced by the nutritional microenvironment.��
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• Yun Teng,��(Department of Medicine), who will focus on the blood-brain barrier (BBB). Increased permeability of the BBB accelerates the aging process and the progression of age-related diseases.��

View the press conference .��

Watch the press conference:

“Aging is not inevitable; it is an opportunity. Not everyone has the chance to grow old,” said Robert Friedland, professor of neurology at the University of Louisville and an expert on aging. “How well we age depends on what we do.”

Inspired by his grandfather’s struggle with dementia, Friedland has spent nearly five decades as a neurologist and researcher, studying the causes of neurological diseases and seeking new ways to treat and prevent them. In addition to seeing patients with a focus on cognitive, behavioral and geriatric neurology, his ongoing research investigates the connection between microbes in the gut and mouth and the development of Alzheimer’s and Parkinson’s disease and other neurodegenerative conditions.

Based on this work, Friedland says it is possible for people to preserve health into later years by stockpiling reserves in cognitive, physical, psychological and social health.

Although Friedland admits that certain physical declines are inevitable with age and that genetics can predispose a person to certain diseases, he believes in many cases these reserves can prevent diseases or lessen their effects, delay age-related declines and allow an older person to recover from accidents and illness.

“Genetics do have a role in our health but they are not the whole story. Choices we make throughout life affect whether diseases develop and how much they reduce our health when they do,” Friedland said. “We can do things that delay or mitigate heart disease, diabetes and cognitive and neurological diseases and allow us to recover from life events that otherwise may cause permanent declines in health.”

Each of Friedland’s four factors, described below, is dependent on the others. Friedland provides tips on increasing reserves of each area. By developing habits that add to these reserves, you can maximize your opportunity to remain active and healthy as you get older.

Cognitive reserve – The ability of the brain to work effectively, solve problems and make decisions.

Since the brain controls every system in the body, it makes sense that a healthy brain will support other reserve factors (physical, psychological, social).

Keep the brain healthy by seeking opportunities to learn new things and challenge your ways of thinking throughout life. Learn a new language or a new skill, such as playing a musical instrument or crochet. Play chess or other games. Any activity that involves learning and strategy will strengthen your brain.

“Watching television is not a good activity since it is completely passive and does not require participation. Reading is a better choice as it demands involvement,” Friedland said. “Telling stories is good for your memory and attention skills.”

Physical reserve��– The health of the body’s cardiovascular, neurological, musculoskeletal and other systems.

These reserves depend on eating the right food, engaging in physical activity every day and receiving regular health care.

A diverse diet of healthy foods supports both your body and your microbiota, the microorganisms that live in and on the body and are essential to your overall health. Friedland recommends a diet that is mostly plants, high in fiber and low in sugar, salt and saturated fat. When you improve your diet, you also can improve the health of your microbes which aids your own health.

“I call it gene therapy in the kitchen,” Friedland said. “By making the best choices in your food, you can alter the genetic makeup of your microbiota and improve your overall health in as little as two weeks.”

Exercising for 30 minutes each day, regardless of weather or circumstance, is enough to improve physical health, Friedland says. More is better, of course, and when you combine physical activity with social interactions and cognitive activity by playing a sport such as golf or tennis, the benefits multiply.

Taking steps to protect yourself from injury or illness also is important. Wear a helmet when you are riding a bike, wash your hands and avoid exposure to toxins.

It also is important to get enough quality sleep each night, practice good dental hygiene, avoid excess alcohol and have regular medical checkups.

Polypharmacy is another problem to avoid. Friedland said that as people age, they may accumulate prescriptions for multiple health concerns that can interact or alter the effectiveness of each other. If you are taking several prescriptions, regularly evaluate all of them with your health care provider.

Psychological reserve��– A healthy mental state that is free of agitation, anxiety and depression.

Poor mental health can affect your ability to interact with others or maintain your physical health. Practice a positive mental attitude, engage in activities that are meaningful to you and manage stress with meditation or other measures.

“Depression is common in older people, and that can lead to memory problems,” Friedland said. “Physical factors can contribute to depression, such as poor sleep or vitamin deficiency. A lack of social interactions and physical activity also can cause or aggravate depression.”

Social reserve��– Personal relationships and the ability to function in society.

The company of others can motivate people to take care of themselves and encourage them to maintain healthful behaviors. Positive relationships can be with a spouse, a group of friends or professional colleagues.

“Studies indicate that dementia is more common among people whose social activity declines later in life,” Friedland said. “Humans need relationships with others in order to maintain good health.”����

Social engagement can go hand in hand with the other types of activity by including friends in physical exercise, games, a craft or work. Involvement in community or religious activities also can increase a sense of belonging and a desire to stay active.

Ideally, you will begin developing habits that contribute to these reserves early in life, but Friedland says it is possible to add to reserves and improve your health at any age – even once you reach an age when you experience the effects of deficits.

“Aging is not inevitable,” Friedland said. “The chance to be alive should be recognized as an opportunity – an opportunity to manage our lifestyle factors to maximize survival, health, fitness and meaning as we age.”

More detailed advice from Friedland that may help people live longer, healthier lives and a deeper discussion of the reasons he makes these recommendations are available in his book, “.” Published in October by Cambridge University Press, the book was cited by the Wall Street Journal as one of the five best books on aging and retirement published in 2022.

The researchers at UofL have determined that Urolithin A (UroA) and its synthetic counterpart, UAS03, mitigate IBD by increasing proteins that tighten epithelial cell junctions in the gut and reducing gut inflammation in animal models. Tight junctions in the gut barrier prevent inappropriate microorganisms and toxins from leaking out, causing inflammation characteristic of IBD. Preclinical research published today in shows the mechanism by which UroA and UAS03 not only reduce inflammation and restore gut barrier integrity, but also protect against colitis.

“The general belief thus far in the field is that urolithins exert beneficial effects through their anti-inflammatory, anti-oxidative properties. We have for the first time discovered that their mode of function also includes repairing the gut barrier dysfunction and maintaining barrier integrity,” said Rajbir Singh, PhD, a postdoctoral fellow at UofL and the paper’s first author.

Venkatakrishna Rao Jala, PhD, assistant professor of microbiology and immunology at UofL, led the research, conducted by Singh and other collaborators at UofL, the Institute for Stem Cell Biology and Regenerative Medicine (inStem) in Bangalore, India, the University of Toledo College of Medicine and Life Sciences, and Dalhousie University in Nova Scotia. Jala, Singh and other researchers at UofL have been investigating how metabolites produced by the human microbiota – bacteria, viruses and fungi that inhabit the human body – affect many areas of health. By understanding the effects of specific metabolites, they hope to use them directly as therapeutic agents in treating disease.

It has been reported that the microbe Bifidobacterium pseudocatenulatum INIA P815 strain in the gut has the ability to generate UroA from ellagic acid (EA), a compound found in berries and pomegranates. Variations in UroA levels, despite consumption of foods containing EA, may be the result of varied populations of bacteria responsible for the production of UroA from one individual to another, and some individuals may not have the bacteria at all. While encouraging natural levels of UroA in the gut by consuming the appropriate foods and protecting populations of beneficial bacteria should have positive health effects, the researchers believe the use of the more stable synthetic UAS03 may prove to be therapeutically effective in cases of acute colitis. Further experiments and clinical testing are needed to test these beliefs.

“Microbes in our gut have evolved to generate beneficial microbial metabolites in the vicinity of the gut barrier,” Jala said. “However, this requires that we protect and harbor the appropriate gut microbiota and consume a healthy diet. This study shows that direct consumption of UroA or its analog can compensate for a lack of the specific bacteria responsible for production of UroA and continuous consumption of pomegranates and berries.”

Haribabu Bodduluri, PhD, professor of microbiology and immunology at UofL and an author of the article, said another key finding of the research is that UroA and UAS03 show both therapeutic and protective effects. Administration of UroA/UAS03 after the development of colitis reverses the condition and administration prior to development of colitis prevents it from occurring.

This research was facilitated by funding from the National Cancer Institute to Jala and the , established at UofL in 2018 with funding from the National Institute of General Medical Sciences.

To further understand these associations linking the microbiome — bacteria, yeasts, fungi, viruses and protozoans — with inflammation and disease, the University of Louisville has received an $11.2 million federal grant over five years to establish an interdisciplinary research program.

The grant, awarded through the National Institute of General Medical Sciences, establishes a Center of Biomedical Research Excellence (COBRE) and pairs well-funded scientists with junior faculty in the Schools of Dentistry, Medicine and Engineering. This arrangement facilitates the career development of junior faculty, and aims to advance the study of the interface between microbiome, inflammation and disease development.

“Although the microbiome contributes to many beneficial aspects of our physiology, when these communities are out of balance, or dysbiotic, they are implicated in an array of diseases such as inflammatory bowel disease, periodontitis, vaginosis, colorectal cancer, and distant sites like rheumatoid arthritis, even neurological disorders like Parkinson’s disease and autism spectrum,” said Richard Lamont, PhD, chair of the School of Dentistry’s Department of Oral Immunology and Infectious Diseases and principal investigator for the grant.

Furthermore, Lamont said, inflammation is a process that provides the mechanism connecting the microbiome and disease.

“The interplay of the pro and anti-inflammatory components of the immune system with microbes often dictates whether a person remains healthy or develops a disease, as well as controls aspects of recovery, chronic infection and the level of tissue destruction,” he said.

Microbiology and Immunology in the School of Medicine is the other primary department participating in the COBRE. Researchers in the J.B. Speed School of Engineering’s bioengineering department will provide expertise as possible new discoveries show potential for new therapeutic technology against disease.

“This program will synergize with, and augment, existing research priorities at UofL centered around microbial community-associated diseases,” said Greg Postel, MD, interim UofL president. “We are confident that establishing a critical mass of investigators with unique complementary expertise will propel UofL to a position of preeminence in this important field.”

“We are thrilled to add this COBRE multidisciplinary program in research, education and mentoring to facilitate and accelerate the transition of junior faculty to independent extramural funded status, advancing our overall research enterprise,” said T. Gerard Bradley, BDS, MS, Dr.Med.Dent., dean of the School of Dentistry.

The grant will support five junior faculty and their specific research focused on the mouth, GI tract, arthropod (flea) vector environments, vagina and lungs:

• Juhi Bagaitkar, PhD, will study how oxidants change neutrophil, or white blood cell, responses in the mouth. She is focused on inflammatory pathways regulated by Reactive Oxygen Species essential in host responses to oral bacteria. She hopes to provide insights into neutrophil biology, and enhance the understanding of immune pathways related to inflammation of the gums and the interface with microbes.

• Venkatakrishna Jala, PhD, will investigate the beneficial effects of the microbial metabolite, uronlithin A (UroA) and its structural analogue UAS03 in inflammatory bowel disorders. He will examine their impact on both immune responses and maintenance of the epithelial barrier in the gastrointestinal mucosal membrane.
• Matthew Lawrenz, PhD, will study the pathogenic mechanisms of pestis, a bacterium that causes bubonic plague. Humans can become sick after being bitten by a rodent flea. Lawrenz will further investigate several mechanisms, including how Y. pestis evades macrophages, a kind of white blood cell first on the scene of infection. As the project develops, Lawrenz also hopes to explore the relationship of Y.pestis and microbial communities of the flea, which may impact colonization and transmission.
• Jill Steinbach-Rankins, PhD, will investigate a new nanotherapeutic approach to treat bacterial vaginosis (BV), a dysbiotic condition where vaginal microbial communities are disrupted. With expertise in materials science engineering and biomedical engineering, Steinbach-Rankins aims to develop targeted community engineering to restore the balance between the microbiome and host to prevent the manifestation of disease.
• Jonathan Warawa, PhD, will investigate Burkholderia pseudomallei (Bp), the bacterium responsible for respiratory melioidosis, an inflammatory disease of the lungs that progresses into a fatal systemic disease involving major organs. This project drills down into innate immune responses contributing either to protection and resolution of diseases or to increased morbidity. Through greater understanding of immune responses, therapeutic intervention is possible.

The COBRE also helps establish a functional microbiomics core research facility at UofL. The facility will provide germ-free animal facilities, oxygen-free culture capability, microbiome sequencing and bioinformatics, assessment of inflammatory markers and pathology services.��

Check out more from the press conference below:��

“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, 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 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, PhD, 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.”

Robert Friedland, MD, professor in the Department of Neurology at the University of Louisville, has conducted research showing that the microorganisms in the intestines can affect the brain, and may be responsible for causing Alzheimer’s, Parkinson’s and other neurodegenerative diseases. He will discuss this research and other valuable insights on microbiota at the next event, Feb. 15.��

“These partner microbes have more than 100 times more genes than our own DNA. Since they are dependent upon our diet for their nutrition and sustenance, we can substantially alter the microbiota through alteration of food intake, performing a type of ‘gene therapy,’” Friedland said.��“We will discuss the role of the microbiota in health and disease and review what people can do to lower their risk of cancer, stroke, and Alzheimer’s and Parkinson’s diseases.”

Friedland is a clinical and research neurologist and has researched neurodegenerative diseases and other brain disorders associated with aging for more than 30 years. He is collaborating on research projects with investigators in Ireland, the United Kingdom and Japan.

The Beer with a Scientist event begins at 8 p.m. on Wednesday, Feb. 15, at Against the Grain Brewery, 401 E. Main St. in Louisville. A 30-minute presentation will be followed by an informal Q&A session. Admission is free. Purchase of beer, other beverages or menu items is not required but is encouraged.

The next Beer with a Scientist is scheduled for March 15.