Hariom Yadav, PhD, of the USF Center for Microbiome Research, and Ji Li, PhD, of the USF Health Heart Institute  — Photos by Allison Long, USF Health Communications

Two researchers from the USF Health Morsani College of Medicine have received Florida Department of Health (FDOH) grants to help advance discoveries in Alzheimer’s disease and in tobacco-related heart disease.

Hariom Yadav, PhD, an associate professor of neurosurgery and brain repair and director of the USF Center for Microbiome Research, was awarded total expected funds of $743,661 over four years from the FDOH Ed and Ethel Moore Alzheimer’s Disease Research Program. The multidisciplinary consortium project is titled “Role of Microbiome in the Aging of Gut and Brain in Floridian Older Adults.”

Researchers at USF and several other sites across Florida will study how diet affects the gut and oral microbiomes linked to brain health in adults ages 60 and older. Age is a key risk factor for Alzheimer’s disease and related dementias (ADRD); no effective treatment exists, and early risk detection remains a challenge. The FDOH-supported research seeks to determine whether unique microbiome signatures can differentiate older adults suffering cognitive decline and ADRD from their healthy counterparts and predict disease progression. The study will also examine whether abnormalities in microbe-derived metabolites, excessive gut “leakiness” and inflammation definitively contribute to cognitive impairment and ADRD—with the ultimate aim of identifying measures to prevent or delay these devastating conditions.

Ji Li, PhD, professor of surgery and a member of the USF Health Heart Institute, was awarded total expected funds of $583,200 over three years from the FDOH James and Esther King Biomedical Research Program. The grant is titled “Sirtuin 1 and Cardiovascular Impairment by Cigarette Smoking.”

Dr. Li’s laboratory has shown that the anti-aging protein sirtuin 1 (SIRT1) plays a role in cardiovascular disease development, and emerging evidence suggests that SIRT1 is a component of signaling pathways that allow cells to sense and react to cigarette smoking. The FDOH-supported preclinical project will test whether and how SIRT1 signaling helps control the harmful effects of cigarette smoking on the heart’s pumping function in hypertension (abnormally high blood pressure). The study’s outcome could lead to the discovery of SIRT1 agonists or other drugs that may reduce damage and death from hypertensive heart disease associated with chronic smoking.

The new research may help identify measures to prevent or delay mild cognitive impairment and dementia

Can what you eat influence the health of your brain now and in the future?

That is a key question that USF Health Morsani College of Medicine researchers hope to answer with the help of a noninvasive Microbiome in the Aging Gut and Brain (MiaGB) study.

The new clinical study expects to enroll 400 adults ages 60 and older in the Tampa Bay region and beyond — both those who are cognitively healthy as well as those diagnosed with mild cognitive impairment and early-stage dementia.

The researchers will analyze the composition of bacteria in stool samples and saliva samples (oral swabs) donated by study participants one time at the beginning of the study and then once a year for at least five years. They will track alterations over time in the populations of oral and gut microorganisms, collectively known as the microbiome. Using an interactive mobile app, study participants will complete a daily dietary recall questionnaire and yearly tests of their memory, speed of thinking, and other cognitive abilities.

“We want to know, based on changes in the microbiome ‘signature’ from the saliva and stool samples, if we can predict an older person’s risk of developing cognitive decline or dementia. And can we do that early enough to delay or prevent those age-related diseases – either by modifying the individual’s diet or the microbiome itself,” said Hariom Yadav, PhD, an associate professor of neurosurgery and brain repair at the Morsani College of Medicine and director of the USF Center for Microbiome Research.

Several studies have correlated healthy guts, characterized by a well-balanced diversity of microorganisms, with healthy aging. Alzheimer’s disease and other dementias are among the growing number of medical conditions linked to an imbalance of microorganisms (more bad bugs than good bugs) within the intestines. Emerging evidence also suggests that oral health and brain health are interconnected, including a large National Institute on Aging study last year linking gum disease with dementia.

Hariom Yadav, PhD, (standing) and Shalini Jain, PhD, are faculty members at the USF Center for Microbiome Research, based in the USF Health Morsani College of Medicine. Their research focuses on the gut-brain connection (gut-brain axis) in relation to cognitive function.  — Photo by Allison Long, USF Health Communications and Marketing

The daily food intake logged by study participants will indicate any deficiencies in their usual diets, said Shalini Jain, PhD, the MiaGB study’s IRB principal investigator and USF Health assistant professor of neurosurgery and brain repair. “We’ll be able to evaluate the effects that certain types of foods (i.e, protein, fruits, vegetables, dairy, carbohydrates, fermented foods, and junk food) have on the growth of certain types of bacteria and see how the mix of bacteria changes if the diet is modified.”

Study participants may benefit by learning more about the calories and nutritional balance (or imbalance) in their diets, Dr. Jain added. Based on the dietary information reported, the mobile app suggests healthy habits that can be incorporated into the individual’s lifestyle.

Ronald Day and his wife Ardell, both 74, were among the first to enroll in the MiaGB study after attending a presentation about the USF Health microbiome research. Day, a retired pastor and volunteer chaplain at his Tampa continuing care retirement community, said he was intrigued by the idea that populations of microorganisms in the gut may affect cognitive skills controlled by the brain.

“On a practical level, I’m hoping to learn something about my eating habits from the food diaries we keep that might indicate what foods I should add to my diet, or which to avoid,” Day said. “And in the future, I’m hoping researchers learn enough from studies like this to suggest individualized diets (or other interventions) tailored to our own microbiomes.”

As someone in “the last third of life,” Day added, he’s keenly aware of the need to prevent or delay cognitive decline. “One of our neighbors is in the early stages of Alzheimer’s disease, and it’s been difficult for the family… Anything that can help maintain mental acuity as we age is so important.”

Photo by Allison Long, USF Health Communications and Marketing

Aging is not a disease, Dr. Yadav emphasized, but as people age it’s particularly important to keep a healthy balance of intestinal microbes so that a potentially harmful strain of bacteria does not overgrow and monopolize the food source of beneficial bacteria. “A healthy gut allows you to adequately absorb the healthier nutrients and keep a check on the stimulation of inflammation, which is a root cause of several age-related conditions, including abnormal cognitive function,” he said.

For more information about the MiaGB study, please email jains10@usf.edu or call (813) 974-6281.

A USF Health-led team finds that the compound fenchol has the same beneficial effect as gut-derived metabolites in reducing neurotoxic amyloid-beta in the brain

TAMPA, Fla. (Oct. 5, 2021) – Fenchol, a natural compound abundant in some plants including basil, can help protect the brain against Alzheimer’s disease pathology, a preclinical study led by University of South Florida Health (USF Health) researchers suggests.

The new study published Oct. 5 in the Frontiers in Aging Neuroscience, discovered a sensing mechanism associated with the gut microbiome that explains how fenchol reduces neurotoxicity in the Alzheimer’s brain.

Emerging evidence indicates that short-chain fatty acids (SCFAs)– metabolites produced by beneficial gut bacteria and the primary source of nutrition for cells in your colon — contribute to brain health. The abundance of SCFAs is often reduced in older patients with mild cognitive impairment and Alzheimer’s disease, the most common form of dementia. However, how this decline in SCFAs contributes to Alzheimer’s disease progression remains largely unknown.

Gut-derived SCFAs that travel through the blood to the brain can bind to and activate free fatty acid receptor 2 (FFAR2), a cell signaling molecule expressed on brain cells called neurons.

“Our study is the first to discover that stimulation of the FFAR2 sensing mechanism by these microbial metabolites (SCFAs) can be beneficial in protecting brain cells against toxic accumulation of the amyloid-beta (Aβ) protein associated with Alzheimer’s disease,” said principal investigator Hariom Yadav, PhD, professor of neurosurgery and brain repair at the USF Health Morsani College of Medicine, where he directs the USF Center for Microbiome Research.

Study principal investigator Hariom Yadav, PhD, directs the USF Microbiome Research Center housed at the USF Health Morsani College of Medicine. | Photo by Allison Long, USF Health Communications and Marketing

One of the two hallmark pathologies of Alzheimer’s disease is hardened deposits of Aβ that clump together between nerve cells to form amyloid protein plaques in the brain. The other is neurofibrillary tangles of tau protein inside brain cells. These pathologies contribute to the neuron loss and death that ultimately cause the onset of Alzheimer’s, a neurodegenerative disease characterized by loss of memory, thinking skills and other cognitive abilities.

Dr. Yadav and his collaborators delve into molecular mechanisms to explain how interactions between the gut microbiome and the brain might influence brain health and age-related cognitive decline. In this study, Dr. Yadav said, the research team set out to uncover the “previously unknown” function of FFAR2 in the brain.

The researchers first showed that inhibiting the FFAR2 receptor (thus blocking its ability to “sense” SCFAs in the environment outside the neuronal cell and transmit signaling inside the cell) contributes to the abnormal buildup of the Aβ protein causing neurotoxicity linked to Alzheimer’s disease.

Then, they performed large-scale virtual screening of more than 144,000 natural compounds to find potential candidates that could mimic the same beneficial effect of microbiota produced SCFAs in activating FFAR2 signaling. Identifying a natural compound alternative to SCFAs to optimally target the FFAR2 receptor on neurons is important, because cells in the gut and other organs consume most of these microbial metabolites before they reach the brain through blood circulation, Dr. Yadav noted.

Dr. Yadav’s team narrowed 15 leading compound candidates to the most potent one. Fenchol, a plant-derived compound that gives basil its aromatic scent, was best at binding to the FFAR’s active site to stimulate its signaling.

Alzheimer’s disease model of the worm C. elegans treated with the plant-derived compound fenchol (Above) and with a DMSO placebo (Below). Fenchol reduced accumulation of amyloid-β (green dots) in the organism’s head, compared to the placebo. | Images courtesy of Hariom Yadav, PhD, of the University of South Florida, first appeared as Fig. 4d in Frontiers in Aging Neuroscience, DIO: 10.3389/fnagi.2021.735933

Further experiments in human neuronal cell cultures, as well as Caenorhabditis (C.) elegans (worm) and mouse models of Alzheimer’s disease demonstrated that fenchol significantly reduced excess Aβ accumulation and death of neurons by stimulating FFAR2 signaling, the microbiome sensing mechanism. When the researchers more closely examined how fenchol modulates Aβ-induced neurotoxicity, they found that the compound decreased senescent neuronal cells, also known as “zombie” cells, commonly found in brains with Alzheimer’s disease.

Zombie cells stop replicating and die a slow death. Meanwhile, Dr. Yadav said, they build up in diseased and aging organs, create a damaging inflammatory environment, and send stress or death signals to neighboring healthy cells, which eventually also change into harmful zombie cells or die.

“Fenchol actually affects the two related mechanisms of senescence and proteolysis,” Dr. Yadav said of the intriguing preclinical study finding. “It reduces the formation of half-dead zombie neuronal cells and also increases the degradation of (nonfunctioning) Aβ, so that amyloid protein is cleared from the brain much faster.”

Before you start throwing lots of extra basil in your spaghetti sauce or anything else you eat to help stave off dementia, more research is needed — including in humans.

In exploring fenchol as a possible approach for treating or preventing Alzheimer’s pathology, the USF Health team will seek answers to several questions. A key one is whether fenchol consumed in basil itself would be more or less bioactive (effective) than isolating and administering the compound in a pill, Dr. Yadav said. “We also want to know whether a potent dose of either basil or fenchol delivered by nasal spray would be a quicker way to get the compound into the brain.”

The USF Health-led research was supported in part by grants from the National Institutes of Health, the U.S. Department of Defense, and the NIH-funded Wake Forest Clinical and Translational Science Institute.

About USF Health
USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the Taneja College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and USF Health’s multispecialty physicians group. The University of South Florida is a high-impact global research university dedicated to student success. Over the past 10 years, no other public university in the country has risen faster in U.S. News and World Report’s national university rankings than USF. For more information, visit health.usf.edu

About Frontiers
Frontiers is one of the largest and highest-cited open access publishers in the world. Access to research results and data is open, free and customized online to help solve the critical challenges we face as humanity. All journals are led and peer-reviewed by editorial boards of more than 100,000 top researchers across more than 900 academic disciplines. https://twitter.com/FrontNeurosci

Hariom Yadav focuses on microbiome’s role in the gut-brain axis, including creating fermented foods, probiotic mixtures, and modified diets to regulate gut “leakiness”

Hariom Yadav, PhD, is on the frontier of exploring the connection between the microbes in our gut and our brain health – including the impact on age-related cognitive decline and moods.

Dr. Yadav, an associate professor of neurosurgery and brain repair, was recruited to the USF Health Morsani College of Medicine to direct the Center for Microbiome Research, a key component of the newly launched USF Institute for Microbiomes. When he joined USF Health this April from Wake Forest School of Medicine in North Carolina, he brought more than $4 million in research awards from the National Institutes of Health and the U.S. Department of Defense.

“The major focus of our laboratory is investigating whether and how a leaky gut caused by disturbances in the gut microbiome contributes to the risk of dementia and other age-related chronic diseases such as diabetes, cardiovascular disease, and cancer,” Dr. Yadav said. “We also work to develop evidence-based products — probiotics, prebiotics, fermented foods, modified ketogenic diets — that can modulate the microbiome to help prevent bad effects of abnormal leakiness in the gut.”

The human body’s largest population of microorganisms lives in the intestinal tract, numbering in the trillions. These communities of microbes, mainly various strains of bacteria and to a lesser extent fungi and protozoa, are collectively called the gut microbiome. Unique to each individual, the gut microbiome performs various functions, including helping to digest food, control glucose metabolism and nutrient storage, boost the immune system, and moderate inflammatory responses.

Some gut microbes are beneficial, and others can be harmful. If the bugs coexist in harmony – for instance, without a potentially disease-causing strain of bacteria overgrowing and monopolizing the food of useful bacteria – then the digestive tract functions normally, Dr. Yadav said. “A healthy gut microbiome is characterized by a diverse, balanced collection of microorganisms.”

Hariom Yadav, PhD, associate professor of neurosurgery and brain repair at USF Health, stands in front of the anerobic chamber used to grow bacteria under oxygen-free conditions that mimic the gut. He was recently recruited to direct the USF Center for Microbiome Research | Photo by Allison Long, USF Health Communications

Our diet plays the predominant role in determining gut health. Lifestyle factors like exercise, sleep, stress, or the use of antibiotics and other medications, can also alter the gut microbiome’s composition.

Using modern genetic sequencing to precisely characterize the genetic makeup of microbes, scientists like Dr. Yadav have begun to unlock how the gut microbiome works and its massive implications for health and disease.

What does a “leaky gut” mean?

A “leaky gut,” also known as increased intestinal permeability, happens when the mucosal barrier lining the intestines becomes structurally and functionally damaged. That impairs this natural barrier’s ability to prevent infection and maintain general health.

As people age, Dr. Yadav explained, the mucus barrier of the bowel walls thins and becomes more porous than usual, making it easier for harmful bacteria and other toxins to pass from the intestines into the blood and circulate to other organs, including the brain. The microbiome of older guts also has diminished capacity to remove undigested food particles and to clear dead epithelial cells shed from the gut lining to make way for new ones, which contributes to leakiness, he said.

Dr. Yadav and assistant professor Shalini Jain, PhD, (front right) with members of their  research team. | Photo by Allison Long

Alzheimer’s disease and other dementias are among the growing number of medical conditions linked to imbalance in the gut bacteria, known as gut dysbiosis.

A preclinical study by Dr. Yadav and colleagues, published in JCI Insight, showed that the gut microbiomes of older mice were associated with chronic inflammation stimulated by increased gut leakiness via disruption of the intestine’s mucus barrier. The same study indicated that a human-derived probiotic “cocktail” mixing strains of bacteria isolated from healthy infant guts could suppress gut leakiness and improve both the metabolic and physical functions in older mice.

Probiotics are usually live bacteria that, when consumed in appropriate amounts, interact beneficially with other bacteria present in the human gut. Another study by Dr. Yadav’s team, published in GeroScience, found that a probiotic does not need to be alive to confer health benefits. The researchers discovered that a probiotic strain of Lactobacillus paracasei D3.5, even in its heat-killed or inactive form, decreased leaky gut and inflammation and improved cognitive function in older mice. This technology is under commercial development with the Postbiotics Inc., a N.C. biotechnology company cofounded by Dr. Yadav.

Brandi Miller (right), a PhD student, with Dr. Yadav and Dr. Jain. | Photo by Allison Long

Emerging research defining how gut microbiome abnormalities lead to leaky gut and harmful inflammation holds great promise for treating a growing number of age-related diseases. But interactions between the gut microbiome, its human host, and the outside environment are very complex.

The science is in its early stages, Dr. Yadav emphasized. “We still need to prove whether the long-term inflammation triggered by a leaky gut (causally) contributes to Alzheimer disease, cognitive decline or other age-related conditions in people at high risk.”

The gut-brain connection

The human gut contains as many nerve cells as the brain, and in some ways serves as a “second brain,” Dr. Yadav said. That’s because the intestines and the brain can send neuronal signals back and forth directly through a circuit known as the gut-brain axis.

.

This bidirectional gut-brain communication can affect processes like how hungry we feel, how much food we eat, how individual food tastes differ, and whether certain foods upset our stomach. Studies have also begun to unravel how the gut microbiome may affect executive brain function, including its influence on depression, anxiety and cognition.

Several gut bacteria make neurotransmitters, including serotonin and dopamine – two chemical messengers linked to mood and mental health. The “gut neurons” can shoot these neurotransmitters to the brain through the gut-brain axis and the mood-modifying chemicals can also be released into circulating blood, Dr. Yadav said.

Research in mice and humans indicates that the high-fat, low carbohydrate ketogenic diet is a powerful regulator of brain function, improves Alzheimer’s disease pathology, and alters the gut microbiome.

With that in mind, an earlier pilot study led by Dr. Yadav and colleagues reported that specific harmful fungi interacting with bacteria in the guts of older patients with mild cognitive impairment (which increases the Alzheimer’s disease risk) can be beneficially changed by eating a modified ketogenic diet. The research appeared last year in the Lancet journal EBioMedicine.

PCR-amplified DNA used to study microbiome-sensing mechanisms. | Photo by Allison Long

Supported by a National Institute on Aging grant, Dr. Yadav’s team is now working to distinguish the gut microbiomes of those who respond to a modified ketogenic diet, versus the microbiomes of non-responders. The researchers want to determine exactly how the gut microbiome promotes the metabolic action of the modified ketogenic diet to possibly reduce age-related cognitive decline and Alzheimer’s disease.

“Our goal is to identify alternatives that can either supplement this ketogenic diet or mimic the diet’s effect on the gut microbiome (in non-responders) to improve brain health,” Dr. Yadav said.

Dr. Yadav’s laboratory plans to launch a Microbiome in Aging Gut and Brain (MiAGB) clinical study led by assistant professor Shalini Jain, PhD. The investigators will collect clinical samples (stool, blood, cerebrospinal fluid) from people age 60 and older with no age-related cognitive decline as well as those diagnosed with mild cognitive impairment (MCI) and dementia. They will track alterations in the gut microbiomes of healthy older adults over time to see if certain biomarkers can accurately predict, early in the disease process, which individual are most likely to develop MCI or dementia.

.

Baby poop: A source of beneficial probiotics?

With a project he calls “Foods for Mood,” Dr. Yadav aims to identify microbial therapies to create a more balanced, varied gut microbiome — both to help maintain overall health as we age and to prevent or delay Alzheimer’s disease and other forms of dementia.

The probiotic strains his laboratory tests and refines as potential biotherapeutics come from a readily available source: baby poop. “Babies are usually pretty healthy and clearly do not suffer from age-related diseases,” Dr. Yadav said.

Using fecal samples from the diapers of infants, his team follows a rigorous protocol to isolate, purify and validate the safety of those strains of microbes most promising for promoting gut health. These probiotics (health-promoting bacteria), prebiotics (primarily fiber substances that the beneficial bacteria eat) or synbiotics (combinations of prebiotics and probiotics) are being incorporated into prototype high-fiber or fermented foods like yogurts, milk, or butter. The laboratory-grown strains need to be tested in clinical trials and follow the regulatory path to be commercialized as food products before they appear on supermarket shelves.

The “Foods for Moods” project led  by Dr. Yadav includes incorporating probotics, prebiotics and synbiotics into high-fiber and fermented food products. | Photo by Allison Long

The bacterial strains in baby feces are particularly good at helping produce short-chain fatty acids (SCFAs), a byproduct of gut microbe digestion that reduces inflammation, Dr. Yadav said. People with diabetes, cancers and age-related illnesses often have fewer SCFAs, and accumulating evidence indicates that the neuropathology underlying Alzheimer’s disease may be partly regulated by SCFAs.

“We are interested in targeting the source of (harmful) inflammation, which we think is the leaky gut. If we can fix that early enough, perhaps we can reduce the risk of chronic inflammatory response-mediated diseases, which mainly develop later in life,” Dr. Yadav said. “A healthy gut absorbs the nutrients we need from foods and supplies them to the body to help prevent age-related diseases and conditions, or to improve their management.”

The synbiotic yogurt developed at USF Health combines strains of prebiotics and probiotics that have been isolated, purified and preclinically validated for safety and effectiveness in promoting gut health. | Photo by Allison Long

Advancing technologies for microbiome research

Dr. Yadav received a PhD in biochemistry from the National Dairy Research Institute, India, in 2006. He conducted postdoctoral training in cell biology and metabolic diseases at the NIH’s National Institute of Diabetes and Digestive and Kidney Disease in Bethesda, Maryland.

Dr. Yadav has published more than 130 peer-reviewed papers and serves on the editorial boards and as a reviewer for several high-impact journals. He speaks frequently to scientific audiences and the media about the role of the gut microbiome and its modulators in age-related disorders, the gut-brain axis, probiotics and other biotherapeutics.

As director of the university-wide Center for Microbiome Research based at USF Health, he organizes technologies to advance microbial studies, including human microbiome/probiotics biorepositories, tools to grow bacteria and perform fecal microbiome transplantation, machines to sequence the genomes of microbes, and bioinformatics pipelines to robustly analyze massive volumes of sequencing data.

The image on the computer monitor depicts the movement of food through mice intestines labeled with a fluorescent dye. | Photo by Allision Long

Something you might not know about Dr. Yadav

Dr. Yadav attributes his interest in gut microbiome research in part to his mother’s severe gastrointestinal reactions to the widely prescribed type 2 diabetes medication metformin. Years later, he discovered that metformin and other drugs interact with microbes in an individual’s gut to influence medication effectiveness and the patient’s drug tolerance.

While metformin does not work for every diabetes patient, Dr. Yadav’s team recently presented findings at the American Physiological Association (APS) Experimental Biology 2021 meeting showing that metformin inhibited the spread of Clostridioides difficile or C. diff — a potentially life-threatening infection commonly acquired during hospital stays.

Dr. Yadav describes himself as a “grower” who enjoys growing flowers, plants and vegetables in his family’s backyard, growing bacteria in the laboratory, and helping his students grow in their scientific proficiency. A vegetarian, he makes his own probiotic-fortified yogurt and smoothies.

3-D illustration of bacteria Peptostreptococcus, which are part of the human microbiome in the gut and can cause inflammation.

TAMPA, Fla (July 21, 2021) – USF Health today announced the launch of a major university-wide institute dedicated to harnessing the huge populations of bacteria, viruses, fungi and other microbes inhabiting our bodies and our planet – known as microbiomes – to improve health and develop new treatments.

Based at USF Health Morsani College of Medicine, the new USF Institute for Microbiomes builds upon an ambitious microbiome initiative begun two years ago. That USF Initiative on Microbiomes has sparked interdisciplinary collaborations across the university to better understand how the diverse collections of microorganisms, unique to each person, might be exploited to benefit human health. It has also included studies of marine and soil microbial communities, which hold the potential to protect environmental as well as human health by mitigating climate change and food insecurity and generating alternative energy sources.

“As the university’s key constituent in this groundbreaking area of research, USF Health looks forward to accelerating microbiome discoveries and learning opportunities and applying this new knowledge to solve some of the most challenging real-world health problems,” said Charles J. Lockwood, MD, senior vice president for USF Health and dean of the Morsani College of Medicine. “The USF Institute for Microbiomes will unite investigators with different perspectives, both within and outside USF, to create stronger cross-disciplinary teams and provide shared resources needed to garner external grants, contracts and other funding sources.”

Christian Bréchot, MD, PhD, is director of the new USF Institute for Microbiomes,  based at the USF Health Morsani College of Medicine.

The institute will strengthen existing microbiota-related collaborations with Moffitt Cancer Center as well as partner with other leading academic institutions and pharmaceutical/biotechnology companies to advance the research and development of innovative treatments and other microbiome-based solutions.

“The institute will play an important role in raising the university’s visibility as a pioneer of microbiome research, education and training, community engagement, and entrepreneurship,” said USF Health’s Christian Bréchot, MD, PhD, director of the USF Institute for Microbiomes. “Unraveling the behavior, interactions and function of microbial communities in different environments has the potential to transform not only medicine and other health fields, but also disciplines like marine science, ecology, chemistry, engineering, data science and anthropology.”

Still in the early stages, microbiome research has exploded globally as more studies probe how unbalanced microbial composition in the gut, skin, lungs and other parts of body influences disease, said Dr. Bréchot, who also serves as president of the Global Virus Network, associate vice president for International Partnerships and Innovation at USF Health; and professor of medicine (infectious diseases) at the USF Health Morsani College of Medicine.

Altering these microorganisms to restore balance holds promise for treating a growing number of medical conditions, including cancer, inflammatory bowel disease, metabolic disorders such as diabetes and obesity, prematurity, cardiovascular diseases, and neurodegenerative disorders such as Alzheimer’s disease. Evidence also suggests that the gut microbiome affects the sensitivity to and mitigation of viral infections, in particular COVID-19. Scientists continue to learn more about complex microbe-host interactions that might be used to identify individuals more likely to respond favorably to, or resist, a particular drug or immunotherapy.

Hariom Yadav, PhD, leads the institute’s Center for Microbiome Research.

The USF Institute for Microbiomes will expand the scholarly activities started by the university’s Initiative on Microbiomes, including:

• Recruitment of federally funded faculty: Hariom Yadav, PhD, associate professor of neurosurgery and brain repair, was recently recruited as the first core faculty member of the USF Institute for Microbiomes. Dr. Yadav’s NIH and U.S. Department of Defense-supported research focuses on role of the microbiome in the gut-brain axis, including how microbiome modulators like probiotics, diet, and medications may improve mood. He directs the institute’s Center for Microbiome Research, which organizes technologies and resources for microbial studies, including human microbiome/probiotics biorepositories, tools to grow bacteria and perform fecal microbiota transplantation in transgenic models, and machines to sequence the genomes of microbes.
• Member of national microbiome cooperative network: USF recently became one of only 38 U.S. academic institutions granted membership to the Microbiome Centers Consortium over the last two years.
• USF Microbiome Research Awards: USF Health established competitive internal seed grants (up to $100,000 for two years) to advance early-phase microbiome research projects teaming investigators from two or more USF colleges or departments.
• Microbiome, Immunology and Infection Mitigation Hub: This research focus area, created as part of the Pandemic Response Research Network at USF, aims to develop precision therapies to reduce COVID-19 and other infections by investigating both nutritional regimens and nanoparticle delivery systems to modify gut microbiota.
• Partnership with the Global Virus Network: USF Health partnered with the Global Virus Network to offer the online course Microbiomes and their Impact on Viral Infections. World-renowned experts share the latest knowledge on the intestinal microbiome’s potential role in preventing, reducing, and treating infectious diseases, including
  COVID-19.

Can the community of microbes in our digestive track influence our mental state and, if so, how?

That’s a focus of study by Monica Uddin, PhD, a professor in USF’s College of Public Health, where she contributes to the Genomics Program within the Center for Global Health and Infectious Disease Research, focusing on the genomics of stress-related mental disorders. As part of USF’s ambitious Initiative on Microbiomes, Uddin wants to better understand how gut microbiota is linked to the symptoms of depression.

Monica Uddin, PhD

“Historically, we’ve always thought about our organs as working independently from one another, so it’s a bit hard to wrap your mind around this,’’ said Uddin, whose research just won a $150,000 seed grant from USF.  Her USF Health coprincipal investigators are Glenn Currier, MD, professor and chair of psychiatry, and Adetola Louis-Jacques, MD, assistant professor of obstetrics and gynecology.

“We now know that the gut microbiota can make neurotransmitters that influence mental health in ways that can cross the blood/brain barrier.”          

Monica Uddin, PhD, professor in the USF College of Public Health

Major depressive disorder (MDD) is a disabling mental condition worldwide. Treatment resistant depression (TRD) is a particularly severe form in which antidepressant trials have failed. Resistance occurs at a high rate, with more than 35% failing to respond to two different classes of antidepressant.

Recent research, however, is shedding light on the role of microscopic organisms such as bacteria, fungi and viruses on human health, both physical and mental. Such work reveals that a person’s intestinal florae is strongly associated with depressive symptoms and MDD. Work from animal models indicates that microbiota is causally linked to depressive behaviors.

Currently, very little is known about the relationship between the microbiome and TRD, and how patients respond to treatment depending on their microbiota. Researchers need to know more about how this florae differs in patients who respond to anti-depression treatment versus those who do not respond despite multiple attempts.

Up to one-third of adults with major depression battle symptoms that do not respond to several treatment attempts.

To address this significant health need, Uddin is working with a team that focuses on patients electing a treatment known as transcranial magnetic stimulation (TMS), which has shown some promise in treating TRD. The treatment uses magnetic fields to stimulate brain nerve cells to improve depression symptoms. While it has been effective in treating certain types of depression, it does not provide relief to all patients.

Uddin is studying microbiome-related biomarkers that could one day be used to inform treatment choices and, ultimately, enhance therapy response. Her work is part of a collaboration across professions in which diverse research and solutions can move from the laboratory to the patient bedside.

“The science is at the stage of being more than just descriptive; we’re moving toward function,’’ she said. “And by understanding the function, the hope is 10 or 20 years down the road we can potentially engineer the gut microbiota of people who get depressed.’’

Uddin’s seed grant will help her provide the preliminary results needed to pursue full National Institutes of Health or National Science Foundation grant applications.

-Story by Kurt Loft

The treatment of cancer may soon get a shot in the arm as researchers come closer to understanding the link between the disease and the diversity of microbes, fungi and viruses in a person’s gut.

Recently, oncologists found that the variety and composition of what lives in the gastrointestinal tract affects how patients respond to cancer treatments. A key is a person’s gut microbiome, which could serve as a predictor to identify patient populations and potential therapeutic targets.

Hua Pan, PhD, MBA

A better understanding of this relationship could lead to new techniques for improving cancer outcomes and reducing the toxicity of anti-cancer treatments, according to researchers at the USF Health Heart Institute and the USF Initiative on Microbiomes project.

By far, knowledge is limited on how cancer treatments alter gut microbiome, and how dysbioisis – a microbial imbalance – caused by these treatments impair normal cardiovascular function, said Hua Pan, PhD, MBA, assistant professor of medicine at the Institute.

“We now have over 18 million cancer survivors, but many are facing the problem of cardiovascular complications. Cancer cells use newly generated blood vessels to support their growth, and anti-cancer treatment destroys the blood vessels for the cancer but also for the normal part of the body.’’         

Hua Pan, PhD, MBA, assistant professor at the USF Health Heart Institute

Pan wants to connect the dots. She’s focusing on the interplay among the microbiome, vessel damage, and heart failure after patients receive cancer treatment. This research is important, she said, because cardiovascular complications caused by the toxins in cancer treatment are a leading cause of death among cancer survivors. Moreover, cardiotoxicity is one of the reasons cancer patients don’t continue receiving treatment.

Armed with more knowledge about how the microbiome affects cardiovascular complications, researchers hope to identify high-risk patient populations for next-generation nanotherapy. Rather than a general treatment, these high-risk populations might receive more personalized treatment based on their microbiome.

Certain cancer therapies can increase the risk of damage to the heart and cardiovascular system.

“We hope to generate a product (from the microbiome) that could have a predictive value for cancer patients who are more susceptible to cardiovascular problems,’’ Pan said. “That would help us identity the right population for a certain therapy. It’s a personalized treatment.’’

Although many questions remain about the effect of microbiota on cancers and treatments, the Initiative on Microbiomes is bringing researchers closer to the right answers.

“It’s very promising, definitely,’’ she said. “And it one day could reduce health care costs, which today are almost 18% of the gross national product in the United States.’’

-Story by Kurt Loft

The future of medicine depends in part on a better understanding of the microbiome – communities of bacteria, fungi and other microbes in our bodies – and their relationship to a variety of illnesses, such as cancer. By learning how a person’s estimated 30 trillion bacterium influence health, aging and disease, researchers with USF’s Initiative on Microbiomes are stepping closer to interventions they hope will address some of health care’s greatest challenges.

J. Ryan Williams, MD

How, for instance, can the bacteria in a person’s gastrointestinal tract serve as a pathway for the growth of certain types of cancer?  J. Ryan Williams, MD, a researcher at USF Health’s Division of Colon and Rectal Surgery, studies the relationship between the microbiome and cancer of the rectum, and the microbiota of patients with different kinds of disease. This could lead to a positive change in cancer survival rates.

“We’ve been able to take some patients with about a 15-percent chance of having their cancer disappear and increase it up to 38 percent,’’ Williams said. “But we can’t predict who that person is.’’

The microbiome is key in that prediction. Specific bacteria can move with a cancer, so genetic material can be traced from the gut to wherever a cancer might travel or set up a home in the body.

The relationship of the microbiome to colorectal surgery might seem intuitive, Williams said, but researchers need to know more about its cause and effect. Can a person’s microbiome be the actual instigator of cancer itself? Several peer-reviewed papers have been published on this subject, describing the possible association between the oral bacterium F. nucleatum and colon cancer.

“Cancer could be related to the microbiome and the bacteria that’s there. If we find an association, we might be able to predict who is a responder or not a responder and save them from surgery or a radiation that may not work. In fact, we might find new targets for treatment with something as simple as antibiotics.’’             

Colorectal surgeon J. Ryan Williams, MD, USF Health Morsani College of Medicine

Other intriguing research looks at whether the microbiome has an adverse effect on patients following surgery to attach two sections of intestine, a procedure known as an anastomosis. Sometimes, the suture will leak, possibly due to an error during surgery. But Williams said that such leaks “may be associated with specific gut microbiota that degrade collagen.’’

Researchers also want to further study the use of probiotics, the so-called “good’’ bacteria, and how they interact with microbiota in patients with inflammatory bowel disease. “Again, the pathways and specific microbiota have not been fully explored,’’ Williams said.

.

Many questions remain about the influence of microbiota on cancers and treatments as well as the impact of illness on microbiota. Williams and other members of the USF Initiative on Microbiomes seek solutions they hope will ultimately save lives and improve the quality and cost of health care.

The future of this research is exciting, he said. “Everybody is looking at the microbiome now, because we’re now able to better analyze the data.’’

-Story by Kurt Loft

USF Health’s Christian Brechot, MD, PhD, who leads the USF Initiative on Microbiomes, speaks with Maureen Groer, PhD, Gordon Keller Professor at the USF College of Nursing, about her research on the altered gut microbiome of premature infants. | Photo by Allison Long

Maureen Groer, PhD, looks at the health of preterm infants literally from the gut. As part of  the USF Initiative on Microbiomes, Groer studies how the beneficial balance of trillions of bacteria, viruses and other microorganisms in the digestive tract – known as the gut microbiome – might be altered in prematurely born babies, and what impact it might have on their long-term health.

“As nurses, we want to do research that translates to better health care and better health outcomes,’’ she said. “And for me, that’s mothers and infants.’’

Groer is a pediatric nurse, family nurse practitioner and the Gordon Keller Professor at the USF College of Nursing. Her work examines the molecular mechanisms underlying immunology, biology and behavior and how the “crosstalk” among these systems may affect the health of infants, children and their mothers.

Funded by a grant from the National Institutes of Health (NIH), Groer studies what happens to the equilibrium of the gut microbiome of premature babies who spend weeks, or even months, in a hospital’s neonatal intensive care unit (NICU). While there, they often receive antibiotics that can lead to dysbiosis, an imbalance in the normal microbes that live in the gut. Because no two babies are alike, treatment can be complicated.

“Everybody has a signature microbiome,’’ Groer said. “We have within our body populations of bacteria, viruses and fungi that live in a relationship that’s beneficial.”

“Every NICU has its own brand of microorganisms and they’re not the natural organisms that should be populating the gut. So, these NICU babies are at risk, and that might translate into health risks later.’’

Maureen Groer, PhD, Gordon Keller Professor in the USF College of Nursing

Most healthy babies develop a balanced gut microbiome by age 3. But when infants are born too early, the evolution of the gut may be disrupted by various factors, including delivery by Cesarean section, poor organ development, and extended time in the NICU. Dysbiosis can impair an infant’s ability to gain weight, among other conditions.

Extended time in the neonatal intensive care unit may contribute to disrupted development of a premature infant’s gut.

While prenatal hospital care provides lifesaving support, babies who spend their first weeks or months there receive multiple antibiotics, undergo stressful invasive procedures, interact less with their mothers, and typically ingest more formula milk than breast milk, which would transfer the mother’s own beneficial gut bacteria to the lactating infant. As a result, Groer said “NICU babies don’t have normal microbiomes.’’

By learning more about how a person’s estimated 30 trillion bacteria influence health, aging and disease, Groer and other researchers with the Initiative on Microbiomes hope to address some of the greatest challenges in health care.

In another study, Groer is following pregnant Hispanic women who have antibodies to toxoplasmosis, a chronic infection caused by a parasite affecting more than 40 million people in the United States. A third of the women who tested positive for the infection experience adverse prenatal events, such as miscarriage or preterm birth. Groer is writing an NIH grant to fund further research on the topic, and said “it would be of interest to determine both gut and placental microbiome in this population’’ of women.

– Story by Kurt Loft

National Science Foundation research by USF Health’s Larry Dishaw has relevance for debilitating digestive disorders like inflammatory bowel disease

What can we learn about human health from the lowly sea squirt?

More than you may think.

In his laboratory at the USF Children’s Research Institute in St. Petersburg, microbiologist Larry Dishaw, PhD, uses the sea squirt known as Ciona intestinalis to study how the innate immune system interacts with microbes that settle in the gut in ways that seem to facilitate homeostasis (stability) and promote survival and health.

Supported by a four-year, $867,581 grant from the National Science Foundation (NSF), Dr. Dishaw’s immune research explores the populations of microbes living together in the gut – trillions of bacteria, viruses, fungi and even some parasites – collectively known as the gut microbiome. His team is also interested in defining how disruption of a stable gut microbiome relates to the onset of inflammatory bowel disease, an autoimmune disorder affecting 1.6 million Americans.

Microbiologist Larry Dishaw, PhD, associate professor of pediatrics at the USF Health Morsani College of Medicine

“Many factors are at play in regulating the microbiome,” said Dr. Dishaw, an associate professor of pediatrics at USF Health Morsani College of Medicine. “And a lot of researchers around the world are interested in how the microbiome colonizes in animals, how this microbial community achieves stability, how it can shift out of balance, and how it is relevant to protecting human health.”

One of closest evolutionary invertebrate relatives of humans

Ciona intestinalis, an invertebrate marine animal resembling a spongy plant, spends its life attached to underwater structures like boat hulls and pier pilings where it continually siphons in water through one end, filtering out plankton and algae to eat and then squirting water and waste out the other end.

If you look under the microscope at the translucent juvenile sea squirts cultivated by Dr. Dishaw’s lab you can see a gut (with a stomach and intestinal compartment) similar to the digestive tract of vertebrates.  Despite its primitive appearance, the sea creature – a protochordate — is considered one of the closest evolutionary invertebrate relatives of humans.

Unlike humans, sea squirts rely their entire lives solely on naturally present innate immunity for host defense. They lack the other more evolved arm of immunity know as adaptive immunity, which differs from one animal species to the next and activates in response to specific foreign invaders.

The adult sea squirt Ciona intestinalis

That, Dr. Dishaw says, is what helps make the sea creature a good model for investigating the evolution of the host immune system and its role in creating and maintaining a well-balanced gut microbiome.

“When humans are born, they do not develop adaptive immunity until ages 3 to 5… so the initial process of colonizing bacteria and other microbes that make up their microbiomes is all mediated by innate immunity,” he said.

With a simpler model system like the sea squirt, the researchers can look at innate immunity in isolation. They can monitor how the immune system responds when encountering microbes for the first time, how microbes initially “choose” where to colonize in the gut, and how the animal maintains homeostasis – that is, a healthy balance of gut microbes needed to digest food and absorb nutrients throughout its life.

Ultimately, the not-so-lowly sea squirt may provide better insight into gut defense evolution and define ways that beneficial (non-pathogenic) bacteria may help prevent the overgrowth of disease-causing (pathogenic) bacteria.

Tipping the “good” microbe – “bad” microbe balance

Dr. Dishaw’s NSF grant builds upon the work of his mentor Gary Litman, PhD, USF professor emeritus of pediatrics, whose lab discovered the genes for a family of variable region-containing chitin-binding proteins, or VCBPs, made and secreted by the gut wall in a different protochordate, the ancient fish-like organism amphioxus. These immune proteins appear to help regulate how bacteria and fungi interact and grow such that intestinal barrier function is enhanced, Dr. Dishaw said. The VCBPs also seem to influence the production or release of phages, viruses that infect and destroy specific gut bacteria, he added.

Dr. Dishaw with some laboratory team members. From left: Michael Schepps, undergraduate research assistant; Zachary Graham, lab technician; and Julie Voelschow, undergraduate research assistant. Not pictured are Ojas Natarajan, PhD, postdoctoral scientist; and Celine Atkinson, graduate student.

“The goal of our project is to find out what happens when we muck with that system. When the VCBPs don’t bind fungi or bacteria correctly, how is the physiological fitness of the animal affected?” Dr. Dishaw said. “We believe these immune effectors can shape the ecology of the gut microbiome in ways that promote (or deter) health. And we think the sea squirt model can help us understand how that happens.”

The researchers can rear germ-free juvenile Ciona, then introduce into their water whatever microbes they choose. Because the sea squirt filters water constantly, they can quickly track where in this controlled environment the newly introduced gut microbe populations settle and thrive as well as examine the role host-microbe interactions play in developing a frontline immune defense system.

In a series of experiments published last year in Open Biology, the USF researchers induced colitis-like inflammation and damage in sea squirts by exposing their guts to the chemical dextran sulfate sodium (DSS). They showed that DSS altered the production and settlement of the secreted immune molecule that binds bacteria.

The laboratory grows its own algae, cultured in beakers shown on the windowsill, to feed to the juvenile sea squirts.

Most invertebrates, including sea squirts, defend their gut walls against potential microbial attack and prevent infection with mucous rich in chitin. The researchers found that pretreatment with microparticles of chitin, a fibrous substance prevalent in Ciona’s epithelium-associated gut mucous, protected the animal from the colitis-like effects of subsequent DSS exposure.

Ciona, which permits the study of innate immunity in isolation, “may help us determine how innate immunity modulates recovery from colitis and the re-establishment of (gut microbiome) homeostasis,” the study authors concluded.

Promising power of phages to treat drug-resistant infections

Dr. Dishaw is also co-investigator for a National Institutes of Health grant led by the USF College of Nursing’s Maureen Groer, PhD. The project is investigating the link between the gut microbiome of premature infants and their health as they age.

Lab tech Zachary Graham and Dr. Dishaw look over culture plates of bacterial biofilms stained with crystal violet. The bacteria were recovered from the gut of the sea squirts.

“We think early colonization of microbes is critically important in establishing lifelong gut microbiome features,” Dr. Dishaw said. “So, early life events that shape the (evolving) microbiome — like spending 4 to 6 weeks in a neonatal intensive care unit where the infant receives multiple antibiotics to treat or prevent infections — could translate into long-term changes in health.”

The ultimate goal of microbiome research is to come up with effective treatments to reset the equilibrium of a microbial community gone awry – whether by diet, stress, pathogens, or even the medications used to fight disease.

Fecal microbiota transplants, which insert a healthy donor’s fecal matter into a recipient’s colon to reconstitute a stable gut microbiome, have already become a relatively common treatment for Clostridium difficile (C. diff) infection, a debilitating gastrointestinal disease resistant to many antibiotics.

The crystal violet-stained cultures allow researchers to estimate the amount of biofilm formed during stationary growth of the bacteria.

In an age of growing multidrug resistance, Dr. Dishaw believes that phage therapy also offers promise as an alternative or supplement to antibiotics for patients suffering from recurrent, difficult-to-treat infections.  In another NSF grant with co-principal investigator Mya Breitbart of the USF College of Marine Sciences, he is colonizing a variety of bacteria in the sea squirts in an effort to test how phages – the viruses that infect bacteria – can be used to selectively eliminate harmful gut bacteria.

Phages, which specifically target single types of bacteria, might be harnessed to chase pathogens out of the microbial community without having to rely on antibiotics, which can wipe out both harmful and beneficial bacteria, Dr. Dishaw said. “In theory, you could use a C diff phage with high precision to target and kill only C. diff bacteria.”

Dr. Dishaw also participates in a clinical study with the USF Health Department of Pediatrics and Johns Hopkins All Children’s Hospital to characterize the gut microbiomes of patients with primary immune deficiencies.  The research may provide a better understanding of how different aspects of immunity regulate the gut microbiome.

Microscopic image of a juvenile sea squirt shows its gut colonized by fluorescently labeled bacteria

-Video and photos by Torie Doll, USF Health Communications and Marketing