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.

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.

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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.

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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.