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.

//www.youtube.com/watch?v=8Bf9W1POK_4

Distinguished USF Health Professor Cesario Borlongan, PhD, is internationally recognized for translational research on the neuroprotective and neurorestorative effects of stem cell therapies in stroke.

Over the last 22 years, his innovative work in the field of neuroscience has encompassed other neurodegenerative diseases and traumatic brain injury as well as stroke.  Dr. Borlongan, director of the Center of Excellence for Aging and Brain Repair at USF, does not hesitate to take calculated risks when it comes to following a different path of inquiry that may lead to a new discovery.

Take, for example, his recent study — with lead author Sandra Acosta, PhD, a postdoctoral fellow in Dr. Borlongan’s laboratory – published in the September issue of the American Heart Association journal Stroke.  The study showed that human bone marrow stem cells intravenously administered to post-stroke rats migrated to the spleen, an abdominal organ that plays a critical role in immune function, and significantly reduced chronic inflammation in the stroke brain.

“Next we want to explore whether transplanting these cells directly into the spleen, rather than peripherally, can lead to better functional recovery, including central nervous system improvement,” Dr. Borlongan said. “Even though stroke is a brain disorder, it has a major peripheral component – and in this case it may be the spleen that should be monitored more closely in our stroke patients.”

USF neuroscientist Cesario Borlongan, PhD, does not hesitate to take calculated risks when it comes to following a different path of inquiry that may lead to a new discovery.

In another study published in the journal PLOS ONE in 2013, Dr. Borlongan and colleagues suggested a new view of how stem cells may help repair the brain following trauma.   In a series of preclinical experiments they reported that transplanted cells appear to build a “biobridge” that links an uninjured brain site where new neural cells are born with the damaged region of the brain.  Based in part on the data reported by Dr. Borlongan’s group, the U.S. Food and Drug Administration approved a limited clinical trial to transplant SanBio 623 cells (an adult stem cell therapy) in patients with traumatic brain injury.  The trial has begun enrolling patients at Stanford University Medical Center.

Additionally, Dr. Borlongan’s bench to bedside research has led to to five FDA-approved clinical trials of cell transplantation in stroke, including the first cell therapy in adult stroke patients.

“One thing that distinguishes our center at USF from many others is its emphasis on translational research” he said. “We like basic science, but we want to see the discoveries in the petri dish translated to animal models of brain disorders and eventually go into the clinics…  At the end of the day, we ask the question:  Can this science be translated into saving lives and make a difference in the lives of patients with stroke and traumatic brain injury?”

National Institutes of Health (NIH) Scientist Emeritus Barry Hoffer, MD, PhD, says despite Dr. Borlongan’s relative youth as a scientist, his insight and creativity has yielded many discoveries advancing the understanding of ischemic brain injury, blood-brain barrier pathophysiology, traumatic brain injury, and stem cell transplantation.

“If I were to make a list of young neuroscientists who are already superstars, Dr. Borlongan would be at the top of my list,” said Dr. Hoffer, an adjunct professor of neurosurgery and proteomics and genomics at Case Western Reserve University School of Medicine.

Dr. Borlogan with Sandra Acosta, PhD, one of the postdoctoral fellows in his laboratory at the USF Center of Excellence for Aging and Brain Repair. “They are the ones who come up with the paradigm-shifting approaches to the experiments and drive the science,” he says of the trainees and students.

Dr. Borlongan has received continuous federal funding totaling more than $15 million from the U.S. Department of Veterans Affairs, the Department of Defense and the NIH since 2002 and also serves as the principal investigator on several industry grants.  Recently, he was awarded a two-year R21 grant from the National Institute of Neurological Disorders and Stroke to study the effects of endothelial stem cells on inflammation in the stroke vasculome — specific genes expressed on the interior surface of blood vessels in the brain following stroke.  The research may have implications for regulating inflammatory genes to treat chronic stroke.

The 30-member laboratory led by Dr. Borlongan includes graduate and doctoral students, a neurosurgery resident, and postdoctoral fellows – emerging scientists who contribute greatly to the research team’s vibrancy, innovation and passion for scientific discoveries.

“We need these young minds to challenge the existing paradigm. They are the ones who come up with the paradigm-shifting approaches to experiments and drive the science,” Dr. Borlongan said.  “I encourage, help facilitate and direct them to the literature, but it’s their show… I try to stay in the background rather than get in their way. That’s the most valuable thing I learned from my mentors.”

He also lets students know that it’s OK when experiments yield unexpected or negative results, because they can learn and move forward even if the initial hypothesis does not hold up. “Be logical, but follow the data; don’t change its direction,” he said. “It may lead you to something novel.”

Dr. Borlonghan with some of the emerging young scientists in his laboratory. They were recently filmed by LabTV.

Dr. Borlongan received his PhD in physiological psychology in 1994 at Keio University in Tokyo, Japan. He pursued fellowships in neuroscience at USF and the NIH, National Institute on Drug Abuse.  He was an associate professor at Medical College of Georgia, where he directed the Department of Neurology Cell Transplantation, before returning to USF as a faculty member in 2008.

He regularly serves on peer review panels for the NIH, VA and the American Heart Association and is an editorial board member for numerous scientific journals, including Cerebral Blood Flow and Metabolism, Stem Cells, PLOS ONE and Brain Research.  He holds several patents for inventions related to investigational cell therapies for brain disorders.

A fellow of the American Association for the Advancement of Science and member of the USF chapter of the National Academy of Inventors, Dr. Borlongan is 2015-16 president of the American Society for Neural Therapy and Repair.

Photos and video by Sandra Roa,  USF Health Communications and Marketing

Two Morsani College of Medicine faculty members whose work bridges the basic and clinical sciences — David Birk, PhD, and Cesario Borlongan, PhD  — were recently designated as Distinguished USF Health Professors for 2014-15.

The promotion recognizes outstanding faculty who have clearly distinguished themselves in their fields and are known nationally and internationally for their research and scholarly activity.

David Birk, PhD

An international expert in the field of extracellular matrix (ECM) biology and pioneer in electron microscopy, Dr. Birk is a professor in the Department of Molecular Pharmacology and Physiology.  His decades of research and ongoing work with collagens and a family of proteins known as small leucine rich proteoglycans have led to a groundbreaking understanding of the extracellular matrix or framework involved in the development of connective tissue. Dr. Birk’s work on the regulation of ECM assembly has major implications for current and future treatments of connective tissue disorders including poor wound healing and scarring, progressive fibrotic diseases, corneal blindness, and congenital diseases such as Ehlers-Danlos syndrome.

Dr. Birk’s major accomplishments, including success in obtaining National Institutes of Health grants, have made him sought after as a collaborator with well-recognized laboratories.  He is consistently invited to serve on national scientific committees including NIH study sections and the research committees and advisory boards of Shriners Hospitals for Children.

A world leader in stem cell therapy research for stroke and traumatic brain injury, Dr. Borlongan is a professor in the Department of Neurosurgery and Brain Repair and director of the Center for Excellence in Aging and Brain Repair. His translational bench to clinic research has led to five FDA-approved clinical trials of cell transplantation in stroke, including the first cell therapy in stroke patients.  Recently a team led by Dr. Borlongan offered a new concept for how transplanted stem cells help prod the brain’s own repair mechanism following traumatic brain injury. Based in part on this preclinical study, the U.S. Food and Drug Administration approved a limited clinical trial to transplant an adult stem cell therapy in patients with traumatic brain injury.

Cesario Borlongan, PhD

Dr. Borlongan has received continuous federal funding totaling more than $15 million from the Department of Veterans Affairs, the Department of Defense and the NIH since 2002. A fellow of the American Association for the Advancement of Science, Dr. Borlongan is president-elect of the American Society for Neural Therapy and Repair for 2015.

The Distinguished USF Health Professor award recognizes senior faculty across all USF Health colleges and programs for their substantial achievements in the areas of research, teaching and service. Faculty members are nominated by their deans, recommended by their peers and selected through a rigorous process of internal and external review of each nominee’s credentials.

In addition to receiving a $5,000 base salary adjustment, Dr. Birk and Dr. Borlongan are invited to give a USF Health address during the academic year, and are granted the State University System title of Distinguished USF Health Professor.  A commemorative medallion will be awarded to each at the Annual Research Day Lectureship in February.

Since the inaugural awards were bestowed in 2007, 19 faculty members have been named Distinguished USF Health Professors. Other MCOM faculty with the designation include Shyam Mohapatra, PhD; Benjamin Djulbegovic, MD, ScD; and David Morgan, PhD; David Sheehan, MD; Michael Barber, DPhil; Jeffrey Krischer, PhD; Bruce Lindsey, PhD; and Richard Lockey, MD.

Research with rat models finds chronic inflammation, suppression of cell regeneration, and neuronal cell loss contribute to wide range of motor and cognitive deficits

TAMPA, FL  (Jan. 4, 2013) – Researchers from the University of South Florida and colleagues at the James A. Haley Veterans’ Hospital studying the long-term consequences of traumatic brain injury (TBI) using rat models, have found that, over time, TBI results in progressive brain deterioration characterized by elevated inflammation and suppressed cell regeneration. However, therapeutic intervention, even in the chronic stage of TBI, may still help prevent cell death.

Their study is published online in the current issue of the journal PLOS ONE.

“In the U.S., an estimated 1.7 million people suffer from traumatic brain injury,” said the study’s senior author Cesar V. Borlongan, PhD, professor and vice chair of the Department of Neurosurgery and Brain Repair at USF.  “In addition, TBI is responsible for 52,000 early deaths, accounts for 30 percent of all injury-related deaths, and costs approximately $52 billion yearly to treat.” 

While TBI is generally considered an acute injury, secondary cell death caused by neuroinflammation and an impaired repair mechanism accompany the injury over time, the authors said. Long-term neurological deficits from TBI related to inflammation may cause more severe secondary injuries and predispose long-term survivors to age-related neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and post-traumatic dementia.

Since the U.S. military has been involved in conflicts in Iraq and Afghanistan, the incidence of traumatic brain injury suffered by troops has increased dramatically, primarily from improvised explosive devices (IEDs), according to Martin Steele, Lieutenant General, U.S. Marine Corps (retired), USF associate vice president for veterans research, and executive director of Military Partnerships. In response, the U.S. Veterans Administration has increasingly focused on TBI research and treatment.

Dr. Cesar Borlongan (left), senior author, and Dr. Paul R. Sanberg, co-author

“Progressive injury to hippocampal, cortical and thalamic regions contributes to long-term cognitive damage post-TBI,” said study co-author Paul R. Sanberg,  PhD, DSc, USF senior vice president for research and innovation and executive director of the Center of Excellence for Aging and Brain Repair at USF Health. “Both military and civilian patients have shown functional and cognitive deficits resulting from TBI.”

Because TBI involves both acute and chronic stages, the researchers noted that animal model research on the chronic stages of TBI could provide insight into identifying therapeutic targets for treatment in the post-acute stage.

“Using animal models of TBI, our study investigated the prolonged pathological outcomes of TBI in different parts of the brain, such as the dorsal striatum, thalamus, corpus callosum white matter, hippocampus and cerebral peduncle,” said Dr. Borlongan, principal investigator for the study. “We found that a massive neuroinflammation after TBI causes a second wave of cell death that impairs cell proliferation and impedes the brain’s regenerative capabilities.”

 Upon examining rat brains eight weeks post-trauma, the researchers found “a significant up-regulation of activated microglia cells, not only in the area of direct trauma, but also in adjacent as well as distant areas.”  The location of inflammation correlated with the cell loss and impaired cell proliferation researchers observed.

Microglia cells act as the first and main form of immune defense in the central nervous system and make up 20 percent of the total glial cell population within the brain. They are distributed across large regions throughout the brain and spinal cord.

“Our study found that cell proliferation was significantly affected by a cascade of neuroinflammatory events in chronic TBI and we identified the susceptibility of newly formed cells within neurologic niches and suppression of neurological repair,” wrote the authors.

The researchers concluded that, while the progressive deterioration of the TBI-affected brain over time suppressed efforts of repair, intervention, even in the chronic stage of TBI injury, could help further deterioration.

The study was supported by the U.S. Department of Defense, the USF Signature Interdisciplinary Program in Neuroscience funds, the USF and Veterans Administration Reintegration Funds, and the USF Neuroscience Collaborative Program.

Citation:  Acosta SA, Tajiri N, Shinozuka K, Ishikawa H, Grimmig B, et al. (2013) Long-Term Upregulation of Inflammation and Suppression of Cell Proliferation in the Brain of Adult Rats Exposed to Traumatic Brain Injury Using the Controlled Cortical Impact Model. PLOS ONE 8(1): e53376. doi:10.1371/journal.pone.0053376

– About USF – 

The University of South Florida is a high-impact, global research university dedicated to student success. USF ranks 50th in the nation for federal expenditures in research and total expenditures in research among all U.S. universities, public or private, according to the National Science Foundation. Serving more than 47,000 students, the USF System has an annual budget of $1.5 billion and an annual economic impact of $3.7 billion. USF is a member of the Big East Athletic Conference.

News release by Randy Fillmore, special to USF Research News

Media contact:
Judy Lowry, USF Research & Innovation
813-974-3181, or jhlowry@usf.edu