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.

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.

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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

The University of South Florida played a coordinating role in the international TEDDY study

//www.youtube.com/watch?v=kbJOwVra3ds

Tampa, FL (Nov. 9, 2015) — Probiotic exposure during the first 27 days of an infant’s life may be associated with reduced risk of islet autoimmunity among children at increased genetic risk for type 1 diabetes, although further studies are needed before any recommendations for probiotics can be made, according to a University of South Florida-led study published online by JAMA Pediatrics.

Probiotics are live organisms that may confer health benefits. Animal studies have looked at manipulation of gut microbiota by probiotics and the risk of developing type 1 diabetes (T1DM) related to autoimmunity.

Ulla Uusitalo, PhD, of the University of South Florida, and coauthors examined the association between supplemental probiotic use during the first year of life and islet autoimmunity. Islet autoimmunity occurs when antibodies attacks islet cells in the pancreas that produce insulin. The condition, which precedes the symptoms of type 1 diabetes, can be detected by measuring these islet autoantibodies in the blood.

“We have taken a baby step forward, and there is the possibility that in the future we may find preventive measures for Type 1 diabetes using probiotics, among children at high risk,” said Dr. Uusitalo, associate professor of pediatrics at the USF Health Morsani College of Medicine.

Ulla Uusitalo, PhD, associate professor of pediatrics based at the USF Health Informatics Institute, was lead author of the international study on probiotics and islet autoimmunity.

Dr. Uusitalo and colleagues report the results of The Environmental Determinants of Diabetes in the Young (TEDDY) study, which started in 2004 with children from six clinical centers, three in the United States (Colorado, Georgia/Florida and Washington) and three in Europe (Finland, Germany and Sweden).

The children were followed-up for T1DM-related autoantibodies with blood samples drawn every three months between 3 and 48 months of age and every six months thereafter to determine persistent islet autoimmunity. Questionnaires and diaries were used to detail infant feeding, including probiotic supplementation and infant formula use.

A final study sample consisted of 7,473 children who ranged in age from 4 to 10 years old. Probiotic supplementation from dietary supplements or infant formula varied by country and was most pervasive in Finland and Germany during the first year of a child’s life.

Receiving probiotics through a dietary supplement or fortified infant formula, or both, by 27 days of age may be associated with a reduced risk of islet autoimmunity compared with those children who first received probiotics after 27 days of age or not at all. Early probiotic exposure appeared to be associated with a 60-percent decrease in the risk of islet autoimmunity among children with the highest-risk HLA genotype DR3/4 but not among other genotypes.

An association does not imply causality and further research needs to be done, the authors note.

“Early exposure to supplemental probiotics may decrease the risk of IA [islet autoimmunity] among children at elevated risk of T1DM. … These results have to be confirmed before making recommendations on the use of probiotic supplementation,” the study concludes.

Infants in the study received probiotics through a dietary supplement of oral drops or fortified infant formula,

The probiotics and islet autoimmunity study is one of many overseen by the Data Coordinating Center of the University of South Florida’s Health Informatics Institute led by Dr. Jeffrey Krischer, Distinguished University Health Professor. The center coordinates, analyzes and maintains research data from several large clinical networks investigating the causes and outcomes of type 1 diabetes, including TEDDY, TrialNet, TRIGR and DPT-1.

This NIH-supported hub also maintains a communication network to enhance collaboration and pooling of data among researchers across the world. Professionals in data management, software developing, biostatistics, epidemiology, psychology, nutrition, and other life sciences work seamlessly as a team, seeking to understand the triggers of type 1 diabetes and related autoimmune diseases and to develop strategies for prevention or improved treatment.

Article citation:

Ulla Uusitalo, PhD; Xiang Liu, PhD; Jimin Yang, PhD, RD: Carin Andren Aronsson, MS; Sandra Hummel, PhD; Martha Butterworth, MS; Ake Lernmark, PhD: William Hogopian, MD, PhD; Jin-Xiong She, PhD;  Olli Simell, MD, PhD; Jorma Toppari, MD, PhD; Anette G. Ziegler, PhD; Beena Akolkar, PhD; Jeffrey Krischer, PhD; Jill M. Norris, PhD; Suvi M. Virtanen, MD, PhD; for the TEDDY Study Group. “Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study,”  JAMA Pediatrics. Published online November 9, 2015. doi:10.1001/jamapediatrics.2015.2757.

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Video and photos by Sandra C. Roa, USF Health Marketing & Communications