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.

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NT-020, a proprietary supplement including blueberries and green tea, improved cognitive processing speed in clinical trial participants without impaired memory

Tampa, FL (Feb. 6, 2014) – Declines in the underlying brain skills needed to think, remember and learn are normal in aging. In fact, this cognitive decline is a fact of life for most older Americans.

Therapies to improve the cognitive health of older adults are critically important for lessening declines in mental performance as people age. While physical activity and cognitive training are among the efforts aimed at preventing or delaying cognitive decline, dietary modifications and supplements have recently generated considerable interest.

Now a University of South Florida (USF) study reports that a formula of nutrients high in antioxidants and other natural components helped boost the speed at which the brains of older adults processed information.

The USF-developed nutritional supplement, containing extracts from blueberries and green tea combined with vitamin D3 and amino acids, including carnosine, was tested by the USF researchers in a clinical trial enrolling 105 healthy adults, ages 65 to 85.

University of South Florida researchers Paula Bickford, PhD, and Brent Small, PhD, teamed up to investigate the effects of a USF-developed, antioxidant-rich nutritional supplement on the cognitive performance of older adults.

The two-month study evaluated the effects of the formula, called NT-020, on the cognitive performance of these older adults, who had no diagnosed memory disorders.

Those randomized to the group of 52 volunteers receiving NT-020 demonstrated improvements in cognitive processing speed, while the 53 volunteers randomized to receive a placebo did not. Reduced cognitive processing speed, which can slow thinking and learning, has been associated with advancing age, the researchers said.

The study, conducted at the USF Health Byrd Alzheimer’s Institute, appears in the current issue of Rejuvenation Research (Vol. 17 No. 1, 2014).  Participants from both groups took a battery of memory tests before and after the interventions.

“After two months, test results showed modest improvements in two measures of cognitive processing speed for those taking NT-020 compared to those taking placebo,” said Brent Small, PhD, a professor in USF’s School of Aging Studies. “Processing speed is most often affected early on in the course of cognitive aging. Successful performance in processing tasks often underlies more complex cognitive outcomes, such as memory and verbal ability.”

Blueberries, a major ingredient in the NT-020 formula, are rich in polyphenols, a type of antioxidant containing a polyphenolic, or natural phenol substructure.

“The basis for the use of polyphenol-rich nutritional supplements as a moderator of age-related cognitive decline is the age-related increase in oxidative stress and inflammation,” said study co-principal investigator Paula C. Bickford, PhD, a professor in the Department of Neurosurgery and Brain Repair, USF Health Morsani College of Medicine, and senior research career scientist at the James A. Haley Veterans’ Hospital in Tampa. “Non-vitamin polyphenols are the most abundant modulators of oxidative stress and inflammation in our diet. NT-020 is 95 percent polyphenols.”

One of the main ingredients of the supplement, called NT-20, is extracted from blueberries.

In several preclinical trials, researchers gave aging laboratory rats NT-020 to see if it boosted memory and other cognitive performance by promoting the health of neurons in the aging brain. Those studies demonstrated that NT-020 promoted the growth of stem cells in the brain, produced an overall rejuvenating effect, benefitted animals with simulated stroke, and led to better cognitive performance.

The researchers plan future clinical trials with longer intervention periods so that the optimal time for taking the formula may be better understood.  The researchers speculated that if the study had included participants cognitively less healthy, or those with memory impairments, they may have observed “more robust findings.”

“In the future, having markers of oxidative stress and inflammation, as well as brain-based measures of functioning, may allow us to identify the manner by which this compound, as well as others, may influence functioning,” they concluded.

The NT-020 formula was patented by the University of South Florida, in partnership with the James A. Haley Veterans’ Hospital, and licensed to Natura Therapeutics, Inc.  The supplement is commercially available as NutraStem®.

The study was supported by a grant from the University of South Florida Neuroscience Collaborative to Dr. Small and Dr. Bickford.

Dr. Bickford is a co-founder of Natura Therapeutics, Inc.

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Video Editor:  Klaus Herdocia, USF Health Communications

Media contact:
Anne DeLotto Baier, USF Health Communications
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Media release by Florida Science Communications, Inc.