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Dr. Hariom Yadav stands in his lab.

A new study led by a USF Health researcher explains how old microbiota in an old person’s gastrointestinal tract may cause cognitive decline, and reveals clues for how it can be protected.

Tracing the link between aging microbes and the brain

Hariom Yadav, Ph.D., has a gut feeling about how bacteria in a person’s digestive tract can affect their mental health.

In a new study, Dr. Yadav and a team of researchers from around the United States say that age-related abnormalities in gut microbiota – the collection of bacteria, viruses and other cellular organisms -- are associated with cognitive decline, depression and anxiety. They hope their findings could one day lead to improved treatments in these critical areas.

Titled “Abnormalities in microbiota-butyrate-FFAR3 signaling in aging gut impair brain function,’’ the study describes the link between changes in the gastrointestinal system and the brain. It has been published in JCI Insight, a peer-reviewed journal of the American Society for Clinical Investigation.

“In nutshell, this study tells how microbes living in an older gut send creeping signals to the brain and cause cognitive decline, which deteriorates brain health,’’ said Dr. Yadav, senior author of the study and director of the USF Health Center for Microbiome Research, Microbiomes Institute. “In other words, it’s about how microbiome signals creep into our brain when we’re getting older.’’ 

Dr. Yadav also is an associate professor of Neurosurgery and Brain Repair and of Internal Medicine - Digestive Diseases and Nutrition.  

Brain abnormalities such as cognitive decline, Alzheimer’s disease, depression, and anxiety become more common as we age. The study describes transplanting old gut microbiota into young mice, which induced leakiness in gut that allowed the inflammatory signals to leak out from the gut into the blood, causing systemic inflammation that reaches to the brain. Consequently, this led to cognitive decline and stress on the nervous system. 

“Among the multitude of potential causes, inflammation (caused by aging microbiota) is the prime suspect,’’ Dr. Yadav said.

Biochemical and neuropathologic studies show that inflammatory pathways are activated in the brains of older adults and individuals with Alzheimer’s and clinical studies confirm the correlation between high inflammation and brain dysfunction. Systemic chronic inflammation begins several years before cognitive decline and dementia are diagnosed, but the precise origin and mechanisms are not fully known.

The study notes that old microbiota can disrupt intestinal barriers, leading to a decrease in a lubricating protein called mucin and to increased inflammation. It also can make the gut more permeable, a condition known as “leaky gut.’’ Fatty acid receptors called butyrate-FFAR2/3, which can help restore the gut barrier, are jeopardized by aging microbiota. Replacing them with “young’’ microbes helps to restore their regenerative powers.

“FFAR2/3 is important because it senses good signals of the microbiome,’’ Dr. Yadav explained. “For example, the microbiome ferments fibers that we eat, and this produces good metabolites like butyrate that stimulate FFAR2/3 and benefit human cells. But this signaling goes down as we grow older, because our microbiome reduces butyrate production.’’

The study showed how young mice with a loss of FFAR2/3 exhibited gut and brain abnormalities akin to those in older mice. The team’s results demonstrate that reduced butyrate-producing bacteria in aged gut microbiota result in low butyrate levels and reduced FFAR2/3. This led to leaky gut, inflammation, and brain abnormalities. 

The human brain is protected by blood barriers that deter toxins and inflamed molecules from entering. However, when blood inflammation rises due to leaks in the gut of older people, it can find its way around these barriers, leading to neuroinflammation and cognitive decline.

This raises the question of diet. If a person maintains a healthful balance of high fiber foods, the study notes, their gut will be less likely to significantly decline with age.

“Because this study explains how poor gut health can deteriorate brain health, then taking care of your gut is certainly important,’’ Dr. Yadav. “So, feeding our microbes the right food, like fiber, can maintain a better microbiome, which will keep our brain healthy.’’

The researchers hope to increase awareness of how gut-related issues are linked to mental decline, and that further research may lead to therapies focused on age-related diseases of the brain. 

“Dementia and Alzheimer’s are debilitating public health problems in older people with no effective prevention and treatment yet,’’ Dr. Yadav said, “and they pose a high toll on patients, families and the health care system.’’

- Photo by Allison Long, USF Health News 

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USF Health News highlights the great work of the faculty, staff and students across the four health colleges – Morsani College of Medicine, College of Public Health, College of Nursing and Taneja College of Pharmacy – and the multispecialty physicians group. USF Health, an integral part of the University of South Florida, integrates research, education and health care to reach our shared value - making life better.