The Gut Brain Axis Connection

September 3, 2026

A compound produced by bacteria in most people’s digestive tract increases the risk of developing Alzheimer’s disease and speeds up cognitive decline in dementia patients, making it an attractive target for a treatment that could reduce Alzheimer’s risk, according to a new study led by Barbara Bendlin, PhD, MA, professor, Geriatrics and Gerontology.

Nearly ten years ago, a research team headed by Dr. Bendlin and Federico Rey, PhD, professor, University of Wisconsin Department of Bacteriology, discovered that the communities of microbes living in the intestines of Alzheimer’s disease patients differ from those of healthy people.

“Since then, we’ve been trying to figure out how this difference in the gut perhaps leads to changes in the brain,” says Bendlin, a professor of medicine in the UW School of Medicine and Public Health.

In a recent study published in the journal Nature Communications, Bendlin, Rey and collaborators show that a compound called imidazole propionate (ImP) — produced in the gut by some types of bacteria — plays an important role in brain changes that result in Alzheimer’s disease and related cases of dementia. Some people have guts that seem to produce a lot of ImP; some people don’t.

“ImP-producing bacteria are present in a large fraction of people, but they’re not very abundant in most people,” says Rey, a UW–Madison professor of bacteriology. “But something we have learned over the years is that a microbe doesn’t have to be abundant to have an impact on the host.”

Portrait of Professor Frederico Rey.

ImP can spread from the gut to other parts of the body,

By Federico Rey

Where it has been implicated in type 2 diabetes and coronary artery disease. The researchers showed that ImP that reaches the brain in mice increases the build-up of clumps of two abnormal proteins, called beta-amyloid and tau.

“That process eventually results in the death of neurons, and in humans is a key feature of Alzheimer’s disease,” Rey says.

By looking at ImP in the blood of almost 1,200 people who have participated in the Wisconsin Registry for Alzheimer’s Prevention and studies at the Wisconsin Alzheimer’s Disease Research Center, the researchers found that people with high ImP levels were far more likely to also show markers of dementia-related protein and neuron dysfunction.

“And because we have the results of cognitive tests these volunteers took over time, we can see that the people with the highest ImP levels also experienced much faster cognitive decline,” Rey says.

The researchers also identified a genetic variation, present in about 43% of the people in the study, linked to accumulating much higher levels of ImP in the blood. The genetic difference might affect how well the kidneys sift out ImP so that the body can get rid of it.

“This genetic variation has been associated with increased Alzheimer’s risk in large genetic studies before, and now we may understand why it’s connected,” Rey says.

The most significant implication of the new study may be that ImP could represent a way to help people avoid Alzheimer’s disease and related types of dementia. Unfortunately, ImP is produced by bacteria making energy from an amino acid called histidine, which is essential to human health and present in a lot of common foods — especially protein-rich ones.

“Generally improving your diet would probably help,” Bendlin says. “But it’s not as easy as saying, ‘Stop eating eggs’ or ‘Don’t eat so much red meat.’ Because you need histidine, and it’s all over the place.”

But narrowing the biochemical target to a single molecule in the blood or a single genetic change opens up exciting possibilities.

“It could be just like cholesterol, where people with elevated cholesterol take a drug, a statin, that reduces their risk for heart disease,” Bendlin says. “If we can find an inhibitor that can help decrease the levels of ImP in the blood, that could hopefully reduce the risk of Alzheimer’s and the speed of cognitive decline for a significant number of people.”

Collaborators on the new study included scientists from the University of California, Los Angeles and the University of Gothenburg.

This research was supported in part by grants from the Wisconsin Partnership Program and the National Institutes of Health (R01AG070973, R01AG083883, R01AG092220, R21AG089348, R01HL168493, R01DK143650 and U54HL170326) and the U.S. Department of Agriculture (WIS03073).

University Place | Alzheimer’s and the Gut-Brain Superhighway | PBS

Your gut could be fueling Alzheimer’s — here’s the molecule to blame

Could the key to understanding Alzheimer’s disease be hiding in your gut?

In this fascinating conversation, Dr. Barbara Bendlin, PhD — Professor of Geriatrics and Gerontology at the University of Wisconsin–Madison and a member of the Wisconsin Alzheimer’s Institute — breaks down more than a decade of groundbreaking research on the gut-brain connection.

Our lab studies aging and Alzheimer’s disease.

Vogt et al, 2020, Cerebral Cortex

Decreased cortical gray matter NODDI metrics in MCI and AD dementia groups from whole-brain analysis. From Vogt et al., 2020 published in Cerebral Cortex.

We are interested in understanding the interplay of factors that contribute to healthy or pathological brain aging. In particular, the effect of factors that contribute to or protect against the development of Alzheimer’s disease.

We use a number of tools in our research, including cognitive testing, MRI, PET, and CSF analysis, to determine how risk factors for Alzheimer’s affect the brain, particularly in mid-life.

Hunt et al, 2020, JAMA Neurology

Voxel-based morphometry and region of interest analyses show significant associations between highest levels of neighborhood disadvantage and gray matter volume. From Hunt et al., 2020 published in JAMA Neurology.

Our NIA funded research program is focused on characterizing the early effects of Alzheimer’s disease on brain myelin and axons, in addition to determining the role of preclinical inflammation in cell and dendritic damage.

Together with collaborators both on and off of the UW campus, the lab is also studying the impact of modifiable factors that may affect trajectories of aging. These include the effect of mid-life metabolic disorders (obesity and insulin resistance), sleep, diet, and microbial influences.

Understanding early brain changes in people who may go on to develop cognitive decline is expected to lead to earlier diagnosis, prevention, and the development of new therapies for Alzheimer’s disease.

Dr. Barbara Bendlin’s Google Scholar profile.Gut Microbes and Alzheimer’s: A Conversation With Barbara Bendlin | Being Patient

Dr. Barbara Bendlin | Update on the Role of Gut Microbiome in Alzheimer’s Disease

Gut inflammation’s impact on brain health

Titles are generated by AI from Meta

Barbara Bendlin, PhD, weighed in on the connection between gut inflammation and brain health in a recent article published by Verywell.

Want to Boost Brain Health? Focus on Your Gut

Gut Microbiome Dynamics in Alzheimer’s Disease

At a Glance

In Wisconsin, Alzheimer’s disease (AD) is the fifth leading cause of death among those aged 65 and older.

Despite decades of research, the etiology of dementia due to AD remains unknown, and there are currently no preventative or disease-modifying treatments available. The overarching goal of this project was to determine the role of the gut microbiome in AD and identify new treatment targets for the disease.

This project was successful in identifying new relationships between gut and brain pathology in AD, defining how timing of microbial colonization influences the development of AD, and determining the role microbe-related metabolites may play in preclinical cognitive decline.

The Challenge

In Wisconsin, Alzheimer’s disease (AD) is the fifth leading cause of death among those aged 65 and older. Despite decades of research, the etiology of dementia due to AD remains unknown and there are currently no preventative or disease-modifying treatments available.

Previous studies using mouse models have revealed that modifying the community of bacteria living in the gut, or gut microbiota, can impact the accumulation of amyloid plaques in the brain. Amyloid plaques are a hallmark of AD as they build up in brain cells and disrupt their function.

In addition, researchers on this project have found that individuals with dementia caused by AD have a less diverse gut microbiome that is distinct in composition compared to cognitively healthy individuals of similar age and gender. While these results provided a strong foundation for further investigation, it remained unclear whether changes in the gut microbiome occur prior to the onset of AD and whether manipulating the gut microbiome could offer protection against the disease.

Project Goals

The overarching goal of this project was to determine the role of the gut microbiome in AD and identify new treatment targets for the disease. This goal was addressed through four specific aims:

Determine the longitudinal relationship between gut microbiota composition and the development and progression of AD
Identify taxa capable of modulating AD
Test the feasibility of gut microbial manipulation in humans
Identify microbial metabolites that can serve as novel biomarkers of AD

Results

Researchers made significant progress toward each of their aims. First, to understand the relationship between the composition of gut bacteria and the development and progression of AD, researchers acquired fecal samples from cognitively healthy participants and participants with AD over time and tested whether changes in the gut microbiome predicted changes in AD pathology through evaluation of cerebrospinal fluid (CSF) and neuroimaging markers.

First, the results indicated that intestinal permeability and inflammation may play a role in AD as antibodies associated with intestinal barrier function were linked with biomarkers of AD and neurodegeneration. Second, higher levels of calprotectin, an established marker of gut inflammation, were associated with greater amyloid burden in individuals with AD.

Next, researchers examined the extent to which abundances of gut microbial phyla were associated with brain volume and found a significant positive correlation between a bacterial phylum called Firmicutes and total brain volume which is consistent with previous studies of AD.

Finally, higher levels of a gut microbial metabolite called phenol sulfate was associated with synaptic degeneration, indicating a potential link between the gut microbiome and the brain in AD pathology.

Researchers utilized germ-and-bacteria-free mice to investigate how the microbiome modulates AD. Researchers introduced the germ-free mice to conventionally raised, microbe-laden mice at either birth or six weeks of age to understand how the timing of colonization influences the development of AD pathology. They found that mice colonized with bacteria at birth had significantly fewer amyloid plaques compared to mice who were colonized at six weeks. These findings suggest that early microbial exposure may influence AD progression later in life.

To test the feasibility of gut microbial manipulation in humans, the researchers recruited 15 individuals with dementia due to AD and 15 healthy individuals to undergo a fecal microbiota transplant (FMT) in which healthy gut bacteria is transferred from a donor to the participants.

This portion of the project was terminated during COVID-19 pandemic due to concerns about the virus being present in the stool samples used for FMT. Instead, researchers explored an alternative approach using probiotic supplementation to modify the gut microbiome and established a partnership with International Flavors & Fragrances to develop a custom probiotic for AD. A new study called “Gut-PRO Study” has been developed, though the researchers are currently seeking new funding for this project.

Lastly, the researchers examined the relationship between the metabolites produced by gut microbes and cognitive function in individuals with AD and cognitively healthy individuals. While the results of machine learning techniques to link the gut microbiome with brain imaging features are still being analyzed, the researchers also investigated whether metabolites in CSF can predict preclinical cognitive decline.

21 metabolites were linked with changes in cognitive performance. Of these, 13 were associated with improvements in performance, seven were associated with declining scores on cognitive measures and one metabolite called creatinine was associated with both improved long-term verbal memory and declining overall cognitive function. These findings suggest that gut microbe-related metabolites may play a role in preclinical cognitive decline though more research is needed to understand these effects.

Looking to the Future

The research team has leveraged their progress from this project for an NIH A1 application to continue their work. They have also received an NIH R01 award, Gut Barrier Function in Alzheimer’s Disease, to expand their research.

Lasting Impact

Researchers on this project have established a relationship with a larger consortium of investigators working on the Alzheimer’s Gut Microbiome Project, and this has led to further collaborations with world leading experts in gut microbiome and disease.

Learn more about WPP Partners Barbara Bendlin and Federico Rey

An association between high blood sugar levels and Alzheimer’s disease is a focus of research led by Barbara Bendlin, PhD, associate professor, Geriatrics and Gerontology.

A Baton Rouge, Louisiana news outlet profiled research on a link between diabetes and Alzheimer’s disease by Dr. Bendlin.

When the body’s ability to respond to insulin is impaired – a condition referred to as insulin resistance or pre-diabetes – it may set the stage for development of Alzheimer’s disease.

“The hypothesis is that diabetes is a risk factor for Alzheimer’s disease, but not everyone with diabetes is going to get Alzheimer’s,” said Dr. Bendlin.

According to the American Diabetes Association, 27 percent of people aged 65 and older in the United States have diabetes and about half have pre-diabetes. People living with diabetes have a doubled risk of developing Alzheimer’s disease.

Dysbiosis with Dr. Richard and Cindy Becker

Dysbiosis Dr Richard Becker Health Show has addressed intestinal dysbiosis on Your Health, including a dedicated segment titled “Dysbiosis – Customer Appreciation” and a longer episode on “Pearls for Chronic Yeast (Herbs for Intestinal Dysbiosis & Yeast)” YouTube.

Where to watch

YouTube playlist: The Beckers’ official Your Health playlist includes the dysbiosis-related videos.
- Pearls for Chronic Yeast (Herbs for Intestinal Dysbiosis & Yeast) – 58:30 minutes, covers herbal approaches to restoring gut balance YouTube.
- Dysbiosis – Customer Appreciation – 59:07 minutes, a general discussion on dysbiosis and its management YouTube.
  You can access them here: Your Health with Dr. Richard and Cindy Becker – YouTube playlist YouTube.
Live TV: Your Health airs daily on Christian networks such as VTN, Lighthouse TV, and LIFE! Christian Broadcasting Network VTN+2.
- VTN: Mon–Fri at 2:00 pm ET VTN.
- Lighthouse TV: Check your local affiliate’s schedule lighthousetv.org.
- LIFE! Christian TV: Multiple daily slots LIFE! Christian Broadcasting Network.
  Many stations also offer on-demand streaming via their websites.

About the topic

On these episodes, Dr. Becker explains intestinal dysbiosis—an imbalance in the gut’s microbial community—and discusses:

Causes and symptoms
Herbal and dietary strategies for restoring balance
Practical tips for supporting gut health YouTube

The “Pearls for Chronic Yeast” episode is particularly relevant for those with yeast overgrowth linked to dysbiosis, offering herbal remedies and lifestyle advice YouTube.