A new study by researchers at the University of Wisconsin School of Medicine and Public Health suggests a link between gut inflammation and changes in the brain and declines in memory, further supporting a connection between the gut and brain in Alzheimer’s disease.

The study, recently published in the Nature journal Scientific Reports, showed that as levels of calprotectin, an inflammatory marker, increased in the volunteer study participants’ stool samples, so did the amount of amyloid plaque accumulating in the brains of those with Alzheimer’s disease. Levels of Alzheimer’s disease biomarkers in cerebrospinal fluid also rose. Meanwhile, test scores of the volunteers’ verbal memory function dropped.

Even volunteers who did not have Alzheimer’s disease had lower scores on a memory test correlated with higher levels of calprotectin, according to Barbara Bendlin, professor of medicine, UW School of Medicine and Public Health.

“We showed [that] people with Alzheimer’s disease have more gut inflammation, and among people with Alzheimer’s, when we looked at brain imaging, those with higher gut inflammation had higher levels of amyloid plaque accumulation in their brains,” said Bendlin, who has a doctorate in psychology.

Barbara Bendlin portrait
Barbara Bendlin

Calprotectin levels in this study and previous studies have been found to rise with older age. One theory is that gut inflammation is caused by changes in the microbiome that occur as people age and this inflammation can further contribute to neurodegenerative diseases. 

However, Bendlin urged caution in interpreting the relationship between inflammation and Alzheimer’s, as additional research is needed to understand whether there is a cause-and-effect link.

“We can’t infer causality from this study; for that, we need to do animal studies,” she said.

Bendlin’s two collaborators and senior authors on this paper, Federico Rey, associate professor of bacteriology, UW–Madison, who holds a doctorate in microbiology, and Tyler Ulland, assistant professor of pathology and laboratory medicine, UW School of Medicine and Public Health, who holds a doctorate in cellular and molecular biology, are now performing animal studies to determine whether inflammation or diet changes can elicit a mouse version of Alzheimer’s. Three UW–Madison graduate students, Margo Heston, Kendra Hanslik and Katie Zarbock, were co-first authors on this study.

In an earlier study published in 2017, the research team found significant differences in the gut microbiome of people with Alzheimer’s dementia and those without it. The authors theorized that gut changes may contribute to systemic inflammation that disrupts the blood-brain barrier, which normally protects the brain from infection and toxins, according to Rey.

“Increased gut permeability could result in higher blood levels of inflammatory molecules and toxins derived from gut lumen, leading to systemic inflammation, which in turn may impair the blood-brain barrier and may promote neuroinflammation, and potentially neural injury and neurodegeneration,” he said.

Rey and Ulland’s labs plan to test these ideas in a mouse model of Alzheimer’s disease, altering gut permeability by making precise changes in the gut microbiome.

The concept that the gut and brain are functionally connected has become more prominent in the last 10 years and this study offers some of the first evidence that asymptomatic gut inflammation and Alzheimer’s disease may be linked, according to Ulland.

“This study, although not definitive, provides additional evidence that changes in gut health could be linked to Alzheimer’s pathology,” he said. “It is therefore very important to continue to study the link between changes in the gut, such as inflammation or increased gut permeability, and Alzheimer’s disease onset and progression.”

The samples for the most recent study came from 125 volunteers in the Wisconsin Alzheimer’s Disease Research Center clinical core, and in the long-running Wisconsin Registry for Alzheimer’s Prevention study. The majority of volunteers were white, college-educated and middle-aged. In addition to providing stool samples for testing, participants underwent positron emission tomography scans, provided cerebrospinal fluid and underwent cognitive testing.

“This is another example of the engagement of our thousands of volunteers from Wisconsin who are making these discoveries possible,” Bendlin said.

The researchers are now working with participants using a “gold standard test” for leaky gut that measures how certain sugars are excreted in urine. Another Wisconsin Alzheimer’s Disease Research Center clinical study will test whether taking probiotics helps improve gut inflammation to assess whether they could possibly prevent cognitive decline caused by Alzheimer’s disease and related dementias.