Antibiotics Altering Gut Bacteria Reduced Alzheimer’s Symptoms, But Only in Male Mice, Study Shows

Long-term antibiotic treatment, aimed at altering the bacterial population in the gut, was found to reduce the inflammation and amyloid plaque formation that is a hallmark of Alzheimer’s disease — but only in male mice.

The same treatment had no effect on female mice, a study found.

The study, “Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes,” was published in the Journal of Experimental Medicine.

Alzheimer’s is characterized by plaques, or clumps, of a toxic protein known as amyloid-beta within nerve cells. These accumulations lead to the activation of a certain type of immune cell in the brain, known as microglia, which can help remove the amyloid plaques.

However, the microglia’s activation may further exacerbate Alzheimer’s by causing inflammation of the central nervous system — a process known as neuroinflammation.

Several factors can influence neuroinflammation, including — notably — the population of bacteria that reside in the intestines. These bacteria are known collectively as the gut microbiome.

“Recent evidence suggests that intestinal bacteria could play a major role in various neurological conditions including autism spectrum disorders, multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease,” Sangram S. Sisodia, director of the Center for Molecular Neurobiology at The University of Chicago, said in a press release.

In fact, it is well-known that people with cognitive impairment exhibit altered gut microbiota. That, in turn, is associated with an increase in the levels of pro-inflammatory molecules in the blood. Therefore, over the last decade, researchers have extensively investigated the link between the gut microbiome and the development of Alzheimer’s disease.

Importantly, a group of American researchers previously documented that long-term use of an antibiotic cocktail in a mouse model of Alzheimer’s led to a reduction in amyloid-beta deposits and inflammation in the brain of male mice only. The researchers, including Sisodia, had designed the cocktail to alter the gut microbiome.

The results were compelling, but the experiments were only conducted on one specific strain of mice. Now, the same team examined the impact of long-term antibiotic treatment in a more aggressive mouse model of Alzheimer’s, known as APPPS1-21.

Results revealed that a long-term antibiotic cocktail treatment reduced amyloid-beta deposits and alterations in microglial cells. Similar to prior studies, the protective effect of antibiotics was restricted only to male mice.

Specifically, the antibiotic treatment was found to change the state of microglial cells from one that promotes neurodegeneration to one that prevents it. It works by lowering the expression levels of neurodegeneration-promoting genes, and increasing the levels of genes that promote a healthy brain. Researchers note that gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

To confirm that these changes were caused by alterations in the gut microbiome, the team transplanted fecal microbiota from non-treated male mice into male mice that had been treated with the long-term antibiotic cocktail.

This, in turn, restored the gut bacterial population and caused an increase in amyloid plaque formation and microglial cell activation.

Thus, these results extend the team’s earlier findings and confirm a “causal relationship between the gut microbiome and [Alzheimer’s]-associated inflammation and [amyloid-beta] pathology [disease symptoms] in this model.”

The results were seen only in male mice. The researchers discovered that long-term antibiotic treatment changed the gut bacteria of male and female mice in different ways. The changes in the microbiome of female mice caused their immune systems to increase production of several proinflammatory factors that could influence the activation of microglia, the team said.

“Our study shows that antibiotic-mediated perturbations of the gut microbiome have selective, sex-specific influences on amyloid plaque formation and microglial activity in the brain,” Sisodia said. “We now want to investigate whether these outcomes can be attributed to changes in any particular type of bacteria.”