Posted October 7, 2022

There are four main groups of bacteria in the human gut, and the level of each type is constantly changing. This component of the human microbiome is essential in maintaining the body’s normal functions, such as resistance to infection and inflammation. Advances in understanding the connection between the gut microbiome and the brain have brought to light that an imbalance in the diversity of gut microbes may trigger neuroinflammation in the brain. Short-term experimental treatment with high-dose antibiotics administered early in the life stage of specialized mice changed the composition of the microbiome and led to a significant reduction of amyloid beta later in life. Interestingly, the manipulation had an effect in male but not female mice. The research also suggests that the gut microbiome-brain connection relies on microglia. Depletion of microglia after the antibiotic treatment overturned the amyloid-reducing effect of the antibiotics, and amyloid persisted.

The results of a recent study led by Dr. Sisodia suggest that the brain’s innate immune cells, the microglia, may be key mediators of the gut microbiome–brain relationship. Dr. Rudy Tanzi, Chair of the CureAlz Research Leadership group, was a contributing author on the paper published in the Journal of Experimental Medicine.

The new study explores the hypothesis that changes in the microbiome early in life may have an impact later in life. For this, the research team explored the effects of short-term experimental treatment with a cocktail of high-dose antibiotics administered early in the life stage of AD mice with high amyloid levels. As the researchers suspected and similarly to the life-long administration, the short-term treatment also changed the composition of the microbiome and led to a significant reduction of amyloid beta later in life. The manipulation had an effect in male mice but not female mice. Late-life microbiome transplant from untreated donor mice also fully restored amyloid-beta deposition.

In the studies that followed, the researchers next assessed how microglia were changing within this experimental paradigm. In Alzheimer’s, microglia switch from their natural clearing state to an activated disease-associated state that promotes neuroinflammation. The activated state is associated with changes in microglia cell morphology and gene expression and is recapitulated in an AD mouse model like the one used in this study. Short-term antibiotic treatment in the AD male mice resulted in a significant reduction in the otherwise expected high levels of activated microglia in these mice. In addition, microbiome transplants from untreated mice fully restored activated microglia and their disease-associated morphology and gene expression profiles.

In search of the final proof of microglia’s role in mediating the relationship between the gut microbiome and the brain’s amyloid beta deposits, the researchers treated the mice with a drug that depleted microglia in mice that received the antibiotic treatment. The manipulation overturned the amyloid-reducing effect of the antibiotics and amyloid beta persisted in the brain.

 “It’s an astounding effect,” said Sisodia in an interview. “What we’re seeing in this study is that after antibiotic treatment early in life, amyloid deposition is significantly reduced in males and not in females. And we see that the microglial transcriptome—their gene expression—is changed as well. But if you feed bacteria present in the feces from another untreated mouse to antibiotic-treated mice, you restore the pathology, as well as the microglial phenotype. The final question is, are the microglia responsible for the amyloidosis, and if so, how are the microglia doing this?”

“In females, the microglia don’t seem to be affected at all by perturbations in the microbiome. Research in the past has shown that microglia from male and female animals are very different during development and during aging, but what are the contributing factors? It’s likely to be an effect of sex hormones, but then what are the effects on the microbiome?”

While the reasons behind the lack of effect in female mice are yet to be determined, the current study adds to the growing body of evidence pointing to a key role microglia play in AD. Some of the first clues pointing to a role for neuroinflammation in AD came from genetic studies supported by CureAlz as the Alzheimer’s Genome Project identified the first Alzheimer’s gene associated with neuroinflammation in microglia.

Sangram Sisodia, Ph.D., The University of Chicago, Rudolph Tanzi, Ph.D., Massachusetts General Hospital

Published Paper: Journal of Experimental Medicine

Link to the interview with Dr. Sisodia: