Posted July 17, 2019

Imagine flying into a major city at night. As the plane descends, the crisscrossing highways and interconnected streets are illuminated by the headlights from the thousands of vehicles speeding through the sprawling metropolis. Now imagine if that city were – in fact – an ecosystem of trillions of microorganisms densely navigating the pathways of the small and large intestines. Just like the cars following the traffic lights in the city, many of the microbes of the human body are symbiotic – these microbes benefit from their human hosts while simultaneously supporting the survival of the human body. But just as there are cars that illegally speed through intersections, there are also microbes that take on pathogenic, disease-promoting roles. The pathogenic and symbiotic microbiota coexist often without problems; however, a disturbance in this balance brought on by the over-use of bacteria-decimating antibiotics, infectious illness, or certain diets can increase the likelihood that the body becomes more susceptible to disease.

In an interview published in the New York Times Science section, Dr. Sam Sisodia of the University of Chicago revealed that he did not initially believe that the gut microbiome would have an impact on the brain let alone Alzheimer’s disease. Despite his misgivings, he recruited members of his laboratory to give mice disease antibiotics in order to wipe out as much of their microbiome as possible. Upon later inspection, Sisodia and his colleagues found fewer beta-amyloid plaques in the brains of mice given antibiotics. Sisodia in collaboration with Dr. Rudy Tanzi, Chair of the Research Leadership Group for Cure Alzheimer’s Fund, published a paper in Scientific Reports in 2017 that reported that a small disruption of the microbiome could strikingly change the deposition of amyloid beta.

This initial paper has led to a series of new insights that were presented as a keynote lecture at the Alzheimer’s Disease / Parkinson’s Disease conference in Lisbon, Portugal. Dr. Sisodia reported to an international group of scientists how Cure Alzheimer’s Fund not only supported the research when other funding agencies found it too outside-the-box but also provided the motivation to study sex differences when a founding board member, Jacqueline Morby, asked Sisodia what happened when he performed his microbiome experiments in female mice?

It turns out there are differences in the results with female mice versus male mice.

A paper published in the Journal of Experimental Medicine with support from Cure Alzheimer’s Fund to the laboratories of Dr. Sam Sisodia and Dr. Oleg Butovsky demonstrated that male and female mice have different responses when their microbiome is disturbed.

If you give an antibiotic cocktail that obliterates the gut microbiota of male mice that are models of Alzheimer’s disease, the researchers found that they subsequently reduced the severity of amyloid-beta plaques in their brains. This antibiotic treatment altered the microglia of these mice. When microbiota-obliterating antibiotics treatment was repeated in female mice that expressed the same genes associated with aggressive amyloid deposition in Alzheimer’s disease that was expressed in the male mice, the researchers found that there was no effect on amyloid deposition. Upon closer examination, it was found that microglia were activated differently in male mice when compared with female mice. This research highlights a crucial aspect of research studies: what is true in male mice is not necessarily true for female mice. This has profound implications for extrapolating clinical data about human patients. An effective treatment strategy for a man might not necessarily work for a woman – and vice versa.

Microbiota perform a wide variety of roles in the human body from stimulating the immune system to synthesizing vitamins and amino acids. The microbiota in a healthy person can confer protection against pathogenic organisms that enter the body through eating contaminated food. Some of the helpful anaerobic bacteria families include Lactobacillus and Clostridium. Beneficial microbes prevent the overgrowth of harmful bacteria by competing for nutrients and producing antimicrobial proteins.