“Our gut harbors a complex community of over 100 trillion microbial cells which influence human physiology, metabolism, nutrition and immune function. The human intestinal tract harbors a diverse and complex microbial community which plays a central role in human health. It has been estimated that our gut contains in the range of 1000 bacterial species and 100-fold more genes than are found in the human genome.” (National Institutes of Health, NIH.com)

Women are more likely to be afflicted by Alzheimer’s disease when compared to men and there are nuanced differences in how male and female brains develop and respond to Alzheimer’s pathology. While women, on average, live longer than men—and age is the most significant risk factor for sporadic Alzheimer’s—longevity alone does not account for the disparate impact of the disease on women. A study reveals unexpected insights into how the gut microbiome and female hormones may work together: that estrogen may suppress the activity of microglia, the brain’s innate immune cells, allowing more amyloid plaque pathology.

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“The microbiome has such an impact on so many physiological processes,” according to Dr. Sangram Sisodia, who studies the role of the gut microbiome in Alzheimer’s disease. It’s not just about digestion—these microbes can influence the functions of all our organs, including the brain. Dr. Sisodia’s work suggests that alterations in the gut microbiome impact the development of Alzheimer’s pathology.

In his prior research, Dr. Sisodia found that wiping out the gut microbiome with antibiotics in Alzheimer’s mice reduced amyloid plaques in their brain. The finding, however, was only observed in male mice, while the female counterparts receiving the same treatment maintained high levels of plaques. The sex-specific results prompted Dr. Sisodia and his team to test the possibility that female hormones could be responsible for the persistence of plaques in the treated females.

The researchers measured estrogen levels in the blood of female Alzheimer’s mice treated with antibiotics. They were surprised to discover elevated levels of the hormone. In females, the ovaries produce estrogen, and the gut bacteria influence its levels in the blood. By examining how the antibiotics altered the types of bacteria in the gut of the female mice, the team observed changes in the bacteria that regulate estrogen. This led to the conclusion that the bacterial changes may explain why estrogen levels remained high in the blood.

When the researchers removed the main source of estrogen production from the female Alzheimer’s mice, they anticipated a reduction in estrogen levels in the blood. To their surprise, plaque pathology in their brain almost disappeared. The researchers then investigated how estrogen influenced amyloid plaque levels in the brain. They show that estrogen could suppress the activity of microglia, the brain’s innate immune cells, which carry an estrogen receptor. When estrogen from the blood crosses the blood-brain barrier and binds to its receptor on microglia, it inhibits the cells’ activation when they encounter amyloid. “So, if they see amyloid, they don’t get activated, which normally happens,” said Dr. Sisodia.

Activated microglia engulf and clear debris from the brain, including amyloid plaques. In Alzheimer’s disease, microglia can become overactivated and release inflammatory molecules that promote neuroinflammation, negatively affecting the health of nerve cells in the brain. On the molecular level, microglial biology was affected by the presence or absence of estrogen. In females with estrogen, microglia in the vicinity of amyloid plaques were expressing markers of neuroinflammation. In contrast, the research team found that three months after estrogen depletion, amyloid plaques were gone, and microglia were expressing neuroprotective markers, suggesting that without estrogen, microglia cleared the amyloid plaques and could return to a steady housekeeping state.

When the researchers reintroduced estrogen to the estrogen-depleted Alzheimer’s female mice, they observed that the plaque pathology and neuroinflammation markers returned. “It’s pretty compelling evidence that estrogen is really the driving force for what we initially saw with antibiotics,” said Dr. Sisodia.

Amyloid plaques can begin to accumulate in the brain as many as twenty years before the onset of cognitive symptoms. With his research, Dr. Sisodia uncovers the complex relationship between changes in estrogen levels, gut microbiome disruption, and amyloid plaque buildup in female Alzheimer’s mice. While more work is needed to fully understand the impact of female sex hormones in the development of Alzheimer’s in women, the findings of the study offer novel insights into how the disease develops and may open new possibilities for treatments that focus on hormonal and microbial factors involved in the development of Alzheimer’s disease.

Published in Scientific Reports

Sangram S. Sisodia, Ph.D., University of Chicago

Rudolph Tanzi, Ph.D., Massachusetts General Hospital/Harvard Medical School

Can (Martin) Zhang, M.D., Ph.D., Massachusetts General Hospital/Harvard Medical School

Early modulation of the gut microbiome by female sex hormones alters amyloid pathology and microglial function