Beyond the brain: The gut microbiome and Alzheimer’s disease
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Trillions of microbes live in our gastrointestinal tract. These different types of bacteria, viruses, fungi, and other microorganisms — collectively known as the gut microbiome — play a vital role in maintaining overall health by helping to digest food and make nutrients. They also support the body’s immune system and produce chemicals that affect brain function. When it gets out of balance, the gut microbiome can contribute to disease.
The idea that a community of microbes living in the gut can affect what happens in the brain may seem surprising. Yet research shows that the brain and the gut microbiome are connected through the gut-brain axis — an intricate network of neurons, proteins, and chemicals that relay messages between the digestive system and the brain.
NIA is funding research with the goal of learning how factors such as aging, diet, and environmental exposures may alter the gut-brain axis, and which gut microbes may benefit or harm the brain. Researchers are also asking whether harmful changes in the gut microbiome might one day be reversed to prevent or slow disease, including Alzheimer’s.
Brain inflammation and the gut microbiome
Research has suggested that chronic inflammation in the brain can contribute to the development of Alzheimer’s. In response to infection or injury, immune cells release inflammatory molecules called cytokines, which sound the alarm to recruit help from other immune cells. If the alarm keeps ringing, the resulting chronic inflammation can lead to neuronal damage and death.
Microglia are immune cells in the brain. Under normal conditions, they help maintain healthy neurons and patrol the brain environment, looking for invaders and cellular debris. When they encounter trouble or receive an alert from other immune cells, they are activated to engulf and clear away the problem and release inflammatory signals. In the aging brain, microglia that become activated are more likely to stay “on” for longer than normal. This exaggerated immune response in the brain has been associated with neurodegenerative diseases such as Alzheimer’s.
This finding led scientists to ask whether reducing inflammation could be beneficial for brain health. Research has suggested that certain high-fiber foods, including whole grains, fruits, and vegetables, may help reduce inflammation. Certain gut bacteria convert the fiber from these foods into compounds called short-chain fatty acids (SCFAs), which have anti-inflammatory properties and have been found to improve memory in animals.
Rodney W. Johnson, Ph.D., a professor and animal nutrition researcher at the University of Illinois, is examining the effects of dietary fiber on microglia activity and inflammation in the brain. His team has found that aging mice have low levels of SCFAs, along with dysregulated, hyperactive microglia.
To test the effects of a diet high in fiber on age-related dysregulation of microglia, Johnson’s team fed adult and aged mice diets with either high or low amounts of inulin, a type of fiber found in certain plant-based foods that is easily converted by gut bacteria into SCFAs. In both adult and aged mice, the high-fiber diet changed the types of bacteria in the gut microbiome, increased the production of SCFAs, and reduced the expression of certain genes that control inflammation in the brain. Moreover, in a follow-up study, a high-fiber diet shifted the majority of microglia in older mice out of a dysregulated state and back to the normal, healthy state seen in younger adult mice.
How SCFAs regulate microglial activity in the aged brain remains an open question. Currently, Johnson’s team is altering specific genes in mice to block different routes to determine which ones SCFAs use to affect the brain. For example, do SCFAs affect the brain directly by crossing the blood-brain barrier, or do they affect the brain indirectly by acting through another body system?
“We’re learning more about how diet might be used to change the gut microbiome and support brain health,” Johnson said. His team’s research is providing important insights into the effects of a high-fiber diet on age-related immune system changes that could point to promising areas to investigate further.
Targeting age-related changes in the gut microbiome
As people and animals age, the bacteria living in their gut change as well. The population of bacteria tends to become less diverse, meaning there are fewer types of bacteria. This loss of diversity can make room for opportunistic bacteria, often associated with illness, to move in. Louise D. McCullough, M.D., Ph.D., a professor and neurologist at UTHealth Houston, is exploring whether age-related changes in the gut microbiome can be reversed to slow or prevent the effects of neurodegenerative disease.
While studying stroke survival in mice, McCullough noticed that “hours after a stroke, the gut barrier becomes leaky. This allows very bad bacteria in the gut to circulate throughout the body and cause serious infections and even death, especially in older mice. Because infections are a common cause of death after stroke, and the risk is higher in older patients, our research may point toward new approaches to help with recovery.”
To determine if the aged gut microbiome was contributing to stroke survival in old mice, McCullough’s team transplanted a young gut microbiome into old mice and an aged microbiome into young mice. They then caused strokes experimentally and tested the mice’s survival and behavior afterwards. In the old mice with a young gut microbiome, survival after a stroke increased by more than 50%. In contrast, the young mice with an aged gut microbiome developed cognitive problems, and many died after a stroke. This result suggested that there was something about the aged microbiome that was toxic to the brain.
What was it about the young and aged microbiomes that led to these differences? To find out, McCullough’s team analyzed the young gut microbiome and found it was rich in beneficial SCFAs, but those SCFAs were lacking in the aged gut microbiome. To see if SCFAs could rejuvenate an aged microbiome, the team created a mixture of SCFA-producing bacteria and the prebiotic inulin. “The combination is very important because the good bacteria need the prebiotic to work,” McCullough says.
When this mixture was given to the aged mice, the amount of SCFAs increased in the blood and brain, and importantly, inflammation and neurological problems were significantly reduced. These results made McCullough wonder if this approach would have similar effects in neurological diseases such as Alzheimer’s and related dementias.
To explore the effects of gut rejuvenation on neurodegenerative disease, McCullough’s team uses two types of mouse models: one for Alzheimer’s (AD mice) and another for cerebral amyloid angiopathy (CAA mice). CAA is a neurological disease that can cause devastating strokes and dementia. Both diseases result in cognitive decline and involve amyloid deposits in the brain. McCullough’s research has shown that the gut microbiomes of the AD and CAA mice change with age and that disruptive changes in the gut occur before any amyloid deposits can be seen in the brain.
Some research suggests that the gut may contribute to amyloid formation. For example, scientists have identified gut bacteria that make amyloid-like particles and propose that these particles may seed the formation of some amyloid plaques in the brain. Similarly, McCullough’s team has found amyloid deposits in the intestinal tissue autopsied from people with Alzheimer’s, but not in people without the disease. Currently, McCullough is exploring whether amyloid deposits and cognitive changes in AD and CAA mice can be prevented or reversed by replacing their gut microbiomes with healthier ones.
In another study, McCullough is examining whether some genes expressed in the brains of aging mice are regulated by the gut microbiome. She is also studying how sex differences may affect an aging gut microbiome. Similar to Johnson’s observation that aged female mice have more gut inflammation and produce fewer SCFAs, other research suggests a link between estrogen levels and gut microbiome diversity. By understanding the effects of age-related hormonal changes on the gut microbiome and the brain in females, McCullough hopes to identify new research targets for preventing and treating neurodegenerative diseases in women of all ages.
Cholesterol metabolism and Alzheimer’s: Role of the gut microbiome
The gut microbiome plays a central role in regulating human metabolism. Different types of gut bacteria influence which substances are produced and released into the bloodstream and central nervous system.
Changes in certain metabolic processes, including the metabolism and transport of cholesterol, have been associated with Alzheimer’s. However, what is happening to these metabolic pathways in people who develop Alzheimer’s is not well understood. Rima Kaddurah-Daouk, Ph.D., a professor in psychiatry and behavioral sciences at Duke University School of Medicine, is leading the NIA-funded Alzheimer’s Disease Metabolomics Consortium to find metabolic changes that correlate with the cognitive decline and structural and functional changes in the brain associated with Alzheimer’s.
To study these connections, Kaddurah-Daouk’s team examined cholesterol clearance in 1,474 older adults with cognitive function ranging from normal to late-stage Alzheimer’s. Cholesterol metabolism and its clearance from the body are a partnership between the liver and the gut microbiome. First, the liver breaks down cholesterol into smaller molecules, called primary bile acids (BAs). Next, certain types of gut bacteria convert the primary BAs to secondary BAs.
Kaddurah-Daouk’s team found that, compared to older adults with normal cognition, individuals with an Alzheimer’s diagnosis had significantly lower amounts of liver-produced BAs but higher amounts of bacterially produced secondary BAs in their blood. These higher levels of secondary BAs were significantly associated with cognitive decline. A follow-up analysis of the same participants showed that altered ratios of primary and secondary BAs in the blood correlated with brain changes associated with Alzheimer’s. Taken together, the study results suggest that changes in the way primary BAs are converted to secondary BAs by the gut microbiome may affect brain function.
Next, Kaddurah-Daouk wanted to know if the BA imbalance appeared in the brains of people with Alzheimer’s. Using samples collected over 25 years from older adults with and without Alzheimer’s, the team measured the levels of BAs in blood and autopsied brain tissue. Again, elevated levels of secondary BAs were associated with cognitive decline, and notably, the bacterially produced secondary BAs were present in brain tissue.
“The brain doesn’t seem able to make these compounds, so we think it’s most likely that the BAs are transported from the blood to the brain,” says Kaddurah-Daouk. Although more research is needed, these findings shed new light on the connections between cholesterol metabolism, the gut microbiome, and Alzheimer’s.
Kaddurah-Daouk and her colleagues continue to uncover clues about the metabolic pathways that go awry in the development of Alzheimer’s. Analysis of these pathways may help identify new targets, such as elevated levels of secondary BAs in the blood, to guide the development of new diagnostic tests or treatments for Alzheimer’s. Kaddurah-Daouk envisions a future where, using wearable devices, a person might be able to get a readout on their metabolic health that would suggest diet or lifestyle changes to improve brain health.
Alzheimer’s Gut Microbiome Project: An open science discovery mission
To learn about the dynamic role of the gut microbiome in the different stages of Alzheimer’s, NIA is funding the Alzheimer’s Gut Microbiome Project. Led by Kaddurah-Daouk, the effort involves more than 40 laboratories with a vast range of expertise and is organized around three subprojects.
The first subproject is led by Rob Knight, Ph.D., a microbiome researcher and professor at the University of California, San Diego. Knight is partnering with NIA-funded Alzheimer’s Disease Research Centers (ADRCs) across the United States to collect fecal and blood samples from more than 1,000 older adults with cognitive function ranging from normal cognition to the late stages of Alzheimer’s. Analysis of these samples, combined with cognitive, metabolic, and brain imaging data collected by the ADRCs, will help Knight’s team map how the types of gut bacteria change across the stages of the disease.
For the second subproject, Kaddurah-Daouk’s team is collaborating with RUSH Alzheimer’s Disease Center. They are collecting and analyzing fecal and blood samples from more than 1,700 participants to investigate the influences of a modified Mediterranean diet, a ketogenic diet, and lifestyle changes on brain health and cognition.
The third subproject is led by Sarkis Mazmanian, Ph.D., a researcher and professor of microbiology at the California Institute of Technology. Mazmanian’s team is transplanting certain gut bacteria found in humans into the intestinal tracts of mouse models of Alzheimer’s. This approach will help determine the effects of these gut bacteria and their products on the brain, cognitive function, and behavior.
To optimize the use of this project’s research, the project data and analysis will be shared with other researchers through the NIA-supported AD Knowledge Portal. In addition, the project results will be incorporated into the Alzheimer’s Disease Atlas, an open-source knowledge base that allows researchers to search for interactions between various molecular, clinical, and pathologic aspects of Alzheimer’s.
In the ever-evolving field of Alzheimer’s research, scientists will continue to investigate how processes in the whole body, not just the brain, may contribute to the disease. NIA-funded research is providing more insight into how the trillions of microbes living in the gut are connected to brain health and, when disrupted, may be associated with disease. Future discoveries in this area could lead to new strategies to detect, treat, and prevent Alzheimer’s.
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