The Gut-Brain Connection

How "Bugs" in the Gut Impact Neurodegenerative Diseases

What if the origins of neurodegenerative diseases like Parkinson’s disease and Alzheimer’s disease lie not in the brain, but in the gut? The gut-brain axis is a two-way communication channel connecting the brain and the digestive system. Emerging research suggests this connection plays a role in the development of these diseases. Buck Institute Postdoctoral Researchers Minna Schmidt, PhD (Andersen Lab) and Priya Makhijani, PhD (Andersen and Winer Labs) are studying how changes in gut health may influence neurodegenerative disease progression.

Priya Makhijani, PhD (Andersen and Winer Labs)

Neurons in the gut form the enteric nervous system, which controls digestion and connects the gut to the gut-brain axis. Gut health is dictated by trillions of microbes—"bugs" as Dr. Makhijani casually calls them—that digest food and produce chemicals called metabolites. These metabolites enter the bloodstream, cross the blood-brain barrier, and impact brain and bodily functions. Immune cells in the gut help maintain the gut microbiome, which in turn supports the immune system in protecting against disease.

With disease and aging, gut health can become imbalanced, or experience dysbiosis, where a healthy diversity of bacterial species is lost. This may present as digestive issues and disrupt the production of essential nutrients. Gut dysbiosis can alter which metabolites enter the bloodstream and reach the brain. It can also cause immune dysregulation, thus increasing the risk of developing diseases, and a “leaky gut” where a weakened intestinal barrier allows microbes to enter the bloodstream, triggering widespread inflammation.

Parkinson’s disease is hypothesized to begin in the gut, with many patients experiencing gastrointestinal issues up to three decades before motor symptoms arise. A key feature of Parkinson’s is the buildup of an aggregated protein in the brain called alpha-synuclein. The Braak hypothesis suggests this aggregation starts in the gut and spreads to the brain via the gut-brain axis, contributing to the progression of disease.

Minna Schmidt, PhD (Andersen Lab)

Dr. Schmidt’s research asks how changes in the gut microbiome can impact aggregated alpha-synuclein. She is interested in examining Lactobacillus bacteria, which produces lactate in the gut, the same metabolite naturally produced during exercise. Exercise is known to ease Parkinson’s non-motor symptoms, though the mechanism is unclear.

Using a genetically modified version of the microscopic worm C. elegans, Dr. Schmidt analyzes how this metabolite, lactate, and yogurt containing lactate-producing bacteria affect harmful alpha-synuclein clumping. Early findings suggest that lactate inhibits the harmful aggregation of alpha-synuclein, potentially benefiting neurons in worm models of Parkinson’s disease, and offering insight into new therapeutic approaches for Parkinson's.

Like Parkinson’s, some Alzheimer’s patients experience gastrointestinal issues before neurodegenerative symptoms appear. However, the gut’s role in Alzheimer’s is still being uncovered.

Alzheimer’s is marked by the misfolding of proteins called amyloid beta and tau in the brain, triggering an immune response that causes neuroinflammation and widespread inflammation in the body. Dr. Makhijani and other researchers hypothesize that the disease may be linked to reduced gut microbiome diversity, which causes a “leaky gut,” allowing microbes to enter the bloodstream and contribute to both systemic and brain inflammation.

In a "chicken or the egg" dilemma, it’s unclear which inflammation-related pathology in Alzheimer’s—either protein misfolding in the brain or a leaky barrier in the gut—comes first or causes the other. Dr. Makhijani and other researchers don’t rule out that gut health plays a role in Alzheimer's development and acknowledge that current mouse models are biased toward disease pathology starting in the brain.

Dr. Makhijani instead focuses her research on understanding how the immune cells responsible for maintaining the gut microbiome influence Alzheimer’s progression. By analyzing the expression profiles of immune cells in genetically modified mice, she discovered that certain gut immune cells may migrate to the dura, the outer border of the brain. With this remarkable discovery, she is now studying why these cells move and what role they may play in disease progression.

Though more research is needed on the gut’s connection to neurodegenerative disease, one thing is clear: gut health matters. Dr. Schmidt reminds us to see the gut “not just as an organ for waste, but as one producing chemicals affecting the brain.” Both she and Dr. Makhijani encourage discussing gut health with your doctor, emphasizing the role of a varied diet to nurture the microbiome and support brain health.