Investigator:
Laura Cox, PhD
Name of Institution:
Brigham and Women’s Hospital, Inc.
Project Title:
Investigating Immunologic Mechanisms by Which Alistipes Contributes to PD Pathogenesis
Investigator Bio:
Dr. Laura (Laurie) Cox is an Assistant Professor in the Department of Neurology at the Ann Romney Center for Neurologic Diseases at Harvard Medical School and Brigham & Women’s Hospital. Her lab is currently investigating the role of the microbiome in neurologic diseases, including Parkinson’s disease (PD), Alzheimer’s disease, dementia with Lewy bodies, multiple sclerosis, and amyotrophic lateral sclerosis. Dr. Cox was originally trained as a clinical microbiologist, identifying infectious agents. She then obtained her PhD in the lab of Dr. Martin Blaser, where she found that early-life antibiotics lead to lasting metabolic consequences. To gain experience with models of neurologic disease, she then pursued postdoctoral training in the lab of Dr. Howard Weiner. Dr. Cox established her lab in the fall of 2021.
Objectives/Background:
Emerging research suggests that the bacteria in the digestive system (gut microbiome) plays a significant role in PD and may contribute to development and worsening of PD by increasing inflammation. However, a major limitation in preventing and treating PD by targeting the microbiome is understanding which bacteria play a role. One of the bacteria that stands out in PD is Alistipes, which is consistently elevated in the gut of people with PD. We discovered that eliminating Alistipes using the antibiotic metronidazole improved motor function and lowered signs of inflammation in the gut and brain in a mouse model of PD. In a second study, we discovered that giving Alistipes to a PD mouse model worsened movement and increased inflammation. These early studies provide the first experimental evidence that Alistipes may contribute to development of PD by increasing inflammation, and establishes a model to study an important environmental contributor to PD.
Methods/Design:
We will investigate whether the gut microbe Alistipes contributes to PD and ask how Alistipes changes inflammation in the body and in the brain. We will test our hypothesis in two different genetic mouse models of PD, an alpha-synuclein model and a LRRK2 model, and determine if administering Alistipes worsens motor function and/or contributes to typical disease-related changes in the brain. To identify changes in the immune system, we will characterize both T cells and microglia, both of which are known to play a role in PD pathology. Finding if Alistipes contributes to increased inflammation will help us understand how a common PD-associated gut microbe worsens disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
By understanding how bacteria in the digestive system contributes to PD, we hope to uncover new insights into the ways that environmental factors increase PD risk. If Alistipes worsens PD, then antibiotics to remove Alistipes could be used in the clinical management of PD. In addition, immune system processes affected by Alistipes have the potential to be therapeutic targets to combat inflammation caused by gut bacteria in PD. This could ultimately lead to new ways to prevent, slow the progression, or treat PD by blocking detrimental functions in the microbiome.