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credit: cell report (2024). DOI: 10.1016/j.celrep.2024.114128
Cleveland Clinic researchers are using artificial intelligence to uncover a link between the gut microbiome and Alzheimer's disease.
Previous studies have shown that Alzheimer's patients experience changes in their gut bacteria as the disease progresses. The newly published cell report This study outlines a computational method to determine how bacterial byproducts, called metabolites, interact with receptors on cells and contribute to Alzheimer's disease.
Dr. Feixion Chen, the founding director of the Cleveland Clinic Genome Center, worked closely with the Luo Lubo Center for Brain Health and the Center for Microbiome and Human Health (CMHH). The study ranks metabolites and receptors by their likelihood of interacting and how likely the pair is to impact Alzheimer's disease. This data provides one of the most comprehensive roadmaps for metabolite-related disease research to date.
When bacteria break down the food we consume for energy, they release metabolites into our system. Metabolites then interact with and influence cells, promoting cellular processes that can be beneficial or harmful to health. In addition to Alzheimer's disease, researchers have linked metabolites to heart disease, infertility, cancer, autoimmune diseases and allergies.
Preventing harmful interactions between metabolites and our cells can help fight disease. Researchers are working to develop drugs that activate or block metabolites from binding to cell surface receptors. Progress in this approach has been slow due to the vast amount of information required to identify target receptors.
“Gut metabolites are the key to many physiological processes in our bodies, and every key has a key to human health and disease,” said Dr. Chen, a genomic medicine staff member. “The problem is that there are tens of thousands of receptors and thousands of metabolites in the system, so manually determining which key goes into which lock was time-consuming and expensive. So we decided to use AI.”
Dr. Chen's team believes that known gut metabolites in the human body with existing safety profiles, if widely applied, could provide effective prevention or even intervention approaches for Alzheimer's disease and other complex diseases. I tested whether.
Dr. Yunguang Qiu, lead author of the study and postdoctoral fellow at the Chen Institute; He led a team that included Dr. J. Mark Brown, CMMH's director of research. James Leverenz, MD, Director of the Cleveland Clinic Luo Lubo Brain Health Center and Director of the Cleveland Alzheimer's Disease Research Center. and neuropsychologist Jessica Caldwell, Ph.D., ABPP/CN. Director of the Women's Alzheimer's Movement Prevention Center at the Cleveland Clinic in Nevada.
Using a type of AI called machine learning, the research team analyzed more than 1.09 million potential metabolite-receptor pairs and predicted how likely each interaction was to contribute to Alzheimer's disease. .
Integrated analysis:
- Genetic and proteomic data from human and preclinical Alzheimer's disease research
- Different receptor (protein structures) and metabolite shapes
- How different metabolites affect patient-derived brain cells
The research team investigated the metabolite and receptor pairs most likely to influence Alzheimer's disease in brain cells from Alzheimer's patients.
One of the molecules they focused on was a protective metabolite called agmatine, which was thought to protect brain cells from inflammation and the damage that comes with it. The study found that agmatine most likely interacts with a receptor called CA3R in Alzheimer's disease.
Treatment of neurons affected by Alzheimer's disease with agmatine directly reduced CA3R levels, indicating that the metabolite and receptor interact. Neurons treated with agmatine also had reduced levels of phosphorylated tau protein, a marker of Alzheimer's disease.
Dr. Chen says these experiments demonstrate how his team's AI algorithms can open up new research avenues for many diseases other than Alzheimer's disease.
“Although we focused specifically on Alzheimer's disease, metabolite-receptor interactions are involved in almost all diseases that involve the gut microbiome,” he said. “We hope that our method can provide a framework for advancing the field of metabolite-related diseases and human health as a whole.”
Currently, Dr. Chen and his team are studying the interactions between genetic and environmental factors (including food and gut metabolites) on human health and disease, including Alzheimer's disease and other complex diseases. We are further developing and applying these AI technologies to achieve this goal.
For more information:
Yunguang Qiu et al., Systematic characterization of the multi-omic landscape between gut microbial metabolites and GPCRomes in Alzheimer's disease, cell report (2024). DOI: 10.1016/j.celrep.2024.114128
Magazine information:
cell report