Findings could lead to new biomarkers for targeted therapies and clinical laboratory tests for several diseases
Once again, the human gut flora is being linked to the progression of a chronic disease. Using artificial intelligence (AI), researchers at the Cleveland Clinic Lerner Research Institute found that “metabolites produced by bacteria in the gut” can influence the course of a patient’s Alzheimer’s disease, according to a press release. Findings from the study could lead to useful biomarkers for clinical laboratory tests and as a target for prescription drugs.
Researchers have been studying the role of metabolites in disease development for some time. Alzheimer’s is a progressive, degenerative brain disease typically associated with age, family history, and deposits of certain proteins in the brain that cause the brain to shrink and eventually brain cells to die. Alzheimer’s is the most common form of dementia, accounting for an estimated 60 to 80% of all dementia cases. According to the Alzheimer’s Association, there is no cure or proven method of prevention.
Nearly seven million people in the United States live with Alzheimer’s disease, and 55 million people worldwide suffer from the disease or other forms of dementia. Patients are usually over 65 years of age, but younger patients can also be affected.
The scientists at the Cleveland Clinic published their results in the journal Cell reports entitled “Systematic characterization of the multi-omics landscape between gut microbiota metabolites and GPCRome in Alzheimer’s disease.”
“Gut metabolites are the key to many physiological processes in our bodies, and with every key comes a lock to human health and disease,” said Feixiong Cheng, PhD (above), founding director of the Cleveland Clinic Genome Center, in a press release. “The problem is that we have tens of thousands of receptors and thousands of metabolites in our system, so manually figuring out which key fits which lock was slow and costly. That’s why we decided to use AI.” The study’s findings could lead to new clinical laboratory biomarkers for dementia screening tests. (Photo Copyright: Cleveland Clinic Lerner Research Institute.)
Changes in intestinal bacteria
Metabolites are substances released by bacteria when the body breaks down food, drugs, chemicals, or its own tissues such as fat or muscle. They fuel cellular processes in the body that can be either helpful or harmful to a person’s health.
The researchers at the Cleveland Clinic believe that preventing harmful interactions between metabolites and cells can help prevent the disease. Previous studies have shown that changes in the intestinal flora occur in Alzheimer’s patients as the disease progresses.
To complete their study, the scientists used AI and machine learning (ML) to analyze more than 1.09 million potential metabolite-receptor pairs to determine the likelihood of developing Alzheimer’s disease.
They then examined genetic and proteomic data from studies of Alzheimer’s disease and looked at different receptor protein structures and metabolite shapes to determine how different metabolites might affect brain cells. The researchers found significant interactions between the gut and the brain.
They discovered that the metabolite agmatine most likely interacts with a receptor called CA3R in Alzheimer’s patients. Agmatine is thought to protect brain cells from inflammation and damage. They found that CA3R levels decrease when Alzheimer’s neurons are treated with agmatine. Levels of the phosphorylated tau protein, a biomarker for Alzheimer’s, also decrease.
The researchers also looked at a metabolite called phenethylamine. They found that it too can significantly alter the levels of phosphorylated tau proteins, a finding they believe could be beneficial for Alzheimer’s patients.
New therapies for Alzheimer’s and other diseases
One of the most compelling findings of the study was the identification of specific G protein-coupled receptors (GPCRs) that interact with metabolites present in the gut microbiome. By focusing on orphan GPCRs, the researchers found that certain metabolites could activate these receptors, which could help develop new therapies for Alzheimer’s.
“We focused specifically on Alzheimer’s disease, but metabolite-receptor interactions play a role in almost every disease involving gut microbes,” said Feixiong Cheng, PhD, founding director of the Cleveland Clinic Genome Center in the press release. “We hope our methods can provide a framework to advance the entire field of metabolite-associated diseases and human health.”
The study involved researchers from the Cleveland Clinic Genome Center, the Luo Ruvo Center for Brain Health and the Center for Microbiome and Human Health (CMHH), all three of which are part of the Cleveland Clinic.
The team plans to use AI technology to further develop and study the interactions between genetic and environmental factors on human health and disease progression. More research and studies are needed, but the results of the Cleveland Clinic study suggest that new biomarkers for targeted therapies and clinical laboratory tests for dementia may soon follow.
—JP Schlingman
Related information:
AI links metabolic products of intestinal bacteria to the progression of Alzheimer’s disease
Researchers use AI to improve Alzheimer’s disease treatment via the “gut-brain axis”
Machine learning reveals link between metabolites and Alzheimer’s
Systematic characterization of the multi-omics landscape between gut microbiota and GPCRome in Alzheimer’s disease
Phosphorylated tau in Alzheimer’s and other tauopathies
Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets
