AI connects gut bacteria metabolites to Alzheimer's disease progression

In a new study published in Cell Reports, researchers have developed a sophisticated systems biology approach that combines artificial intelligence (AI), genetics, and multi-omics analyses to explore how metabolites produced by gut bacteria might influence Alzheimer’s disease.

The study identifies specific receptors in the human body that these metabolites interact with, potentially opening new avenues for therapeutic intervention. This significant finding could lead to the development of novel drugs that target these interactions, offering hope for treating or even preventing Alzheimer’s disease.

Alzheimer’s disease is a progressive neurodegenerative disorder primarily affecting older adults, characterized by the decline of cognitive functions such as memory and reasoning. It is marked by the accumulation of amyloid-beta plaques and tau protein tangles in the brain, which interfere with neural function and lead to cell death.

The exact cause of Alzheimer’s is not fully understood, but it is believed to involve a combination of genetic, lifestyle, and environmental factors that affect the brain over time. As the disease advances, it severely impacts daily living and independence, making it one of the most common causes of dementia among the elderly.

Previous research has established that patients with Alzheimer’s disease experience changes in their gut bacteria as the disease progresses. These bacteria produce metabolites that can influence brain health, potentially contributing to the disease’s development. However, the specific pathways through which these metabolites act have remained largely a mystery.

This gap in understanding prompted the new study, aiming to map out the interactions between these metabolites and the human receptors they affect. The study was conducted by Feixiong Cheng and his team, bringing together experts from the Cleveland Clinic Genome Center, the Luo Ruvo Center for Brain Health, and the Center for Microbiome and Human Health.

The researchers analyzed over a million potential metabolite-receptor pairs using machine learning algorithms to predict interactions most likely to influence the disease. Genetic data, including Mendelian randomization, complemented these predictions by assessing causality and receptor involvement.

“Gut metabolites are the key to many physiological processes in our bodies, and for every key there is a lock for human health and disease,” said Cheng. “The problem is that we have tens of thousands of receptors and thousands of metabolites in our system, so manually figuring out which key goes into which lock has been slow and costly. That’s why we decided to use AI.”

The study also involved experimental validation using neurons derived from Alzheimer’s patients, where specific metabolites were tested for their effects on tau protein levels, a key biomarker of the disease’s progression. This multifaceted approach allowed the researchers to map out significant interactions within the gut-brain axis, shedding light on potential therapeutic targets for Alzheimer’s disease.

One of the most striking outcomes of the study was the identification of specific G-protein-coupled receptors (GPCRs) that interact with metabolites produced by gut bacteria. The researchers focused on orphan GPCRs—receptors whose natural activators are unknown—and discovered that certain metabolites can activate these receptors. This finding is particularly intriguing because it opens new pathways for drug development, targeting these receptors to potentially modulate their activity in favor of disease prevention or mitigation.

Among the metabolites studied, phenethylamine and agmatine stood out due to their effects on tau proteins, which are involved in the neurological degradation characteristic of Alzheimer’s disease. The study demonstrated that these metabolites could significantly alter the levels of phosphorylated tau proteins in neurons derived from Alzheimer’s patients. Agmatine, in particular, showed a protective effect by reducing harmful tau phosphorylation, suggesting it could be a potential candidate for therapeutic development.

The application of machine learning models was pivotal in predicting the interactions between over a million metabolite-receptor pairs. This high-throughput approach not only streamlined the identification of relevant interactions but also enhanced the understanding of the complex mechanisms by which gut microbiota can influence brain health. By integrating genetic analyses and experimental data, the researchers were able to validate these predictions and refine their understanding of the gut-brain axis in the context of Alzheimer’s disease.

While promising, the study’s authors acknowledge several limitations. The complexity of the gut-brain axis means that the findings are preliminary and require further validation through experimental and clinical studies. Future research will need to confirm these interactions in living organisms and explore the therapeutic potential of modulating these pathways.

Additionally, the study mainly focused on the biochemical interactions at a molecular level, without considering the broader physiological and environmental factors that might influence these processes in a living system.

Nevertheless, the research has provided a valuable framework for understanding how metabolites from gut bacteria could influence brain health and disease. The implications of these findings extend beyond Alzheimer’s disease, as the methodologies and insights could potentially be applied to other neurological and systemic diseases influenced by gut microbiota.

“We specifically focused on Alzheimer’s disease, but metabolite-receptor interactions play a role in almost every disease that involves gut microbes,” Cheng said. “We hope that our methods can provide a framework to progress the entire field of metabolite-associated diseases and human health.”

The study, “Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer’s disease,” was authored by Yunguang Qiu, Yuan Hou, Dhruv Gohel, Yadi Zhou, Jielin Xu, Marina Bykova, Yuxin Yang, James B. Leverenz, Andrew A. Pieper, Ruth Nussinov, Jessica Z.K. Caldwell, J. Mark Brown, and Feixiong Cheng.