- Research has suggested that the gut microbiome is disrupted in people with Alzheimer’s disease, and researchers from Ohio now propose this could be a target for treatment.
- They propose receptors that are present in the gut and brain could be the key to targeting the gut-brain axis.
- Using existing artificial intelligence (AI) tools researchers predicted which metabolites, the by-products of bacteria in the gut, would bind with which receptors by predicting their shape.
- They then used machine learning tools to predict which receptors and metabolites could have an influence on Alzheimer’s disease, and tested lab-created neurons to observe the effect of two metabolites on tau levels, a protein whose overaccumulation is linked to cognitive impairment.
Machine learning has been used to predict how metabolites created in the gut bind with receptors found in the gut and brain.
A library of metabolites and receptor binding pairs, recently created by researchers, could be used by researchers to shed some light on the role of the microbiome in Alzheimer’s disease.
Researchers from the Cleveland Clinic, OH recently evaluated the shapes of over 1 million potential pairs of metabolites and receptors to see which ones might bind together.
By identifying which metabolites bound with specific receptors, researchers were able to identify the biological pathways these metabolites might affect, and also identify the purpose of some receptors.
Lead author of the research — which appears in Cell Reports — Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, explained in a press release:
“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. 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 presence of certain metabolites in the gut is partly indicative of the presence of certain bacteria in the gut, as these metabolites are created via the breakdown of food in the gut by the bacteria.
Alzheimer’s disease has previously been
Steve Gendron, PhD, who specializes in immunology and endocrinology, and was not involved in the recent study, made the following analogy in explaining the potential mechanisms to Medical News Today:
“Imagine the gut as a bustling market where all sorts of chemicals are being exchanged. These chemicals can hop on the bloodstream express and make their way to Brain Central Station. Scientists think this line of communication might influence brain health because if the market (gut) starts selling the wrong stuff (like inflammatory chemicals), it might contribute to the brain’s decline, seen in Alzheimer’s. It’s a bit like if bad ingredients were used in a cake — you end up with a baking disaster.”
While the role of the immune system in Alzheimer’s disease is not well understood, research has linked inflammation to increased risk of Alzheimer’s disease and chronic inflammation could play a role in the initiation of the disease.
Cheng, the study’s lead author, told MNT that “Alzheimer’s disease is a challenging disease by lack of effective treatment.“
However, he added, the “'[b]rain-gut axis’ has showed potential to treat brain disorders.“
“We posit that [the] ‘brain-gut axis’ may be a good target for Alzheimer’s disease drug development because we don’t have to deliver molecules/compounds to brain via improving gut health.”
– Feixiong Cheng, PhD
If potentially harmful binding of metabolites to receptors could be prevented, then potentially Alzheimer’s disease risk could be reduced. To identify the binding pairs, the researchers behind the current study first carried out a genetic analysis to identify relationships between 408 receptors and Alzheimer’s disease.
Using the genetic code for these receptors researchers used existing artificial intelligence (AI) resources to predict the shape of the proteins that they code for. This gave a good idea of the shape of the binding regions of the receptors.
Researchers were then able to predict which metabolites would bind to these receptors and how. Most of the metabolites discovered were lipid, or lipid-like metabolites.
They also looked at how these receptors might respond to the microbiome of somebody with Alzheimer’s disease. By investigating bacteria known to be abundant in the microbiome of somebody with Alzheimer’s disease researchers identified two metabolites — agmatine and phenethylamine, which are abundantly produced by Bacteroides fragilis and Ruminococcus, respectively.
Researchers then decided to observe the impact of these metabolites on the neurons of people with Alzheimer’s disease by creating forebrain neurons using induced pluripotent stem cells of people with Alzheimer’s disease.
They found that agmatine reduced levels of p-tau181, p-tau205, and total tau. Further studies on phenethylamine showed that it significantly reduced levels of p-tau181, p-tau205, and total tau in human induced pluripotent forebrain neurons in a dose-dependent manner.
This is a promising find, since overaccumulation of tau is associated with the development of Alzheimer’s disease.
“In the current studies, we only quantified tau phosphorylation because tau phosphorylation is a more robust assay established by our lab and other scientists,“ Cheng said.
“We are doing more preclinical [animal] studies to further test efficacy of gut metabolites (i.e., agmatine) and we may test it in future trials we get very successful in our ongoing and future preclinical studies, including both safety in older individuals and high efficacy,” he added.
The study authors point out that 99% of clinical trials into pharmaceutical interventions for Alzheimer’s disease have not been successful, and Cheng says their findings could point to a new target:
“This is exact[ly] our hypothesis: Improving gut health may influence the tau levels in the brains and further prevent or even treat Alzheimer’s disease. However, we need more research to be done in the future to investigate this hypothesis further and we are working on it now using animal and human samples.”
Other researchers are welcome to use the findings from this study, in the hope it will help future studies, Cheng told us.
“We are working on open science approaches to help Alzheimer’s disease research community and help our colleagues free access of all our ‘big data’ findings to guide their future research to fight Alzheimer’s disease crisis,” said Cheng.
