New Study Reveals How Gut Metabolites Influence Brain Health

Machine learning is used to predict how metabolites created within the gut bind with receptors found within the gut and brain. A series of metabolites and receptor binding pairs, recently created by researchers, are used to shed light on the role of the microbiome in Alzheimer’s disease. By identifying which metabolites bound with specific receptors, researchers were able to identify the biological pathways these metabolites might affect, and identify the purpose of some receptors. 

According to a study published in Cell Reports, the presence of certain metabolites within the gut is partly indicative of the presence of certain bacteria in the gut since they are created with the breakdown of food in the gut by the bacteria. Alzheimer’s disease has previously been linked to changes in the gut microbiome in humans, and it is likely that the gut affects brain health due to its role in immune function. Even though the role of the immune system in Alzheimer’s disease has been understood, research has linked inflammation to an increased risk of this disease. 

If potentially harmful binding of metabolites to receptors can be prevented, then Alzheimer’s disease risk can be reduced. To identify the binding pairs, research behind the current study carries out a genetic analysis to identify the relation 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 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. 

Some of them also looked at how these receptors might respond to the microbiome of 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. 

Researchers say that this is a promising find and over accumulation of tau is linked to development of Alzheimer’s. The study authors point out that 99% of clinical trials into pharmaceutical interventions for Alzheimer’s disease have not been successful, and researchers say their findings could point to a new target.