Nuclear receptors and the Microbiome: Does the road to happiness go through the gut?
The microbiome or microbiota are the terms used for the microbes that live on and inside the human body. Trillions of microorganisms make up the microbiome including bacteria, fungi, parasites, and viruses. It is estimated that there are more microbial cells than human cells in the body and the majority of these microbes reside in the gut. There is a growing amount of research that has recently changed our understanding of the microbiome from being just a collection of symbiotic organisms to actively participating in a bidirectional communication system called the gut-brain axis.
The gut-brain axis is the bidirectional communication system between the central and the enteric nervous systems, which links the emotional and cognitive parts of the brain with peripheral intestinal functions. Some of the intestinal functions that the gut-brain axis monitors and influences are immune activation, intestinal permeability, enteric reflex, and entero-endocrine signaling. One of the underlying mechanisms that researchers are looking to better understand is the communication between the microbiome and the gut-brain axis through nuclear receptors.
Nuclear Receptors and the Gut-Brain Axis
It has been discovered that some microbes in the microbiome secrete metabolites including indole derivatives, secondary bile acids, choline, short chain fatty acids, and hormones which can act as natural ligands for various nuclear receptors involved in the functioning of the gut-brain axis. These natural ligands influence the gene expression of cells and allow the microbiome in the gut to directly influence its environment. Multiple nuclear receptors have been shown to be involved in this process including constitutive androgen receptors (CAR) 1–3, pregnane X receptor (PXR), aryl hydrocarbon receptor (AHR), farnesoid X receptor (FXR), and peroxisome-proliferator activated receptors (PPARs), which help regulate metabolism, CNS development, and inflammation, as well as mood and behavior.
Through the signaling of nuclear receptors the bacteria in the gut microbiome and the body work together to maintain homeostasis, but imbalances in the microbiome can occur. With the microbiome’s ability to modulate gene expression, these imbalances can change metabolic processes in the body and potentially lead to disease. In fact, research has associated irregularities in the microbiome to diseases such as diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, and fibromyalgia. This makes understanding which organisms in the microbiome influence nuclear receptors and how they affect them important within drug discovery.
The Microbiome and Drug Discovery
With the vast number of microbes and the high variability in the composition of the microbiome between people due to various environmental factors, nuclear receptors within this system have become promising targets for drug discovery. Researchers are looking for pharmacological, as well as nutritional, interventions that might modulate nuclear receptor signaling by the microbiome to potentially fix imbalances and thereby treat diseases. Concurrently, it is important for researchers to understand how compounds can affect and potentially interrupt this communication system by understanding off-target nuclear receptor activation and inhibition. This makes the use of in vitro cell-based assays to understand the interactions a compound of interest might have with various nuclear receptors an important step prior to in vivo trials in drug development.
INDIGO Biosciences is a leading provider of all-inclusive cell-based nuclear receptor assays. INDIGO’s kits and services can provide researchers with critical data to understand receptor functioning and inform drug development decisions early in the identification process.