Neurotransmitter modulation by the gut microbiota

Abstract

The gut microbiota - the trillions of bacteria that reside within the gastrointestinal tract - has been found to not only be an essential component immune and metabolic health, but also seems to influence development and diseases of the enteric and central nervous system, including motility disorders, behavioral disorders, neurodegenerative disease, cerebrovascular accidents, and neuroimmune-mediated disorders. By leveraging animal models, several different pathways of communication have been identified along the "gut-brain-axis" including those driven by the immune system, the vagus nerve, or by modulation of neuroactive compounds by the microbiota. Of the latter, bacteria have been shown to produce and/or consume a wide range of mammalian neurotransmitters, including dopamine, norepinephrine, serotonin, or gamma-aminobutyric acid (GABA). Accumulating evidence in animals suggests that manipulation of these neurotransmitters by bacteria may have an impact in host physiology, and preliminary human studies are showing that microbiota-based interventions can also alter neurotransmitter levels. Nonetheless, substantially more work is required to determine whether microbiota-mediated manipulation of human neurotransmission has any physiological implications, and if so, how it may be leveraged therapeutically. In this review this exciting route of communication along the gut-brain-axis, and accompanying data, are discussed.

Keywords: Gut microbiota; Gut-brain-axis; Human microbiota; Neurotransmitters.

FIGURE 1. From microbiome discovery to mechanism

An example of the path from observing the microbiome may be involved in a disease to a mechanistic understanding. One approach to explore whether or not the microbiota is involved in a given disease is to transfer the gut microbiota from a patient suffering a disease into an animal via fecal microbiome transplant (FMT) and then pass that animal through the appropriate disease model. If transplantation of the gut microbiota from a diseased patient affects the end points in the model (but transplant of a microbiota from health controls do not), effort should go into understanding a potential underlying mechanism. Generally, this is achieved by using a broad -omic approaches, ideally through the combination of metagenomics, metabolomics, and/or transcriptomics of host stool and other tissues. By comparing the results from disease-presenting animals to controls, candidate bacterium and/or metabolites that may be influencing the disease end points can be identified. If introduction of the candidate trigger organism(s) or metabolite(s) results in the same change in end points, it is likely they are involved in presentation of the phenotypes.

FIGURE 2. Communication routes of the gut microbiota to the brain

The gut microbiota has been found to communicate with the brain through several different mechanisms. This includes production of neurotransmitters or modulation of host neurotransmitter catabolism, innervation via the vagus nerve, or activation of the HPA axis.