The existence of a link between the gut and the brain has been discussed for centuries, but in the past two decades research in this area has exploded and studies have started to report direct effects of the gut microbiota on both the brain and behaviour, and the underlying molecular mechanisms have started to unravel. The term gut–brain axis has been coined to describe these complex relationships and represents a bi-directional communication system that integrates neural, endocrine and immune signalling between the gut and the brain. A number of studies have highlighted that gastrointestinal illnesses are associated with behavioural alterations or neurological diseases, which are also often associated with dysbiosis of the gut microbiota.
Based on the emerging appreciation of a connection between the brain and the gut microbiota, a pioneering study showed that gastrointestinal defects could be replicated by modelling the behavioural features of autism spectrum disorder (ASD) in a mouse model1. ASD has been reported to be associated with a series of gastrointestinal abnormalities in a subset of individuals. This study supported the existence of a gut–brain axis, as behavioural and neuropathological symptoms correlated with altered intestinal permeability and dysbiosis, similarly to what was reported in cases of human ASD. Moreover, these defects in the mouse model could be ameliorated by oral treatment with the human commensal Bacteroides fragilis, due at least in part to the ability of this bacterium to normalize the levels of specific serum metabolites. Although the molecular mechanisms that underlie how the gut microbiota could regulate brain function and behaviour were still unclear, this study highlighted the importance of regulation of the host metabolome by commensal bacteria.
As indirect evidence supporting interactions between the microbiota and nervous system, more than 90% of body’s serotonin (or 5-hydroxytryptamine; 5-HT) is known to be synthesized in the gastrointestinal tract and to regulate diverse functions including platelet aggregation, immune responses and gastrointestinal motility. Early studies have shown the existence of a link between the microbiota and the concentration of serum 5-HT. However, whether this was a direct effect, and how gut microorganisms regulated 5-HT, were unknown until spore-forming bacteria were shown to be causally implicated in this process2. These bacteria play a critical role in the regulation of colonic 5-HT biosynthesis in mice and humans through the production of specific metabolites that induce tryptophan hydroxylase (TPH1) expression in enterochromaffin cells, leading to 5-HT synthesis. This effect was inducible and reversible, and the regulation of serotonin levels could be measured in the colon and serum, as well as affecting gastrointestinal motility and platelet function in the host. While 5-HT is known to regulate neuronal activity in the gut, how microbial modulation of intestinal 5-HT impacts brain function or behaviour remains unclear.
The gut microbiota has also been linked to neurodegenerative diseases. One important step in this direction, following previous evidence that reported gastrointestinal symptoms and dysbiosis in patients with Parkinson’s disease (PD), found that the gut microbiota played a critical role in the pathogenesis of synucleinopathies, such as PD3. In a PD mouse model, the presence of gut microbiota correlated with motor deficits, intestinal dysfunction and aggregation of alpha-synuclein in the frontal cortex, which in turn promoted activation of microglia within brain regions that are involved in disease, and contributed to neuroinflammation. Interestingly, short-chain fatty acids, which are known to be actively produced by the microbiota and have been implicated in regulating mucosal immunity, were identified as potential molecular mediators of this gut–brain signalling pathway. Colonization of mice with the microbiota of patients with PD, enhanced motor dysfunction compared to transplants from healthy human donors, emphasizing the functional contribution of the microbiota to features of PD in animals.
Altogether, these and other studies have highlighted the emerging role of the gut microbiota in the regulation of both physiological and pathological processes within the host nervous system, ranging from biosynthesis of neurotransmitters to neurodevelopmental and neurodegenerative disorders. They have also highlighted the importance of bacterial metabolites as molecular mediators of such complex host–microorganism interactions, opening the door for exploration of new therapeutic approaches, such as microbiome- and metabolite-based treatments.
Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451−1463 (2013).
Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264−276 (2015).
Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469−1480 (2016).