Invited reviewKynurenine pathway metabolism and the microbiota-gut-brain axis
Introduction
The importance of the gut microbiota has moved front and centre on the healthcare agenda. One of the most exciting developments in gut microbiota research over recent years has been the discovery that the collection of microorganisms in our gut can regulate aspects of brain function and behaviour (Cryan and Dinan, 2012, Mayer et al., 2014). Understanding the neurobiological mechanisms underpinning the extent of the influence exerted by this microbial organ on host physiology, brain and behaviour is now a key research priority. A number of pathways and potential mechanisms which may regulate microbiota-brain interactions are under investigation. One focal point in this regard is the microbial regulation of circulating tryptophan availability, with a dual emphasis on the regulation of serotonin synthesis and the regulation of kynurenine pathway metabolism. In addition to the ability to modulate the expression of relevant central nervous system (CNS) receptor subtypes, this attribute gives the gut microbiota a broad neuropharmacological repertoire and makes it an appealing and tractable target for the treatment of a range of stress-related disorders.
This review places the kynurenine pathway under the spotlight. We first briefly describe the structural and functional dynamics of the gut microbiota across the lifespan and frame its importance in general to health and wellbeing. We then discuss the broad scope of influence across physiology, brain and behaviour as it recruits the scaffolding and reciprocal communication network of the brain-gut axis to mediate both positive and negative effects. Using well established preclinical and clinical examples from the field of neurogastroenterology, we outline the potential translational significance of a dysregulated microbiota-gut-brain axis in the context of kynurenine pathway metabolism. We also explore possible mechanisms, neurodevelopmental implications and the opportunities for intervention arising from this research, integrating evidence ranging from prenatal and postnatal studies to the older extreme of life.
Section snippets
The gut microbiota: structural and functional dynamics
The microbes that reside in our gastrointestinal tract (GI) are together known as our gut microbiota and their collective genomes constitute our gut microbiome (Turnbaugh et al., 2007). When comparing the gut microbiota composition between healthy humans, substantial taxonomic variability is evident. Such inter-individual diversity may be accounted for by a number of environmental, physiological, genetic and psychological factors (Cryan and Dinan, 2012, Lozupone et al., 2012, Penders et al.,
Microbiota -gut-brain axis signalling
Communication between the brain and gut occurs along a network of pathways collectively termed the brain-gut axis (see Fig. 1). The brain-gut axis encompass the CNS, enteric nervous system (ENS), sympathetic and parasympathetic branches of the autonomic nervous system, neuroendocrine and neuroimmune pathways, and the gut microbiota (Cryan and Dinan, 2012). A complex reflexive network of efferent and afferent fibers between the GI tract and the CNS facilitate interactions within the axis (
Anxiety & depression
A number of approaches have been utilised in preclinical models to investigate how the gut microbiota influences brain function and behaviour, including the use of germ-free (GF) mice, pre/probiotic treatment, antibiotic treatment, deliberate bacterial infection of the GI tract and faecal microbiota transplant (Cryan and Dinan, 2012). Such studies have demonstrated, with relative consistency, that the gut microbiota modulates anxiety (Arentsen et al., 2015, Clarke et al., 2013, Diaz Heijtz
Tryptophan metabolism, serotonin & the kynurenine pathway
As the precursor molecule to serotonin (5-HT), kynurenine and downstream metabolites of the kynurenine pathway (Badawy, 2015a, Palego et al., 2016), changes in the supply and availability of the essential amino acid tryptophan has many implications for ENS and CNS functioning and thus brain-gut axis signalling. Around 95% of the body’s 5-HT is located within the GI tract, primarily synthesised by enterochromaffin cells, and 5% in the CNS (Camilleri, 2002, Gershon and Tack, 2007, Mayer et al.,
Stress, the gut microbiota and the implications for kynurenine pathway metabolism
It has become clear that there is an intricate relationship between the gut microbiota and stress. Over a decade ago a seminal study was the first to demonstrate that GF mice subjected to a mild restraint stress exhibited an exaggerated hypothalamic-pituitary-adrenal (HPA) axis (the core mammalian neuroendocrine system) response when compared to specific pathogen free control animals (Sudo et al., 2004). Of note, bacterial colonisation with faecal matter from specific pathogen free mice was
The immune system, the gut microbiota and implications for kynurenine pathway metabolism
As noted above, kynurenine pathway metabolism is tightly regulated by inflammatory mediators and multiple enzymes in the pathway are immunoresponsive (Campbell et al., 2014). The gut microbiota engages dynamically with the host across the lifespan to educate and regulate the immune system (El Aidy et al., 2015, Round and Mazmanian, 2009). This is clear not just from GF animals, but also in the compromised immune response to infection of animals whose gut microbiota is depleted using antibiotics
Preclinical evidence supporting a role for the gut microbiota in regulating the availability of tryptophan for kynurenine metabolism
The link between the availability of tryptophan metabolism for kynurenine metabolism and the composition of the gut microbiota is underlined by a number of different preclinical approaches. Firstly, using both targeted and unbiased analysis in GF animals, it has been demonstrated that circulating total tryptophan levels are increased in the absence of a gut microbiota (Clarke et al., 2013, El Aidy et al., 2012a, Mardinoglu et al., 2015, Wikoff et al., 2009). Despite increased circulating
Microbial regulation of CNS receptors, neurogenesis and myelination
One of the remarkable features of the gut microbiota is the impact on gene expression in the CNS as indicated, for example, by studies in GF animals (Diaz Heijtz et al., 2011). This includes GABA receptor expression in the amygdala following ingestion of L. rhamnosus (Bravo et al., 2011, Stilling et al., 2015b) and 5-HT1A receptor expression in the hippocampus under GF conditions (Neufeld et al., 2011). The intersection between the pharmacodynamic interactions of kynurenine pathway metabolites
Microbial regulation of features relevant to CNS tryptophan and kynurenine pathway metabolism
Both the regulation of circulating tryptophan availability, and distribution and subsequent kynurenine pathway metabolism, in the periphery and CNS, is tightly regulated during all stages of life (Badawy, 2015a, Badawy, 2015b, Ruddick et al., 2006). This is desirable, especially in the context of having checks and balances in place for the control of CNS availability of neuroactive metabolites with such a broad pharmacodynamic impact (Muller and Homberg, 2015, Schwarcz et al., 2012). From a
Microbial metabolism of tryptophan and the impact of microbial metabolites generated from tryptophan on host physiology
The metabolic transformation of tryptophan by bacteria is an important but neglected feature which might be important in microbial regulation of circulating tryptophan availability to the host for kynurenine pathway metabolism in the periphery and CNS. Most tryptophan supplied for bacterial metabolism in the colon comes in the form of undigested protein and the major metabolite is indole (Berstad et al., 2015). Indole production by bacteria is catalysed by tryptophanase, an enzyme not present
Behaviours influenced by the gut microbiota and tryptophan metabolites
As outlined above, the gut microbiota has been shown to influence an array of behaviours in preclinical, and to a lesser degree, clinical studies, many of which are also influenced by tryptophan metabolism (Berger et al., 2009). Over recent years, the influence of kynurenine pathway metabolites on brain function and behaviour has been the focus of increasing investigation (Schwarcz et al., 2012, Stone and Darlington, 2013). Despite methodological difficulties in definitively linking the gut
The importance of tryptophan supply and availability in neurogastroenterology
Tryptophan metabolism along kynurenine pathway has important implications for neurogastroenterology due to the dual effects of kynurenine and downstream metabolites in GI and CNS function, and thus brain-gut axis signalling. IBS is the best characterised microbiota-gut-brain axis disorder and there is evidence for immune related tryptophan metabolism along the kynurenine pathway (Clarke et al., 2009c, Clarke et al., 2012b, Keszthelyi et al., 2013), which has been linked to the severity of GI
Perspectives and conclusions
One of the important implications of our discussion to date is that the gut microbiota might be a tractable target to regulate circulating tryptophan availability and kynurenine pathway metabolism in the periphery and CNS across the lifespan, either via direct or indirect mechanisms. For example, restoring intestinal permeability via the gut microbiota might be an important point of control (Kelly et al., 2015b). Similarly, promoting gut microbiota diversity during old age might improve health
Acknowledgements
The APC Microbiome Institute is funded by Science Foundation Ireland (SFI), through the Irish Government’s National Development Plan (SFI grant number SFI/12/RC/2273). This review is specifically supported by a Health Research Board Health Research Award (Grant number HRA-POR-2014-64) G.C. is also supported by a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (Grant Number 20771). P.J.K., T.D. and J.F.C. are also funded by the European Community’s Seventh
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