Kynurenine pathway metabolism and the microbiota-gut-brain axis

Jul 10, 2016Neuropharmacology

Kynurenine Metabolism and Its Role in the Gut Microbes-Brain Communication System

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Abstract

The gut microbiota may influence central nervous system function through modulation of tryptophan metabolism.

Microbial regulation of tryptophan metabolism is linked to serotonin synthesis and kynurenine pathway metabolism.
The gut microbiota is associated with various aspects of central nervous system physiology, including anxiety, depression, social behavior, cognition, and visceral pain.
Kynurenine pathway metabolism could be regulated by microbial control over neuroendocrine function and immune system components.
Preclinical evidence suggests that the gut microbiota may directly and indirectly influence tryptophan availability for kynurenine pathway metabolism.
Targeting the gut microbiota could provide a means to modulate kynurenine pathway metabolism and enhance understanding of its effects on brain function.

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It has become increasingly clear that the gut microbiota influences not only gastrointestinal physiology but also central nervous system (CNS) function by modulating signalling pathways of the microbiota-gut-brain axis. Understanding the neurobiological mechanisms underpinning the influence exerted by the gut microbiota on brain function and behaviour has become a key research priority. Microbial regulation of tryptophan metabolism has become a focal point in this regard, with dual emphasis on the regulation of serotonin synthesis and the control of kynurenine pathway metabolism. Here, we focus in detail on the latter pathway and begin by outlining the structural and functional dynamics of the gut microbiota and the signalling pathways of the brain-gut axis. We summarise preclinical and clinical investigations demonstrating that the gut microbiota influences CNS physiology, anxiety, depression, social behaviour, cognition and visceral pain. Pertinent studies are drawn from neurogastroenterology demonstrating the importance of tryptophan and its metabolites in CNS and gastrointestinal function. We outline how kynurenine pathway metabolism may be regulated by microbial control of neuroendocrine function and components of the immune system. Finally, preclinical evidence demonstrating direct and indirect mechanisms by which the gut microbiota can regulate tryptophan availability for kynurenine pathway metabolism, with downstream effects on CNS function, is reviewed. Targeting the gut microbiota represents a tractable target to modulate kynurenine pathway metabolism. Efforts to develop this approach will markedly increase our understanding of how the gut microbiota shapes brain and behaviour and provide new insights towards successful translation of microbiota-gut-brain axis research from bench to bedside. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.

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Kynurenine pathway metabolism and the microbiota-gut-brain axis

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