Kynurenine pathway metabolism and the microbiota‐gut‐brain axis
By P. Kennedy, J. Cryan, Ted G. Dinan, G. Clarke. Neuropharmacology, 2017
614 citations recorded by the source corpus.
ABSTRACT 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’. HIGHLIGHTSBrain function and behaviour are under substantial microbial control.Kynurenine pathway metabolism is critical in a range of CNS and GI functions.Gut microbiota may regulate kynurenine pathway metabolism via numerous mechanisms.The gut microbiota may be targeted to modulate kynurenine pathway metabolism.Microbial‐modulated kynurenine metabolism may prove beneficial for CNS function.
Subfields: Biological Psychiatry, Molecular Biology, Social Psychology
View Paper: https://www.semanticscholar.org/paper/6e28e2aff34bc199d2e2e0a2b643f7cb4cd871b7
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Citations in the corpus
- Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. (2018, neutral): “Kynurenine pathway Trp metabolism through the KP in the gut is mediated by the rate-limiting enzyme IDO1 and leads to the production of kynurenine (Kyn) and downstream products such as quinolinic acid (QA), niacin, nicotinamide adenine dinucleotide (NAD) and kynurenic acid (Kna) (Cervenka et al., 20”
- Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice. (2017, neutral): “It is unclear whether the current alteration in tryptophan availability reflects increased bacterial utilization of this important precursor or arises as a consequence of bacterial metabolite mediated impact on local host tryptophan metabolism into serotonin (39, 40).”
- Tryptophan Metabolism: A Link Between the Gut Microbiota and Brain. (2019, background): “KYNA can be neuroprotective against QUINinduced excitotoxicity, while it can also induce cognitive impairments when excessively elevated (34).”