The microbiome: A key regulator of stress and neuroinflammation

Abstract

There is a growing emphasis on the relationship between the complexity and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiota) and health/disease, including brain health and disorders of the central nervous system. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the brain, glands, gut, immune cells and gastrointestinal microbiota that communicate in a complex multidirectional manner to maintain homeostasis. Changes in this environment can lead to a broad spectrum of physiological and behavioural effects including hypothalamic-pituitary-adrenal (HPA) axis activation, and altered activity of neurotransmitter systems and immune function. While an appropriate, co-ordinated physiological response, such as an immune or stress response are necessary for survival, a dysfunctional response can be detrimental to the host contributing to the development of a number of CNS disorders. In this review, the involvement of the gastrointestinal microbiota in stress-mediated and immune-mediated modulation of neuroendocrine, immune and neurotransmitter systems and the consequential behaviour is considered. We also focus on the mechanisms by which commensal gut microbiota can regulate neuroinflammation and further aim to exploit our understanding of their role in stress-related disorders as a consequence of neuroinflammatory processes.

Fig. 1

Schematic for microbiota regulation of neuroinflammation and HPA axis activity. Communication within the microbiota-gut-brain axis involves the complex co-ordination of a number of factors and systems. The microbiota can govern events in the periphery and CNS by various means of communication including vagal nerve activation, cytokine production, neuropeptide and neurotransmitter release, SCFA release and microbial by-products, and by utilising the lymphatic and systemic circulation. Once these signals penetrate the blood brain barrier and reach the brain, they can influence the maturation and activation state of the microglia. Once activated, microglia play a key role in immune surveillance, synaptic pruning and clearance of debris. They also facilitate a number of everyday functions in the brain, including the regulation of HPA axis activation state. The release of glucocorticoids (cortisol) as a consequence of HPA axis activation can in turn regulate the activation state of brain microglia, as well as influence cytokine release and trafficking of monocytes from the periphery to the brain. HPA Hypothalamic-Pituitary-Adrenal; BDNF Brain derived neurotrophic factor; LTP Long term potentiation; BBB Blood-brain barrier; GC Glucocorticoids; GR Glucocorticoid receptor; FFAR Free fatty acid receptor; SCFA Short chain fatty acid; NP Neuropeptide; NT Neurotransmitter; DC Dendritic cell; EEC Enteroendocrine cell.