Monocyte mobilisation, microbiota & mental illness
Introduction
There is a growing recognition of the role of the gastrointestinal microbiota in regulating brain and behaviour, which has been coined the microbiota-gut-brain axis (Rhee et al., 2009, Collins et al., 2012, Cryan and Dinan, 2012, Cryan et al., 2019). It is crucial to understand the signalling pathways underlying this axis in order to inform future therapeutics in improving CNS functionality in both health and disease. Some pathways have already been extensively described, such as host immunity (Rea et al., 2016, Rieder et al., 2017), the vagus nerve (Bonaz et al., 2018, Fulling et al., 2019), gut microbial metabolite production (Rooks and Garrett, 2016), and enteroendocrine signalling (Plovier and Cani, 2017, van de Wouw et al., 2017, Lach et al., 2018). In tandem, there is a growing appreciation of the role of monocyte trafficking in regulating brain homeostasis and aiding the brain’s response to insult or injury (Ramirez et al., 2017). In this review, we will shed more light on the role of monocyte trafficking as a relay of microbiota signals to the host CNS and its behavioural implications. In addition, we cover how this system can be modified using various microbiota-targeted strategies.
Section snippets
Monocytes: from bone to brain
Monocytes are mononuclear phagocytes that play crucial roles in tissue homeostasis and immunity, where they are especially important in inflammation and pathogen challenges. Monocytes, in particular those characterised by a high LY6C expression (i.e. LY6Chi), originate in the bone marrow, after which they enter the peripheral circulation. These cells subsequently either differentiate into LY6Clow monocytes (Varol et al., 2007, Yona et al., 2013), or differentiate into dendritic cells or
The microbiota in monocyte trafficking
Proof-of-principle studies using mice devoid of any microbiota (i.e. germ-free – GF) have revealed that the microbiota is essential for hematopoiesis, as these mice show decreased levels of monocytes in the bone marrow, spleen, and circulation (Balmer et al., 2014, Khosravi et al., 2014). These deficits are ameliorated upon recolonisation of the microbiota or by the administration of microbial-associated molecular patterns (MAMPs) (Khosravi et al., 2014). Similar to GF mice, depletion of the
Gut microbiota-targeted therapeutics
There are at many ways by which the gut microbiota can be targeted (long-Smith et al., 2019). For instance, by administrating live bacterial strains that confer health benefits (i.e. probiotics) (Hill et al., 2014, Derrien and van Hylckama Vlieg, 2015). Alternatively, administration of host-indigestible dietary fibers, which undergo bacterial fermentation, subsequently stimulates the growth of certain types of bacteria (i.e. prebiotics) (Bindels et al., 2015, Gibson et al., 2017, Stephen et
Acute and chronic stress
Stress can be defined as a complex condition wherein the homeostasis of an organism is disturbed (McEwen et al., 2015). This results in an internal response of the organism governed by the hypothalamic-pituitaryadrenal axis (HPA-axis), where the hypothalamus secretes corticotropin-releasing hormone (CRH), stimulating the pituitary gland to secrete adrenocorticotropic hormone (ACTH), resulting in a secretion of cortisol (corticosterone for rodents) by the adrenal glands (Uschold-Schmidt et al.,
Conclusion
It is crucial that we appreciate the complex role of monocyte trafficking in regulating brain function and its behavioural consequences in order to understand their role in brain health and disease. Deficiencies in monocyte trafficking in absence of sickness or injury results in impaired adult hippocampal neurogenesis and memory retention (Mohle et al., 2016), whereas excessive monocyte trafficking is associated with negative consequences in conditions such as viral encephalitis (Getts et al.,
Competing interests
J.F.C. and T.G.D. received research funding from Dupont Nutrition, Cremo SA, Alkermes Inc., 4D Pharma PLC, Mead Johnson Nutrition and Nutricia Danone.
Funding
The APC Microbiome Institute is a research institute funded by Science Foundation Ireland (SFI) through the Irish Government's National Development Plan (Grant No. SFI/12/RC/2273), and SFI Grant AMBROSIAC (15/JP‐HDHL/3270).
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