Newtobilogy of Ses (2017) 1-13 Contents lists available at ScienceDirect Neurobiology of Stress ELSEVIER — journal homepage: http://www.journals.elsevier.com/neurobiology-of-stress/ Stress & the gut-brain axis: Regulation by the microbiome Jane A. Foster *, Linda Rinaman ”*", John F. Cryan “* $ beponment of Phir & Behera Newesceces MeMaster Uns, Hotton. nto, nade “APC Microbiome Insitute, Univesity College Cork, Cork Ireland | ‘Depart of Antony ond Neurcence Universy Calg Cok Cork, Weland ARTICLE INFO ABSTRACT aero The importance ofthe gar brain as Tn Yequlating aveselated responses as Tong been appreciated Rcened 3 sce More recently. the microbiota has emerged a5 a key player in the conto ofthis ais, especialy during ‘Received in revised conditions of stress provoked by real or perceived homeostatic challenge. Diet is one of the most tema 200 important non factor of the cobain as. The rote of communication teen the ced 2 Mah ‘merits and brain ae slowly being orale, and nce the vagus neve, hormone sgsaling {he immune system. typtophsn metsbolim, and microbial metabolites sich shor chin fty ai The importance of the eal if get microbiota n shaping late health tcomes aso semering, Rests tom precincts inate that aleratons ofthe ety microbial composton by way of antbioe ‘pone lack of reasteeding. Sth by Caesarean secon infection, sess exposure, and oer env ‘omental ences = coupled wth the intuence a hom genes an ein fongerm maglton ot ses-reated ptysoiogyané behavior The gu mitobiea hasbeen plicated in vaety af sess related conitions ncding anxiety, depresion ad table bowel syndrome altho thi ately based on animal sais or corlative analysis inpatient populations. Additional research in humans is sorely nese to evel the eltive impact and eatlcontibiton of he microbioms fo streserlsted dtrorers In ths reac the concept of payehobinc is being developed and refined #0 encompass ‘ethos of targeting the mirobiora in ode fo pestvey pact mental lth outcomes A the 2078 Neobiongy of Stes Workshop sn Newport Beach, CA gro of experts presented the symposiim “The Micobiome: Development Ses, and Disease” Thi epotsunmariaes and bls pon some of the key concepts in that smposims within the context o we micabita might indence the neo ‘ology of stress £2017 Published by Elsevier Ine. This ian open access ale Under the CC Y-NCND lens (sp realvecomonsorglicensesy-ne-d}0) Contents 1. tnoduction 00 2 The gut microbiome 00 3. Gut microbiota and sres-elaed behaviours 00 4. The microbiome and central ses effects 00 5. Mechanism of communication from gut microbiota to brain 00 51. Neural pathways 00 52. Enterendocine signaling 00 53. Serotonin & tryptophan metabolism 00 54 Immune signaling 90 6. Stress-elated disorders andthe miccobiome—gutbrain axis 00 GL Major depresive disorder (MDD) 00 62. table bowel syndrome * Coresponéing autor, Curent aééress: Department of Psychology. Herida State Uniersty Tallahasee, FL United Sates ‘Pmal addres naman bp se (Raman utp door t02016ymste2017.02.001 2352-2895/0 2017 Published by seve In This an open acess article under the CC BY-NC-ND cense (ip reatvecmensrgeensesby-ned 0) Please cite this article in press as: Foster, JA. etal, Stress & the gut-brain axis: Regulation by the microbiome, Neurobiology of Stess (2017), bttp:/léxdoi.org/101016)iynstr201703.001,2 JA Foster ea 1. Wigh-at diet. stress, and the gut microblome 8. Future directions ‘Acknowledgements References ewe of es (207) Fs 1. Introduction ‘The concept of the gut influencing brain and behaviour, and vice-versa, has perhaps been best appreciated and studied as it felates to the cephalic (preparatory) phase of digestion, visceral pain and malaise, and the ability of emotional stress to disrupt digestive functions. Nonetheless, despite wide integration of the ‘gut-brain” concept into our everyday vernacular (eg, gut feelings, gut-wrenching, gut instinct, gutted, gutsy, i takes guts, butterflies in one’s stomach), neuroscientists have only recently developed adequate tools with which to reveal the bi-directional links be- ‘ween gut physiology and brain function, and to determine how these links operate under normal and stressful conditions. At the 2016 Neurobiology of Stress Workshop in Newport Beach, CA, a ‘group of experts presented the symposium “The Microbiome: Development, Stress, and Disease”, This report summarizes and ‘expands upon some of the key points from this symposium focused on current understanding of how microbiota influence the neurobiology of stress, ‘The complex and multifaceted system of gut-brain communi- ‘ation not only ensures proper maintenance and coordination of _rastrointestinal functions to support behaviour and physiological rocesses, ut also permits feedback from the gut to exert profound ‘effects on mood, motivated behaviour, and higher cognitive func tions. The linkage between gut functions on the one hand and ‘emotional and cognitive processes on the other is afforded through afferent and efferent neural projection pathways, bi-directional neuroendocrine signaling. immune activation and signaling from ntestinal permeability, modulation of enteric sensory-motor reflexes, and entero endocrine signaling (Mayer fetal, 2014a; Sherwin et al, 2016). Gut microbiota have emerged a5 a critical component potentially affecting all of these neuro- immuno-endocrine pathways (Carabott etal, 2015; Bailey, 2014). For example, even short-term exposure to stress can impact the ‘microbiota community profile by altering the relative proportions ‘of the main microbiota phyla (Calley et al, 2014), and experimental alteration of gut microbiota influences stress. responsiveness, anxiety-lke behaviour, and the set point for activation of the neuroendocrine hypothalamic-pituitary-adrenal (HPA) stress axis (Carabotti etal, 2015; Golubeva etal, 2015; De Palma etal, 2015; Moussaoui et al, 1610; Crumeyrolle-Arias et al.. 2014). Disease- felated animal models such as mild and chronic social defeat stress also lead to significant shifts in cecal and fecal microbiota ‘composition: these changes are associated with alterations in ‘microbiota-related metabolites and immune signaling pathways suggesting that these systems may be important in siress-related conditions including depression (Sharwani et al, 2016; Aoki- Yoshida etal, 2016), 2. The gut microbiome Within the past decade it has become clear that the gut microbiota isa key regulator of the gut-brain axis. The gut is home to a diverse array of tilions of microbes, mainly bacteria, but also archaea, yeasts, helminth parasites, viruses, and protozoa (Lankelma et al, 2015: Eckburg et al, 2005; Gact et al, 2014; Scarpellini etal. 2015; Williamson et al, 2016). The bacterial gut ‘microbiome is largely defined by two dominant phylotypes, Bac- teroidetes and Fitmicutes, with Proteobacteria, Actinobacteria, Pusobacteria, and Verrucomicrobia phyla present in relatively low abundance (Iankelma et al, 2015; Qin et al, 2010), Although the ratio of microbial to human cells has been recently revised down- ward (Sender et al, 2016), it is evident that microbial cells outnumber human cells. The total weight of these gut microbes is 1-2 kg, similar to the weight of the human brain (stilling et al 2014), Mierobiota and their host organisms co-evolved and are ‘mutually co-dependent for survival, and mammals have never existed without microbes, except in laboratory situations Gordenstein and Theis, 2015) Inhumans and other mammals, colonization of the infant gut is, thought to largely begin at birth, when delivery through the birth canal exposes the infant to its mother’s vaginal microbiota, thereby initiating a critical maternal influence over the offspring’s lifelong ‘microbial signature (Backiied et a, 2015; Collada et al, 2012+ Donnet-Hughes et al, 2010), Advances in sequencing technoto- gies are revealing that the early developmental microbiota signa- {ure influences almost every aspect of the organism's physiology, throughout its life. The role of microbiota composition as a sus- ceptibility factor for various stressful insults, especially at key nneurodevelopmental windows, is rapidly emerging (Borre et al. 2014), and there is growing evidence that targeted manipulations of the microbiota might confer protection tothe brain to ameliorate the negative effects of stress during vulnerable developmental periods. 3. Gut microbiota and stress-related behaviours Several lines of evidence support the suggestion that gut microbiota influence stress-related behaviours, including those relevant to anxiety and depression. Work using germ-free (GF) rice (Le, delivered surgically and raised in sterile isolators with no ‘microbial exposure) demonstrates a link between microbiota and anxiety-lke behaviour (Neufeld etal, 2011; Diaz Heitz et al, 2011; Clarke et al 2012) In particular, reduced anxiety-like behaviour in GF mice was shown in the light-dark box test and in the elevated plus maze (see (Luicevinski etal. 20%a) for review). On the other hand, GF rats display the opposite phenotype, and are characterized by increased anxiety-ke behaviour (Crumeyrolle-Arias et al, 2014), Interestingly, che transfer of stress-prone BalbjC microbiota to GF Swiss Webster (SW) mice has been shown to increase anxiety-related behaviour compared to normal SW mice, while Uwansfer of SW microbiota to GF BalbjC mice reduced anxiety: related behaviour compared to normal BalbjC mice suggesting 2 itect role for microbiota composition in behaviour (Bercik et al 20112}, Further, monocolonization of GE mice with Lactobacillus plantarum P5128 increased locomotor activity in comparison to control GF mice, a behavioural change that was associated with increased levels of dopamine, serotonin and their metabolites in the striatum (Liu et al, 2016a). Furthermore, antibiotic treatment during adolescence in mice altered microbiota composition and beep fax doi. org/10.1016)jst.201703,001 ‘lease cite this article in press as: Foster, JA, et al, Suess & the gut-brain axis: Regulation by the microbiome, Neurobiology of Stress (2017),1A Faster ej Neuoblogyof tess (201) Pts 3 diversity with concomitant reduction in anxiety-like behaviour (Desbonnet et a, 2015). Interestingly, the reduced anxiety-like behaviour was accompanied by cognitive deficits, reduced levels of hippocampal brain-derived neurotrophic factor (BDNF) mRNA, and reduced levels of oxytocin and vasopressin in the hypothala- ‘mus (Desbonnet et al, 2015), 4, The microbiome and central stress effects Individual differences in life-long stress responsiveness and susceptibility to stress-related disorders have been linked both to genetic and environmental factors, particularly ealy-life exposures that can alter the developmental assembly and function of central neural circuits. Intriguingly, it has become increasingly clear that bacteria are required for normal brain development (Neufeld a. 2011: Diaz Heijtz etal, 2011; Clarke etal, 2013; Bercik et al 2011a: Hsiao et al, 2013; Stiling etal, 2015) as well as brain funtion in adulthood. Indeed, key processes associated with neuroplastcity in the adult brain such as neurogenesis (Ogbonnaya et al, 2015) and ‘microglia activation (Esny et al, 2015) have been shown to be regulated by the microbiota, Findings such as these have contrib- uted to a paradigm shift in neuroscience and psychiatry (Mayer et al, 2014b: Cryan anid Dinan, 2012), such that the early devel- ‘opment and later function of the brain may be modified by tar- geting the microbiome. Evidence for a crucial role for the microbiota in regulating stress-related changes in physiology, behaviour and brain function hhas emerged primarily from animal studies. A very important dis- covery was made in 2004, when GF mice were found to have an exaggerated HPA axis response to stress, which could be reversed by colonization with a specific Bifidebacteria species (Sudo et al. 2004). Results from subsequent studies have continued to sup- port 2 connection between gut microbiota and stress responsive- ness, inchading reports that stress exposure early in life or in adulthood can change the organism's microbiota composition, and that microbial populations can shape an organism's stress responsiveness (Golubeva et al, 2015; De Palma et al, 2015; Bharwani ef al, 2016; O'Mahony et al, 2009; Bailey et al, 2011 Jasarevie et al, 2015). Recently, investigators have used fecal ‘microbiota transplantation approaches to demonstrate that stress- felated microbiota composition play a causal role in behavioural changes, In one example, investigators showed that transplanting the microbiota from stressor-exposed conventional mice to GF mice resulted in exaggerated inflammatory responses to Citrobacter rodentium infection (Willing etal, 2011), A link between disease- felated microbiota and behaviour was also recently demon- strated, where fecal microbiota transplantation from depressed patients to microbiota-depleted rats increased anhedonia and anxiety-like behaviours (Kelly t al. 2016) ‘A key question in the field is whether treatments targeting the ‘microbiota-brain axis may have therapeutic benefits in stress- related disorders. To this end, several studies have shown that di- ets that modify the microbiota, prebiotics, and probiotics can reduced stress-related behaviour and HPA activation, For example, dietary supplementation with the 1-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), in socially isolated mice reduces anxiety and depressive-like behaviours in male but not female mice (Davis et al, 2015). These behavioural effects were associated with ‘male-specific changes in microbiota composition suggesting that these protective effects were mediated by microbiota (Davis eta. 2016). Similarly, long-term supplementation with eicosapentae- nnoic acid (EPA)/DHA mixture normalized the microbiota profil in rats exposed to early life stress and attenuated stress reactivity (Pusceddu et al, 2015). Prebiotics are non-digestible food in- redients that promote growth of commensal bacteria. Mice ‘exposed to a social disruption stressor displayed increased anxiety like behaviour and a reduced number of immature neurons in the hippocampus, whereas stressed mice that received human mille oligosaccharides 2sialyllactose or 6sialyllactose for 2 weeks prior to stress were protected from stress-related changes in behaviour and CNS effects (Tarr et al, 2015). Interestingly, prebiotic admin- {stration of bimuno-galactooligosaccharides (B-GOS) reduced sali- vary cortisol awakening response in healthy people (Schmidt etal 2015). The reversal of stress effects by probiotics has also been demonstrated, For example, administration of Lactobacillus helve- ricus NSB to Sprague Dawley rats improved stress-induced behav- jour deficits and attenuated the stress-induced levels of corticosterone (Liang. et a. 2015) Similarly, administration of L heleveticus RO0S2 and Bifidobacterium longum ROY7S prevented stress-induced changes in neurogenesis, barsier integrity, and stress-reactvity (Ait-Belgnaoui etal, 2012) ‘As mentioned above, the experimental use of GP mice has been instrumental in revealing the impact of microbiota on early brain development (Luczynski et al, 2016a; Gareau, 2014; Sampson and ‘Mazmanian, 2015). A lack of microbes impacts multiple stress- related neurotransmitter systems, across multiple brain regions. Using a genome-wide transcriptomic approach to compare normal control mice to GF mice, Diaz Heijtz and colleagues demonstrated, that the GF condition was accompanied by upregulation of many genes associated with a variety of plasticity and metabolic path- ‘ways including synaptic long-term potentiation, steroid hormone ‘metabolism and cyclic adenosine S-phosphate-mediated signaling (Diaz Heitz etal, 2011), The functional consequences ofthis altered {gene expression is evident in many brain regions. For example. GF mice display increased expression of myelin-associated genes within the prefrontal cortex, accompanied by hypermyelination ‘within the same brain region (Hoban etal, 2016). Similar findings have been reported within the prefrontal cortex of mice treated ‘with antibiotics in order to deplete the microbiome in adulthood (Gacias et al, 2016). Gene expression within the hippocampus also is markedly different in GE mice compared to notmal controls. The hippocam- bus exerts strong control over the HPA stress axis, and GF mice are characterized by markedly increased hippocampal 5-HT concen- trations (Clarke et al, 2013). accompanied by decreased 5-HTyq receptor gene expression in the dentate gyrus in female (but not ale) GF mice (Neufeld et al, 2011). Intriguingly, other CNS alter= ations in GF mice also are sex-dependent; eg. altered expression of BDNF has been documented only in male GF mice (Clarke et al 2013), BDNF is an important plasticity-related protein that pro- ‘motes neuronal growth, development and survival, with Key roles inlearning, memory and mood regulation. BDNF gene expression is lower in the cortex and amygdala in male GF mice compared with, controls (Diaz Heijtz et al, 2011), whereas hippocampal BDNF levels in GF mice have been reported to either increase (Neufeld et al, 2011) o decrease (Diaz Heljte et al, 2011; Clarke et al, 2013; Sudo et al, 2004). Hippocampal neurogenesis also is regu lated by the microbiome, such that GF mice exhibit increased neurogenesis in the dorsal hippocampus (Ogbonnaya et al, 2015}. ‘Adult hippocampal neurogenesis plays a critical role not only in ‘modulating learning and memory, but also in mediating behav ioural responses to stress and antidepressant drugs (O'Leary and Cyan, 2014). Although adult GF mice display modest increases in hippocampal volume, ventral hippocampal pyramidal neurons and dentate granule cells are chatacterized by reduced dendritic branching, with pyramidal neurons displaying fewer stubby and ‘mushroom spines (Luczyisti etal, 2016b). Postweaning microbial colonization of GF mice failed to reverse the changes in adult hip- pocampal neurogenesis, suggesting that there is a critical pre- ‘weaning developmental window during which the microbiota bttp:/iéxdoi.org/101016)iynstr201703.001, Please cite this article in press as: Foster, JA. etal, Stress & the gut-brain axis: Regulation by the microbiome, Neurobiology of Stess (2017),4 JA Foster ea shapes life-long capacity for hippocampal _ neurogenesis (Ogboninaya et al, 2015), Conversely hippocampal neurogenesis is reduced in normal adult mice after they are exposed to an antibiotic regimen to deplete microbiota, an effect that is reversible by ex- ‘excise or administration of a probiotic cocktail (Noble etal, 2016) ‘The microbiome also affects the structure and function of the amygdala, another key stress-related brain region. The amygdala is ‘critical for emotional learning and social behaviour, and is critical, for the gating of behavioural and physiological responses to stressful stimull, especially those that trigger anxiety andjor fear (Galling et al. 2015; LeDoux, 2007), Altered amygdalar processes ate associated with a variely of neuropsychiatric disorders, ranging from autism spectrum (Schumann and Amaral, 2006; Mosconi ‘etal. 2008) to anxiety disorders (LeDoux. 2007; Janak and Tye, 2015), GF mice (on a SW background) display increased amygdala volume, accompanied by dendritic hypertrophy within the baso- lateral amygdala (BLA). Accordingly, BLA pyramidal neurons are characterized by increased numbers of thin, stubby and mushroom spines in GF mice compared to normal controls (Luczynski etal. 201Gb). RNA sequencing studies have revealed significant differ- ‘ences in differential gene expression, exon usage, and RNA-editing, ‘within the amygdala. The amygdala of GF mice displays increased ‘expression of immediate early response genes such as Fos, Fsb, Egr2 and Nrdal, along with increased signaling of the transcription, factor CREB (stilling et al, 2015), Differential amygdalar expression and recoding of genes involved in neuronal plasticity, metabolism, neurotransmission, and morphology also were identified in GF mice. A significant downregulation of immune system-related genes was noted in GF mice (Stiling etal, 2015), consistent with 2 reportedly underdeveloped immune and brain microglia systems (Esny e€ al, 2075), Indeed, the immune system may provide a ‘crucial link for microbiota effects on brain physiology and behav- jour, pethaps via the recently discovered lymphatic branches ‘within the central nervous system (Loven et al, 2015) ‘Although GF mice have been instrumental in advancing all as- pects of microbiome research, including. microbiome-to-brain signaling (Luczynski etal, 2016a; Grover and Kashyap, 2014), the ‘expetimental GF mice model has many drawbacks that limie its utility for clinical translation (Nguyen et al, 2015; Al-Asmalkh and Zadjali, 2015: Arrieta and Finlay, 2014). Nevertheless, GF mice provide a platform on which to explore the role of bacteria on early host development and function (Nguyen et al, 2015; Al-Asmaklt and Zadjali, 2015; Faith etal, 2010; Arrieta etal, 2014), Antibiotic treatment is an alternative approach that can bypass the perinatal developmental period. Antiobiotic treatment in adult mice alters BONE protein levels in both the amygdala and hippocampus (8ercik ‘etal, 2011a). When administered uring postnatal development. antibiotics promote visceral hypersensitivity in adult male rats ‘without affecting anxiety, cognitive, immune or stress-related re- sponses (O'Mahony et 2), 2014). In this model, visceral hypersen- sitivity was paralleled by specific changes in the spinal expression fof pain-associated genes (transient receptor potential cation ‘channel subfamily V member 1, the 4-2A adrenergic receptor and ‘cholecystokinin B receptor) (O'Mahony et al, 2014). Conversely, antibiotic depletion of microbiota later in life (te, in adolescent mice after weaning) led to reduced anxiety coupled with cognitive deficits measured in adulthood (Desbonnet et al. 2015), Altered tryptophan metabolism also was observed in the same animals, along with significantly reduced BDNF, oxytocin and vasopressin ‘gene expression (Diesbonnet et al, 2015). More recently, antibiotic depletion in adult rats reportedly nas been reported to have a limited impact on stress, anxiety or HPA axis function, but increases depressive-ike behaviours, reduces visceral pain responses, and impairs cognition (Vioban et al, 2015). Together these results highlight the importance of microbiome integrity at key ewe of es (207) Fs {developmental windows. 5. Mechanisms of communication from gut microbiota to brain The precise role played by the microbiota in gut-brain-gut, signaling pathways remains (o be elucidated. Hindering out ef- forts is the limited current state of knowledge regarding the iden- tity and function of the gut's vast and diverse microbial composition, However, advances in the field of metagenomics promise to address this concern (Clarke et al, 2012; Fraher etal 2012). For example, a recent paper (Matsumoto et al, 2013) examining the role of gut microbiota in cerebral metabolism re- ports that GF mice have an altered metabolic profile compared to their conventionally colonised counterparts, with 10 of these me- tabolites thought to be specifically involved in brain function. However, the key question remains: through what mechanisms do the gut microbiota influence the CNS, and vice-versa? ‘A complex communication network exists between the gut and the CNS, which includes the enteric nervous system (ENS), sym- pathetic and parasympathetic branches of the autonomic nervous system (ANS), neuroendocrine signaling pathways, and neuro- immune systems (Greniiam et al. 2011), Afferent spinal and vagal sensory neurons carry visceral feedback from the gut to the thoracic and upper lumbar spinal cord and to the nucleus of the solitary tract within the caudal brainstem, engaging polysynaptic inputs to higher brain regions, including the hypothalamus and limbic forebrain. Bi-directional contro! is provided by descending pre- autonomic neural projections from the cingulate and insular cortices, amygdala, bed nucleus of the stria terminalis, and hypo- thalamus, all of which are positioned to alter vagal and spinal autonomic outflow to the gut (0’Mahony et al, 2011). Collectively, the mierobiotabrain—gut axis is thought to communicate not only via these neural routes, but also via humoral signaling molecules and hormonal components. Together, ths intricate network exerts effects which alter both Gl and brain funetion (Mayer etal, 2015, Rhee et al, 2009). 5.1. Neural pathways ‘The gut is innervated by the ENS, a complex peripheral neural circuit embedded within the gut wall comprising sensory neurons, ‘motor neurons, and interneurons. While the ENS is capable of independently regulating basic gastrointestinal (Gl) functions (i. ‘motility, mucous secretion, and blood flow), central control af gut functions is provided by vagal and, toa lesser extent, spinal motor inputs that serve to coordinate gut functions with the general ho- ‘meostatic state ofthe organism (Mertz, 2003). This central control over the ENS is important for adaptive gut responses during stressful events that signal homeostatic threat tothe organism, The ‘vagus nerve has been proposed to serve as the most important neural pathway for bidirectional communication between gut mi- ‘robes and the brain Forsythe etal, 2012, 2014: Gochiler, 2006), For example, an intact vagal nerve appears necessary fr several effects induced by two separate probiotic strains in rodents (Perer-Burgos et al, 2014). Specifically, chronic treatment with Lactobacilus rhammosus (JB-1) led to region-dependent alterations in central GABA receptor expression, accompanied by reduced anxiety- and depression-like behaviour and attenuation of ‘stress-induced corticosterone response; these effects required an intact vagus nerve (Bravo etal, 2011). Similarly, in a colitis model, the anxiolytic effect of Bifidobacterium longum was absent in vagotomised mice (ercik et al, 2011b). In contrast to effects mediated by probiotics (Le, microbial supplementation), changes inthe microbial ecology as a consequence of antibiotic treatment in mice did not depend on hetp fax doi. org/10.1016)jmst.201703,001 ‘lease cite this article in press as: Foster, JA, et al, Suess & the gut-brain axis: Regulation by the microbiome, Neurobiology of Stress (2017)1A Faster ej Neuoblogyof tess (201) Pts 5 vagal nerve integrity (Bercik et al, 20112). Thus, additional signaling pathways are likely involved in microbiota—brain—gut communication (Barrett et al, 2012). In a subset of ENS neurons (ie, sensory after-hyperpolarization neurons), the probiotic Lactobacillus reuteri was found to increase excitability and the number of action potentials per depolarizing pulse, to decrease calcium-dependent potassium channel opening, and to decrease the slow after-hyperpolarization, Thus, L reuteri appears to target an jon channel in enteric sensory neurons which ‘may mediate its effects on gut motility and pain perception (Ksinze et al, 2009). More recently, the electrophysiological properties of myenteric neurons were found to be altered in GF mice, in which myenteric sensory neurons displayed rediced excitability that was restored after colonization with normal gut microbiota (McVey Neufeld et al, 2013), 52. Enteroendocrine signaling {A functional microbiotaneurohumoral relationship is estab- lished during early microbial colonization ofthe gut. A multitude of biologically active peptides are present at numerous locations hroughout the braingut axis, and have a broad artay of functions that include not only gut motility and secretion, but aso regulation cof emotional afect and stress resilience, Bacterial by-products that come into contact with the gut epithelium are known to stimulate enteraendocrine cells (EFCS) to produce several neuropeptides such as peptide YY, neuropeptide Y (NPY), cholecystokinin, slucagon-like peptide-1 and -2, and substance P (Cani etal, 2013, Cani and Knauf, 2015). After their secretion by ECs, these neuro- peptides presumably diffuse throughout the lamina propria, which 's occupied by 2 variety of immune cells, en route to the blood- stream andjor local receptor-mediated effects on intrinsic ENS neurons or extrinsic neural innervation (e.., vagal sensory affer- tents) (Holzer an Far), 2014), However it still is unknown whether any of these EEC peptides are necessary or sufficient for bidirec- tional communication between the microbiota and CNS. Adiferent type of potential signaling pathway was revealed more recently (Gohorque2 et al, 2015), demonstrating direct paracrine commu- hication between EECs and neurons innervating the small intestine and colon (Bohorquez et al. 2015). This newly-identified neuro- epithelial circuit may act as a sensory channel for signaling from luminal gut microbiota to the CNS via the ENS, and vice versa, The physical innervation of sensory BECS suggests the presence of an accurate temporal transfer of sensory signals originating in the gut Jomen with a real-time modulatory feedback to EECS 53, Serotonin & tryptophan metabolism Serotonin [S-hydroxytryptamine (5-HT)] is a biogenic amine that functions as a neurotransmitter within the brain and. also within the ENS. Indeed, approximately 95% of S-HT within the body is produced by gut mucosal enterochromaffin cells and ENS neu- rons. Peripherally, 5-HT is involved in the regulation of Gl secretion, ‘motility (smooth muscle contraction and relaxation), and pain perception (Costedio etal, 2007: Micvean et al, 2007), whereas in the brain 5-HT signaling pathways are implicated in regulating ‘mood and cognition (Wrase etal, 2006). Thus, dysfunctional 5-HT signaling may underlie pathological symptoms related to both Gl and mood disorders. and may also contribute to the high co- ‘morbidity of these disorders (Folks, 2004). Supporting this idea, drugs that modulate serotonergic neurotransmission, such as ti cyclic antidepressants and specific serotonin reuptake inhibitors, also have efficacy for treating irritable bowel syndrome (185) and other GI disorders (Creed, 2008; Gershon and Tack, 2007). I also recently has been shown that the microbiota can regulate 5-HT synthesis in the gut. Specifically, indigenous spore-forming bacte- ria from the mouse and human microbiota have been shown to promote 5-HT biosynthesis from colonic enterochromaffin cells (Yano et al. 2015) Serotonin synthesis is crucially dependent on the availability of ‘uyptophan, an essential amino acid which must be supplied by the diet. Clinical depression is associated with reduced plasma tryp- tophan concentrations and enhanced enzyme activity (Myint etal 2007) Interestingly, the eatly life absence of microbiota in GF mice leads to increased plasma tryptophan concentrations and increased hippocampal levels of 5-1T in adulthood (Clarke et al, 2013) These effects are normalized following the introduction of bacteria to GF ‘mice post-weaning, with the probiotic B infantis reported to affect tuyptophan metabolism (Desboninet et al 2008). Therefore, gut ‘microbiota may play a crucial role in tryptophan availability and ‘metabolism to consequently impact central 5-HT concentrations. Although the specific mechanisms underlying this putative ‘modulatory interaction are unknown, they are potentially medi- ated indirectly through an immune-telated mechanism linked to ‘microbial colonization (F1 Aidy et al, 2012), 54, Immune signaling ‘The immune system plays an important intermediary role in the dynamic equilibrium that exists between the brain and the gut (Wengmarl, 2013). The HPA axis, ANS and ENS all directly interact with the immune system (Bateman etal, 1989; Genton and Kudsk, 2003: Hori et al, 1995; Leonard, 2006; Nance and Sanders, 2007), and the gut itself is an important immune organ that provides a vital defensive barrier between externally-derived pathogens and the internal biological environment. Gut-associated lymphoid tis sues form the largest immune organ of the human body, comprising more than 70% ofthe total immune system {Vight etal 22008). A direct link between infection and brain function has long. bbeen known, mainly through the observation that syphilis and lyme disease often promote psychiatric symptoms (Biesiada etal 2012), Research using animal models has clearly demonstrated that infectious microorganisms affect behavioural measures through activation of the immune signaling pathways from body to the brain, For example, the pathogenic bacteria Campylobacter jejuni, ‘when administered to mice at subclinical des, results in anxiety- like behaviour (lye etal, 1998). Peripheral administration of pro- inflammatory cytokines in rodents induces a variety of depressive- like behaviours, including sleep disturbances, reduced appetite, and suppression of exploratory behaviour, collectively referred t0 as sickness behaviours (Bilbo and Schwarz, 2012), Although gut ‘microbes are known fo contribute tothe maturation and fortiica- tion of the immune response, the molecular basis of these contri Dbutions is not yet clear, The immunoregulatory effects of probiotic ‘microorganisms have been proposed to occur through the gener ation of T regulatory cell populations and the synthesis and secre- tion of the anti-inflammatory cytokine, L-10 (Dinan et al, 2013). In support of this, oral consumption of Bifidobacterium infantis 35624 in bumans is associated with enhanced IL-10 expression in pe- ripheral blood (bo an Schwarz, 2012}, Furthermore, feeding of a ‘commensal bacteria to GF mice promotes Treg production and IL-10 synthesis (Macpherson an¢é Uhr, 2002). Therefore, the balance of {ul microbes may closely regulate host inflammatory responses. Disturbances to this microbial balance, particularly in early life (O'Mahony etal, 2008), may promote a chronic inflammatory state that can lead to maladaptive changes in mood and behaviour, including increased responsiveness to stress and increased inci- dence of stress-related disorders. bttp:/iéxdoi.org/101016)iynstr201703.001, Please cite this article in press a: Foster, JA. etal, Stress & the gut-brain axis: Regulation by the microbiome, Neurobiology of Stess (2017),‘ JA Foster ea 6, Stress-related disorders and the microbiome—gut—brain 6.1. Major depressive disorder (MDD) One of the principal mechanisms proposed to underlie a gut- brain link in stress-related disorders is Via distupted gut bartier function commonly known as the “leaky gut" phenomenon (WVaes ‘etal, 2009), which is proposed to contribute to MDD. The pro- posed mechanism of action is that the epithelial barrier of the Gl ‘tract becomes compromised as a result of psychological or organic stress, eading to increased intestinal permeability and subsequent translocation of gram-negative bacteria across the mucosal lining, to access immune cells and the ENS (Gareau et al, 2008), Bacterial, translocation leads to activation of an immune response charac- terized by increased production of inflammatory mediators such as 16 and IFNy. In mice, pre-treatment with the probiotic LL Jarciminis attenuates the ability of acute restraint stress to in- ‘crease intestinal permeability and HPA axis responsivity (Ait Belgnaoui et al, 2012). In further support of the “leaky gut” hy- pothesis, serum concentrations of IgM and IgA against LPS of ‘enterobacteria is significantly higher in MDD patients compared to healthy controls (Mises and Lewis, 2008), This wold suggest that bacterial translocation from the gut is increased in MDD, and the resulting inflammatory response may contribute to the mood dis- order. Currently, however, clinical evidence linking MDD with al- terations in the gut microbiota is relatively sparse. Naseribafrouei and colleagues failed to identify any diflerences in terms of mi ‘robial diversity within faecal samples abtained from MDD patients and conttols, although the levels of Bacteroidetes were lower in MDD patients (Naseribatrouei ef al, 2014), Conversely, fang and colleagues reported increased diversity (using the Shannon index) in the composition of faecal sample microbiota in MDD patients ‘compared to healthy controls, inching increased diversity in the Bacteroidetes and Proteobacteria (which include the LPS- ‘expressing Enterobacteriaceae) phyla, countered by a concomi- tant redaction in the diversity of Firmicutes (iang et al, 2015) The basis for conflicting results between these two studies is unclea, but may stem from the different control groups that were used (ie. ‘outpatients from a neurological unit versus healthy control sub- jects). More recently, a decteased gut microbial richness and di- versity was observed in depressed patients (Kelly ¢ al, 1016), Animal models have improved our understanding of how the ‘gut microbiota may influence stress-related disorders, including ‘depressive-ike behaviours, Maternal separation is frequently used as a model of early life stress that provokes an adult depressive and anxiety-like phenotype, along with alterations in monoamine turnover, immune function and HPA axis activation (O'Mahony et al, 2008; O'Mahony et al, 2011; Desbonnet et al, 2010) Early ‘work from Bailey and Coe demonstrated that maternal separation decreased faecal Lactobacillus in rhesus monkeys 3 days post separation (Bailey and Coe, 1998) In rodents, eat life maternal Separation distupts the offspring’s microbiota and promotes colonic hypersensitivity (O'Mahony et al, 2009; O'Mahony et al 2011). More recent work by De Palma and colleagues has elabo- rated upon the role of the gut bacterial commensals in the devel- ‘opment of behavioural despair using the maternal separation model (De Palma et al, 2015). In their study, a developmental history of maternal separation was associated with increased circulating corticosterone in adult GF mice, but not dep: anxiety-lke behaviours. Thus, the presence of gut microbiota may be unnecessary for the ability of early life maternal separation to alter stress-related HPA axis activity, but may be necessary to alter ‘the development of anxiety- and depressive-like behaviours. Other animal models of chronic stress/depression have been, ewe of es (207) Fs shown to induce alterations in the microbiota. In rodents, olfactory bulbectomy produces an array of physiological and behavioural symptoms with features similar to MDD, including altered neuro- endocrine and neuroimmune responses. The model also has strong predictive validity, as the depressive-ike behaviours are normal- ized only after long-term treatment with antidepressant drugs (Hation et al, 1999), Interestingly, Park and colleagues demon- strated that bulbectomy affects gut transit and the composition of the microbiota by redistributing the relative abundances of bacte- ‘ial phyla (Park etal, 2013).While these findings ae intriguing, itis difficult to extrapolate how an altered composition of the gut ‘microbiota in bulbectomized animals might relate to clinical depression, or even to other animal models of depression (Dinan and Cyan, 2013), For example, social defeat stress profoundly al- ters the operational taxonomic units of the gut microbiota, asso- ciated with deficits in sociability. A reduction in diversity was associated with decreases in the abundance of Clostridium species, as well as decreases in fatty acid production and biosynthesis pathways leading to dopamine and 5-IT production (Sharwani 1 al, 2016). This decrease in Clostridium abundance following so- cial defeat stress is in contrast to previous work from Bailey and colleagues, who demonstrated an increase in the relative abun- dance of Clostridium species following social disruption stress Gailey et al, 2011), Despite their considerable differences in experimental approach, these animal studies collectively highlight an association between altered gut microbiota and depressive-like behaviour, While clinical studies have not yet assessed whether probiotics or prebiotics are successful inthe treatment of MDD, several groups have documented the beneficial effects af probiotis and prebiotics in healthy individuals (see Table 1). Indeed, the idea that Lactoba- villus strains may improve quality of life and mental health is not new. Dr George Porter Philips first reported in 1910 that a gelatin- whey formula with live lactic acid bacteria improved depressive symptoms in adults with melancholia (Philips. 1910). More recently, 3-week supplementation with the prebiotic B-GOS was found to decrease the cortisol awakening response and to increase attentional vigilance towards positive stimuli (Scimidt et al, 2015). ‘This finding 1s consistent with those of a functional magnetic resonance imaging (ARI) study. which demonstrated that long- term administration of a probiotic mixture of various Bifdobacte- rium and Lactobacillus species resulted in reduced neutral activity in a widely distributed brain network in response to 2 task probing attention towards negative stimuli (Dilisch etal, 2013). A recent study by Steenbergen and colleagues further demonstrated the beneficial effects of a Lactobacillus and Bifidobacterium mixed probiotic on mood in healthy individuals (Steenbergen etal, 2015). Moreover, clinical data from healthy participants suggest that probiotis are also effective in alleviating behavioural symptoms of Anxiety (Messaoici et al, 2011a). While the reported effects of prebiotics and probiotics to improve mood in healthy individuals lends support to their use in treating depression and anxiety, carefully controlled clinical trials will be necessary to fully deter- ‘mine their efficacy in treating depression and anxiety. 62. Iritable bowel syndrome (185) Stress, including early life stress, isa key risk factor for TBS, the ‘most common functional gastrointestinal disorder (Moloney e* a. 2016). IBS is considered to reflect pathologically altered gut-brain axis homeostasis, This disorder is associated with abdominal Visceral pain and altered bowel habits, and is strongly comorbid with anxiety and depression. Various animal models of visceral hypersensitivity have been exploited to determine the involvernent of gut microbiota on viseeral pain pathways (Larauche etal, 2012, hetpl fax doi. org/10.1016)jst.2017.03,001 ‘lease cite this article in press as: Foster, JA, et al, Suess & the gut-brain axis: Regulation by the microbiome, Neurobiology of Stress (2017)1A Faster ej Neuoblogyof tess (201) Pts ated with targeting thee mirbiaa (media rom reference sherwin st 2018) yon ouleores elven Redlced psychological dstess as measued by jdebecterian gun, -Multepectesprebiacie formulstio:Lotabacus ane _rsdoacreru species Predinil evidence Preble FOS snd COs Reduced cogntive processing of sad med decreased aggresive felng nd urination Anneepressant and anolyte effets in adult mice Reversed the behavioural eect of cron payehosocal sess in mice Prebiati- 605 « poidenioe itsaceriu nets Aavilye elle ip tepdowa nhbiay preference in ELS mice iidsbacesu longum tobi plantar PS128 Lactobacis rhamnosus Rede smelly time in the forced sia test Decreased stessanduced ety ike behaviour Lactobacits fermentum NS9—_ Reduced mpicilinsinduced awity behaviour ute aie elce immobility time in Finders sense line rs exposed toa fered swim est Aetoced tis awaling repmnse (Schmit a Increased numbers of latobacilus and Bifdabacterium in aeeal (220, 2009) Ne (Benton et. Reduced 244 UFC levels iotesaouet Na (steenergen eeal2013) Increased BDNF, NRYan4 NRZA RNA. and protein expression in the deeae gyrus and frontal cortex Reduced acute and chronic seseindoced corticosterone rlese. Notice specie rene expression inte hippecampus and hypothalamis Reduced chon stesendeed elevtons in pro- (Savignac ea eval, 2017) Garr eta (rempson eralzote) Felang concanavalin A smalaton tal 2010) Ne elect upon eculating cortcotarone (Sivignae ea Annoy elect mediated via the vagus neve Gere Decreased basal and seseinduced ccultingconicosterone (eta levels attevatedcvelating Ti abt eels while 20350) Ineeasng I-10 levels sn 218 mice Decreased stress-induced exulatngcorcosterone secretion and (3:20 aleced ental GABA receptor subunit expression 20 ‘atemuated chronic stresselated acvaven of denéitic els (sharvan ea we increasing I-10 + regulatory Tees 201 Decreased ampeilinsnduced corucesterone secretion and (an a increase hippocampal mineraloorcid receptor and NMDA 20: receptor levels Increased HDNE expression wit the pretontal cortex (weietal. 2014) ‘Moloney et al, 2015), Assessing visceral sensitivity most often oc- curs with the use of a balloon inflated to specific pressures using a barostat (O'Mahony et al, 2012; Ness and Gebhart, 1988). Many of the preclinical models of increased visceral pain are induced by applying a psychological or physical stressor that relate to factors known to predispose to IBS, a clinical disorder characterized by Visceral hypersensitivity to pain (Mayer et al. 2001)-Eatly life stress ‘or chronic stress later in life ae thought to potentiate visceral pain responses and associated co-morbidities (Moloney et al, 2016), Antibiotics administered early in life have been shown to induce Tong-lasting effects on visceral pain responses, coupled with alter ations in pain signaling pathways (O'Mahony et al, 2014). Results from animal studies of antibioti-induced dysbiosis demonstrate that microbiota influence the wiring of pain pathvvays early in development, and that visceral hypersensitivity can persist into adulthood despite later microbial normalization (O'Mahony et al, 2014), Disturbance of the gut microbiota in adult mice also induces local changes in immune responses and enhanced visceral pain signaling (Verdu et al, 2006), Studies using GF mice before and alter bacterial colonization indicate that commensal intestinal microbiota are necessary for the normal excitability of gut sensory neurons (McVey Newel et al, 2013). Furthermore, live luminal Lactobacillus reuteri (DSM 17938) reduced jejunal spinal nerve firing evoked by distension or capsaicin (Pevez-Buigos etal, 2015}. It has also recently been shown that IBS-like abnormal gut fermentation and visceral hypersensitivity can be induced in rats after transplantation of fecal microbiota fom constipation predominant IBS patients (Crouzet et al, 2013) ‘The gut microbiota has emerged as an important factor that potentially contributes to the pathophysiology of IBS (De Palma ft al, 2014; Hyland et al, 2014), despite conflicting evidence regarding the organisation and function of the gut microbiota in both adult and paediatric patients. In this regard, prolonged exposure of mice (oa high ft diet (HFD) induces low-grade chronic intestinal inflammation, changes the microbiota composition, and increases bacterial translocation across the intestinal mucosal barrier (Sun etal, 2016: Gullane etal, 2016). Further, diets high in saturated fat are a risk factor for the development of human in- flammatory bowel diseases, including IBS, Exposure to stress im- pacts colonic motor activity, which can alter gut microbiota profiles, including lower numbers of potentially beneficial Lactobacillus bttp:/éxdoi.org/101016)iynstr201703.001, Please cite this article in press as: Foster, JA. etal, Stress & the gut-brain axis: Regulation by the microbiome, Neurobiology of Stess (2017),‘ JA Foster ea (Lutgendoutf et al, 2008), Thus, stress may interact with diet to ‘contribute to IBS, Several studies comparing normal controls to IBS patients have reported decreased proportions of the genera Lacto- bacillus and Bifdebacterium with increased ratios of Firmicutes to Bacteroidetes at the phylum level (Nagel et a. 2016; Raiilc~ Stojanovic et al, 2011) (for review see (Rajlic-Stojanovic et al. 2015), One study indicates that subtypes of IBS patients cluster ‘with regard to changes in diversity and Firmicutes to Bacteroidetes ratios compared to healthy controls (jeTexy t al, 2012). This study is particularly interesting, as it highlights evidence that subtypes of [BS patients have a relatively “normal” microbiota phenotype while ‘others display either decreased or increased diversity. Those with, the “normal” microbiota were more likely to display comorbid depression, which also was associated with deceased intestinal transit time. This subtype clustering may also be linked to difer- ‘ential responses to microbiota manipulation. For example, one study reported that individuals suffering from anxiety and depression showed improvement of these symptoms after con- sumption of Lactobacius and Bifdobacteria, whereas other studies reported 2 lack of improvement after similar probiotic treatment (Mayer et al, 20149; Benton et al, 2007), In a recent systematic Teview of specified probiotics in the management of IBS and other lower gastrointestinal disorders, an overall beneficial effect of probiotics was evident in terms of reduced abdominal pai, Dloating, andjor distension in a subset of patients (unit etal 2013), However, results from clinical trials testing probiotis in 1B remain difficult to compare, due to widespread differences in study design, probiotic dose, and probiotic strain (Clarke et al. 2012), Interestingly there has been some success with the gastro- intestinal selective antibiotic rifaxamin in treating IBS (Pimentel ‘etal, 2077) Future studies should also focus on the relationship between rifaxamin-induced changes in microbiota and stress responses, 7. High-fat diet, stress, and the gut microbiome ‘As reviewed in previous sections of this article, the gut-brain ‘axis exerts a substantial physiological impact on mood, behaviout, and stress responsiveness, Acute and chronic exposure to stress can alter both the quality and quantity of calories consumed, and siess-induced alterations in food intake and energy balance can interact with emotional state (pel et al, 2001). In particular, ingestion of foods rich in fat has been reported to modulate ‘emotional states in bummans and animal models (Wlvicl-Lai eta 2015), Using the diet-induced obesity (DIO) animal_ model, Sharma and Fulton demonstrated that adult C57BI6 mice ‘consuming a diet containing 58% of calories as trans-fat for 12 ‘weeks develop depressive-like behaviours, including increased immobility inthe forced swim task and reduced time spent in open areas of the elevated-plus maze and open field tests (Sharma snd Fulton, 2013), These behavioural indices of despair and anxiety Were accompanied by elevated basal HPA activity and increased corticosterone secretion in response to stress (Wi etal. 2013), ‘Arole for gut microbiota in the long-known link between diet and emotion has emerged over the past few years, including evi- dence that high-fat diet feeding promotes a “leaky gut” (ie. increased intestinal permeability (Cani ct al. 2008; Hildebrand: ‘et al, 2009; Kim et al, 2012), similar to the effect of chronic stress alone (Gareau et al, 2008; Maes and Leunis, 2008: Ait- Belgnzoui et al, 2014), and the combination of high-fat diet and stress exposure may promote even greater bacterial translocation. In mice, chronic stress combined with a diet high in fat and sugar has been reported to exacerbate changes in intestinal tight junction proteins that were associated with altered behaviours and altered inflammatory markers within the hippocampus, with the ewe of es (207) Fs hippocampal and behavioural effects shown to be diet-dependent (We Sousa Rodrigues et al, 2017), A direct link between high-fat Giet, gut microbiota, and behaviour was demonstrated in a recent study in which microbiota from high-fat fed donor mice were transferred to chow-fed recipients whose awn microbiota had been depleted by antibiotic treatment (Bruce-Keller et al, 2015). Intriguingly transfer of the high-fat-related donor microbiota led to increased intestinal permeability and inflammatory markers in the chow-fed recipient mice, accompanied by anxiety-like behaviours (Bruce-Keller etal, 2015), These results are consistent with a large literature supporting the view that increased circulating cytokines subsequent fo bacterial translocation can sensitize the HPA axis to stress-induced activation, and also can increase anxiety- and epressive-like behaviours (Keightley et al, 2015, Smythies and Smythies, 2014; Luna and Foster, 2015; Maes’ et al, 2013), Conversely, probiotic treatment in mice was found to be sulficient fo prevent the ability of chronic stress to increase intestinal permeability, and also was sufficient to reduce stress-induced sympathetic outflow and HPA axis activation (Ait-Belgnaaui etl 2014}, Interestingly, however, high-fat diet exposure does not al- ways exacerbate the deleterious effects of stress (Ulrichi-Lai et al 2015), Indeed, one study using mice found that high fat diet ameliorated the ability of chronic social stress to increase arxiety- and depressive-like behaviours; in other words, high fat dies had a selective "protective effect” (Finger et al, 2011). These results emphasize the complex influence of dietary factors on stress- related outcomes, and highlight the need for additional research to unravel complex interactions and causal relationships among diet, stess exposure, and the microbial gut-brain axis. 8. Future directions The concept of psychobiotics, bacteria with positive effects on, ‘mental health, was coined in 2013 (Dinan et al, 2013) and has recently been expanded to include other microbiota-targeted in- terventions that can positively modify mental health including in healthy volunteers (Sarkar et al, 2015), Animal studies have fed the way in showing that specific strains of Biidobacteria, Lactobacilus tr Bacteroides can have positive effects on brain and behaviour (Gsiao etal, 2013; Bravo etal, 2011: Bercik et al, 2011b; Savignac et al, 2014; Savighac et al, 2015), including evidence that certain bacteria can enhance cognitive processes and affect emotional learning (Liang et al. 2015; Gareau, 2014; Bravo et al, 2011; Savignac et al, 2015; Distruti et al, 2014), However, results from these studies are only slowly being translated to humans, primarily through research using healthy volunteers (Filisch et al, 2013, Steenbergen et al, 2015; Messaoudi et al, 2011a, 2011b: Kato- Kataoka et al, 2016). Indeed, recent studies have highlighted the difficulties of translating such responses even within the same laboratory, Bifidobacterium longum 1714 is a bacterium with posi- tive anti-stress and pro-cognitive effects in an anxious mouse strain (Savignac etal, 2014, 2015) Ingestion of this potential psychobiotic by healthy male volunteers was able to attenuate the increases in cortisol output and subjective anxiety in response to the socially evaltated cold pressor test, Furthermore, daily reported stress was reduced by psychobiatic consumption. Finally subtle improve- ‘ments in hippocampus-dependent visuospatial memory perfor- mance, aswell as enhanced frontal midline electroencephalographic mobility were observed following the consumption of Biidebacteria (Allen et al. 2015). On the other hhand, while Lactobacilus rttamnosus (JB-1) has one of the strongest preclinical profiles of any potential psychobiotic(S1avo et al, 2011), it had no discernible effect wien tested in a similar battery of h- ‘man stress and neuropsychology tests as the Bifidobacterium lon: ‘gum (Kelly etal, 1015) hetp fa doi.org/10.1016)jst.201703,001 ‘lease cite this article in press as: Foster, JA, et al, Suess & the gut-brain axis: Regulation by the microbiome, Neurobiology of Stress (2017)aT aS 1A Faster el Neurobiology of tess (201) Pts ° Fig 1. Key communication patos of he microbiota gut—brain ais There ae numerous mechanisms trough which the gut mrobita can signal tothe brain. These inde activation ofthe vars nerve proeecson of microbial atizens that recut amine Bel sponses, rodtos of eb metabees ve sharchain ay acs [SPAS ab fneroendocine signaling tome epithe cel ees that reease CCK. an el that reas LP-.PYY an the pees Tvaeh these roe of oman the trerobiotaqubrain ai eontels central psig processes, suchas neutransmssion. neropeess, newreislanmation and neuroendocrine signaling that eal Impliated in ssese-elated responses Dyteulton athe ut mibios subsequent leet aeration nal tes entl processes and patel Orbe te TeS- rete rarer [SAT serotonin CCX cholecystokinin, GABA y-aminobutrie ai, CL? agente ppt. I. iveeakin YY ppt VY, TNE tumour neces ator Over the next few years it is hoped that the mechanisms un- derpinning the beneficial effects of specific bacterial strains will be elucidated. Improved understanding of the developmental impact of microbiota perturbations on behaviours relevant to stress and cognitive-related disorders is sorely needed (Desbonnet et al, 2014; Foster and MeVey Neufeld. 2013), Finally. a greater invest- ‘ment in large-scale clinical trials is needed to determine whether psychobiotic-based interventions have elficacy in stress-related disorders. Moreover, the relationship between diet and the _mierobiota-gut-brain axis is ripe for exploitation to develop ther- apeutic strategies for treating stress-related disorders (See Fg. 1) ‘Acknowledgements The authors would like to thank Dr. Kieran Rea for Editorial, assistance and Dr. Kiran Sandhu for drawing Fi. 1. Support pro- vided by Ontario Brain Institute and NSERC - RGPIN-312435-12 GAP), and by the National Institutes of Health grant numbers MHOS9911 and DK100685 (LR), JFC is supported by Science Foundation Ireland (SFI) [Grant Numbers 07/CE)B1368 and 12/RC/ 2273); the Department of Agriculture, Food and the Marine; JPl ERA-HDHL Transnational Call "Biomarkers for Nutrition and Health” Grant ~ HEALTHMARK: JPI HDHL “Nutrition & Cognitive Function” Grant - AMBROSIA, JFC also receives research funding from 4D-Pharma, Mead Johnson, Suntory Wellness. Nutricia and (Cremo and has been an invited speaker at meetings organized by ‘Mead Johnson, Yakult, Alkermes and Janssen. References “oudens Poramont . eno, L, Theedoro 2012 Prevention 9 gut Teaknes by priest leads to ateusted HPA response oan aie pvehologia sess as. Psyehoneutoendocinlogy 3718851695, ‘chronic paheloiea!iesesnciced ran acer sbraraliy in mie, Nee {ogaswoenterlogy and moult. offeal ) Eu Castoieest Met. 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