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The fields of microbiology and neuroscience in modern medicine have largely developed in distinct trajecto- ries, with the exception of studies focused on the direct impact of infectious agents on brain function, including early investigations of syphilis and, more recently, stud- ies of the neurological complications of AIDS. However, it has recently become evident that microbiota, especially microbiota within the gut, can greatly influence all aspects of physiology1,2, including gut–brain communication, brain function and even behaviour. Indeed, the initiation of large-scale metagenomic projects such as the Human Microbiome Project has allowed the role of the micro- biota in health and disease to take centre stage3,4.
In this Review we discuss recent studies showing that the gut microbiota can influence brain function. We highlight the different methods that have enabled us to increase our understanding of how the microbiota is integrated into the gut–brain axis and how it modulates behaviour. We then summarize the burgeoning knowl- edge of the contribution of the gut microbiota to a range of CNS disorders. Harnessing such pathways may pro- vide a novel approach to treat various disorders of the gut–brain axis.
The gut–brain axis: from satiety to stress The reciprocal impact of the gastrointestinal tract on brain function has been recognized since the middle
of the nineteenth century through the pioneering work of Claude Bernard, Ivan Pavlov, William Beaumont, William James and Carl Lange. Even Charles Darwin recognized the importance of this interaction in his clas- sic The Expression of the Emotions in Man and Animals (1872), in which he wrote: “The manner in which the secretions of the alimentary canal and of certain other organs … are affected by strong emotions, is another excellent instance of the direct action of the sensorium on these organs, independently of the will or of any serviceable associated habit.” In the late 1920s, Walter Cannon, the founding father of the study of gastroin- testinal motility, emphasized the primacy of brain pro- cessing in the modulation of gut function (see REFS 5–7 for historical perspectives). It is now increasingly being recognized that the gut–brain axis provides a bidirec- tional homeostatic route of communication that uses neural, hormonal and immunological routes, and that dysfunction of this axis can have pathophysiological consequences6.
Although much research on the gut–brain axis has focused on its contribution to the central regula- tion of digestive function and satiety 8,9, there has been an increasing emphasis on its role in other aspects of physiology 7. The role of the enteric nervous system in gut–brain signalling has been well delineated, as has our understanding of how the brain modulates the enteric
1Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. 2Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. 3Department of Psychiatry, University College Cork, Cork, Ireland. Correspondence to J.F.C. e-mail: [email protected] doi:10.1038/nrn3346 Published online 12 September 2012
Microbiota The collection of microorganisms in a particular habitat, such as the microbiota of the skin or gut.
Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour John F. Cryan1,2 and Timothy G. Dinan1,3
Abstract | Recent years have witnessed the rise of the gut microbiota as a major topic of research interest in biology. Studies are revealing how variations and changes in the composition of the gut microbiota influence normal physiology and contribute to diseases ranging from inflammation to obesity. Accumulating data now indicate that the gut microbiota also communicates with the CNS — possibly through neural, endocrine and immune pathways — and thereby influences brain function and behaviour. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain. Thus, the emerging concept of a microbiota–gut–brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders.
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Stress response The name given to the hormonal and metabolic changes that follow exposure to a threat. It involves the activation of the hypothalamus–pituitary– adrenal axis.
Microbiome The collective genomes of all of the microorganisms in a microbiota.
Hypothalamus–pituitary– adrenal (HPA) axis The HPA axis is the endocrine core of the stress system. Its activation results in the release of corticotropin-releasing factor from the hypothalamus, adrenocorticotropic hormone from the pituitary and cortisol (corticosterone in rats and mice) from the adrenal glands.
Maternal separation A model of stress in early life. Isolation of pups from their mother in early life alters maternal behaviour upon being reunited and results in permanent changes in brain and behaviour in the offspring.
nervous system and therefore gastrointestinal functions. It is now clear that alterations in brain–gut interactions are associ ated with gut inflammation, chronic abdomi- nal pain syndromes and eating disorders6, and that modulation of gut–brain axis function is associated with alterations in the stress response and behaviour 10. The high co-morbidity between stress-related psychiatric symptoms — such as anxiety — and gastrointestinal dis- orders — including irritable bowel syndrome (IBS) and inflammatory bowel disorder11 — is further evidence of the importance of this axis in pathophysiology. Thus, modulation of the gut–brain axis is viewed as an attrac- tive target for the development of novel treatments for a wide variety of disorders ranging from obesity, mood and anxiety disorders to gastrointestinal disorders such as IBS6. Moreover, the gut microbiota has emerged as a new player that can have marked effects on this axis.
The gut microbiota The human gastrointestinal tract is inhabited by 1 × 1013 to 1 × 1014 microorganisms — more than 10 times that of the number of human cells in our bodies and contain- ing 150 times as many genes as our genome12,13 — and the gut microbiota is therefore often referred to as the forgotten organ14. Our appreciation of the relationship between the microbiota, the microbiome and the host is changing rapidly and it is now viewed as being mutu- alistic (with both partners experiencing increased fit- ness)15. In addition, gut microbiota are now known to have a crucial role in the development and functional- ity of innate and adaptive immune responses16,17, and in regulating gut motility, intestinal barrier homeostasis, nutrient absorption and fat distribution18,19. Over the past 5 years substantial advances have been made in the development of technologies for assessing microbiota composition at the genetic level13,20, and this has had, and continues to have, an immense impact on our understanding of host–microorganism interactions.
The estimated number of species in the gut micro- biota varies greatly, but it is generally accepted that the adult microbiota consists of more than 1,000 species13 and more than 7,000 strains21. Bacteroidetes and Firmicutes are the two predominant bacterial phylo- types in the human microbiota, with Proteobacteria, Actinobacteria, Fusobacteria and Verrucomicrobia phyla present in relatively low abundance22. This coloni- zation is a postnatal event; it commences at birth, when vaginal delivery exposes the infant to a complex micro- biota. The initial microbiota has a maternal signature and after 1 year of age a complex adult-like microbiota is evident23–25.
Although bacterial communities vary greatly between individuals and their precise composition is thought to be at least partially genetically determined26, they have been proposed to fall into just three distinct types (ente- rotypes) that are defined by their bacterial composition. Each enterotype is characterized by relatively high levels of a single microbial genus: Bacteroides spp., Prevotella spp. or Ruminococcus spp.27. It is becoming clear that the microbiota normally has a balanced compositional signa- ture that confers health benefits and that a disruption of
this balance confers disease susceptibility 28. Diet is one of the key factors that can substantially affect microbiota composition. For example, the Bacteroides spp. entero- type has been associated with diets that are high in fat or protein, whereas the Prevotella spp. enterotype has been associated with high-carbohydrate diets29. Other factors, including infection, disease and antibiotics, may tran- siently alter the stability of the natural composition of the gut microbiota and thereby have a deleterious effect on the well-being of the host30. Interestingly, the core microbiota in the elderly has been reported to be differ- ent from that of younger adults31, and its composition is directly correlated with health outcomes32.
Given the overarching influence of gut bacteria on health it is perhaps not surprising that a growing body of literature focuses on the impact of enteric microbiota on brain and behaviour and that, as a result, the con- cept of the microbiota–gut–brain axis has emerged10,28,33 (FIG. 1). It is worth noting, however, that it is still debated in the field whether the role of the microbiota is suffi- ciently predominant to warrant its nomenclature being included in an axis independent from the well-described gut–brain axis or whether it should simply be recognized as an important node within the gut–brain axis. What is clear is that there is communication between the gut microbiota and the CNS. The neuroendocrine, neuro- immune, the sympathetic and parasympathetic arms of the autonomic nervous system and the enteric nervous system are the key pathways through which they com- municate with each other (FIG. 1), and the gastrointesti- nal tract provides the scaffold for these pathways. These components converge to form a complex reflex network, with afferents that project to integrative cortical CNS structures and efferents that innervate smooth mus- cle in the intestinal wall6. Crucially, there is a growing appreciation that this communication functions bidirec- tionally 6: microbiota influence CNS function, and the CNS influences the microbiota composition through its effects on the gastrointestinal tract. How such com- munication occurs is not fully understood and probably involves multiple mechanisms (BOX 1).
Microbiota and stress Although the vast majority of research to date has focused on the impact of the microbiota on CNS function and stress perception (see below), it has long been known that stress and the associated activity of the hypothala- mus–pituitary–adrenal (HPA) axis can influence the com- position of the gut microbiota34. However, the functional consequences of this influence are only now being unrav- elled35. Maternal separation is an early life stressor that can result in long-term increases in HPA axis activity36. Maternal separation (between 6–9 months of age) in rhesus monkeys resulted in a substantial decrease in fae- cal lactobacilli (as assessed by enumeration of total and Gram-negative aerobic and facultative anaerobic bacte- rial species) 3 days after the initiation of the separation procedure, which returned to baseline by day seven37. Stress early in life can also have long-term effects on the composition of the gut microbiota. Analysis of the 16S rRNA diversity in the faeces of adult rats that had
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Probiotic A living microorganism that, when ingested by humans or animals, can beneficially influence health.
Inflamm-ageing A neologism to reflect the concept that ageing is accompanied by a global reduction in the capacity to cope with various stressors and a concomitant progressive increase in pro-inflammatory status.
undergone maternal separation for 3 hours per day from postnatal days 2–12 revealed an altered faecal microbiota composition when compared with the non-separated control animals38.
Chronic stress in adulthood also affects the gut microbiota composition. For example, a study using deep-sequencing methods demonstrated that the composition of microbiota from mice exposed to chronic restraint stress (a physical stressor) differed from that in non-stressed control mice39. Specifically, exposure to chronic psychosocial stress decreased and increased the relative abundance of Bacteroides spp. and Clostridium spp., respectively, in the caecum. It also
increased circulating levels of interleukin-6 (IL-6) and the chemokine CCL2 (also known as MCP1), which is indicative of immune activation. IL-6 and CCL2 levels correlated with stressor-induced changes in the lev- els of three other bacterial genera: Coprococcus spp., Pseudobutyrivibrio spp. and Dorea spp. As these genera have only recently been described in humans, the func- tional importance of these findings to host physiology is unknown. Nevertheless, these data show that exposure to repeated stress affects gut bacterial populations in a manner that correlates with alterations in levels of pro- inflammatory cytokines39.
In addition to altering the gut microbiota compo- sition, it is important to note that chronic stress also disrupts the intestinal barrier, making it leaky and increasing the circulating levels of immunomodula- tory bacterial cell wall components such as lipopolysac- charide40,41. These effects can be reversed by probiotic agents42,43. In line with these findings, human studies show increased bacterial translocation in stress-related psychiatric disorders such as depression44. Recent studies have shown that the potential probiotic Lactibacillus far- ciminis can prevent barrier leakiness, and this underlies its capacity to reverse psychological stress-induced HPA axis activation43, further confirming the importance of the gut–brain axis in modulating the stress response.
It is worth noting that not all aspects of stress have a negative effect on an animal45, and the relative contribu- tion of microbiota to the positive stress response and vice versa remains unexplored. Given that we now appreci- ate that there is a distinct microbiota in the elderly 31,32 and that age is accompanied by a marked diminution in the capacity to cope with a variety of stressors and by a progressive increase in pro-inflammatory status46, future studies should also focus on the relative contribution of the gut microbiota to this ‘inflamm-ageing’ process.
Effects on behaviour and cognition Approaches that have been used to elucidate the role of the gut microbiota on behaviour and cognition include the use of germ-free animals, animals with pathogenic bacterial infections, and animals exposed to probiotic agents or to antibiotics28 (FIG. 2). Most of these studies highlight a role for the microbiota in modulating the stress response and in modulating stress-related behav- iours that are relevant to psychiatric disorders such as anxiety and depression.
Germ-free animals. The use of germ-free animals ena- bles the direct assessment of the role of the microbiota on all aspects of physiology. This approach takes advan- tage of the fact that the uterine environment is sterile and that colonization of the gastrointestinal tract occurs postnatally in normal rodents and humans. Germ-free animals are maintained in a sterile environment in gnotobiotic units, thus eliminating the opportunity for postnatal colonization of their gastrointestinal tract and allowing for direct comparison with the conventionally colonized gut of their counterparts (FIG. 2).
In a landmark study, Sudo and colleagues47 provided evidence that intestinal microbiota have a role in the
Figure 1 | Pathways involved in bidirectional communication between the gut microbiota and the brain. Multiple potential direct and indirect pathways exist through which the gut microbiota can modulate the gut–brain axis. They include endocrine (cortisol), immune (cytokines) and neural (vagus and enteric nervous system) pathways. The brain recruits these same mechanisms to influence the composition of the gut microbiota, for example, under conditions of stress. The hypothalamus–pituitary– adrenal axis regulates cortisol secretion, and cortisol can affect immune cells (including cytokine secretion) both locally in the gut and systemically. Cortisol can also alter gut permeability and barrier function, and change gut microbiota composition. Conversely, the gut microbiota and probiotic agents can alter the levels of circulating cytokines, and this can have a marked effect on brain function. Both the vagus nerve and modulation of systemic tryptophan levels are strongly implicated in relaying the influence of the gut microbiota to the brain. In addition, short-chain fatty acids (SCFAs) are neuroactive bacterial metabolites of dietary fibres that can also modulate brain and behaviour. Other potential mechanisms by which microbiota affect the brain are described in BOX 1. ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor. Figure is modified from REF. 23.
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Mono-association The inoculation of germ-free animals with a specific bacterium.
Bacteriocins Proteinaceous toxins produced by bacteria to inhibit the growth of similar or closely related bacterial strain(s).
development of the HPA axis. In adult germ-free mice, exposure to a mild restraint stress induced an exagger- ated release of adrenocorticotropic hormone and cor- ticosterone compared with control mice with a normal composition of microbiota and no specific pathogens (known as specific-pathogen-free mice). The stress response in the germ-free mice could be partially reversed by colonization with faecal matter from control
animals and was fully reversed by mono-association with Bifidobacterium infantis. Interestingly, the earlier the col- onization, the greater the reversal of the effects, and full reversal occurred in the adult offspring when germ-free mothers were inoculated with specific bacterial strains before giving birth47.
These data clearly demonstrated that the micro- bial content of the gastrointestinal tract influences the
Box 1 | Potential mechanisms by which microbiota affect CNS function
Altering microbial composition. Exogenously administered potential probiotic bacteria or infectious agents can affect the composition of the gut microbiota in multiple ways121. For example, they can compete for dietary ingredients as growth substrates, bioconvert sugars into fermentation products with inhibitory properties, produce growth substrates (for example, exocellular polysaccharide or vitamins) for other bacteria, produce bacteriocins, compete for binding sites on the enteric wall, improve gut barrier function, reduce inflammation (thereby altering intestinal properties for colonization and persistence), and stimulate innate immune responses121. All of these can have marked effects on gut–brain signalling.
Immune activation. Microbiota and probiotic agents can have direct effects on the immune system122,123. Indeed, the innate and adaptive immune system collaborate to maintain homeostasis at the luminal surface of the intestinal host– microbial interface, which is crucial for maintaining health123. The immune system also exerts a bidirectional communication with the CNS124,125, making it a prime target for transducing the effects of bacteria on the CNS. In addition, indirect effects of the gut microbiota and probiotics on the innate immune system can result in alterations in the circulating levels of pro-inflammatory and anti-inflammatory cytokines that directly affect brain function.
Vagus nerve. The vagus nerve (cranial nerve X) has both efferent and afferent roles. It is the major nerve of the parasympathetic division of the autonomic nervous system and regulates several organ functions, including bronchial constriction, heart rate and gut motility. Moreover, activation of the vagus nerve has been shown to have a marked anti-inflammatory capacity, protecting against microbial-induced sepsis in a nicotinic acetylcholine receptor α7 subunit-dependent manner126. Approximately 80% of nerve fibres are sensory, conveying information about the state of the body’s organs to the CNS127. Many of the effects of the gut microbiota or potential probiotics on brain function have shown to be dependent on vagal activation66,75,76,128. However, vagus-independent mechanisms are also at play in microbiota–brain interactions, as vagotomy failed to affect the effect of antimicrobial treatments on brain or behaviour60. Moreover, the mechanisms through which vagal afferents become activated by the gut microbiota are currently unclear.
Tryptophan metabolism. Tryptophan is an essential amino acid and is a precursor to many biologically active agents, including the neurotransmitter serotonin129. A growing body of evidence points to dysregulation of the often-overlooked kynurenine arm of the tryptophan metabolic pathway — which accounts for over 95% of the available peripheral tryptophan in mammals130 — in many disorders of both the brain and gastrointestinal tract. This initial rate-limiting step in the kynurenine metabolic cascade is catalysed by either indoleamine-2,3-dioxygenase or the largely hepatic-based tryptophan 2,3-dioxygenase. The activity of both enzymes can be induced by inflammatory mediators and by corticosteroids129. There is some evidence to suggest that a probiotic bacterium (Bifidobacterium infantis) can alter concentrations of kynurenine82. However, this is not a universal property of all Bifidobacterium strains, as Bifidobacterium longum administration had no effect on kynurenine levels61.
Microbial metabolites. Gut bacteria modulate various host metabolic reactions, resulting in the production of metabolites such as bile acids, choline and short-chain fatty acids that are essential for host health131. Indeed, complex carbohydrates such as dietary fibre can be digested and subsequently fermented in the colon by gut microorganisms into short-chain fatty acids such as n-butyrate, acetate and propionate, which are known to have neuroactive properties110,111,132.
Microbial neurometabolites. Bacteria have the capacity to generate many neurotransmitters and neuromodulators. It has been determined that Lactobacillus spp. and Bifidobacterium spp. produce GABA; Escherichia spp., Bacillus spp. and Saccharomyces spp. produce noradrenalin; Candida spp., Streptococcus spp., Escherichia spp. and Enterococcus spp. produce serotonin; Bacillus spp. produce dopamine; and Lactobacillus spp. produce acetylcholine133–135.
Probiotics modulate the concentrations of opioid and cannabinoid receptors in the gut epithelium. However, how this local effect occurs or translates to the anti-nociceptive effects seen in animal models of visceral pain is currently unclear. It is conceivable that secreted neurotransmitters of microorganisms in the intestinal lumen may induce epithelial cells to release molecules that in turn modulate neural signalling within the enteric nervous system, or act directly on primary afferent axons136.
Bacterial cell wall sugars. The outer exocellular polysaccharide coating of probiotic bacteria is largely responsible for many of their health-promoting effects. Indeed, the exocellular polysaccharide of the probiotic Bifidobacterium breve UCC2003 protects the bacteria from acid and bile in the gut and shields the bacteria from the host immune response137. Such studies open up the possibility of non-viable bacterial components as microbial-based therapeutic alternatives to probiotics. Indeed, as with neuroactive metabolites, cell wall components of microorganisms in the intestinal lumen or attached to epithelial cells are poised to induce epithelial cells to release molecules that in turn modulate neural signalling or that act directly on primary afferent axons136.
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development of an appropriate stress response later in life. Moreover, it seems that there is a critical window in early life during which colonization must occur to ensure normal development of the HPA axis. At the neuronal level, germ-free animals had decreased levels of brain- derived neurotrophic factor (BDNF), a key neurotrophin involved in neuronal growth and survival, and decreased expression of the NMDA receptor subunit 2A (NR2A) in the cortex and hippocampus compared with controls47.
It took a further 7 years for these findings to be fol- lowed up at a behavioural level. Three independent groups have now shown that germ-free animals (of different strains and sex) show reduced anxiety in the elevated plus maze or light–dark box tests48–50 (but see REF. 51, which failed to show a clear anxiety phenotype); these tests are widely used to assess anxiety-related behaviour 52. These findings are somewhat puzzling, as an exaggerated HPA axis response to stress is often accompanied by increased anxiety-like behaviour. Interestingly, one study 50 also reported changes in
hippocampal Bdnf mRNA and 5-hydroxytryptamine (serotonin) 1A (5-HT1A) receptor mRNA expression, as well as Nr2b mRNA levels in the amygdala in germ-free mice, but the direction of these changes was not in agree- ment with data reported in another study47. The reasons for these discrepancies are currently unclear. Moreover, although alterations in BDNF, serotonin and glutamate receptor levels have all been implicated in anxiety 53–55, further studies are required to establish how these changes at the molecular level contribute to the mani- festation in reduced anxiety-like behaviour observed in germ-free animals.
At the cognitive level, germ-free mice displayed defi- cits in simple non-spatial and working memory tasks (novel object recognition and spontaneous alternation in the T-maze)51. Future studies should focus on enhanc- ing the repertoire of behavioural cognitive assays used. However, maintaining animals in a germ-free environ- ment and conducting complex behavioural studies is not a trivial logistical hurdle.
Figure 2 | Strategies used to investigate the role of the microbiota–gut–brain axis in health and disease. Although the microbiota–gut–brain axis is a relatively new concept, information about communication along this axis has been delineated through different, converging means. Germ-free mice can be used to assess how loss of microbiota during development affects CNS function. It is worth noting that the clinical translation of such analyses is limited, as no equivalent obliteration of the microbiota can be said to exist in humans. However, germ-free mice also enable the study of the impact of a particular entity (for example, a probiotic) on the microbiota–gut–brain axis in isolation. Moreover, studies in germ-free mice can be expanded to enable research on the ‘humanization’ of the gut microbiota; that is, transplanting faecal microbiota from specific human conditions or from animal models of disease. Administration of various potential probiotic strains in adult animals or humans can be used to assess the effects of these bacterial ‘tourists’ on the host. Major strain and species differences occur in terms of their effects on the gut–brain axis. Infection studies have been used to assess the effects of pathogenic bacteria on brain and behaviour, which are mediated largely (although not exclusively) through activation of the immune system. Finally, administration of antimicrobial (that is, antibiotic) drugs can perturb microbiota composition in a temporally controlled and clinically realistic manner and is therefore a powerful tool to assess the role of the gut microbiota on behaviour. However, many …
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