J Neurogastroenterol Motil 2016; 22(2): 201-212  https://doi.org/10.5056/jnm15146
Modulatory Effects of Gut Microbiota on the Central Nervous System: How Gut Could Play a Role in Neuropsychiatric Health and Diseases
Shadi S Yarandi1, Daniel A Peterson2, Glen J Treisman3, Timothy H Moran3, and Pankaj J Pasricha1,*
1Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA, 2Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, 3Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Correspondence to: Pankaj J Pasricha, MD, Department of Medicine, Johns Hopkins Center for Neurogastroenterology, Johns Hopkins School of Medicine, 720 Rutland Street, Ross 958, Baltimore, MD 21205, USA Tel: +1-410-502-7173, Fax: +1-410-550-7861, E-mail: ppasric1@jhmi.edu
Received: September 16, 2015; Revised: January 12, 2016; Accepted: January 27, 2016; Published online: April 30, 2016.
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Gut microbiome is an integral part of the Gut-Brain axis. It is becoming increasingly recognized that the presence of a healthy and diverse gut microbiota is important to normal cognitive and emotional processing. It was known that altered emotional state and chronic stress can change the composition of gut microbiome, but it is becoming more evident that interaction between gut microbiome and central nervous system is bidirectional. Alteration in the composition of the gut microbiome can potentially lead to increased intestinal permeability and impair the function of the intestinal barrier. Subsequently, neuro-active compounds and metabolites can gain access to the areas within the central nervous system that regulate cognition and emotional responses. Deregulated inflammatory response, promoted by harmful microbiota, can activate the vagal system and impact neuropsychological functions. Some bacteria can produce peptides or short chain fatty acids that can affect gene expression and inflammation within the central nervous system. In this review, we summarize the evidence supporting the role of gut microbiota in modulating neuropsychological functions of the central nervous system and exploring the potential underlying mechanisms.

Keywords: Anxiety, Brain-Gut axis, Depression, Gut microbiota, Stress
Introduction

Over the past decade, experimental data has suggested a complex and bidirectional interaction between the gastrointestinal (GI) tract and the central nervous system (CNS), the so-called “Gut-Brain axis.”1 Derangements of this axis (typically in the brain-to-gut direction) have been implicated in the pathogenesis of symptoms of many functional bowel disorders such as the irritable bowel syndrome (IBS).2,3 In recent years, however, emerging knowledge about gut microbiota has compelled us to re-examine the directionality of this process.411 The presence of a healthy and diverse gut microbiota appears to be imperative not only for normal gastrointestinal function, but may also influence a variety of systemic and mental processes. Our understanding of the interaction between gut microbiota and the CNS is incomplete and only at its starting point. In this article, we will review the current evidence in the literature that points towards a role for gut microbiota in various developmental and psychiatric disorders such as anxiety, depression, schizophrenia and autism. We will also review the possible mechanisms through which gut microbiota might be involved in the pathogenesis of these disorders.

The gut microbiota at infancy is usually diverse and highly variable, trending towards its final composition between 6–12 months of age,12 reflecting a combination of genetic factors, maternal health, method of delivery, subsequent nutrition, and maternal and postnatal exposure to antibiotics.1316 Germ-free mice show developmental abnormality in the GI tract that can be reversed by reconstructing the gut microbiota, suggesting a role for gut microbiota in postnatal development of the enteric nervous system (ENS).17,18 This period is also critical for the development of the CNS leading to the suggestion, based on experimental models, that gut microbiota may be an important factor participating in the development of cognitive, emotional, and behavioral processes shortly after birth.19,20 For example, germ free mice show significant alteration in the concentration of the key neurotransmitters such as serotonin in the hypothalamus.21 Alterations in serotonin concentration can in turn affect several aspects of the development of central nervous system, including synapse formation and connectivity between various regions in the central nervous system and their plasticity.22 The picture becomes more complicated because serotonin is also a key factor in the development of the ENS, and alteration of its concentration in the blood may modulate ENS structure and function23; in turn this can affect the composition of gut microbiota, thus potentially providing a closed loop system for mutual regulation of the 2 nervous systems.

Microbiota and Modulation of the Central Nervous System—General Mechanisms

A central issue in any discussion on this topic relates to the question of how microbes that live in the colon can influence a remote organ such as the brain. We are just beginning to scratch the surface of this problem, but theoretically there are multiple, possible overlapping mechanisms, that amplify each other in short as well as long loops (Figure). With the exception of the microbe-epithelial interface, all these mechanisms imply some degree of access of either the microorganism itself or its products to the deeper layers of the gut, in turn activating a myriad of factors. Thus, as is being increasingly recognized, gut permeability is perhaps the most important factor in initiating microbial interactions with the rest of the body. These factors will now be briefly described.

Effect of Gut Microbiota on Intestinal Permeability

The normal intestinal barrier consists of multiple layers that includes gut flora and external mucus layer, epithelial layer, and lamina propria, to name them from outside to inside.24 Mucus is secreted by goblet cells and acts as a mechanical protective layer that also contains digestive and antibacterial enzymes and antibodies, and will hydrate the epithelial layer and helps it regenerate.25 The epithelial layer, in addition to playing an important part in absorption of the nutrients, also serves as a physical barrier due to the tight junctions between the epithelial cells. Furthermore, enteroendocrine cells are distributed through the epithelial layer.26 This layer along with lamina propria is also the host of the largest repository of immune cells in the body which is known as mucosa-associated immune cells. The population of immune cells in the epithelial layer is mostly CD8+ lymphocytes, while the immune cells in the lamina propria are more diverse and consisted of macrophages, plasma cells, antigen presenting cells, and mast cells in addition to lymphocytes.27

Normal gut microbiota is essential in preventing colonization of the harmful bacteria by competing with them for vital resources such as food and growth factors. If the population of normal gut microbiota is reduced, for example due to antibiotic therapy, pathogenic organisms find the opportunity to colonize the gut epithelium. Toxins produced by pathogenic microorganisms and the focal inflammation created by immune responses to them can increase gut permeability.28 For example, Clostridium difficile that can colonize the gut in the absence of normal gut flora produces an enterotoxin that increase the gut permeability by impairing epithelial tight junctions through damaging aggregation of actin filaments.29 Another way that gut microbiota can enhance the function of the intestinal barrier is through protecting and improving epithelial tight junctions. Most of the evidence that supports this role of microbiota in the normal function of the intestinal barrier comes from studies that have shown that probiotic treatment can reduced gut permeability in models of GI tract disorders. For example, in experimental models of colitis, several species of probiotics including Lactobacillus, Escherichia coli, and Bifidobacterium can reduce gut permeability by upregulating trans-membrane proteins that are important in preserving tight junctions between epithelial cells.3033 It has also been shown that treatment with these probiotics can enhance mucus production and consequently improve the physical barrier protecting the epithelial layer.34,35 Products of bacterial fermentation can also play an important role in maintaining the intestinal barrier. It has been shown that short-chain fatty acids can act as trophic factors for mucosal and epithelial layers. Also, normal bacteria can produce trophic peptides such as glucagon-like peptide-2 (GLP-2) that can enhance the proliferation of crypt cells and villi.36,37

Impaired intestinal barrier function and consequent increased gut permeability can lead to increased translocation of gut bacteria across the intestinal wall and into the mesenteric lymphoid tissue.34 Increased exposure of the ENS or mucosal immune cells to bacteria can provoke an immune response that can lead to release of inflammatory cytokines and activation of the vagus nerve and spinal afferent neurons. Inflammatory cytokines and the vagal system in turn can modulate the activity of the CNS and ENS.38,39 Furthermore, increased permeability of the gut can also increase the translocation of metabolic products such as lipopolysaccharide (LPS) or neuro-active peptides created by the bacteria that can alter the activity of the ENS and CNS.40 For example, LPS can activate Toll-Like receptors that are present on epithelial cells, enteric neurons, sensory afferent neurons in the spine, and various cells in the brain, modulating their activity and affecting the function of both ENS and CNS.4144

As mentioned above, the interaction between the gut and brain is bidirectional- the CNS can affect gut permeability and increased gut permeability in turn can alter CNS function. In both animal models of stress and human subjects who were exposed to stress, the intestinal barrier is impaired. It has been shown that both acute and chronic stress can reduce water secretion and increase ion secretion in the intestine, and therefore impair the physical protection of the epithelial layer and lamina propria against adhesion of harmful bacteria and nociceptive chemicals.4547 Activation of the hypotha-lamic-pituitary-adrenal (HPA) axis and increased production of corticotropin-releasing factor (CRF), altered activation of the vagal system, mast cell activation, and release of certain cytokines such as IFN-γ, TNF-α, and IL-4 are suggested culprits in this interaction.4854 Additionally, stress can change the function of mucosal-associated immune cells and cause increased antigenic and bacterial uptake.55,56 Multiple studies have been published that have shown that the composition of gut microbiota is changed in the face of acute or chronic stress, and this in turn can subsequently change the function of intestinal barrier as explained above.5760 There is limited data regarding the changes in intestinal barrier or GI physiology and the underlying mechanisms of it in neuropsychiatric disorders. It has been reported that the frequency of GI symptoms is increased in children with autism but the mechanism is not known.61 In patients with schizophrenia, there are increased intestinal permeability and change in intestinal function.62 Emotional stress and depression have been shown to increase prevalence of disorders of the digestive system.63

Effect of Bacterial Metabolites on the Central Nervous System

Theoretically, bacterial products like other luminal contents, can be absorbed into the blood stream and affect remote sites in the brain. Alternatively, or in addition, bacteria can interact with local elements in the gut such as nerves or endocrine cells that then in turn signal to the brain. Experimental data suggest that a variety of biologically active products derived from gut microbiota can directly or indirectly influence the brain. These include well known, although non-specific, factors such as LPS, which can influence the CNS directly by activating Toll-like receptor 4 on microglial cells causing release of inflammatory cytokines by them within the CNS, or indirectly by inducing release of inflammatory cytokines from the GI tract.64,65 LPS can cause behavioral changes during an acute illness or cause a delayed change in mood after sickness.66,67 IgA and IgM against LPS of gut bacteria are found in the blood of patients with depression or chronic fatigue syndrome, suggesting a potential role for LPS in the pathogenesis of these diseases.66 Other bacterial products reflect the role of colonic microbiota in the fermentation of undigested carbohydrates to short chain fatty acids (SCFA).68 SC-FAs can act as signaling molecules by binding to G protein-coupled receptors, Gpr41, and Gpr43.6971 It has been shown that Gpr41 and Gpr43 receptors are abundantly present on the surface of gut epithelial and immune cells and are activated by SCFAs. This activation can provoke an inflammatory and immune response that can be helpful in the setting of an acute infection, but dysregulation can produce an exaggerated response leading to increased gut permeability and increased absorption of neuro-active metabolites.72,73 SCFAs can also directly activate the sympathetic nervous system through Gpr41 receptors that are found on sympathetic ganglionic neurons.74 Furthermore, it has been shown that SCFAc can pass through the blood-brain barrier and influence behavior, neural signaling, the production of neurotransmitters and, ultimately, behavior.7577

Change in Central Nervous System Neurotransmitters

Studies have reported on CNS neurotransmitter changes in response to more specific biological factors that may be restricted to certain types of bacteria, thus providing a mechanistic link to changes in microbial metabolism. Germ free mice have elevated levels of dopamine and tryptophan in striatum, but not serotonin or gama-amino butyric acid (GABA).78 Another study has reported increased levels of serotonin in the hippocampus of germ free mice.79 It has been recently shown that indigenous bacteria from gut of mice and humans can induce serotonin production in entrochromaffin cells and increase the level of serotonin in blood.80 Histaminergic pathways are found in areas of the limbic system and also areas in the brain heavily involved in cognitive functions.81Lactobacillus reuteri, a commensal in the human gut, expresses histidine decar-boxylase that converts histidine to histamine. Therefore, a change in the population of this gut microbe can potentially modulate the levels of circulating histidine and histamine,82 which in turn can affect the concentration of CNS histamine.83 In another example, rats that are given Bifidobacterium infantis for 14 days showed increased concentrations of the serotonin precursor tryptophan in plasma, an effect that may be mediated by the altered expression of indoleamine-2,3-dioxygenase, a key enzyme in the kynurenine pathway of tryptophan degradation.84,85 In addition to pathogen-specific alterations in neurotransmitters within the CNS, specific structural microbial molecules that are often referred to as microbe-associated molecular patterns (MAMPs) are found in the brain. The profile of MAMPs has been shown to be significantly influenced by the composition of gut microbiota.21,86,87

Vagus Nerve as a Mediator of the Effect of Gut Microbiota on the Central Nervous System

One potential unifying mechanism through which these various processes can influence the activity of CNS is via vagal nerve activity. In animal models, administration of Campylobacter jejuni into the gut can induce anxiety like behavior. These animals show increased fos activity in vagal sensory nucleus and other areas in brain stem related to this nucleus.88 Furthermore, intraduodenal administration of a non-pathogenic bacterium, Bifidobacterium longum, is anxiolytic but also requires an intact vagus.89 Another anxiolytic probiotic, Lactobacillus rhamnosus, results in region specific change in the expression of GABA receptor subunits. GABA type B subunit 1 isoform b (GABAB1b) mRNA was decreased in the amygdala and hippocampus, while increased in cortical areas. On the other hand, GABAAα 2 receptor mRNA showed the opposite changes.90 These effects were abolished by subdiaphragmatic vagotomy.90 The vagus nerve might also be involved in behavioral effects of microbial LPS. It is known that LPS can induce depressive-like and anxious behavior in animal models.91 Studies have shown that rat or mice that undergo vagotomy before exposure to LPS, do not show the expected cytokine profile changes in the CNS92 or the same depressive or anxious behavior.93,94 However, the role of the vagus may be restricted to specific models or pathogenic processes. Thus, mice infected with the noninvasive parasite Trichuris muris exhibit anxiety-like behavior, associated with colitis and decreased hippocampal brain derived neurotrophic factor (BDNF) expression, along with increases in circulating TNF-α and IFN-γ, as well as the kynurenine and kyn-urenine/tryptophan ratio. Although anxiety behavior was normalized by both anti-inflammatory agents and the probiotic B. longum, it persisted in infected animals after a vagotomy.95

Gut Microbiota and Specific Neuropsychological Processes and Phenotypes

Stress Response and Anxiety

It has been shown that stress can alter gut permeability as well as the composition of gut microbiota.46,57 In a mice model of stress due to social disruption, Bacteroids are reduced while Clostridia are increased, resulting in a pro-inflammatory change in the profile of cytokines produced by gut microbiota.58 More recently, the interaction between stress and gut microbiome has been shown to be bidirectional, and that gut microbes can modulate the stress response and the activity of the corticosterone pathway orchestrated by the HPA, a key stress regulatory system in the CNS. Germ-free mice show an exaggerated HPA response to stress and the amount of CRF released in response to stress.96 Introduction of B. infantis corrects the abnormal response of the HPA to stress in this model, but only if administered within the first 6 weeks of age in this model.96 This finding is in line with the idea that the effect of microbes on the host is confined to a window of opportunity during neonatal life, and the presence or absence of any specific microbe during that window might have a durable and long-life effect.97 Germ-free mice also show reduced anxiety in behavioral tasks78 which can be reversed by re-introduction of gut microbiota.98 An anxiety prone behavioral phenotype is also seen in germ-free rats, along with elevated CRF expression in the hypothalamus and reduced glu-cocorticoid receptor (GR) expression in the hippocampus, (GR in this region regulates the CRF response in a negative feedback loop) and along with a lower dopaminergic turnover rate in specific CNS regions.99

Exposing rats in the early postnatal period to stress by maternal separation also leads to a change in composition of gut microbiota, which is linked to a long-term increase in anxiety-like behavior.100102 Introducing probiotics containing Lactobacillus in early stages of separation can ameliorate the effects of separation on HPA and reduce the corticosterone release.60 Other events that lead to a change in the composition of gut microbiota such as infection or use of probiotics can also change the level of anxiety.89,103105

Further, it is shown that the behavioral phenotype of anxietyprone strains of mice is also dependent on their existing microbiota. For example, BALB/c mice exhibit a highly anxious phenotype that does not show much exploratory locomotion in a new environment, while NIH Swiss mice show less anxiety and more exploratory motions in the same environment. Transferring gut microbiota from one of the species to another can change their behavior to the one typical of the donor.106 In another study, described above, infecting mice with Trichuris led to anxiety related behavior in mice, an effect that was reversed by administration of B. longum but not lactobacillus showing a species specific effect for gut microbiota.95 The underlying mechanisms, however, remain unclear as this was not vagally mediated. Further, anti-inflammatory agents normalized behavior and reduced cytokine and kynurenine levels without an effect on BDNF expression, whereas B. longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels.

It has also been suggested that the modulatory effects of gut microbiota on the level of anxiety are exerted through alterations in serotonin signaling.84 This idea is in part based on the finding that reduced anxiety-like behavior in germ free mice is associated with increased expression of serotonin receptor 1A in the hippocampus.78 However, experimental data from mice showed that while reintroduction of gut microbiota to germ free mice can normalize the anxious behavior, it fails to reverse the changes in serotonin levels in the hypothalamic-pituitary pathway.79 Another mechanism that has been described is increased release of the adreno-corticotropin hormone from the HPA axis in response to stress.96 A link between hypersensitivity of the HPA axis and reduced BDNF expression in the prefrontal cortex and hippocampus, and subsequently reduced N-methyl-d-aspartate receptor expression in germ-free mice is observed and was thought to play a role in regulation of HPA activity.78 Alteration of BDNF expression in the hippocampus was seen in mice that were treated with non-absorbable antibiotics such as neomycin, but not in mice treated with systemic intraperitoneal injection of antibiotics, suggesting that this effect is a result of elimination of gut microbiota, not the antibiotic treatment itself.106

Gut Microbiota and Depression

In animal models of depression, it has been reported that the composition of gut microbiota has been changed.107,108 These data however, have not been validated in patients with depression. In one study on human subjects with depression, no significant difference in the composition of gut microbiota was found between depressed patients and a control group.109 However, another recent study examined the composition of fecal microbiota in 46 patients with depression and 30 healthy controls, and reported significant differences with increased population of Bacteroidetes, Proteobacteria, and Actinobacteria, and decreased population of Frimicutes in patients with depression.110 Other evidence that might suggest a role for gut microbiota in the pathogenesis of depression is from studies that have shown certain probiotics can alleviate depressive symptoms in rodent models. Rats that are exposed to stress in early stages of life show behavior traits that are consistent with mood disorder that persists through their adulthood. Treatment of these rats with probiotics containing B. infantis can reduce the mood disturbance and correct the abnormalities in the concentration of norepinephrine in the brain.111L. rhamnosus and L. helveticus strains have also been reported to ameliorate maternal separation-induced depression through a corticosterone and GABA mediated mechanism.60,90 In a model of depression post myocardial infarction, treatment with probiotics including L. helveticus and B. longum has been reported to reduce the depression, presumably by reducing the pro-inflammatory cytokines and gut permeability.112,113 Some antibiotics such as minocycline have been shown to be effective in treatment of depression. Their mechanism of action is not exactly understood, and a potential role for changes in gut microbiota has been proposed, although not studied in detail.114,115

Gut Microbiota and Cognition

In mice, elimination of gut microbiota can alter performance in tasks that require intact spatial memory, hippocampal function or working memory.116 Similarly, altering the composition of gut microbiota in mice by infection or dietary modifications also can change the performance of the animal in memory tasks.117 For example, adding lean beef to the mice diet will alter composition of gut microbiota and will improve their performance in cognitive tasks. In this experiment, a temporal relationship with dietary induced changes in gut microbiota and working memory performance was reported.118 Mice infected with Citrobacter rodentium show impairment of cognitive function that can be reversed with probiotics.117 Diabetic rats are known to have impaired memory and learning due to impaired long-term potentiation and long-term depression in hippocampal synapses.119 It has been reported that treating the diabetic rats with a mixture of Lactobacillus acidophilus, Bifidobacterium lacti, and Lactobacillus fermentum, can ameliorate this effect of diabetes on memory and behavior, as well as electrophysiological changes.120 Evidence of similar effects in humans is limited but it has been shown that in normal human subjects, consumption of probiotics can alter the functional activity of the areas in the brain that are involved in cognitive functions.121

Emerging Areas

Given the explosion of interest in the microbiota and the gut-brain axis, it is not surprising that investigators are moving beyond more traditional phenotypes such as anxiety/depression to other neuropsychological syndromes including schizophrenia and autism. Increased gut permeability and translocation of gut bacteria has been shown in schizophrenic patients.122 The fundamental cause of this is unknown and could include both the controversial association with gluten sensitivity and celiac disease123 as well as primary changes in gut microbiota.62,124 These theories may not be mutually exclusive as it is possible that certain compositions of gut microbiota can lead to changed metabolism of certain food products such as gluten, and subsequent production of neuroactive peptides, increased absorption of these products due to local inflammation, and alteration of dopaminergic and serotonergic pathways in individuals who are genetically susceptible to schizophrenia.62 Germ-free mice tend to show a schizoid type behavior, not spending more time in a chamber with another mice in it when put in a 3-chamber sociability test.125 In a mice model that shows behavioral changes that resemble schizophrenia, treatment with Bacteroides fragilis can ameliorate the symptoms.126 However, a randomized clinical trial of a probiotic regimen containing Lactobacillus and Bifidobacterium strains failed to show any significant change in the psychiatric outcome measures was observed.127

Another area in which information is rapidly evolving is that of autism spectrum disorders (ASD). In a study in rodent model, it was found that the composition of gut microbiota in animals with ASD-like behavior is significantly changed compared with control animals. These changes were similar to those found in human patients with most changes observed in Clostridia and Bacterioidia species (see below). Treatment of these animals with B. fragilis restored the altered composition of gut microbiota and significantly reduced the stereotypical behavior.128 It has been hypothesized that these effects are mediated by specific chemical metabolites produced by gut microbes. For example, in the same rodent model of autism, elevated circulating levels of 4-ethylphenylsulfate normalized after probiotic treatment. However, systemic administration of this metabolite did not cause autistic behavior and only created anxiety-related behavior. Other mechanisms involve changes in the availability of tryptophan and histidine, and consequent alterations in serotonin and histamine in the CNS.129 Propionic acid, a SFCA that is produced by gut microbiota can also induce significant changes in social development and behavior and create a similar picture to ASD.130,131 Intraventricular administration of propionic acids to rats can cause structural abnormalities similar to those found in patients with ASD.132,133

Some of these findings have parallels in humans. Children with ASD also show altered composition of gut microbiota with a reduced population of Bacteroides and increased levels of Clostridium species.134136 It has been postulated that altered gut microbiota in children with ASD can lead to potential imbalances in metabolism of carbohydrates and amino acids in the gut, and altered levels of metabolites in the blood and urine. To test this hypothesis, a few studies of metabolic products have been performed in patients with ASD. For example, studies using metabolomics techniques have reported a different urinary amino acid profile in patients with ASD compared to healthy subjects with lower anti-oxidant levels in the urine, and abnormal levels of hippurate and N-methyl nicotinic acid in children with ASD.137,138 Hippurate is an end-product of the metabolism of dietary proteins and phenolic acids, and is formed by the liver from benzoic acid.139 Benzoic acid is a product of protein metabolism by gut microbiota, and altered hippurate level points towards altered metabolism in protein, potentially caused by altered gut microbiota.140 Another study has reported significant difference in children with autism and normal children in the fatty acid composition of phospholipids, with autistic children having an increased level of most of the saturated fatty acids, except for propionic acid, and a decreased level of polyunsaturated fatty acids.141 This change in composition of fatty acids can lead to abnormalities in oxidative stress, or cause mitochondrial dysfunction that might play a role in pathogenesis of ASD.142

Another bacterial genus that has been linked to autism is Desulfovibrio. This microbe is found with significantly higher prevalence in children with autism compared to developmentally normal children, and has sulfur-reducing properties that can explain the known sulfur deficiency in children with autism.143 Sulfate deficiency can potentially lead to inefficient detoxification through sulfation, leading to accumulation of neurotoxins. Increased gut permeability and elevated level of bacterial metabolic products such as LPS leading to increased proinflammatory cytokines such as IL-6 have also been shown in children with ASD.144

A few small clinical trials have shown beneficial effects for gluten free and casein free diets on symptoms of children with ASD145,146 that could potentially be attributed to the change in gut microbiota.4,8,19,61,128,147 Furthermore, in children with autism, the frequency of GI symptoms is increased148,149 and has been attributed to a low-grade chronic inflammation in the GI tract caused by altered gut microbiota. In a clinical study, oral vancomycin was used as a minimally absorbed antibiotic to treat the GI problems, based on this theory. Interestingly, in addition to improvement in GI symptoms, autistic behavior was also improved in these children.150

Conclusions

The influence of gut microbiota on several aspects of CNS function is increasingly supported by a growing body of experimental data. The mechanism of this influence is complex and involves multiple direct and indirect pathways. Increased gut permeability appears to be the cornerstone of the microbiome-gut-brain interaction. This provides a pathway for gut bacteria and their metabolic products to access the immune system, ENS, the blood stream, and centripetal neural pathways. Much of this evidence comes from rodent studies, and considerable work has to be done to validate these findings in humans before we can understand how best, if at all, to modulate the gut microbiota for clinical benefit.

Figures
Fig. 1. Bidirectional interactions between gut microbiota, gut permeability and central nervous system (CNS). Increased gut permeability can lead to translocation of gut microbiota or metabolic products such as lipopolysaccharides through the intestinal barrier. Exposure of epithelial cells or mucosal immune cells to bacterial or metabolic products can lead to activation of an immune response and release of pro-inflammatory cytokines. Additionally, metabolic products can directly affect the function of enteric neurons, spinal sensory neurons and vagus nerve through activation to Toll-like receptors or translocation and release of neuroactive peptides and hormones. On the other hand, stress can lead to activation of the hypothalamus-pituitary axis and excessive release of the corticotropin-releasing factor. This hormone along with altered vagal activity can modulate the local activation of mast cells in the intestinal wall and release of cytokines, causing increased gut permeability. ENS, enteric nervous system.
References
  1. Mayer, EA (2011). Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 12, 453-466.
    Pubmed KoreaMed CrossRef
  2. Collins, SM, and Bercik, P (2009). The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology. 136, 2003-2014.
    Pubmed CrossRef
  3. Mayer, EA, Savidge, T, and Shulman, RJ (2014). Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology. 146, 1500-1512.
    Pubmed KoreaMed CrossRef
  4. Al-Asmakh, M, Anuar, F, Zadjali, F, Rafter, J, and Pettersson, S (2012). Gut microbial communities modulating brain development and function. Gut Microbes. 3, 366-373.
    Pubmed KoreaMed CrossRef
  5. Borre, YE, Moloney, RD, Clarke, G, Dinan, TG, and Cryan, JF (2014). The impact of microbiota on brain and behavior: mechanisms & therapeutic potential. Adv Exp Med Biol. 817, 373-403.
    CrossRef
  6. Bravo, JA, Julio-Pieper, M, and Forsythe, P (2012). Communication between gastrointestinal bacteria and the nervous system. Curr Opin Pharmacol. 12, 667-672.
    Pubmed CrossRef
  7. Collins, SM, Surette, M, and Bercik, P (2012). The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol. 10, 735-742.
    Pubmed CrossRef
  8. Cryan, JF, and Dinan, TG (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 13, 701-712.
    Pubmed CrossRef
  9. Cryan, JF, and O’Mahony, SM (2011). The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil. 23, 187-192.
    Pubmed CrossRef
  10. Mayer, EA, Knight, R, Mazmanian, SK, Cryan, JF, and Tillisch, K (2014). Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 34, 15490-15496.
    Pubmed KoreaMed CrossRef
  11. Rhee, SH, Pothoulakis, C, and Mayer, EA (2009). Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol. 6, 306-314.
    Pubmed KoreaMed CrossRef
  12. Palmer, C, Bik, EM, DiGiulio, DB, Relman, DA, and Brown, PO (2007). Development of the human infant intestinal microbiota. PLoS Biol. 5, e177.
    Pubmed KoreaMed CrossRef
  13. Azad, MB, Konya, T, and Maughan, H (2013). Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ. 185, 385-394.
    Pubmed KoreaMed CrossRef
  14. Dominguez-Bello, MG, Costello, EK, and Contreras, M (2010). Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA. 107, 11971-11975.
    Pubmed KoreaMed CrossRef
  15. Penders, J, Thijs, C, and Vink, C (2006). Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 118, 511-521.
    Pubmed CrossRef
  16. Zivkovic, AM, German, JB, Lebrilla, CB, and Mills, DA (2011). Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci USA. 108, 4653-4658.
    KoreaMed CrossRef
  17. McVey Neufeld, KA, Mao, YK, Bienenstock, J, Foster, JA, and Kunze, WA (2013). The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse. Neurogastroenterol Motil. 25, Array.
    CrossRef
  18. Saulnier, DM, Ringel, Y, and Heyman, MB (2013). The intestinal microbiome, probiotics and prebiotics in neurogastroenterology. Gut Microbes. 4, 17-27.
    KoreaMed CrossRef
  19. Borre, YE, O’Keeffe, GW, Clarke, G, Stanton, C, Dinan, TG, and Cryan, JF (2014). Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med. 20, 509-518.
    Pubmed CrossRef
  20. Clarke, G, O’Mahony, SM, Dinan, TG, and Cryan, JF (2014). Priming for health: gut microbiota acquired in early life regulates physiology, brain and behaviour. Acta Paediatr. 103, 812-819.
    Pubmed CrossRef
  21. Wikoff, WR, Anfora, AT, and Liu, J (2009). Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA. 106, 3698-3703.
    Pubmed KoreaMed CrossRef
  22. Lavdas, AA, Blue, ME, Lincoln, J, and Parnavelas, JG (1997). Serotonin promotes the differentiation of glutamate neurons in organotypic slice cultures of the developing cerebral cortex. J Neurosci. 17, 7872-7880.
    Pubmed
  23. Liu, MT, Kuan, YH, Wang, J, Hen, R, and Gershon, MD (2009). 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J Neurosci. 29, 9683-9699.
    Pubmed KoreaMed CrossRef
  24. Farhadi, A, Banan, A, Fields, J, and Keshavarzian, A (2003). Intestinal barrier: an interface between health and disease. J Gastroenterol Hepatol. 18, 479-497.
    Pubmed CrossRef
  25. Liévin-Le Moal, V, and Servin, AL (2006). The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: mucins, antimicrobial peptides, and microbiota. Clin Microbiol Rev. 19, 315-337.
    Pubmed KoreaMed CrossRef
  26. Ménard, S, Cerf-Bensussan, N, and Heyman, M (2010). Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol. 3, 247-259.
    Pubmed CrossRef
  27. Gill, N, Wlodarska, M, and Finlay, BB (2011). Roadblocks in the gut: barriers to enteric infection. Cell Microbiol. 13, 660-669.
    Pubmed CrossRef
  28. Lyte, M (2013). Microbial endocrinology in the microbiome-gut-brain axis: how bacterial production and utilization of neurochemicals influence behavior. PLoS Pathog. 9, e1003726.
    Pubmed KoreaMed CrossRef
  29. Hecht, G, Pothoulakis, C, LaMont, JT, and Madara, JL (1988). Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J Clin Invest. 82, 1516-1524.
    Pubmed KoreaMed CrossRef
  30. Qin, HL, Zheng, JJ, and Tong, DN (2008). Effect of Lactobacillus plantarum enteral feeding on the gut permeability and septic complications in the patients with acute pancreatitis. Eur J Clin Nutr. 62, 923-930.
    CrossRef
  31. Zyrek, AA, Cichon, C, Helms, S, Enders, C, Sonnenborn, U, and Schmidt, MA (2007). Molecular mechanisms underlying the probiotic effects of Escherichia coli Nissle 1917 involve ZO-2 and PKCzeta redistribution resulting in tight junction and epithelial barrier repair. Cell Microbiol. 9, 804-816.
    CrossRef
  32. Patel, RM, Myers, LS, Kurundkar, AR, Maheshwari, A, Nusrat, A, and Lin, PW (2012). Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function. Am J Pathol. 180, 626-635.
    KoreaMed CrossRef
  33. Lin, PW, Nasr, TR, Berardinelli, AJ, Kumar, A, and Neish, AS (2008). The probiotic Lactobacillus GG may augment intestinal host defense by regulating apoptosis and promoting cytoprotective responses in the developing murine gut. Pediatr Res. 64, 511-516.
    Pubmed KoreaMed CrossRef
  34. Dicksved, J, Schreiber, O, and Willing, B (2012). Lactobacillus reuteri maintains a functional mucosal barrier during DSS treatment despite mucus layer dysfunction. PLoS One. 7, e46399.
    Pubmed KoreaMed CrossRef
  35. Ukena, SN, Singh, A, and Dringenberg, U (2007). Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PLoS One. 2, e1308.
    Pubmed KoreaMed CrossRef
  36. Cani, PD, Possemiers, S, and Van de Wiele, T (2009). Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 58, 1091-1103.
    Pubmed KoreaMed CrossRef
  37. Caricilli, AM, Picardi, PK, and de Abreu, LL (2011). Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol. 9, e1001212.
    Pubmed KoreaMed CrossRef
  38. Maes, M (2008). The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett. 29, 287-291.
    Pubmed
  39. Gareau, MG, Silva, MA, and Perdue, MH (2008). Pathophysiological mechanisms of stress-induced intestinal damage. Curr Mol Med. 8, 274-281.
    Pubmed CrossRef
  40. Holzer, P, Danzer, M, Schicho, R, Samberger, C, Painsipp, E, and Lippe, IT (2004). Vagal afferent input from the acid-challenged rat stomach to the brainstem: enhancement by interleukin-1beta. Neuroscience. 129, 439-445.
    Pubmed CrossRef
  41. Abreu, MT (2010). Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol. 10, 131-144.
    Pubmed CrossRef
  42. Barajon, I, Serrao, G, and Arnaboldi, F (2009). Toll-like receptors 3, 4, and 7 are expressed in the enteric nervous system and dorsal root ganglia. J Histochem Cytochem. 57, 1013-1023.
    Pubmed KoreaMed CrossRef
  43. Anitha, M, Vijay-Kumar, M, Sitaraman, SV, Gewirtz, AT, and Srinivasan, S (2012). Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. Gastroenterology. 143, Array-1016.
    Pubmed KoreaMed CrossRef
  44. van Noort, JM, and Bsibsi, M (2009). Toll-like receptors in the CNS: implications for neurodegeneration and repair. Prog Brain Res. 175, 139-148.
    Pubmed CrossRef
  45. Saunders, PR, Kosecka, U, McKay, DM, and Perdue, MH (1994). Acute stressors stimulate ion secretion and increase epithelial permeability in rat intestine. Am J Physiol. 267, G794-G799.
    Pubmed
  46. Barclay, GR, and Turnberg, LA (1987). Effect of psychological stress on salt and water transport in the human jejunum. Gastroenterology. 93, 91-97.
    Pubmed
  47. Barclay, GR, and Turnberg, LA (1988). Effect of cold-induced pain on salt and water transport in the human jejunum. Gastroenterology. 94, 994-998.
    Pubmed
  48. Santos, J, Benjamin, M, Yang, PC, Prior, T, and Perdue, MH (2000). Chronic stress impairs rat growth and jejunal epithelial barrier function: role of mast cells. Am J Physiol Gastrointest Liver Physiol. 278, G847-G854.
    Pubmed
  49. Vicario, M, Guilarte, M, and Alonso, C (2010). Chronological assessment of mast cell-mediated gut dysfunction and mucosal inflammation in a rat model of chronic psychosocial stress. Brain Behav Immun. 24, 1166-1175.
    Pubmed CrossRef
  50. Meddings, JB, and Swain, MG (2000). Environmental stress-induced gastrointestinal permeability is mediated by endogenous glucocorticoids in the rat. Gastroenterology. 119, 1019-1028.
    Pubmed CrossRef
  51. Saunders, PR, Santos, J, Hanssen, NP, Yates, D, Groot, JA, and Perdue, MH (2002). Physical and psychological stress in rats enhances colonic epithelial permeability via peripheral CRH. Dig Dis Sci. 47, 208-215.
    Pubmed CrossRef
  52. Ferrier, L, Mazelin, L, and Cenac, N (2003). Stress-induced disruption of colonic epithelial barrier: role of interferon-gamma and myosin light chain kinase in mice. Gastroenterology. 125, 795-804.
    Pubmed CrossRef
  53. Wallon, C, Yang, PC, and Keita, AV (2008). Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro. Gut. 57, 50-58.
    CrossRef
  54. Vanuytsel, T, van Wanrooy, S, and Vanheel, H (2014). Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 63, 1293-1299.
    CrossRef
  55. Kiliaan, AJ, Saunders, PR, and Bijlsma, PB (1998). Stress stimulates transepithelial macromolecular uptake in rat jejunum. Am J Physiol. 275, G1037-G1044.
    Pubmed
  56. Velin, AK, Ericson, AC, Braaf, Y, Wallon, C, and Soderholm, JD (2004). Increased antigen and bacterial uptake in follicle associated epithelium induced by chronic psychological stress in rats. Gut. 53, 494-500.
    Pubmed KoreaMed CrossRef
  57. Bailey, MT, and Coe, CL (1999). Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev Psychobiol. 35, 146-155.
    Pubmed CrossRef
  58. Bailey, MT, Dowd, SE, Galley, JD, Hufnagle, AR, Allen, RG, and Lyte, M (2011). Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. 25, 397-407.
    KoreaMed CrossRef
  59. Eutamene, H, and Bueno, L (2007). Role of probiotics in correcting abnormalities of colonic flora induced by stress. Gut. 56, 1495-1497.
    Pubmed KoreaMed CrossRef
  60. Gareau, MG, Jury, J, MacQueen, G, Sherman, PM, and Perdue, MH (2007). Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Gut. 56, 1522-1528.
    Pubmed KoreaMed CrossRef
  61. Mayer, EA, Padua, D, and Tillisch, K (2014). Altered brain-gut axis in autism: comorbidity or causative mechanisms?. Bioessays. 36, 933-939.
    Pubmed CrossRef
  62. Severance, EG, Yolken, RH, and Eaton, WW (). Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res.
    CrossRef
  63. Lee, SP, Sung, IK, Kim, JH, Lee, SY, Park, HS, and Shim, CS (2015). The effect of emotional stress and depression on the prevalence of digestive diseases. J Neurogastroenterol Motil. 21, 273-282.
    Pubmed KoreaMed CrossRef
  64. Shi, H, Kokoeva, MV, Inouye, K, Tzameli, I, Yin, H, and Flier, JS (2006). TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 116, 3015-3025.
    Pubmed KoreaMed CrossRef
  65. Kim, KA, Gu, W, Lee, IA, Joh, EH, and Kim, DH (2012). High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One. 7, e47713.
    Pubmed KoreaMed CrossRef
  66. Maes, M, Twisk, FN, Kubera, M, Ringel, K, Leunis, JC, and Geffard, M (2012). Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord. 136, 909-917.
    CrossRef
  67. Flierl, MA, Rittirsch, D, and Nadeau, BA (2007). Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature. 449, 721-725.
    Pubmed CrossRef
  68. Macfarlane, S, and Macfarlane, GT (2003). Regulation of short-chain fatty acid production. Proc Nutr Soc. 62, 67-72.
    Pubmed CrossRef
  69. Brown, AJ, Goldsworthy, SM, and Barnes, AA (2003). The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 278, 11312-11319.
    CrossRef
  70. Kimura, I, Ozawa, K, and Inoue, D (2013). The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun. 4, 1829.
    Pubmed KoreaMed CrossRef
  71. Xiong, Y, Miyamoto, N, and Shibata, K (2004). Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci USA. 101, 1045-1050.
    Pubmed KoreaMed CrossRef
  72. Kim, MH, Kang, SG, Park, JH, Yanagisawa, M, and Kim, CH (2013). Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. 145, Array-Array.
    Pubmed CrossRef
  73. Milo, LA, Reardon, KA, and Tappenden, KA (2002). Effects of short-chain fatty acid-supplemented total parenteral nutrition on intestinal pro-inflammatory cytokine abundance. Dig Dis Sci. 47, 2049-2055.
    Pubmed CrossRef
  74. Kimura, I, Inoue, D, and Maeda, T (2011). Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA. 108, 8030-8035.
    Pubmed KoreaMed CrossRef
  75. Frost, G, Sleeth, ML, and Sahuri-Arisoylu, M (2014). The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun. 5, 3611.
    Pubmed KoreaMed CrossRef
  76. Mitchell, RW, On, NH, Del Bigio, MR, Miller, DW, and Hatch, GM (2011). Fatty acid transport protein expression in human brain and potential role in fatty acid transport across human brain microvessel endothelial cells. J Neurochem. 117, 735-746.
    Pubmed
  77. DeCastro, M, Nankova, BB, and Shah, P (2005). Short chain fatty acids regulate tyrosine hydroxylase gene expression through a cAMP-dependent signaling pathway. Brain Res Mol Brain Res. 142, 28-38.
    Pubmed CrossRef
  78. Neufeld, KM, Kang, N, Bienenstock, J, and Foster, JA (2011). Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neuro-gastroenterol Motil. 23, Array-264.
    CrossRef
  79. Clarke, G, Grenham, S, and Scully, P (2013). The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 18, 666-673.
    CrossRef
  80. Yano, JM, Yu, K, and Donaldson, GP (2015). Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 161, 264-276.
    Pubmed KoreaMed CrossRef
  81. Panula, P, and Nuutinen, S (2013). The histaminergic network in the brain: basic organization and role in disease. Nat Rev Neurosci. 14, 472-487.
    Pubmed CrossRef
  82. Thomas, CM, Hong, T, and van Pijkeren, JP (2012). Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One. 7, e31951.
    Pubmed KoreaMed CrossRef
  83. Wu, G (2009). Amino acids: metabolism, functions, and nutrition. Amino Acids. 37, 1-17.
    Pubmed CrossRef
  84. O’Mahony, SM, Clarke, G, Borre, YE, Dinan, TG, and Cryan, JF (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 277, 32-48.
    CrossRef
  85. Desbonnet, L, Garrett, L, Clarke, G, Bienenstock, J, and Dinan, TG (2008). The probiotic Bifidobacteria infantis: an assessment of potential antidepres-sant properties in the rat. J Psychiatr Res. 43, 164-174.
    Pubmed CrossRef
  86. Tremaroli, V, and Bäckhed, F (2012). Functional interactions between the gut micro-biota and host metabolism. Nature. 489, 242-249.
    Pubmed CrossRef
  87. Nicholson, JK, Holmes, E, and Kinross, J (2012). Host-gut microbiota metabolic interactions. Science. 336, 1262-1267.
    Pubmed CrossRef
  88. Goehler, LE, Gaykema, RP, Opitz, N, Reddaway, R, Badr, N, and Lyte, M (2005). Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni. Brain Behav Immun. 19, 334-344.
    Pubmed CrossRef
  89. Bercik, P, Park, AJ, and Sinclair, D (2011). The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 23, 1132-1139.
    Pubmed KoreaMed CrossRef
  90. Bravo, JA, Forsythe, P, and Chew, MV (2011). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA. 108, 16050-16055.
    Pubmed KoreaMed CrossRef
  91. Bluthe, RM, Walter, V, and Parnet, P (1994). Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism. C R Acad Sci III. 317, 499-503.
    Pubmed
  92. Laye, S, Bluthé, RM, and Kent, S (1995). Subdiaphragmatic vagotomy blocks induction of IL-1 beta mRNA in mice brain in response to peripheral LPS. Am J Physiol. 268, R1327-R1331.
    Pubmed
  93. Luheshi, GN, Bluthé, RM, and Rushforth, D (2000). Vagotomy attenuates the behavioural but not the pyrogenic effects of interleukin-1 in rats. Auton Neurosci. 85, 127-132.
    CrossRef
  94. Konsman, JP, Luheshi, GN, Bluthé, RM, and Dantzer, R (2000). The vagus nerve mediates behavioural depression, but not fever, in response to peripheral immune signals; a functional anatomical analysis. Eur J Neurosci. 12, 4434-4446.
    Pubmed CrossRef
  95. Bercik, P, Verdu, EF, and Foster, JA (2010). Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology. 139, Array-2112.
    Pubmed CrossRef
  96. Sudo, N, Chida, Y, and Aiba, Y (2004). Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol. 558, 263-275.
    Pubmed KoreaMed CrossRef
  97. Zeissig, S, and Blumberg, RS (2014). Life at the beginning: perturbation of the microbiota by antibiotics in early life and its role in health and disease. Nat Immunol. 15, 307-310.
    Pubmed CrossRef
  98. Matthews, DM, and Jenks, SM (2013). Ingestion of Mycobacterium vaccae decreases anxiety-related behavior and improves learning in mice. Behav Processes. 96, 27-35.
    Pubmed CrossRef
  99. Crumeyrolle-Arias, M, Jaglin, M, and Bruneau, A (2014). Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology. 42, 207-217.
    Pubmed CrossRef
  100. Lippmann, M, Bress, A, Nemeroff, CB, Plotsky, PM, and Monteggia, LM (2007). Long-term behavioural and molecular alterations associated with maternal separation in rats. Eur J Neurosci. 25, 3091-3098.
    Pubmed CrossRef
  101. O’Mahony, SM, Hyland, NP, Dinan, TG, and Cryan, JF (2011). Maternal separation as a model of brain-gut axis dysfunction. Psychopharmacology (Berl). 214, 71-88.
    CrossRef
  102. O’Mahony, SM, Marchesi, JR, and Scully, P (2009). Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 65, 263-267.
    CrossRef
  103. Goehler, LE, Park, SM, Opitz, N, Lyte, M, and Gaykema, RP (2008). Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain Behav Immun. 22, 354-366.
    CrossRef
  104. Lyte, M, Varcoe, JJ, and Bailey, MT (1998). Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation. Physiol Behav. 65, 63-68.
    Pubmed CrossRef
  105. Messaoudi, M, Violle, N, Bisson, JF, Desor, D, Javelot, H, and Rougeot, C (2011). Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes. 2, 256-261.
    Pubmed CrossRef
  106. Bercik, P, Denou, E, and Collins, J (2011). The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 141, Array-Array.
    Pubmed CrossRef
  107. Park, AJ, Collins, J, and Blennerhassett, PA (2013). Altered colonic function and microbiota profile in a mouse model of chronic depression. Neurogastroenterol Motil. 25, Array.
    Pubmed KoreaMed CrossRef
  108. Dinan, TG, and Cryan, JF (2013). Melancholic microbes: a link between gut microbiota and depression?. Neurogastroenterol Motil. 25, 713-719.
    Pubmed CrossRef
  109. Naseribafrouei, A, Hestad, K, and Avershina, E (2014). Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil. 26, 1155-1162.
    Pubmed CrossRef
  110. Jiang, H, Ling, Z, and Zhang, Y (2015). Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun. 48, 186-194.
    Pubmed CrossRef
  111. Desbonnet, L, Garrett, L, Clarke, G, Kiely, B, Cryan, JF, and Dinan, TG (2010). Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience. 170, 1179-1188.
    Pubmed CrossRef
  112. Arseneault-Breard, J, Rondeau, I, and Gilbert, K (2012). Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces post-myocardial infarction depression symptoms and restores intestinal permeability in a rat model. Br J Nutr. 107, 1793-1799.
    CrossRef
  113. Gilbert, K, Arseneault-Bréard, J, and Flores Monaco, F (2013). Attenuation of post-myocardial infarction depression in rats by n-3 fatty acids or probiotics starting after the onset of reperfusion. Br J Nutr. 109, 50-56.
    CrossRef
  114. Mello, BS, Monte, AS, and McIntyre, RS (2013). Effects of doxycycline on depressive-like behavior in mice after lipopolysaccharide (LPS) administration. J Psychiatr Res. 47, 1521-1529.
    Pubmed CrossRef
  115. Soczynska, JK, Mansur, RB, and Brietzke, E (2012). Novel therapeutic targets in depression: minocycline as a candidate treatment. Behav Brain Res. 235, 302-317.
    Pubmed CrossRef
  116. Gareau, MG (2014). Microbiota-gut-brain axis and cognitive function. Adv Exp Med Biol. 817, 357-371.
    Pubmed CrossRef
  117. Gareau, MG, Wine, E, and Rodrigues, DM (2011). Bacterial infection causes stress-induced memory dysfunction in mice. Gut. 60, 307-317.
    CrossRef
  118. Li, W, Dowd, SE, Scurlock, B, Acosta-Martinez, V, and Lyte, M (2009). Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria. Physiol Behav. 96, 557-567.
    Pubmed CrossRef
  119. Kamal, A, Biessels, GJ, Ramakers, GM, and Hendrik Gispen, W (2005). The effect of short duration streptozotocin-induced diabetes mellitus on the late phase and threshold of long-term potentiation induction in the rat. Brain Res. 1053, 126-130.
    Pubmed CrossRef
  120. Davari, S, Talaei, SA, Alaei, H, and Salami, M (2013). Probiotics treatment improves diabetes-induced impairment of synaptic activity and cognitive function: behavioral and electrophysiological proofs for microbiome-gut-brain axis. Neuroscience. 240, 287-296.
    Pubmed CrossRef
  121. Tillisch, K, Labus, J, and Kilpatrick, L (2013). Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 144, Array-1401.
    Pubmed KoreaMed CrossRef
  122. Severance, EG, Gressitt, KL, and Stallings, CR (2013). Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res. 148, 130-137.
    Pubmed KoreaMed CrossRef
  123. Dohan, FC, Harper, EH, Clark, MH, Rodrigue, RB, and Zigas, V (1984). Is schizophrenia rare if grain is rare?. Biol Psychiatry. 19, 385-399.
    Pubmed
  124. Morgan, C, Charalambides, M, Hutchinson, G, and Murray, RM (2010). Migration, ethnicity, and psychosis: toward a sociodevelopmental model. Schizophr Bull. 36, 655-664.
    Pubmed KoreaMed CrossRef
  125. Desbonnet, L, Clarke, G, Shanahan, F, Dinan, TG, and Cryan, JF (2014). Microbiota is essential for social development in the mouse. Mol Psychiatry. 19, 146-148.
    KoreaMed CrossRef
  126. Dinan, TG, Borre, YE, and Cryan, JF (2014). Genomics of schizophrenia: time to consider the gut microbiome?. Mol Psychiatry. 19, 1252-1257.
    Pubmed CrossRef
  127. Dickerson, FB, Stallings, C, and Origoni, A (2014). Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord. 16.
    Pubmed KoreaMed
  128. Hsiao, EY, McBride, SW, and Hsien, S (2013). Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 155, 1451-1463.
    Pubmed KoreaMed CrossRef
  129. de Theije, CG, Wopereis, H, and Ramadan, M (2014). Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun. 37, 197-206.
    CrossRef
  130. MacFabe, DF, Cain, NE, Boon, F, Ossenkopp, KP, and Cain, DP (2011). Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: relevance to autism spectrum disorder. Behav Brain Res. 217, 47-54.
    CrossRef
  131. Thomas, RH, Meeking, MM, and Mepham, JR (2012). The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. J Neuroinflammation. 9, 153.
    Pubmed KoreaMed CrossRef
  132. Shultz, SR, Macfabe, DF, and Martin, S (2009). Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long-Evans rat: further development of a rodent model of autism. Behav Brain Res. 200, 33-41.
    Pubmed CrossRef
  133. Shultz, SR, MacFabe, DF, and Ossenkopp, KP (2008). Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism. Neuropharmacology. 54, 901-911.
    Pubmed CrossRef
  134. Finegold, SM, Dowd, SE, and Gontcharova, V (2010). Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 16, 444-453.
    Pubmed CrossRef
  135. Parracho, HM, Bingham, MO, Gibson, GR, and McCartney, AL (2005). Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol. 54, 987-991.
    Pubmed CrossRef
  136. Song, Y, Liu, C, and Finegold, SM (2004). Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol. 70, 6459-6465.
    Pubmed KoreaMed CrossRef
  137. Ming, X, Stein, TP, Barnes, V, Rhodes, N, and Guo, L (2012). Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res. 11, 5856-5862.
    Pubmed
  138. Emond, P, Mavel, S, and Aïdoud, N (2013). GC-MS-based urine metabolic profiling of autism spectrum disorders. Anal Bioanal Chem. 405, 5291-5300.
    Pubmed CrossRef
  139. Schwab, AJ, Tao, L, Yoshimura, T, Simard, A, Barker, F, and Pang, KS (2001). Hepatic uptake and metabolism of benzoate: a multiple indicator dilution, perfused rat liver study. Am J Physiol Gastrointest Liver Physiol. 280, G1124-G1136.
    Pubmed
  140. Yap, IK, Angley, M, Veselkov, KA, Holmes, E, Lindon, JC, and Nicholson, JK (2010). Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 9, 2996-3004.
    Pubmed CrossRef
  141. Bell, JG, MacKinlay, EE, Dick, JR, MacDonald, DJ, Boyle, RM, and Glen, AC (2004). Essential fatty acids and phospholipase A2 in autistic spectrum disorders. Prostaglandins Leukot Essent Fatty Acids. 71, 201-204.
    Pubmed CrossRef
  142. El-Ansary, AK, Bacha, AG, and Al-Ayahdi, LY (2011). Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi Arabia. Lipids Health Dis. 10, 63.
    Pubmed KoreaMed CrossRef
  143. Finegold, SM (2011). Desulfovibrio species are potentially important in regressive autism. Med Hypotheses. 77, 270-274.
    Pubmed CrossRef
  144. Emanuele, E, Orsi, P, and Boso, M (2010). Low-grade endotoxemia in patients with severe autism. Neurosci Lett. 471, 162-165.
    Pubmed CrossRef
  145. Elder, JH, Shankar, M, Shuster, J, Theriaque, D, Burns, S, and Sherrill, L (2006). The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial. J Autism Dev Disord. 36, 413-420.
    Pubmed CrossRef
  146. Millward, C, Ferriter, M, Calver, S, and Connell-Jones, G (2008). Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev, CD003498.
    Pubmed KoreaMed
  147. Diaz Heijtz, R, Wang, S, and Anuar, F (2011). Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA. 108, 3047-3052.
    Pubmed KoreaMed CrossRef
  148. Coury, DL, Ashwood, P, and Fasano, A (2012). Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics. 130, S160-S168.
    Pubmed CrossRef
  149. McElhanon, BO, McCracken, C, Karpen, S, and Sharp, WG (2014). Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics. 133, 872-883.
    Pubmed CrossRef
  150. Sandler, RH, Finegold, SM, and Bolte, ER (2000). Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 15, 429-435.
    Pubmed CrossRef


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