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The Gut Microbiome and the Brain

Written by Leo Galland
Foundation for Integrated Medicine, New York, New York, USA.
Published in the JOURNAL OF MEDICINAL FOOD J Med Food 17 (12) 2014, 1–12

ABSTRACT

The human gut microbiome impacts human brain health in numerous ways: (1) Structural bacterial components such as lipopolysaccharides provide low-grade tonic stimulation of the innate immune system. Excessive stimulation due to bacterial dysbiosis, small intestinal bacterial overgrowth, or increased intestinal permeability may produce systemic and/or central nervous system inflammation. (2) Bacterial proteins may cross-react with human antigens to stimulate dysfunctional responses of the adaptive immune system. (3) Bacterial enzymes may produce neurotoxic metabolites such as D-lactic acid and ammonia. Even beneficial metabolites such as short-chain fatty acids may exert neurotoxicity. (4) Gut microbes can produce hormones and neurotransmitters that are identical to those produced by humans. Bacterial receptors for these hormones influence microbial growth and virulence. (5) Gut bacteria directly stimulate afferent neurons of the enteric nervous system to send signals to the brain via the vagus nerve. Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome. Their role in multiple sclerosis and the neurologic manifestations of celiac disease is being studied. Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics.

INTRODUCTION

The most surprising revelation of the Human Genome Project is the small size of the human gene pool—about 26,000 functioning units1 —compared with the genomes of much simpler organisms. Rice (Oryza sativa), for example, has about 46,000 functioning genes that have evolved over 15 million years.2 Researchers call this the ‘‘genome[1]complexity conundrum,’’3 and some speculate that human physiologic and behavioral complexity may depend on the large number of microbial genes present in the human body.

The term gut microbiome, in its strictest sense, describes the composite microbial genome found in the mammalian gastrointestinal tract. The hundred trillion bacteria in the body of an adult human contain about 4 million distinct bacterial genes, with more than 95% of them located in the large intestine.4 Since most of these genes encode for enzymes and structural proteins that influence the functioning of mammalian cells, the gut microbiome can be viewed as an anaerobic bioreactor programmed to synthesize molecules which direct the mammalian immune system,5 modify the mammalian epigenome,6 and regulate host metabolism.7 A study of germ-free (GF) mice found that the vast majority of chemicals circulating in blood are dependent on the microbiome for their synthesis, although many are subsequently modified by the host.8 These chemicals have a profound effect on mammalian behavior and neuroendocrine responses. This review will focus on research done in humans, but work done with GF rodents signals the evolutionary importance of the microbiome in shaping mammalian behavior, with important implications for human health. The developmental abnormalities found in GF mice are totally reversible by colonization with intestinal bacteria early in life but not in adulthood, suggesting that the microbiome influences brain development.9,10

When compared with conventional mice, GF mice show greater exploratory activity in an open-field activity box, suggesting less vigilance and caution.11 Similar behavioral changes are produced in conventional mice by administration of a mixture of nonabsorbed antibiotics for 7 days.12 Although some researchers have attributed these behavioral changes to diminished anxiety, elevation of striatal norepinephrine, dopamine, and serotonin turnover in the brains of GF mice11 and elevated plasma levels of adrenal corticotrophic hormone and corticosterone in response to restraint stress13 demonstrate heightened stress reactivity in GF mice, an effect also seen in GF rats, who are, however, less active and more cautious than conventional rats.14 It appears that Manuscript received 9 September 2014. Revision accepted 9 October 2014. Address correspondence to: Leo Galland, MD, Foundation for Integrated Medicine, New York, NY, 10011, USA, E-mail: Lgallandmd@aol.com. JOURNAL OF MEDICINAL FOOD J Med Food 17 (12) 2014, 1–12 # Mary Ann Liebert, Inc., and Korean Society of Food Science and Nutrition DOI: 10.1089/jmf.2014.7000 1both timidity, a behavior pattern associated with mice, and aggressiveness, a behavior pattern associated with rats, re[1]quire a microbiome for their characteristic expression. Either behavioral deviation—the increased risk taking of GF mice or the withdrawal of GF rats—can significantly impair survival in the wild, where the need to gather food should be balanced against the need to avoid predators. These rodent studies suggest that the gut microbiome has strategic evolutionary importance by modulating stress responses and influencing behaviors that impact the survival of species.15

Studies with different strains of laboratory mice indicate that there may be specific behavioral effects induced by specific microbiota. Balb/C mice, for example, are more susceptible to stressors and to the effects of the anxiogenic neurohormone corticotrophin-releasing factor than are NIH Swiss mice.16 When GF variants of either strain are colonized by gut microbes of the other strain, they begin be[1]having similar to conventional versions of the strain whose microbiome they have received.12 Balb/C mice become less stress reactive, and NIH Swiss mice become more stress reactive than their conventional counterparts.

Central nervous system (CNS) effects of the microbiome may be produced by immunologic, biochemical, or neuro[1]endocrine mechanisms.17

IMMUNOLOGIC MECHANISMS

The innate immune system

Structural components of the microbial cell wall continually stimulate the innate immune system to produce cytokines, creating a basal state of immune activation that begins at the intestinal mucosal surface and impacts the entire body.18

The gut microbiome interacts with the hypothalamic[1]pituitary-adrenal (HPA) axis to shape the normal architecture of sleep. Bacterial peptides induce intestinal macrophages and T-cells to produce the cytokines interleukin-1beta (IL-1b) and tumor necrosis factor alpha (TNFa)19; bacterial cell wall lipopolysaccharides (LPS) induce synthesis of IL-18.20 The adult human gut is believed to contain about one gram of LPS.15 IL-1b,21 TNFa22, and IL-1823 are inducers of nonrapid eye movement (nREM) sleep. Cortisol inhibits immune cell synthesis of these cytokines. IL-1b and TNFa show a circadian rhythm in human blood, with peak levels at midnight, when cortisol is the lowest, and trough levels in the early morning, as plasma cortisol surges.24 The cortisol-induced decline in microbiome-stimulated circulating IL-1b may orchestrate the normal shift from early sleep, which is predominantly nREM, to late sleep, which is dominated by REM.25

Although cytokine secretion induced by low-level expo[1]sure of immune cells to bacterial cell wall components contributes to normal sleep patterns, excessive cytokine levels are associated with disrupted sleep.26 Parenteral administration of LPS to humans in nanogram quantities (0.4 ng/kg body weight) increases plasma concentration of pro-inflammatory cytokines IL-6 and TNFa and the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist, along with salivary and plasma cortisol and plasma norepinephrine. These changes are accompanied by depressed mood, increased anxiety, and impaired long-term memory for emotional stimuli.27 In addition, visceral pain sensitivity thresholds are reduced and visceral pain (provoked by rectal distension) is rated as more unpleasant after administration of low-dose LPS.28

Increased exposure to gut microbiome-derived LPS (endotoxemia) may occur in the elderly, in whom it is diminished by yogurt consumption,29 as a consequence of small intestinal bacterial overgrowth (SIBO),30,31 and secondary to increased intestinal permeability resulting from extreme physiologic stress,32 ethanol exposure,33 or a ‘‘fast-food style’’ Western diet, high in both carbohydrate and saturated fat.34

LeClercq et al.35 have reported increased intestinal permeability, elevated blood LPS and peptidoglycan levels, and low-grade systemic inflammation associated with psycho[1]logical symptoms of alcohol dependence in alcohol-dependent subjects. They tested inflammatory responses of peripheral blood mononuclear cells (PBMCs) to gut-derived bacterial products in healthy controls and in chronic alcoholics before and during ethanol detoxification. They found activation of Toll-like receptors by LPS and peptidoglycans in PBMCs of alcoholics, associated with increased messenger RNA and plasma levels of IL-8, IL-1b, and IL-18. Levels of IL-8 and IL-1b were positively correlated with alcohol consumption and alcohol-craving scores. Using Cr51-EDTA as a probe of intestinal permeability, they divided their population of chronic alcoholics into those with high and normal permeability.36 The high permeability group had higher scores of depression, anxiety, and alcohol craving than the low permeability group, as well as a distinct pattern of changes in the gut microbial population, characterized by decreased colonization with bacteria known to have anti-inflammatory effects, Bifidobacterium species and Faecalibacterium prausnitzkii in particular. Those alcoholics who showed persistence of intestinal hyperpermeability after 3 weeks of ethanol withdrawal also demonstrated persistence of depression, anxiety, and alcohol craving. Their theory is that for some alcoholics (probably 30–50% of the total), ethanol consumption alters the gut microbiome to deplete protective bacteria, increasing intestinal permeability and producing systemic inflammation provoked by absorption of bacterial peptidoglycans and LPS, which amplifies the psychopathology of ethanol addiction.

Increased intestinal permeability has also been described in patients with chronic fatigue syndrome (CFS),37 fibromyalgia, and complex regional pain syndrome.38 SIBO by itself can increase intestinal permeability39; SIBO is as[1]sociated with fibromyalgia40 and restless legs syndrome (RLS),41 with treatment of SIBO producing clinically significant improvement in a small group of patients with RLS.41 The CNS effects of elevated gut-derived LPS or peptidoglycan exposure might contribute to the pathogenesis of these disorders.

Researchers at Johns Hopkins University School of Medicine found evidence of increased gut bacterial translocation in schizophrenic patients, unrelated to antipsychotic treatment. Presence of the translocation marker soluble CD14 tripled the risk of schizophrenia and was positively associated with C-reactive protein (CRP) but not with LPS-binding protein (LBP), suggesting that gut bacterial components other than LPS may be stimulating monocyte activation and inflammation in schizophrenics.42

In summary, the gut microbiome stimulates a chronic state of low-level activation of the innate immune system in humans, which is influenced by the circadian pattern of adrenal cortical function. Altered exposure to structural components of the microbiome, which may occur because of increased intestinal permeability or SIBO, may disrupt normal neuroendocrine regulation and has been associated with several disorders linked to abnormal CNS function.

Adaptive immunity

The adaptive immune system responds to specific microbes with antibodies or antigen-specific cellular immune responses and can produce CNS dysfunction through auto-immune re[1]actions caused by molecular mimicry between bacterial and self proteins. Although this is an area of ongoing investigation, there is presently little evidence for a link between the gut microbiome, the adaptive immune system, specific auto[1]immunity, and disorders of the CNS in humans.43,44 However, in a laboratory model of multiple sclerosis, mice sensitized to the autoantigen, myelin oligodendrocyte glycoprotein, only developed experimental autoimmune encephalitis in the presence of commensal bacteria.45

Celiac disease (CD) is a notable exception, although the mechanism is indirect. Alterations in the gut microbiome may play a primary role in the pathogenesis of CD,46 a gluten-sensitive disease in which the adaptive immune system damages not only the gut but also the brain. The most common CNS manifestations of CD are ataxia (with or without myoclonus), headache, and cognitive dysfunction. Gastrointestinal symptoms are often absent in neurologic CD, as are the usual marker of intestinal CD, transglutaminase (TG) antibodies. The autoimmune target in neuro[1]logic gluten sensitivity is TG6 rather than TG2, which is the target for autoantibodies measured in commercial tests.47 Most studies, but not all,48 have found significant differences between healthy children and children with CD in the duodenal49,50 and oral51 microbial populations. Some of these differences are the result of inflammation and disappear during a gluten-free diet, but reduced levels of Bifidobacterium species, a replicable finding, do not become normal with a gluten-free diet.52,53 Infants at high risk of developing CD because of family history and personal genotype show a reduction in Bifidobacteria before the onset of illness.54 Bifidobacteria protect human intestinal cells from the toxic effects of gliadin peptides, the inflammatory triggers of CD, by altering their structure.55 They also induce an anti-inflammatory response in stimulated human mononuclear cells in tissue culture.56 Destruction of protective Bifidobacteria can explain the association between incident CD and previous antibiotic exposure.57 Loss of Bifidobacteria may play a pathogenetic role in CD and contribute to its rising prevalence. Administration of Bifidobacterium longum ameliorates an animal model of gluten enteropathy,58 and Bifidobacteria have been proposed as potential therapeutic agents for prevention of CD in high-risk individuals.59

BIOCHEMICAL MECHANISMS

Intestinal bacteria produce numerous metabolites with potential encephalotoxicity. The most studied are D-lactic acid60 and ammonia.61 Their role in common clinical syndromes will be briefly reviewed, followed by a discussion of the conflicting roles of short-chain fatty acids (SCFA), which may inhibit inflammation but contribute to the pathogenesis of autistic spectrum disorders (ASD).

D-lactic acid

A product of microbial fermentation of carbohydrate, D-lactate is usually produced in excess when small bowel resection allows delivery of a high carbohydrate load to the colon. Elevation of D-lactate in plasma may also occur after other types of abdominal surgery, as a result of increased intestinal permeability and bacterial translocation across the intestinal mucosal barrier.62 Nonsurgical causes of intestinal hyperpermeability also increase absorption of D-lactate from the intestinal lumen.63,64

Increased levels of D-lactate producing bacteria in stool were found in a study of patients with CFS and neurocognitive dysfunction, raising the possibility that microbial D-lactate might contribute to symptoms of patients with CFS.65 Maes et al. found increased intestinal permeability to be common among patients with CFS37 and to improve in response to administration of glutamine, N-acetylcysteine, and zinc along with adoption of a ‘‘leaky gut’’ diet. Improved permeability was demonstrated by reduction in titers of antibodies directed against intestinal flora and was directly related to improvement of symptoms.66 Pimentel et al. demonstrated that eradication of SIBO with antibiotics improved symptoms of patients with CFS and SIBO,67 but did not measure D-lactate production or absorption. Taken together, these studies suggest that increased intestinal permeability or SIBO in patients with CFS may permit excessive absorption of compounds such as D-lactate produced by the gut flora that have direct or indirect neurotoxic effects, contributing to chronic fatigue.

Probiotics and prebiotics may limit production of D-lactic acid in the gut but should be chosen carefully. Some species of Lactobacillus are D-lactate producers 68,69 and high-dose beta-glucan (found in oats and barley) can increase intestinal permeability.70 In a single case report, a man with recurrent D-lactic acidosis due to short bowel syndrome, who had grown unresponsive to antibiotics and dietary restriction, was rescued from repeated neurotoxicity by a combination of Bifidobacterium breve Yakult and Lactobacillus casei Shirota as probiotics and galacto-oligosaccharide as a prebiotic. The combination, called a symbiotic, allowed re[1]duction in colonic absorption of D-lactate by limiting the growth of D-lactate-producing bacteria and stimulating intestinal motility.71 No dietary restrictions were needed. Bifidobacteria and galacto- or fructo-oligosaccharides THE GUT MICROBIOME AND THE BRAIN 3(FOS) favor acetate over lactate as an end-product of carbohydrate metabolism. Horses who had barley added to their diets experienced a change in fecal flora characterized by increased concentrations of lactic acid bacteria belonging to the genera Lactobacillus and Streptococcus, associated with an increase in D-lactate concentration in the stool. These changes were prevented by administration of FOS.72

Ammonia

Ammonia is a well-known neurotoxin, produced in the intestinal tract from urea by the action of bacterial ureases. Gut-derived ammonia is taken up by the liver and consumed in the urea cycle. By creating portosystemic shunts, cirrhosis allows absorbed ammonia to escape hepatic metabolism, increasing blood ammonia, which contributes to the pathogenesis of hepatic encephalopathy (HE).61 In addition to direct neurotoxic injury, ammonia alters function of the blood–brain barrier, impairing intracerebral synthesis of serotonin and dopamine and producing abnormal neuro[1]transmitters such as octopamine.73

Minimal HE (MHE) is a common neurocognitive disorder that occurs in 80% of cirrhotic patients74 and often evades diagnosis.75 It is characterized by subtle intellectual deficits and psychomotor abnormalities that have a significant negative impact on health-related quality of life, impair motor vehicle operation, and increase the incidence of vehicular accidents.76 Failure to diagnose MHE in apparently ‘‘normal’’ patients with chronic liver disease is considered a medical error.77

Cognitive dysfunction in patients with cirrhosis is associated with altered composition of the gut microbiome, which differs between cirrhotics with or without HE.78,79 Levels of urease-producing bacteria are positively associated with cognitive dysfunction in cirrhotic patients.80 The nonabsorbed antibiotic rifaximin, when added to conventional therapy with lactulose, increases the rate of total reversal of HE from 51% to 76% and reduces mortality from 49.1% to 23.8%,81 demonstrating the importance of gut flora in HE pathogenesis. Changing the gut microbiome with synbiotics has also been shown to alleviate cognitive dysfunction in patients with cirrhosis. A combination of B. longum and FOS82 or a cocktail of four freeze-dried, nonurease-producing bacteria (Pediacoccus pentoseceus, Leuconostoc mesenteroides, Lactobacillus paracasei ssp. paracasei, and Lactobacillus plantarum) mixed with beta glucan, inulin, pectin, and resistant starch83 had similar effects. Each regimen reduced serum ammonia and improved cognitive performance when compared with placebo. Administration of synbiotics has been proposed for all patients with cirrhosis as a way to prevent MHE. 82

Short-chain fatty acids

Volatile fatty acids with a chain length of two to four carbon atoms (acetate, propionate, and butyrate) are produced in abundance through bacterial fermentation of indigestible carbohydrate in the normal colon. Health benefits of high fiber consumption have been linked to increased syn[1]thesis of SCFA.84,85 Butyric acid, for example, supplies 70% of energy requirements of the colonic epithelium86 and has direct anti-inflammatory effects, inhibiting activation of nuclear factor kappa-B (NFkB).87 Propionic acid also inhibits NFkB and may improve insulin sensitivity by activating peroxisome proliferator-activated receptor gamma.88

In addition, SCFA impact at least two systems of molecular signaling that have widespread regulatory effects throughout the body: histone deacetylation (HDAC) and G-protein-coupled receptors (GPCRs).89 SCFA are natural inhibitors of histone deacetylases and activators of specific GPCRs. Acetylation and deacetylation of the histone proteins around which DNA coils is a fundamental process in the epigenetic regulation of gene expression. An imbalance in the direction of excessive HDAC has been found in Parkinson’s disease,90 depression, and schizophrenia.91 Inhibition of HDAC has beneficial effects in cancer and a number of animal models of CNS disease, including brain trauma, dementia, and autoimmune encephalitis.92,93 Histone deacetylase inhibitors have been proposed for enhancement of cognitive function.94

GPCRs are transmembrane proteins that recognize molecules in the extracellular milieu and transmit information within cells to regulate cell behavior.95 They represent a major gateway through which cells convert external cues into intracellular signals and respond with appropriate actions. GPCRs are implicated in the pathophysiology of many types of disease, including neurodegenerative disorders. Approximately 40% of clinically approved drugs act by modulating GPCR signaling pathways.96 SCFAs activate two specific GPCRs (GPR41 and GPR43) that have no other known ligands.97 GPR41 is abundant in human sympathetic ganglia, where its activation by propionic acid increases sympathetic nervous system outflow, and one potential mechanism by which dietary fiber can increase basal metabolic rate and help control obesity.98

Despite evidence of anti-inflammatory effects of propionic acid88 and the recommendation of some researchers that increasing propionic acid synthesis in the colon may be of therapeutic value for metabolic disorders,99 MacFabe has identified potential neurotoxicity of propionate and studied its possible role in autism.100 His group found that pathological changes in the brains of animals exposed to intra[1]ventricular propionic acid were identical to abnormalities found in the brains of autistic children and adults. Depletion of glutathione and increased markers of oxidative stress accompanied neuroinflammation. Butyrate demonstrated similar but much milder effects. MacFabe believes that gut[1]derived propionate contributes to the pathogenesis of autism and that SCFA-induced neurotoxicity explains the sensitivity to dietary carbohydrates noted by physicians treating children with ASD.

In support of MacFabe’s hypothesis are the findings of Wang et al. of elevated SCFA101 and propionate102 in the stool of autistic children. Since the most abundant carbohydrate fermenting bacteria are unchanged or reduced in stools of autistic children,103,104 Wang speculates that unusual fermenters, perhaps Clostridial species that are often elevated in the stools of autistic children,105,106 may be responsible for increased propionate production.107 Autism is associated with early weaning from breast milk to infant formula.108 Compared with breast milk, infant formula feeding increases fecal concentration of propionate and butyrate.109

Williams et al. examined ileal biopsies of autistic children with gastrointestinal (GI) complaints and found a deficit of genes encoding disaccharidases and hexose transport enzymes, indicating impairment of the primary pathway for carbohydrate digestion and absorption in enterocytes,110 a finding which suggests that bacterial dysbiosis results from an underlying impairment of digestion and absorption. In a subsequent report, they observed the presence of a unique genus of aerobic gram-negative rods, Sutterella, in ileal biopsies of autistic children with GI complaints but no children with GI complaints who were not autistic.111 Western immunoblots revealed plasma IgG or IgM antibody reactivity to the species Sutterella wadsworthensis in the majority of children with positive biopsies. S. wadsworthensis is a gastrointestinal pathogen that may be mistaken for Campylobacter jejuni and may also be found in the stool of healthy individuals.112 Following the report by Williams et al., Wang et al. confirmed an association between abundance of Sutterella and the presence of autism. They studied stool specimens, not ileal biopsies, so they were able to examine the relationship between Sutterella and GI complaints. There was none. Levels of Sutterella were related to autism only.113

A role for the gut microbiome and its metabolites in ASD is one of the leading areas in autism research these days,114,115 but the findings do not yet permit a single coherent theory on which to base therapeutic decisions. A recent report in the New England Journal of Medicine de[1]scribes structural brain abnormalities in autistic children that began during prenatal brain development,116 indicating that the roots of autism may be found in utero. Perhaps greater focus should be placed on the maternal gestational micro[1]biome. Immune activation of pregnant mice (maternal immune activation [MIA]) can create behavioral changes similar to ASD in their offspring.117 Administration of a single pro[1]biotic, Bacteroides fragilis, corrects excessive gut permeability, alters gut microbial composition, and ameliorates defects in communication and stereotypic, anxiety-like, and sensorimotor behaviors in the MIA model.

NEUROENDOCRINE MECHANISMS

Bacteria can synthesize and respond to hormones and neurotransmitters. Lactobacillus species produce acetyl-choline and gamma-amino butyrate (GABA); Bifidobacterium species produce GABA; Escherichia produce norepinephrine, serotonin and dopamine; Streptococcus and Enterococcus produce serotonin; and Bacillus species produce norepinephrine and dopamine.17 These organisms are responsive to human hormones and neurotransmitters,118 which impact their growth and virulence. Lyte119 has reviewed research indicating that growth of Escherichia coli and other Proteobacteria is greatly enhanced by physiologic concentrations of norepinephrine, explaining a direct impact of stress responses on infection, independent of the effect of stress on host immunity.

The interbacterial communication system known as quorum sensing utilizes hormone-like compounds referred to as inducers to regulate bacterial gene expression. Enterohemorrhagic Escherichia coli (EHEC) serotype O157:H7 is responsible for outbreaks of bloody diarrhea. Sperandio et al. showed that exogenous epinephrine is an inducer of the 0157:H7 virulence factor.120 EHEC growing in a stressed host may be more virulent than in a non-stressed host.

In addition to specific effects on potential pathogens, host stress responses may provoke widespread changes in gut microbial composition. Bailey et al. stressed mice with a process called Social Disruption (SDR), which significantly alters bacterial community structure in the cecum, especially when the microbiota are assessed immediately after exposure to the social stressor. SDR reduces the relative abundance of bacteria from the genus Bacteroides, while increasing the relative abundance of bacteria from the genus Clostridium. It also increases circulating levels of inflammatory cytokines, IL-6 in particular, which are significantly correlated with stressor-induced changes in microbiome composition. Pretreatment of mice with antibiotics alters the changes in community structure and attenuates the cytokine response after SDR.121

A study of college students undergoing the stress of final examinations found a decrease in the relative concentration of lactic acid bacteria in feces after the examination122 (speciation was not performed). Since lactic acid bacteria have immunomodulating effects123,124 and may influence the broader composition of the gut microbiome,125 it seems likely that humans respond to psychosocial stress with responses that are comparable to, if distinct from, the reactions of laboratory animals.

Since gut microbes modify stress responses in laboratory animals, several human clinical trials have been conducted using probiotics to study their impact on stress reactivity and mood. In the most frequently cited study, healthy French adults were administered a combination of Lactobacillus helveticus R0052 and B. longum R0175 (PF) for 30 days in a double-blind, placebo-controlled, randomized parallel group study. They were assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL), and 24 h urinary-free cortisol (UFC). The probiotic combination significantly reduced psychological distress as measured by the HSCL-90 scale (with significant reductions in global severity index, somatization, depression, and anger-hostility scores), the HADS (significant reductions in the global severity index and anxiety), and the CCL (significant increase in problem solving). There was a significant reduction in UFC.126 When administered to laboratory rats subjected to experimental myocardial infarction, the same probiotic combination reduced the increase in intestinal permeability127 and stress-induced cerebral apoptosis128 found in animals that underwent infarction without probiotic pretreatment.

Tillisch et al. administered a fermented dairy product containing Bifidobacterium animalis ssp. Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis ssp. Lactis to a group of healthy women for 4 weeks. Participants underwent functional magnetic resonance imaging before and after to measure resting brain activity and response to an emotional reactivity test.129 A control group received the same dairy product without the probiotics. Use of the probiotic drink was associated with changes in midbrain connectivity and a reduced task-related response in brain regions that control central processing of emotion and visceral sensation.

In an earlier study, researchers in Wales administered a probiotic beverage containing Lactobacillus casei to healthy elderly men and women. Those who began the study with depressed mood reported improved mood after 3 weeks of the probiotic but not the placebo beverage. Paradoxically, their memory performance was negatively impacted by the probiotic.130 The same preparation was administered for 8 weeks by a different research team to adults with CFS. There was no effect on depression, but those receiving the probiotic demonstrated significant improvement on the Beck Anxiety Inventory compared with the placebo group.131 In an uncontrolled study, 15 patients with CFS received a mixture of L. paracasei ssp. paracasei F19, Lactobacillus acidophilus NCFB 1748, and Bifidobacterium lactis Bb12 for 4 weeks. Patients reported improvement in memory and concentration but not in fatigue or physical activity.132 In a study of volunteers with stress-related irritable bowel symptoms, another probiotic combination, L. acidophilus Rosell-52 and B. longum Rosell-175, reduced abdominal pain and nausea but had no effect on psychological symptoms or sleep disturbances.133

Dinan and coworkers have reviewed the pathways by which probiotic supplements may improve depression or anxiety. Studies in mice and rats support the following interrelated mechanisms: (1) decrease in intestinal permeability resulting in reduced absorption of LPS and reduced production of inflammatory cytokines, (2) downregulation of the HPA axis in responding to stressors, and (3) direct effects on neurotransmission. Gut bacteria and their secretions influence neuronal excitation in the enteric nervous system (ENS), regulating both gut motility and sensory afferent signaling to the brain.134 Intrinsic primary afferent neurons (IPANs) are cellular targets of neuroactive bacteria and transmit microbial messages to the brain via the vagus nerve.135,136 Live bacteria may not be needed for these effects; in the case of B. fragilis, a lipid-free polysaccharide is both necessary and sufficient for IPAN activation.137 Al[1]though the vagus nerve is a critical route for communication between gut microbes and the CNS in some experimental systems, it is not the only route. Both behavior and CNS levels of brain-derived neurotrophic factor can be altered in mice by manipulation of the gut microbiome without vagal involvement.12

Most research on the neuroendocrine effects of gut microbes takes a pharmacologic rather than ecologic approach: A specific intervention is undertaken, and certain results are measured. Unlike pharmacologic agents, however, gut microbes exist in a series of interconnected and highly structured living communities. Administering a probiotic does more than just introduce a new bacterial species, which may or may not be able to establish a niche in the community. It may change community structure in unexpected ways, and these changes may or may not alter community function.138 Human studies have unveiled substantial differences in the gut microbial composition among individuals 139–141 that depend on age, genetic background, physiological state, microbial interactions, environmental factors, and diet.142–144 Moreover, the microbiota of the effluent from the ileum is both simpler and less stable than colonic fecal microflora and is dominated by different bacterial phyla.145 This complexity implies that the application of clinical and laboratory research on the health effects of manipulating the microbiome will need to be tailored to specific characteristics of each individual patient.146

DIET AND THE GUT MICROBIOME

Since diet has a significant impact on composition and function of the human gut microbiome, dietary patterns should be considered in attempts to understand the impact of gut microbes on the brain, especially when interventions are designed. Sequence analysis of amplified microbial ribosomal RNA-encoding genes (16S ribosomal DNA) reveals that the human adult microbiota consists of five bacterial phyla: Firmicutes and Bacteroidetes predominate, with Actinobacteria, Proteobacteria, and Verrucomicrobia comprising just 2% of organisms. Most belong to the genera Faecalibacterium, Bacteroides, Roseburia, Ruminococcus, Eubacterium, Coprabacillus, and Bifidobacterium.147 A diet high in animal protein and fat favors abundance of Bacteroides. A vegetarian diet or one high in monosaccharides favors abundance of Prevotella species.148 High consumption of oligosaccharides favors growth of Bifidobacteria, which is the dominant genus of breast-fed infants, who receive most of their carbohydrate in the form of breast milk oligosaccharides.149

The impact of diet on the microbiome is an area of intense study at present, with most research focused on metabolic effects as they relate to obesity, diabetes, and cardiovascular disease. A systematic discussion is outside the scope of this review. There is almost no published research that describes actual diet— > microbiome— > CNS effects in humans, just allusions to such an effect. A role for dietary restriction in the treatment of D-lactic acidosis was previously mentioned. In a single case report, restriction of monosaccharides and sucrose was shown to decrease D[1]lactate production in a patient with short bowel syndrome, preventing neurotoxicity.150

Several aspects of the diet/microbiome relationship deserve further research for their potential importance to brain health in the care of individual patients:

  1. Bacteria can feed or inhibit the growth of each other. Metabolic interactions among components of the microbiome (the microbial metabolome) is at the cutting edge of microbiome research.151 Although inter-bacterial inhibition has been understood for a long time, inter-bacterial growth synergy may be as important. Propionibacterium freudenreichii, a bacterium found in Swiss cheese, produces substances that enhance growth of Bifidobacteria.152 Administration of this bifidogenic substance to patients with ulcerative colitis produced an increase in fecal butyrate associated with clinical improvement.153

  2. Most studies indicate that both health and decreased adiposity are associated with increased diversity of the gut microflora. Dietary restriction increases diversity; dietary excess tends to reduce it.154

  3. Extreme dietary changes, such as adoption of a ketogenic diet, produce immediate profound changes in the human gut microbiome. Less dramatic interventions produce mild to moderate changes that vary from person to person and tend to be less than interindividual variability.155

  4. A normal microbiome increases nutrient bioavailability. In order to maintain their health, GF mice should be fed a diet of higher nutrient quantity and diversity than conventional mice.156 The effect of diet change on the microbiome is not likely to be unidirectional. An altered microbiome may change the effect of food on the host.

  5. Alterations of the microbiome may alter the physio[1]logic effect of nutrients. A critical example of this phenomenon is revealed in the work of Hazen and colleagues at The Cleveland Clinic, who found that higher plasma levels of the vascular toxin trimethylamine-N-oxide (TMAO) conferred an increased risk of major cardiovascular events during a 3-year follow[1]up.157 They also demonstrated that plasma TMAO is the product of gut microbial metabolism of dietary choline to trimethylamine (TMA), followed by hepatic oxidation of TMA to TMAO. The same team demonstrated that the gut microbiome of human vegetarians produces significantly less TMA than the gut microbiome of omnivores when fed L-carnitine, another substrate for TMA synthesis.158 In this way, an essential dietary nutrient (choline) is converted to a vasculopathic substance by the action of a microbiome whose composition is determined by a previous dietary pattern.

  6. Diet involves more than nutrients. Polyphenols are bioactive non-nutrient plant compounds whose bio-availability and physiologic effects greatly depend on their transformation by components of the gut microbiota. Polyphenols, in turn, alter microbial growth patterns. The polyphenol composition of an individual’s diet may be more important than macronutrient composition for determining growth effects on gut microbes.159

  7. Colonic bacteria have been found in biofilms formed around food particles. These organize gut microbes into distinct communities that behave differently from their planktonic counterparts. Bacteria living in food-associated biofilms produce unique signaling molecules and may represent a new dimension in the relationship between food, microbes, and human health.160

CONCLUSION

Experimental studies with human volunteers and with small mammals demonstrate effects of commensal intestinal bacteria on behavior and brain function that are contextually meaningful and which appear to be biologically significant. Gut bacteria influence reactivity of the HPA axis and the induction and maintenance of nREM sleep. They may in[1]fluence mood, pain sensitivity and normal brain development.

Clinical studies have demonstrated distinct pathological CNS effects of commensal gut bacteria in hepatic cirrhosis and short bowel syndrome and have led researchers to speculate on possible adverse effects of gut microbes in alcohol dependence, CFS, fibromyalgia, RLS, ASD, schizophrenia, mood disorders, and degenerative or autoimmune neurologic disease. Adverse effects have been attributed to alterations in bacterial community structure (dysbiosis), SIBO, and increased intestinal permeability.

Several mechanisms, none mutually exclusive, may enable commensal gut bacteria to influence function or dysfunction in the CNS: (1) stimulation of host immune responses leading to diverse patterns of systemic cytokine activation; (2) synthesis of absorbable neuroactive metabolites, including neurotransmitters; and (3) alterations in neuronal circuitry by direct microbial effects on the ENS, with CNS transmission through vagal and other routes. The only mechanisms with a high level of proof in humans are the neurotoxic effects of ammonia in HE and of D-lactic acid in short bowel syndrome.

CNS and neuroendocrine activity, stress responses in particular, may, in turn, influence the composition of the gut microbiome by differentially altering the growth of bacterial species and the production of bacterial virulence factors. Enterobacteriaceae, a family that includes most of the aerobic Gram-negative pathogens, is especially well tuned to exploiting host stress responses for enhancing bacterial growth and virulence.

Dietary patterns also modify microbiome composition and function, in complex ways that vary among individuals and cultures and are the subject of intense ongoing research. Prebiotics, probiotics, and fermented foods such as yogurt may influence the impact of the gut microbiome on the CNS and have shown significant effects on brain function in a number of experimental trials and clinical studies. Along with diet, these functional food components may offer future opportunities for altering the microbiome to enhance cognitive or emotive function and prevent or treat neurologic disorders.

AUTHOR DISCLOSURE STATEMENT

No competing financial interests exist.

REFERENCES

  1. Venter JC, Adams MD, Myers EW, et al.: The sequence of the human genome. Science 2001;291:1304–1351.
  2. Jacquemin J, Ammiraju JS, Haberer G, et al.: Fifteen million years of evolution in the Oryza genus shows extensive gene family expansion. Mol Plant 2014;7:642–656.
  3. Surjyadipta B, Lukiw WJ, Alzheimer’s disease and the micro[1]biome. Front Cell Neurosci 2013;7:153–160.
  4. Qin J, Li R, Raes J, Arumugam M, et al.: A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464:59–65.
  5. Hooper LV: Bacterial contributions to mammalian gut development. Trends Microbiol 2004;12:129–134.
  6. Li M, Wang B, Zhang M, et al.: Symbiotic gut microbes modulate human metabolic phenotypes. PNAS 2008;105:2117– 2122.
  7. Jacobsen UP, Nielsen HB, Hildebrand F, et al.: The chemical interactome space between the human host and the genetically defined gut metabotypes. ISME J 2013;7:730–742.
  8. Wikoff WR, Anfora AT, Liu J, et al.: Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA 2009;106:3698–3703.
  9. Neufeld KM, Kang N, Bienenstock J, Foster JA: Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 2011;23:255–264, e119.
  10. Diamond B, Huerta PT, Tracey K, Volpe BT: It takes guts to grow a brain: increasing evidence of the important role of the intestinal microflora in neuro- and immune-modulatory functions during development and adulthood. Bioessays 2011;33: 588–591.
  11. Diaz Heijtz R, Wang S, Anuar F, et al.: Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA 2011;108:3047–3052.
  12. Bercik P, Park AJ, Sinclair D, et al.: The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil 2011;23: 1132–1139
  13. Sudo N, Chida Y, Aiba Y, et al.: Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 2004;558(Pt 1):263–275.
  14. Crumeyrolle-Arias M, Jaglin M, Bruneau A, et al.: Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 2014;42:207–217.
  15. Bested AC, Logan AC, Selhub EM: Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part II—contemporary contextual research. Gut Pathog 2013;5:3.
  16. Conti LH, Costello DG, Martin LA, et al.: Mouse strain differences in the behavioral effects of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF9-41. Pharmacol Biochem Behav 1994;48:497–503.
  17. Cryan JF, Dinan TG: Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012;13:701–712.
  18. Duerkop BA, Vaishnava S, Hooper LV: Immune responses to the microbiota at the intestinal mucosal surface. Immunity 2009; 31:368–376.
  19. Heumann D, Barras C, Severin A, Glauser MP, Tomasz A: Gram-positive cell walls stimulate synthesis of tumor necrosis factor alpha and interleukin-6 by human monocytes. Infect Immun 1994;62:2715–2721.
  20. Ulevitch RJ, Tobias PS: Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol 1995;13:437–457.
  21. Alam MN, McGinty D, Bashir T, et al.: Interleukin-1beta modulates state-dependent discharge activity of preoptic area and basal forebrain neurons: role in sleep regulation. Eur J Neurosci 2004;20:207–216.
  22. Schuld A, Haack M, Hinze-Selch D, et al.: [Experimental studies on the interaction between sleep and the immune system in humans]. Psychother Psychosom Med Psychol 2005;55: 29–35.
  23. Kubota T, Fang J, Brown RA, Krueger JM: Interleukin-18 promotes sleep in rabbits and rats. Am J Physiol Regul Integr Comp Physiol 2001;281:R828–R838.
  24. Cermakian N, Lange T, Golombek D, et al.: Crosstalk between the circadian clock circuitry and the immune system. Chronobiol Int 2013;30:870–888.
  25. Marshall L, Born J: Brain-immune interactions in sleep. Int Rev Neurobiol 2002;52:93–131.
  26. Yang JY, Huang JW, Chiang CK, et al.: Higher plasma interleukin-18 levels associated with poor quality of sleep in peritoneal dialysis patients. Nephrol Dial Transplant 2007; 22:3606–3609.
  27. Grigoleit JS, Kullmann JS, Wolf OT, et al.: Dose-dependent effects of endotoxin on neurobehavioral functions in humans. PLoS One 2011;6:e28330.
  28. Benson S, Kattoor J, Wegner A, et al.: Acute experimental endotoxemia induces visceral hypersensitivity and altered pain evaluation in healthy humans. Pain 2012;153:794–799.
  29. Schiffrin EJ, Parlesak A, Bode C, et al.: Probiotic yogurt in the elderly with intestinal bacterial overgrowth: endotoxaemia and innate immune functions. Br J Nutr 2009;101:961–966.
  30. Bauer TM, Schwacha H, Steinbru¨ckner B, et al.: Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol 2002;97:2364–2370.
  31. Bondarenko VM, Lykova EA, Matsulevich TV: [Micro[1]ecological aspects of small intestinal bacterial overgrowth syn[1]drome]. Zh Mikrobiol Epidemiol Immunobiol 2006;(6):57–63.
  32. Grimaldi D, Guivarch E, Neveux N, et al.: Markers of intestinal injury are associated with endotoxemia in successfully resuscitated patients. Resuscitation 2013;84:60–65.
  33. Elamin E, Masclee A, Dekker J, Jonkers D: Ethanol disrupts intestinal epithelial tight junction integrity through intracellular calcium-mediated Rho/ROCK activation. Am J Physiol Gastrointest Liver Physiol 2014;306:G677–G685.
  34. Neves AL, Coelho J, Couto L, et al.: Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk. J Mol Endocrinol 2013;51:R51–R64.
  35. Leclercq S, De Saeger C, Delzenne N, et al.: Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. Biol Psychiatry 2014;76:725–733.
  36. Leclercq S, Matamoros S, Cani PD, et al.: Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci USA 2014;pii: 201415174.
  37. Maes M, Mihaylova I, Leunis JC: Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord 2007; 99:237–240.
  38. Goebel A, Buhner S, Schedel R, et al.: Altered intestinal permeability in patients with primary fibromyalgia and in patients with complex regional pain syndrome. Rheumatology (Oxford) 2008;47:1223–1227.
  39. Lauritano EC, Valenza V, Sparano L, et al.: Small intestinal bacterial overgrowth and intestinal permeability. Scand J Gastroenterol 2010;45:1131–1132.
  40. Wallace DJ, Hallegua DS: Fibromyalgia: the gastrointestinal link. Curr Pain Headache Rep 2004;8:364–368.
  41. Weinstock LB, Fern SE, Duntley SP: Restless legs syndrome in patients with irritable bowel syndrome: response to small intestinal bacterial overgrowth therapy. Dig Dis Sci 2008;53: 1252–1256.
  42. Severance EG, Gressitt KL, Stallings CR, et al.: Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res 2013;148:130–137.
  43. Berer K, Krishnamoorthy G: Commensal gut flora and brain autoimmunity: a love or hate affair? Acta Neuropathol 2012; 123:639–651.
  44. Hornig M: The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. Curr Opin Rheumatol 2013;25:488–795.
  45. Berer K, Mues M, Koutrolos M, et al.: Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune de[1]myelination. Nature 2011;479:538–541.
  46. Pozo-Rubio T, Olivares M, Nova E, et al.: Immune development and intestinal microbiota in celiac disease. Clin Dev Immunol 2012;2012:654143.
  47. Hadjivassiliou M, Sanders DS, Gru¨newald RA, et al.: Gluten sensitivity: from gut to brain. Lancet Neurol 2010;9:318–330.
  48. de Meij TG, Budding AE, Grasman ME, et al.: Composition and diversity of the duodenal mucosa-associated microbiome in children with untreated coeliac disease. Scand J Gastroenterol 2013;48:530–536.
  49. Sa´nchez E, Donat E, Ribes-Koninckx C, et al.: Duodenal-mucosal bacteria associated with celiac disease in children. Appl Environ Microbiol 2013;79:5472–5479.
  50. Cheng J, Kallioma¨ki M, Heilig HG, et al.: Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease. BMC Gastroenterol 2013;13:113.
  51. Francavilla R, Ercolini D, Piccolo M, et al.: Salivary microbiota and metabolome associated with celiac disease. Appl Environ Microbiol 2014;80:3416–3425.
  52. Collado MC, Donat E, Ribes-Koninckx C, et al.: Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J Clin Pathol 2009;62:264–269.
  53. Collado MC, Donat E, Ribes-Koninckx C, et al.: Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol 2008;8:232.
  54. Olivares M, Neef A, Castillejo G, et al.: The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease. Gut 2014;pii: gutjnl-2014–306931.
  55. Laparra JM, Sanz Y: Bifidobacteria inhibit the inflammatory response induced by gliadins in intestinal epithelial cells via modifications of toxic peptide generation during digestion. J Cell Biochem 2010;109:801–807.
  56. De Palma G, Cinova J, Stepankova R, et al.: Pivotal advance: bifidobacteria and gram-negative bacteria differentially influence immune responses in the proinflammatory milieu of celiac disease. J Leukoc Biol 2010;87:765–778.
  57. Ma˚rild K, Ye W, Lebwohl B, Green PH, et al.: Antibiotic exposure and the development of coeliac disease: a nationwide case-control study. BMC Gastroenterol 2013;13:109.
  58. Laparra JM, Olivares M, Gallina O, Sanz Y: Bifidobacterium longum CECT 7347 modulates immune responses in a gliadin[1]induced enteropathy animal model. PLoS One 2012;7:e30744.
  59. Medina M, De Palma G, Ribes-Koninckx C, et al.: Bifidobacterium strains suppress in vitro the pro-inflammatory milieu triggered by the large intestinal microbiota of coeliac patients. J Inflamm (Lond) 2008;5:19.
  60. Thurn JR, Pierpont GL, Ludvigsen CW, Eckfeldt JH: D-lactate encephalopathy. Am J Med 1985;79:717–721.
  61. Qureshi MO, Khokhar N, Shafqat F: Ammonia levels and the severity of hepatic encephalopathy. J Coll Physicians Surg Pak 2014;24:160–163.
  62. Qiao Z, Li Z, Li J, et al.: Bacterial translocation and change in intestinal permeability in patients after abdominal surgery. J Huazhong Univ Sci Technolog Med Sci 2009;29:486–491.
  63. Zhao Y, Qin G, Sun Z, et al.: Effects of soybean agglutinin on intestinal barrier permeability and tight junction protein expression in weaned piglets. Int J Mol Sci 2011;12:8502– 8512.
  64. Ying C, Chunmin Y, Qingsen L, et al.: Effects of simulated weightlessness on tight junction protein occludin and Zonula Occluden-1 expression levels in the intestinal mucosa of rats. J Huazhong Univ Sci Technolog Med Sci 2011;31:26–32.
  65. Sheedy JR, Wettenhall RE, Scanlon D, et al.: Increased d-lactic acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo 2009;23:621–628.
  66. Maes M, Leunis JC: Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett 2008; 29:902–910.
  67. Pimentel M, Hallegue D, Chow EJ, et al.: Eradication of small intestinal bacterial overgrowth decreases symptoms in chronic fatigue syndrome: a double blind randomized study. Gastroenterology 2000;118:A414.
  68. Munakata S, Arakawa C, Kohira R, et al.: A case of D-lactic acid encephalopathy associated with use of probiotics. Brain Dev 2010;32:691–694.
  69. Mack DR: D(-)-lactic acid-producing probiotics, D(-)-lactic acidosis and infants. Can J Gastroenterol 2004;18:671–675.
  70. Ewaschuk JB, Johnson IR, Madsen KL, et al.: Barley-derived b-glucans increases gut permeability, ex vivo epithelial cell binding to E. coli, and naive T-cell proportions in weanling pigs. J Anim Sci 2012;90:2652–2662.
  71. Takahashi K, Terashima H, Kohno K, Ohkohchi N: A stand-alone synbiotic treatment for the prevention of D-lactic acidosis in short bowel syndrome. Int Surg 2013;98:110–113.
  72. Respondek F, Goachet AG, Julliand V: Effects of dietary short-chain fructooligosaccharides on the intestinal microflora of horses subjected to a sudden change in diet. J Anim Sci 2008; 86:316–323.
  73. Skowron´ska M, Albrecht J: Alterations of blood brain barrier function in hyperammonemia: an overview. Neurotox Res 2012;21:236–244.
  74. Kawaguchi T, Taniguchi E, Sata M: Effects of oral branched-chain amino acids on hepatic encephalopathy and outcome in patients with liver cirrhosis. Nutr Clin Pract 2013;28:580–588.
  75. Irimia R, Stanciu C, Cojocariu C, et al.: Oral glutamine challenge improves the performance of psychometric tests for the diagnosis of minimal hepatic encephalopathy in patients with liver cirrhosis. J Gastrointestin Liver Dis 2013;22:277–281.
  76. Montgomery JY, Bajaj JS: Advances in the evaluation and management of minimal hepatic encephalopathy. Curr Gastroenterol Rep 2011;13:26–33.
  77. Quero Guille´n JC, Groeneweg M, Jime´nez Sa´enz M, et al.: Is it a medical error if we do not screen cirrhotic patients for minimal hepatic encephalopathy? Rev Esp Enferm Dig 2002;94: 544–557.
  78. Bajaj JS, Ridlon JM, Hylemon PB, et al.: Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012;302:G168–G175.
  79. Bajaj JS, Hylemon PB, Ridlon JM, et al.: Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol 2012;303: G675–G685.
  80. Zhang Z, Zhai H, Geng J, et al.: Large-scale survey of gut microbiota associated with MHE Via 16S rRNA-based pyrosequencing. Am J Gastroenterol 2013;108:1601–1611.
  81. Sharma BC, Sharma P, Lunia MK, et al.: A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol 2013;108:1458–1463.
  82. Malaguarnera M, Greco F, Barone G, et al.: Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Dig Dis Sci 2007;52:3259–3265.
  83. Liu Q, Duan ZP, Ha DK, et al.: Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004;39:1441–1449.
  84. Macfarlane GT, Macfarlane S: Fermentation in the human large intestine: its physiologic consequences and the potential contribution of prebiotics. J Clin Gastroenterol 2011;45 Suppl: S120–S127.
  85. Subaric´ D, Ackar D, Babic´ J, Milicevic´ B: Starch for health. Med Glas (Zenica) 2012;9:17–22.
  86. De Preter V, Geboes KP, Bulteel V, Vandermeulen G: Kinetics of butyrate metabolism in the normal colon and in ulcerative colitis: the effects of substrate concentration and carnitine on the b-oxidation pathway. Aliment Pharmacol Ther 2011;34: 526–532.
  87. Segain JP, Raingeard de la Ble´tie`re D, Bourreille A, et al.: Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn’s disease. Gut 2000;47: 397–403.
  88. Al-Lahham SH, Peppelenbosch MP, Roelofsen H, et al.: Biological effects of propionic acid in humans; metabolism, potential applications and underlying mechanisms. Biochim Biophys Acta 2010;1801:1175–1183.
  89. Tan J, McKenzie C, Potamitis M, et al.: The role of short-chain fatty acids in health and disease. Adv Immunol 2014;121: 91–119.
  90. Harrison IF, Dexter DT: Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson’s disease? Pharmacol Ther 2013;140:34–52.
  91. Mahgoub M, Monteggia LM: Epigenetics and psychiatry. Neurotherapeutics 2013;10:734–741.
  92. Haberland M, Montgomery RL, Olson EN: The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 2009;8:32–42.
  93. Konsoula Z, Barile FA: Epigenetic histone acetylation and deacetylation mechanisms in experimental models of neurodegenerative disorders. J Pharmacol Toxicol Methods 2012;66: 215–220.
  94. Gra¨ff J, Tsai LH: The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol 2013;53:311–330.
  95. Wauson EM, Lorente-Rodrı´guez A, Cobb MH: Minireview: nutrient sensing by G protein-coupled receptors. Mol Endocrinol 2013;27:1188–1197.
  96. Heng BC, Aubel D, Fussenegger M: An overview of the diverse roles of G-protein coupled receptors (GPCRs) in the pathophysiology of various human diseases. Biotechnol Adv 2013; 31:1676–1694.
  97. Tazoe H, Otomo Y, Kaji I, et al.: Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol 2008;59 Suppl 2:251–262.
  98. Kimura I, Inoue D, Maeda T, et al.: Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA 2011;108:8030–8035.
  99. Puertollano E, Kolida S, Yaqoob P: Biological significance of short-chain fatty acid metabolism by the intestinal microbiome. Curr Opin Clin Nutr Metab Care 2014;17:139–144.
  100. MacFabe D. Autism: metabolism, mitochondria, and the microbiome. Global Adv Health Med 2013;2:52–66.
  101. Wang L, Christophersen CT, Sorich MJ, et al.: Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig Dis Sci 2012;57:2096–2102.
  102. Wang L, et al.: Gut bacterial and fermentation profiles are altered in children with autism. J Gastroenterol Hepatol 2010; 25(Suppl. 3):A116–A119.
  103. Gondalia SV, Palombo EA, Knowles SR, et al.: Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Res 2012;5:419–427.
  104. Kang DW, Park JG, Ilhan ZE, et al.: Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One 2013;8:e68322.
  105. Parracho HM, Bingham MO, Gibson GR, McCartney AL. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Micro[1]biol 2005;54:987–991.
  106. Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol 2004;70:6459–6465.
  107. Wang L, Christophersen CT, Sorich MJ, et al.: Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol 2011;77:6718–6721.
  108. Tanoue Y, Oda S: Weaning time of children with infantile autism. J Autism Dev Disord 1989;19:425–434.
  109. Macia L, Viltart O, Verwaerde C, et al.: Genes involved in obesity: adipocytes, brain and microflora. Genes Nutr 2006;1: 189–212.
  110. Williams BL, Hornig M, Buie T, et al.: Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS One 2011;6:e24585.
  111. Williams BL, Hornig M, Parekh T, Lipkin WI: Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. MBio 2012;3:pii: e00261-11.
  112. Engberg J, On SL, Harrington CS, Gerner-Smidt P: Prevalence of Campylobacter, Arcobacter, Helicobacter, and Sutterella spp. in human fecal samples as estimated by a reevaluation of isolation methods for Campylobacters. J Clin Microbiol 2000;38:286–291.
  113. Wang L, Christophersen CT, Sorich MJ, et al.: Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism 2013;4: 42.
  114. Mulle JG, Sharp WG, Cubells JF: The gut microbiome: a new frontier in autism research. Curr Psychiatry Rep 2013;15:337.
  115. De Angelis M, Piccolo M, Vannini L, et al.: Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One 2013;8: e76993.
  116. Stoner R, Chow ML, Boyle MP, et al.: Patches of disorgani[1]zation in the neocortex of children with autism. N Engl J Med 2014;370:1209–1219.
  117. Hsiao EY, McBride SW, Hsien S, et al.: Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013;155:1451–1463.
  118. Freestone PP, Sandrini SM, Haigh RD, Lyte M: Microbial endocrinology: how stress influences susceptibility to infection. Trends Microbiol 2008;16:55–64.
  119. Lyte M: Microbial endocrinology and infectious disease in the 21st century. Trends Microbiol 2004;12:14–20.
  120. Sperandio V, Torres AG, Jarvis B, et al.: Bacteria-host communication: the language of hormones. Proc Natl Acad Sci USA 2003;100:8951–8956.
  121. Bailey MT, Dowd SE, Galley JD, et al.: Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun 2011;25:397–407.
  122. Knowles SR, Nelson EA, Palombo EA: Investigating the role of perceived stress on bacterial flora activity and salivary cortisol secretion: a possible mechanism underlying susceptibility to illness. Biol Psychol 2008;77:132–137.
  123. Elmadfa I, Klein P, Meyer AL: Immune-stimulating effects of lactic acid bacteria in vivo and in vitro. Proc Nutr Soc 2010; 69:416–420.
  124. Li CY, Lin HC, Lai CH, et al.: Immunomodulatory effects of lactobacillus and Bifidobacterium on both murine and human mitogen-activated T cells. Int Arch Allergy Immunol 2011; 156:128–136.
  125. Charlier C, Cretenet M, Even S, Le Loir Y: Interactions between Staphylococcus aureus and lactic acid bacteria: an old story with new perspectives. Int J Food Microbiol 2009;131: 30–39.
  126. Messaoudi M, Lalonde R, Violle N, et al.: Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr 2011;105:755–764.
  127. Arseneault-Bre´ard J, Rondeau I, Gilbert K, et al.: 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 2012;107:1793–1799.
  128. Girard SA, Bah TM, Kaloustian S, et al.: Lactobacillus helveticus and Bifidobacterium longum taken in combination reduce the apoptosis propensity in the limbic system after myocardial infarction in a rat model. Br J Nutr 2009;102:1420–1425.
  129. Tillisch K, Labus J, Kilpatrick L, et al.: Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 2013;144:1394–1401.
  130. Benton D, Williams C, Brown A: Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur J Clin Nutr 2007;61:355–361.
  131. Rao AV, Bested AC, Beauline TM, et al.: A randomized double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog 2009;1:6.
  132. Sullivan A, Nord CE, Evenga˚rd B: Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome. Nutr J 2009;8:4.
  133. Diop L, Guillou S, Durand H: Probiotic food supplement re[1]duces stress-induced gastrointestinal symptoms in volunteers: a double-blind, placebo-controlled, randomized trial. Nutr Res 2008;28:1–5.
  134. Forsythe P, Kunze WA, Bienenstock J: On communication between gut microbes and the brain. Curr Opin Gastroenterol 2012;28:557–562.
  135. Bravo JA, Forsythe P, Chew MV, et al.: Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA 2011;108:16050–16055.
  136. Mao YK, Kasper DL, Wang B, et al.: Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons. Nat Commun 2013;4:1465.
  137. Bercik P, Denou E, Collins J, et al.: The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 2011;141:599–609, 609.e1–e3.
  138. Sanders ME: Impact of probiotics on colonizing microbiota of the gut. J Clin Gastroenterol 2011;45 Suppl:S115–S119.
  139. Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P: Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010;107:14691–14696.
  140. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA: Diversity of the human intestinal microbial flora. Science 2005;308:1635–1638.
  141. Turnbaugh PJ, Quince C, Faith JJ, McHardy AC, Yatsunenko T, Niazi F, Affourtit J, Egholm M, Henrissat B, Knight R, Gordon JI: Organismal, genetic, and transcriptional variation in the deeply sequenced gut microbiomes of identical twins. Proc Natl Acad Sci USA 2010;107:7503–7508.
  142. Turnbaugh PJ, Gordon JI: The core gut microbiome, energy balance, and obesity. J Physiol 2009;587:4153–4158.
  143. Rajilic-Stojanovic M, Heilig HG, Molenaar D, Kajander K, Surakka A, Smidt H, de Vos WM: Development and application of the human intestinal tract chip, a phylogenetic microarray: analysis of universally conserved phylotypes in the abundant microbiota of young and elderly adults. Environ Microbiol 2009;11:1736–1751.
  144. Dethlefsen L, Eckburg PB, Bik EM, Relman DA: Assembly of the human intestinal microbiota. Trends Ecol Evol 2006;21: 517–523.
  145. Booijink CC, El-Aidy S, Rajilic´-Stojanovic´ M, et al.: High temporal and inter-individual variation detected in the human ileal microbiota. Environ Microbiol 2010;12:3213–3227.
  146. Galland L: Patient-centered care: antecedents, triggers, and mediators. Altern Ther Health Med 2006;12:62–70.
  147. Tap J, Mondot S, Levenez F, Pelletier E, et al.: Towards the human intestinal microbiota phylogenetic core. Environ Microbiol 2009;11:2574–2584.
  148. Wu GD, Chen J, Hoffmann C, et al.: Linking long-term dietary patterns with gut microbial enterotypes. Science 2011;334: 105–108.
  149. Walker WA: Initial intestinal colonization in the human infant and immune homeostasis. Ann Nutr Metab 2013;63 Suppl 2: 8–15.
  150. Mayne AJ, Handy DJ, Preece MA, et al.: Dietary management of D-lactic acidosis in short bowel syndrome. Arch Dis Child 1990;65:229–231.
  151. Dorrestein PC, Mazmanian SK, Knight R: Finding the missing links among metabolites, microbes, and the host. Immunity 2014;40:824–832.
  152. Kaneko T, Mori H, Iwata M, Meguro S: Growth stimulator for bifidobacteria produced by Propionibacterium freudenreichii and several intestinal bacteria. J Dairy Sci 1994;77:393–404.
  153. Suzuki A, Mitsuyama K, Koga H, et al.: Bifidogenic growth stimulator for the treatment of active ulcerative colitis: a pilot study. Nutrition 2006;22:76–81.
  154. Joyce SA, Gahan CG: The gut microbiota and the metabolic health of the host. Curr Opin Gastroenterol 2014;30:120–127.
  155. Albenberg LG, Wu GD: Diet and the intestinal microbiome: associations, functions, and implications for health and disease. Gastroenterology 2014;146:1564–1572.
  156. Jeffery IB, O’Toole PW: Diet-microbiota interactions and their implications for healthy living. Nutrients 2013;5:234–252.
  157. Tang WH, Wang Z, Levison BS, et al.: Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013;368:1575–1584.
  158. Koeth RA, Wang Z, Levison BS et al.: Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19:576–585.
  159. Laparra JM, Sanz Y: Interactions of gut microbiota with functional food components and nutraceuticals. Pharmacol Res 2010;61:219–225.
  160. Van Wey AS, Cookson AL, Roy NC, et al.: Bacterial biofilms associated with food particles in the human large bowel. Mol Nutr Food Res 2011;55:969–978.

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