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Furthermore, as GF pups are raised by GF mothers, the absence of fecal microbes may interfere with well-characterized maternal behaviors, such as arched-back nursing and anogenital licking. These behaviors have been associated with epigenetic changes at stress-related genes 62 that regulate the development of systems within the CNS However, in one study where maternal behavior was analyzed on the second and third days postpartum, no effect of the GF status on such maternal behaviors was observed Altered signaling of the cecum to the brain, secondary to the massive cecal dilation associated with this model, could alter development of brain regions processing such input.

GF mice are leaner than control animals, despite consuming more calories 64 , Metabolic changes secondary to the loss of an important source of calories gut microbiota—generated short-chain fatty acids [SCFAs] for the developing organism may affect brain development and alter the activity of brain circuits involved in feeding behavior and metabolism. Finally, the recently reported alterations in the permeability of the blood-brain barrier in GF mice is likely to result in significantly altered access of gut microbial metabolites to the brain Despite the extensive remodeling of biological systems in the GF animal, the fact that some observed behaviors and brain changes could be reversed by reconstitution of pathogen-free microbiota conventionalization validates some of the conclusions drawn.

Nevertheless, as the GF animal has no counterpart in human brain development, premature conclusions about the relevance of these findings to humans should be avoided. Broad-spectrum antibiotics have well-documented transient effects on the composition and diversity of fecal microbiota 35 even though the effects on mucosa-associated microbial communities are not known. Furthermore, antibiotic-related effects may be mediated by the associated mucosal immune activation reported with such interventions Of reports published since using different strains of mice and rats, different strains of probiotics, and different experimental paradigms ref.

Results of these studies are summarized in Tables 1—4. Emotional behavior. A reduction in depression-like behaviors was observed in different rodent models with normal gut microbiota, following administration of a probiotic 42 , Depression-like behavior in these models was induced by maternal separation 47 and experimental myocardial infarction MI Learning and memory.

While improvement of impaired memory function by probiotics was observed in a rodent model of diabetes 71 , several studies showed a worsening with exposure to a pathogen 72 , GF status 39 , and administration of a probiotic Social interactions and ASD-like behaviors. Gut microbiota status was found to reduce social interactions in GF mice 58 , and probiotics improved social interactions in a post-MI rat model 48 , 58 , Gut microbiota—associated behavioral changes were reported in different ASD mouse models using valproic acid administration 59 or maternal infection 60 ; in the latter instance, treatment with the probiotic Bacteroides fragilis had a beneficial effect on some of the behavioral abnormalities Ingestive behavior.

A limited number of studies suggest that gut microbial composition can influence ingestive behavior 54 , 55 , Some of these effects are likely mediated by significant alterations in intestinal taste receptor, fatty acid receptors, intestinal transport mechanisms, and changes in the release of satiety hormones. HPA axis responsiveness. The association of increased HPA axis responses and reduced anxiety-like behaviors observed in several of the studies performed in GF mice suggests that hypothalamic HPA axis and nonhypothalamic anxiety-like behavior components of central stress circuits may be affected differentially by the GF conditions, depending on species and mouse strain, a response pattern not seen in the majority of anxiety models in which these two components of the stress response are generally congruent.

These findings suggest that the increased HPA axis activity in GF animals may represent a response of the organism to the loss of microbiota-related energy sources. Epithelial permeability. Alterations in gut epithelial permeability have been described in IBS 77 and in some patients with autism and schizophrenia Gut microbiota and probiotics play an important modulatory role on intestinal barrier function 79 , Recent evidence has shown that the probiotic B. Brain-signaling systems. Several studies showed reduced expression of brain-derived neurotrophic factor BDNF in the brains of GF animals primarily in hippocampus 35 , 38 , 39 , 72 and increased BDNF expression in infection models Other reported regional changes in receptor expression include GABA receptor A and B subunits which mediate the effects of the major inhibitory neurotransmitter in the brain 42 , NMDA receptor subunits which mediate some of the effects of the excitatory neurotransmitter glutamate 70 , serotonin 1A 40 , and tryptophan and tryptophan metabolite levels Some of these changes in neuroreceptor expression were correlated with altered emotional behaviors 39 , 40 , 42 , 70 , implying an interaction between microbial composition and behavior.

Results of studies in which such measures were assessed are summarized in Tables 1—4. In animal models, prenatal and postnatal stress can alter the composition and total biomass of the enteric microbiota 82 , The majority of studies have compared adult behaviors, brain findings, and physiological responses, such as activation of the HPA axis, between animals born into and raised in a GF environment and animals raised in a laboratory cage environment. A smaller number of studies have reported data showing a role of gut microbiota in the effect of early adverse life events on adult behavior.

Support for such long-lasting consequences for adult phenotypes of early life perturbations of the gut microbiota comes from two recent studies of the effects of early life antibiotic administration on adult visceral pain sensitivity 84 and metabolism Multiple factors affecting the maternal gut microbiota can influence brain development in utero via microbial metabolites, drug-derived chemical metabolites, and inflammatory changes. Modified with permission from Trends in Molecular Medicine Perinatal stress models.

Extensive preclinical literature has characterized the effects of perinatal stress on the adult CNS, including the HPA axis 86 , and brain systems involved in emotion 63 , pain modulation 87 — 89 , and in intestinal function The brain and behavioral effects of perinatal stress observed in rodent models show high translational validity for a range of human diseases, including functional GI disorders 90 , 91 and psychiatric disorders 92 in which early adverse life events have been established as an important vulnerability factor. This extensive body of research, including molecular and epigenetic mechanisms, was generated without taking the gut microbiota into account.

However, more evidence has been reported for the involvement of the gut microbiota in these perinatal stressors in brain and associated behavioral changes, starting with initial reports showing that both maternal stress and maternal separation had an effect on the gut microbiota Monkeys subjected to maternal separation between six and nine months of age showed gut microbiota changes characterized by shedding of lactobacilli three days following separation, with the return of normal lactobacilli levels seven days later.

Adult rats that had undergone maternal separation showed altered fecal microbial composition compared with normally reared control animals It remains unclear whether the reported microbiota changes following perinatal stress are simply a consequence of the well-established changes in stress reactivity and altered regional autonomic nervous system ANS regulation of gut motility and secretion leading to a change in microbiota environment or whether other factors play a role. Adult stress models. Considerable evidence supports the role for stress and its mediators in modulating the intestinal microbiota in adults refs.

In adult mice, psychosocial stress reduced the proportion of Bacteroides but increased the proportion of Clostridia in the cecum In the same study, stress-induced increases in IL-6 and chemokine C-C motif ligand 2 MCP1 were observed, and these changes were correlated with certain bacterial species.

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Additional studies are needed to determine whether gut microbial alterations observed in preclinical studies and some patient studies with stress-sensitive GI disorders, such as IBS, result from stress-induced acceleration of regional intestinal transit, intestinal secretion, or other effects of stress on the intestinal microbiota. When viewed together, these studies support a role of the gut microbiota in modulating emotional, nociceptive, and feeding behaviors in rodents. Comprehensive reviews of these studies, including speculation about possible human implications, have been published 2 , 4 , 17 — 19 , 22 , 23 , 25 , 26 , 96 — The intriguing preclinical results should inform the design of human studies in the future.

In contrast to the emergence of a rich and robust preclinical literature on various aspects of microbiota-brain interactions, limited information is available from human studies. This may be due to a the increased complexity of studying the human microbiota, which is affected by wide variations in diet, environmental influences, sex-related differences, and genetic variation; b the difficulty of measuring subtle changes in human emotional and cognitive function; and c underlying functional and possibly structural changes in the human CNS.

Gut microbial organization patterns have been associated with two clinical phenotypes. A recent study in babies with infant colic, often thought to be a risk factor for the development of IBS and anxiety disorders, showed reduced overall diversity, increased density of Proteobacteria, and decreased numbers of Bacterioides compared with healthy babies A growing number of studies in IBS patients have provided evidence for alterations in gut microbial composition reviewed in refs.

Effect of interventions targeting the gut microbiota.

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Another approach to determining the effects of the gut microbiota on brain function has been to use self-reporting measures as a proxy for changes in brain function after modulating the microbiota with probiotics. In a randomized, placebo-controlled study of healthy men and women, psychological distress and anxiety improved after taking a Lactobacillus- and Bifidobacterium -containing probiotic compared with those taking a matched control product, though another study using a different Lactobacillius probiotic failed to confirm these findings 69 , Limitations in study design, including sample size, baseline mood of the subject sample, instruments used to collect the mood symptoms, interindividual variation in terms of microbial composition, and differences between the probiotics may have accounted for the discrepancy in results.

Another approach has been to use functional MRI fMRI to assess human brain changes in response to modulation of the gut microbiota. One study has shown that chronic ingestion of a probiotic consortium changed functional brain responses in healthy women In this study, the response to an emotional face recognition task was measured with fMRI in healthy women before and after taking four weeks of active probiotic, nonfermented dairy product, or no treatment at all. The women who had ingested the probiotic had a reduced response to the emotional recognition task across a wide network of brain regions that included sensory and emotional regions.

There were no differences in self-reporting of symptoms of anxiety or depression between the treatment groups; however, the fMRI alterations suggest a basic change in responsiveness to negative emotional stimuli in the environment. A second brain imaging study evaluated the effects of gut microbiota modulation via administration of a nonabsorbable antibiotic in patients with hepatic encephalopathy and mild cognitive impairment Performance on a cognitive task improved, along with fMRI evidence for increased subcortical brain activity and improved fronto-parietal connectivity during the task.

In another study using the same underlying disorder and antibiotic treatment, cognitive function was also improved after an eight-week treatment course, in conjunction with changes in serum metabolites presumed to be of bacterial origin Such modulation can be transient, such as in response to transient perturbations, or long lasting, such as in response to chronically altered brain output. The microbiota is in constant bidirectional communication with this interface via multiple microbial signaling pathways, and this communication is modulated in response to perturbations of the microbiota or the brain.

The integrated output of the gut microbial—brain interface is transmitted back to the brain via multiple afferent signaling pathways, including endocrine metabolites, cytokines, and microbial signaling molecules and neurocrine vagal and spinal afferents. While acute alterations in this interoceptive feedback can result in transient functional brain changes GI infections , chronic alterations are associated with neuroplastic brain changes. Potential therapies aim to normalize altered microbiota signaling to the ENS and central nervous system. These CNS influences can affect the enteric microbiota indirectly by altering its environment and directly via a large number of signaling molecules Figure 3 and reviewed in ref.

Both branches of the ANS regulate gut functions such as regional motility, secretion of acid, production of bicarbonates and mucus, maintenance of epithelial fluid, permeability of the intestine, and the mucosal immune response Figure 3 and reviewed in ref. Most of these functions, except for sympathetic- and cortisol-mediated immune regulation, are affected by sympathetic and parasympathetic influences on the circuits of the ENS.

Regional and overall changes in GI transit are expected to affect the rate of delivery of nutrients such as prebiotics, including resistant starches and certain dietary fibers to the enteric microbiota, gas composition, and other aspects of the luminal environment reviewed in ref.

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ANS modulation of the gut microbial environment. Impaired intestinal transit, caused by compromised migrating motor complexes an ENS-generated motor pattern characteristic of the fasting state of the GI tract that is under parasympathetic modulation , is associated with an increase in microbial colonization bacterial overgrowth in the small intestine A reduced number of giant migrating contractions in the colon has been reported in patients with slow-transit constipation and might contribute to symptoms in some patients with IBS and constipation. Alternatively, accelerated intestinal transit, characterized by an increased number of giant migrating contractions, is observed in some patients with diarrheal disorders such as diarrhea-predominant IBS The frequency of regular migrating motor complexes is influenced by the frequency of food intake, quality of sleep, and stress.

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Acute stress is associated with increased parasympathetic output to the small and large intestine and reduced vagal output to the stomach Even though they have not been studied outside the setting of bacterial overgrowth, these alterations in gut transit are likely to have a major impact on the composition and organizational structure of the gut microbiota in different regions of the GI tract. ANS-mediated modulation of mucus secretion is likely to have important effects on the size and quality of the intestinal mucus layer, an important habitat for the biofilm, where most enteric microbiota reside The ANS also affects epithelial mechanisms involved in activation of the immune system by the gut.

This activation can occur directly through modulation of the response of the gut immune cells e. For example, several preclinical studies have demonstrated that stressful stimuli can increase the permeability of the intestinal epithelium, facilitating translocation of luminal organisms and inducing an immune response in the intestinal mucosa — Modulation of gut microbiota by host-derived signaling molecules.

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