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      Stress and the Microbiota–Gut–Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome

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          Summary

          Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders ( FGIDs) such as irritable bowel syndrome ( IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut–brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal ( GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gut–brain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain.

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          Most cited references233

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          Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression.

          The concept that intestinal microbial composition not only affects the health of the gut, but also influences centrally-mediated systems involved in mood, is supported by a growing body of literature. Despite the emergent interest in brain-gut communication and its possible role in the pathogenesis of psychiatric disorders such as depression, particularly subtypes with accompanying gastrointestinal (GI) symptoms, there are few studies dedicated to the search for therapeutic solutions that address both central and peripheral facets of these illnesses. This study aims to assess the potential benefits of the probiotic Bifidobacterium infantis in the rat maternal separation (MS) model, a paradigm that has proven to be of value in the study of stress-related GI and mood disorders. MS adult rat offsprings were chronically treated with bifidobacteria or citalopram and subjected to the forced swim test (FST) to assess motivational state. Cytokine concentrations in stimulated whole blood samples, monoamine levels in the brain, and central and peripheral hypothalamic-pituitary-adrenal (HPA) axis measures were also analysed. MS reduced swim behavior and increased immobility in the FST, decreased noradrenaline (NA) content in the brain, and enhanced peripheral interleukin (IL)-6 release and amygdala corticotrophin-releasing factor mRNA levels. Probiotic treatment resulted in normalization of the immune response, reversal of behavioral deficits, and restoration of basal NA concentrations in the brainstem. These findings point to a more influential role for bifidobacteria in neural function, and suggest that probiotics may have broader therapeutic applications than previously considered. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
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            Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation.

            Two receptor systems for corticosterone (CORT) can be distinguished in rat brain: mineralocorticoid-like or CORT receptors (CR) and glucocorticoid receptors (GR). The microdistribution and extent of occupation of each receptor population by CORT were studied. The CR system is restricted predominantly to the lateral septum and hippocampus. Within the hippocampus, the highest density occurs in the subiculum +/- CA1 cell field (144 fmol/mg protein) and the dentate gyrus (104 fmol/mg protein). Affinity of CR for CORT was very high (Kd, approximately 0.5 nM). The GR system has a more widespread distribution in the brain. The highest density for GR is in the lateral septum (195 fmol/mg protein), the dentate gyrus (133 fmol/mg protein), the nucleus tractus solitarii and central amygdala. Substantial amounts of GR are present in the paraventricular nucleus and locus coeruleus and low amounts in the raphe area and the subiculum + CA1 cell field. The affinity of GR for CORT (Kd, approximately 2.5-5 nM) was 6- to 10-fold lower than that of CR. Occupation of CR by endogenous ligand was 89.5% during morning trough levels of pituitary-adrenal activity (plasma CORT, 1.4 micrograms/100 ml). Similar levels of occupation (88.7% and 97.6%) were observed at the diurnal peak (plasma CORT, 27 micrograms/100 ml) and after 1 h of restraint stress (plasma CORT, 25 micrograms/100 ml), respectively. Furthermore, a dose of 1 microgram CORT/100 g BW, sc, resulted in 80% CORT receptor occupation, whereas GR were not occupied. For 50% occupation of GR, doses needed to be increased to 50-100 micrograms/100 g BW, and for 95% occupation, a dose of 1 mg CORT was required. The plasma CORT level at the time of half-maximal GR occupation was about 25 micrograms/100 ml, which is in the range of levels attained after stress or during the diurnal peak of pituitary-adrenal activity. Thus, CR are extensively filled (greater than 90%) with endogenous CORT under most circumstances, while GR become occupied concurrent with increasing plasma CORT concentrations due to stress or diurnal rhythm. We conclude that CORT action via CR may be involved in a tonic (permissive) influence on brain function with the septohippocampal complex as a primary target. In view of the almost complete occupation of CR by endogenous hormones, the regulation of the CORT signal via CR will, most likely, be by alterations in the number of such receptors. In contrast, CORT action via GR is involved in its feedback action on stress-activated brain mechanisms, and GR occur widely in the brain.(ABSTRACT TRUNCATED AT 400 WORDS)
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              Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.

              Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.
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                Author and article information

                Journal
                CNS Neurosci Ther
                CNS Neurosci Ther
                10.1111/(ISSN)1755-5949
                CNS
                CNS Neuroscience & Therapeutics
                John Wiley and Sons Inc. (Hoboken )
                1755-5930
                1755-5949
                10 December 2015
                February 2016
                : 22
                : 2 , Novel translational approaches for improving drug discovery efforts in chronic pain ( doiID: 10.1111/cns.2016.22.issue-2 )
                : 102-117
                Affiliations
                [ 1 ] Laboratory of Neurogastroenterology APC Microbiome Institute University College Cork Cork Ireland
                [ 2 ] Oklahoma Center for Neuroscience University of Oklahoma Health Science Center Oklahoma City OK USA
                [ 3 ] Department of Anatomy and Neuroscience University College Cork Cork Ireland
                [ 4 ] Department of Psychiatry and Neurobehavioural Science University College Cork Cork Ireland
                [ 5 ] V.A. Medical Center Oklahoma City OK USA
                [ 6 ]Present address: Oklahoma Center for Neuroscience University of Oklahoma Health Science Center Oklahoma City OK USA
                Author notes
                [*] [* ] Correspondence

                John F. Cryan, Ph.D., Department of Anatomy & Neuroscience, University College Cork, Room 386 Western Gateway Building, Western Rd., Cork, Ireland.

                Tel.: +353‐21‐4205426;

                Fax: +353‐21‐4273518;

                E‐mail: j.cryan@ 123456ucc.ie

                and

                Beverley Greenwood‐Van Meerveld, Ph.D., FACG, AGAF, Oklahoma Center for Neuroscience, BRC 272, 975 N.E. 10th St., Oklahoma City, OK 73104, USA.

                Tel.: +1‐405‐4563547;

                Fax: +1‐405‐2901719;

                E‐mail: Beverley-Greenwood@ 123456ouhsc.edu

                Article
                PMC6492884 PMC6492884 6492884 CNS12490
                10.1111/cns.12490
                6492884
                26662472
                611fe84d-d1bf-49aa-b418-5d145f6e509a
                © 2015 John Wiley & Sons Ltd
                History
                : 23 June 2015
                : 05 November 2015
                : 05 November 2015
                Page count
                Pages: 16
                Funding
                Funded by: Science Foundation Ireland (SFI)
                Award ID: SFI/12/RC/2273
                Award ID: 02/CE/B124
                Award ID: 07/CE/B1368
                Award ID: 12/IA/1537
                Funded by: Irish Government's National Development Plan
                Funded by: Health Research Board of Ireland
                Award ID: HRA_POR/2011/23
                Award ID: HRA_POR/2012/32
                Award ID: HRA‐POR‐2014‐647
                Funded by: European FP7
                Funded by: European Community's Seventh Framework Programme
                Award ID: FP7/2007‐2013
                Award ID: 278948
                Funded by: Department of Veterans Affairs
                Award ID: I01BX002188
                Categories
                Review
                Review Articles
                Custom metadata
                2.0
                cns12490
                February 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:02.05.2019

                Stress,Visceral Pain,Brain‐Gut axis,Gut microbiota
                Stress, Visceral Pain, Brain‐Gut axis, Gut microbiota

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