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      Psychobiotics and the Manipulation of Bacteria–Gut–Brain Signals

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          Abstract

          Psychobiotics were previously defined as live bacteria (probiotics) which, when ingested, confer mental health benefits through interactions with commensal gut bacteria. We expand this definition to encompass prebiotics, which enhance the growth of beneficial gut bacteria. We review probiotic and prebiotic effects on emotional, cognitive, systemic, and neural variables relevant to health and disease. We discuss gut–brain signalling mechanisms enabling psychobiotic effects, such as metabolite production. Overall, knowledge of how the microbiome responds to exogenous influence remains limited. We tabulate several important research questions and issues, exploration of which will generate both mechanistic insights and facilitate future psychobiotic development. We suggest the definition of psychobiotics be expanded beyond probiotics and prebiotics to include other means of influencing the microbiome.

          Trends

          Psychobiotics are beneficial bacteria (probiotics) or support for such bacteria (prebiotics) that influence bacteria–brain relationships.

          Psychobiotics exert anxiolytic and antidepressant effects characterised by changes in emotional, cognitive, systemic, and neural indices. Bacteria–brain communication channels through which psychobiotics exert effects include the enteric nervous system and the immune system.

          Current unknowns include dose-responses and long-term effects.

          The definition of psychobiotics should be expanded to any exogenous influence whose effect on the brain is bacterially-mediated.

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          Most cited references89

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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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            Innate immune recognition of the microbiota promotes host-microbial symbiosis.

            Pattern-recognition receptors (PRRs) are traditionally known to sense microbial molecules during infection to initiate inflammatory responses. However, ligands for PRRs are not exclusive to pathogens and are abundantly produced by the resident microbiota during normal colonization. Mechanism(s) that underlie this paradox have remained unclear. Recent studies reveal that gut bacterial ligands from the microbiota signal through PRRs to promote development of host tissue and the immune system, and protection from disease. Evidence from both invertebrate and vertebrate models reveals that innate immune receptors are required to promote long-term colonization by the microbiota. This emerging perspective challenges current models in immunology and suggests that PRRs may have evolved, in part, to mediate the bidirectional cross-talk between microbial symbionts and their hosts.
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              GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes.

              The expression of short-chain fatty acid receptors GPR41/FFAR3 and GPR43/ free fatty acid receptor 2 (FFAR2) was studied in the gastrointestinal tract of transgenic monomeric red fluorescent protein (mRFP) reporter mice. In the stomach free fatty acid receptor 3 (FFAR3)-mRFP was expressed in a subpopulation of ghrelin and gastrin cells. In contrast, strong expression of FFAR3-mRFP was observed in all cholecystokinin, glucose-dependent insulinotropic peptide (GIP), and secretin cells of the proximal small intestine and in all glucagon-like peptide-1 (GLP-1), peptide YY, and neurotensin cells of the distal small intestine. Throughout the colon and rectum, FFAR3-mRFP was strongly expressed in the large population of peptide YY and GLP-1 cells and in the neurotensin cells of the proximal colon. A gradient of expression of FFAR3-mRFP was observed in the somatostatin cells from less than 5% in the stomach to more than 95% in the rectum. Substance P-containing enterochromaffin cells displayed a similar gradient of FFAR3-mRFP expression throughout the small intestine. Surprisingly, FFAR3-mRFP was also expressed in the neuronal cells of the submucosal and myenteric ganglia. Quantitative PCR analysis of fluorescence-activated cell sorting (FACS) purified FFAR3-mRFP positive cells confirmed the coexpression with the various peptide hormones as well as key neuronal marker proteins. The FFAR2-mRFP reporter was strongly expressed in a large population of leukocytes in the lamina propria of in particular the small intestine but surprisingly only weakly in a subpopulation of enteroendocrine cells. Nevertheless, synthetic ligands specific for either FFAR3 or FFAR2 each released GLP-1 from colonic crypt cultures and the FFAR2 agonist mobilized intracellular Ca²⁺ in FFAR2 positive enteroendocrine cells. It is concluded that FFAR3-mRFP serves as a useful marker for the majority of enteroendocrine cells of the small and large intestine and that FFAR3 and FFAR2 both act as sensors for short-chain fatty acids in enteroendocrine cells, whereas FFAR3 apparently has this role alone in enteric neurons and FFAR2 in enteric leukocytes.
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                Author and article information

                Contributors
                Journal
                Trends Neurosci
                Trends Neurosci
                Trends in Neurosciences
                Elsevier Applied Science Publishing
                0166-2236
                1878-108X
                1 November 2016
                November 2016
                : 39
                : 11
                : 763-781
                Affiliations
                [1 ]Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, UK
                [2 ]Institute of Clinical Medicine/Psychiatry, University of Eastern Finland, FI-70211, Kuopio, Finland
                [3 ]Department of Psychiatry, Kuopio University Hospital, FI-70211, Kuopio, Finland
                [4 ]Department of Psychiatry, University College Cork, Cork, Ireland
                [5 ]Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
                [6 ]Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK
                Author notes
                Article
                S0166-2236(16)30113-8
                10.1016/j.tins.2016.09.002
                5102282
                27793434
                a3865e42-6e73-4b7d-a3d5-11d85f88ee11
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Categories
                Review

                Neurosciences
                gut–brain axis,interkingdom signalling,microbiome,microbiota,prebiotics,probiotics
                Neurosciences
                gut–brain axis, interkingdom signalling, microbiome, microbiota, prebiotics, probiotics

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