Gut Permeability and the Microbiome
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Editorial Gut Permeability and the Microbiome: Emerging Roles in CNS Function in Health and Disease André F. Carvalho1, Michael Berk2,3 and Michael Maes 2,4,5,6,7 1
Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; 2IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, P.O. Box 291, Geelong, VIC, 3220, Australia; 3Orygen Youth Health Research Centre and the Centre of Youth Mental Health, The Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, University of Melbourne, Parkville, 3052, Australia; 4Health Sciences Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Parana, Brazil; 5Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 6Department of Psychiatry, Medical University Plovdiv, Plovdiv, Bulgaria; 7Revitalis, Waalre, The Netherlands The resident prokaryotic population in our gastrointestinal tract comprises some 100 trillion microorganisms of 36,000 identified species [1, 2]. The gut microbiota has coevolved with the human host to play notable beneficial roles by protecting against pathogens, fermenting indigestible nutrients, producing micronutrients, and metabolizing drugs and harmful toxins. In addition, a putative role of the microbiome in the regulation of immunity, neurodevelopment, behavior, and cognition is recognized [35]. The composition of the gut microbiota displays significant inter-individual variation due to both genetic factors of the host and environmental features (for example, diet) [6]. The gut microbiota produces several mediators capable of altering brain function [7], and also is involved in complex neuro-immune interactions [8]. As such, the bidirectional communication between the gut microbiota and the brain referred to as the gut-brain axis represents a novel target for therapeutic interventions for several brain disorders [9,10]. Aberrations in microbiota composition, referred to as intestinal dysbiosis, is implicated in the pathophysiology of several brain and metabolic disorders including but not limited to major depressive disorder (MDD) [11, 12], schizophrenia [13], autism [14, 15], multiple sclerosis [16], Parkinson’s disease [17], obesity [18,19], irritable bowel syndrome [20], and type 2 diabetes [21]. Several factors including gut dysbiosis may lead to intestinal inflammation and consequent disruption of tight junctions, also referred to as the "leaky gut", which may result in the translocation of microorganisms and their products into the systemic circulation [22]. For example, the translocation of lipopolysaccharide (LPS) from gramnegative bacteria has been implicated in the pathophysiology of several neuro-immune diseases like MDD [23] and schizophrenia [24]. Activation of the Toll-like receptor 2/4 (TLR 2/4) radical cycle by so-called pathogen activated molecular patterns (PAMPs) including LPS may constitute a common pathophysiological pathway for neuropsychiatric diseases related to the “leaky gut” [25]. For this themed edition of Current Pharmaceutical Design, we invited leading experts from their respective fields to review emerging translational implications of gut-brain axis abnormalities across neuropsychiatric conditions. Morris et al. [26] provide an extensive review of the various pathophysiological mechanisms underpinning the role of intestinal dysbiosis and the leaky gut in neuro-immune diseases. The authors focused their attention on inflammatory bowel disease (IBD), type I diabetes mellitus, and chronic fatigue syndrome (CFS). Severance and colleagues [27] extend this topic proposing an integrative model in which both dietary components and microbial factors may lead to the generation of autoantigens, thereby contributing to the emergence of autoimmunity which is a prevalent mechanism across several neuropsychiatric disorders. Slyepchencko et al. [28] review evidence of gut dysbiosis and intestinal inflammation in the pathophysiology of MDD, obesity and type 2 diabetes. The authors propose that the gut-brain axis may contribute to the significant comorbidity between these diseases. In addition, translational implications of this hypothesis are discussed. Slattery et al. [29] provide a comprehensive review on the factors that may contribute to intestinal dysbiosis in autism spectrum disorders. In addition, the authors review available evidence and perspectives of therapeutic interventions targeting the gut-brain axis for this prevalent set of disorders. Caso et al. [30] review evidence for a putative role of gut dysbiosis and intestinal inflammation in the immunopathogenesis of schizophrenia. The authors conclude that although evidence from human studies remain scarce, experimental data point that disturbances of the gutbrain axis may contribute to the activation of several pathways known to be involved in the pathophysiology of schizophrenia, and thus may constitute a promising therapeutic target. Rodriguez et al. [31] review the extant literature that indicates the role of gut-brain axis abnormalities in the pathophysiology of multiple sclerosis (MS). Furthermore, the authors propose that intestinal inflammation may activate the kynurenine pathway leading to a reduction in
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Gut Permeability and the Microbiome
serotonin, which is a known precursor of melatonin. A down-regulation of melatoninergic pathways may contribute to several manifestations of MS, including depression. Anderson et al. [32] provide evidence that gut dysbiosis and intestinal inflammation may play a pathophysiological role in Parkinson’s disease (PD), in part by driving the activation of neuro-immune and oxidative and nitrosative stress pathways. The authors also propose that gut-brain axis abnormalities may activate the kynurenine pathway leading to a decrease in the biosynthesis of melatonin, with significant pathophysiological consequences in target tissues, including but not limited to glia, gut, neuronal, and immune cells. Finally, Köhler and colleagues [33] provide a review of available evidence, which in sum indicates a relevant pathophysiological role for gut-brain axis abnormalities in the pathophysiology of Alzheimer’s disease (AD). Their review indicates that gut dysbiosis and hyperpermeability may contribute to neuro-inflammation and also to a decrease in the clearance of β-amyloid, which in addition to other mechanisms may contribute to the onset and progression of AD. In sum, these papers show a converging body of literature implicating a common mechanism across seemingly disparate disorders. This has implications not only for understanding the shared and divergent underlying mechanisms, but for the discovery of the next generation of therapies. CONFLICT OF INTEREST MB has received a grant/research support from Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier and Woolworths, and has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay, and Wyeth as well as serving as a consultant to Allergan, Astra Zeneca, Bioadvantex, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck Merck, Pfizer and Servier. ACKNOWLEDGEMENTS As guest editors, we would like to acknowledge the contributors and reviewers for their time and insight. We hope this themed edition may provide a better understanding of the role of gut-brain axis abnormalities in the pathophysiology of brain disorders, along with the significant translational implications of this field. AFC is the recipient of a research fellowship award from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; level II; Brazil). MB is supported by an NHMRC Senior Principal Research Fellowship 1059660. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]
Yu LC, Wang JT, Wei SC, Ni YH. Host-microbial interactions and regulation of intestinal epithelial barrier function: From physiology to pathology. World J Gastrointest Pathophysiol 2012; 3: 27-43. Frank DN, Pace NR. Gastrointestinal microbiology enters the metagenomics era. Curr Opin Gastroenterol 2008; 24: 4-10. Douglas-Escobar M, Elliott E, Neu J. Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr 2013; 167: 374-9. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012; 13: 701-12. Foster JA, Lyte M, Meyer E, Cryan JF. Gut microbiota and brain function: an evolving field in neuroscience. Int J Neuropsychopharmacol 2016; 19. Dash S, Clarke G, Berk M, Jacka FN. The gut microbiome and diet in psychiatry: focus on depression. Curr Opin Psychiatry 2015; 28: 1-6. Morris G, Berk M, Carvalho AF, et al. The role of the microbial metabolites including tryptophan catabolites and short chain fatty acids in the pathophysiology of immune-inflammatory and neuroimmune disease. Mol Neurobiol 2016. Gensollen T, Iyer SS, Kasper DL, Blumberg RS. How colonization by microbiota in early life shapes the immune system. Science 2016; 352: 539-44. Fond G, Boukouaci W, Chevalier G, et al. The "psychomicrobiotic": Targeting microbiota in major psychiatric disorders: A systematic review. Pathol Biol (Paris) 2015; 63: 35-42. Slyepchenko A, Carvalho AF, Cha DS, Kasper S, McIntyre RS. Gut emotions - mechanisms of action of probiotics as novel therapeutic targets for depression and anxiety disorders. CNS Neurol Disord Drug Targets 2014; 13: 1770-86. Zheng P, Zeng B, Zhou C, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Mol Psychiatry 2016; 21: 786-96. Wong ML, Inserra A, Lewis MD, Mastronardi CA, Leong L, Choo J. Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol Psychiatry 2016; 21: 797-805. Severance EG, Yolken RH, Eaton WW. Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res 2016; 176(1): 23-35. Son JS, Zheng LJ, Rowehl LM, et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the simons simplex collection. PLoS One 2015; 10: e0137725. MacFabe DF. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microb Ecol Health Dis 2015; 26: 28177. Chen J, Chia N, Kalari KR, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep 2016; 6: 28484. Scheperjans F, Aho V, Pereira PA, et al. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord 2015; 30: 350-8. Patterson E, Ryan PM, Cryan JF, et al. Gut microbiota, obesity and diabetes. Postgrad Med J 2016; 92: 286-300. Baothman OA, Zamzami MA, Taher I, Abubaker J, Abu-Farha M. The role of gut microbiota in the development of obesity and diabetes. Lipids Health Dis 2016; 15: 108. Zhuang X, Xiong L, Li L, Li M, Chen MH. Alterations of gut microbiota in patients with irritable bowel syndrome: A systematic review and metaanalysis. J Gastroenterol Hepatol 2016; doi: 10.1111/jgh.13471. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015; 528: 262-6. Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stressrelated psychiatric disorders. Front Cell Neurosci 2015; 9: 392. Maes M, Kubera M, Leunis JC, Berk M. Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord 2012; 141: 55-62. Garcia Bueno B, Caso JR, Madrigal JL, Leza JC. Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases. Neurosci Biobehav Rev 2016; 64: 134-47. Lucas K, Maes M. Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol 2013; 48: 190-204.
Gut Permeability and the Microbiome [26]
[27] [28] [29] [30] [31] [32] [33]
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Morris G, Berk M, Carvalho AF, Caso JR, Sanz Y, Maes M. The role of microbiota and intestinal permeability in the pathophysiology of autoimmune and neuroimmune processes with an emphasis on inflammatory bowel disease, type 1 diabetes and chronic fatigue syndrome. Curr Pharm Des 2016; 22(40): 6058-75. Severance EG, Tveiten D, Lindström LH, Yolken RH, Reichelt KL. The gut microbiota and the emergence of autoimmunity: relevance to major psychiatric disorders. Curr Pharm Des 2016; 22(40): 6076-86. Slyepchenko A, Maes M, Machado-Vieira R, et al. Intestinal dysbiosis, gut hyperpermeability and bacterial translocation: missing links between depression, obesity and type 2 diabetes? Curr Pharm Des 2016; 22(40): 6087-106. Slattery J, MacFabe DF, Kahler SG, Frye RE. The enteric microbiota and autism spectrum disorder: pathophysiological and therapeutic implications. Curr Pharm Des 2016; 22(40): 6107-21. Caso JR, Balanzá-Martínez V, Palomo T, García-Bueno B. The microbiota and gut-brain axis: contributions to the immunopathogenesis of schizophrenia. Curr Pharm Des 2016; 22(40): 6122-33. Rodriguez M, Wootla B, Anderson G. Multiple sclerosis, gut microbiota and permeability: role of tryptophan catabolites, depression and the driving down of local melatonin. Curr Pharm Des 2016; 22(40): 6134-41. Anderson G, Seo M, Berk M, Carvalho AF, Maes M. Gut permeability and microbiota in Parkinson’s disease: role of depression, tryptophan catabolites, oxidative and nitrosative stress and melatoninergic pathways. Curr Pharm Des 2016; 22(40): 6142-51. Köhler CA, Maes M, Slyepchenko A, et al. The gut-brain axis, including the microbiome, leaky gut and bacterial translocation: mechanisms and pathophysiological role in Alzheimer’s disease. Curr Pharm Des 2016; 22(40): 6152-66.
André F. Carvalho
Michael Berk
Michael Maes
Department of Clinical Medicine and Translational Psychiatry Research Group Faculty of Medicine, Federal University of Ceará Fortaleza, CE, Brazil E-mails:
[email protected] [email protected]
Orygen Youth Health Research Centre and the Centre of Youth Mental Health The Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry University of Melbourne, Parkville, 3052 Australia E-mail:
[email protected]
Revitalis, Waalre The Netherlands E-mail:
[email protected]
