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Microbiota-gut-brain research: A critical analysis

Published online by Cambridge University Press:  12 September 2018

Katarzyna B. Hooks
University of Bordeaux, CBiB, Bordeaux 33076, France. katarzyna.hooks@u-bordeaux.fr University of Bordeaux, CNRS/LaBRI, Talence 33405, France
Jan Pieter Konsman
University of Bordeaux, CNRS/INCIA, Bordeaux 33076, France.
Maureen A. O'Malley
University of Bordeaux, CNRS/LaBRI, Talence 33405, France University of Bordeaux, CNRS/LaBRI, Talence 33405, France; University of Sydney, School of History and Philosophy of Science, New South Wales 2006,


Microbiota-gut-brain (MGB) research is a fast-growing field of inquiry with important implications for how human brain function and behaviour are understood. Researchers manipulate gut microbes (“microbiota”) to reveal connections between intestinal microbiota and normal brain functions (e.g., cognition, emotion, and memory) or pathological states (e.g., anxiety, mood disorders, and neural developmental disorders such as autism). Many claims are made about causal relationships between gut microbiota and human behaviour. By uncovering these relationships, MGB research aims to offer new explanations of mental health and potential avenues of treatment.

So far, limited evaluation has been made of MGB's methods and its core experimental findings, many of which are extensively reiterated in copious reviews of the field. These factors, plus the self-help potential of MGB, have combined to encourage uncritical public uptake of MGB discoveries. Both social and professional media focus on the potential for dietary intervention in mental health, and causal relationships are assumed to be established.

Our target article has two main aims. One is to examine critically the core practices and findings of experimental MGB research and to raise questions about them for brain and behavioural scientists who may not be familiar with the field. The other is to challenge the way in which MGB findings are presented. Our positive goal is to suggest how current problems and weaknesses may be addressed, in order for both scientific and public audiences to gain a clearer picture of MGB research and its strengths and limitations.

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Copyright © Cambridge University Press 2019 

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Ait-Belgnaoui, A., Colom, A., Braniste, V., Ramalho, L., Marrot, A., Cartier, C., Houdeau, E., Theodorou, V. & Tompkins, T. (2014) Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice. Neurogastroenterology and Motility 26(4):510–20. Scholar
Ait-Belgnaoui, A., Durand, H., Cartier, C., Chaumaz, G., Eutamene, H., Ferrier, L., Houdeau, E., Fioramonti, J., Bueno, L. & Theodorou, V. (2012) Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology 37(11):1885–95. Available at: Scholar
Alcock, J., Maley, C. C. & Aktipis, C. A. (2014) Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. BioEssays 36:940–49. Available at: Scholar
Arrieta, M.-C., Walter, J. & Finlay, B. B. (2016) Human microbiota-associated mice: A model with challenges. Cell Host & Microbe 19:575–78. Available at: Scholar
Asano, Y., Hiramoto, T., Nishino, R., Aiba, Y., Kimura, T., Yoshihara, K., Koga, Y. & Sudo, N. (2012) Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. AJP Gastrointestinal and Liver Physiology 303:G128895. Available at: Scholar
Aziz, Q. & Thompson, D. G. (1998) Brain-gut axis in health and disease. Gastroenterology 114:559–78. Available at: Scholar
Bailey, M. T., Dowd, S. E., Galley, J. D., Hufnagle, A. R., Allen, R. G. & Lyte, M. (2011) Exposure to a social stressor alters the structure of the intestinal microbiota: Implications for stressor-induced immunomodulation. Brain, Behavior, and Immunity 25(3):397407. Available at: Scholar
Bajaj, J. S., Heuman, D. M., Sanyal, A. J., Hylemon, P. B., Sterling, R. K., Stravitz, R. T., Fuchs, M., Ridlon, J. M., Daita, K., Monteith, P., Noble, N. A., White, M. B., Fisher, A., Sikaroodi, M., Rangwala, H. & Gillevet, P. M. (2013) Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLoS ONE 8:e60042. Available at: Scholar
Bassi, G. S., Kanashiro, A., Santin, F. M., de Souza, G. E. P., Nobre, M. J. & Coimbra, N. C. (2012) Lipopolysaccharide-induced sickness behaviour evaluated in different models of anxiety and innate fear in rats. Basic & Clinical Pharmacology & Toxicology 110:359–69. Available at: Scholar
Belzung, C. & Griebel, G. (2001) Measuring normal and pathological anxiety-like behaviour in mice: A review. Behavioural Brain Research 125:141–49. Available at: Scholar
Bercik, P., Denou, E., Collins, J., Jackson, W., Lu, J., Jury, J., Deng, Y., Blennerhassett, P., Macri, J., McCoy, K. D., Verdu, E. F. & Collins, S. M. (2011a) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141:599609, 609.e1–3. Available at: Scholar
Berdoy, M., Webster, J. P. & Macdonald, D. W. (2000) Fatal attraction in rats infected with Toxoplasma gondii. Proceedings of the Royal Society B: Biological Sciences 267:1591–94. Available at: Scholar
Bik, E. M. (2016) The hoops, hopes, and hypes of human microbiome research. Yale Journal of Biology and Medicine 89:363–73. Available at: Scholar
Bluthé, R. M., Dantzer, R. & Kelley, K. W. (1992) Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat. Brain Research 573:318–20. Available at: Scholar
Borre, Y. E., O'Keeffe, G. W., Clarke, G., Stanton, C., Dinan, T. G. & Cryan, J. F. (2014) Microbiota and neurodevelopmental windows: Implications for brain disorders. Trends in Molecular Medicine 20(9):509–18. Available at: Scholar
Bourin, M., Petit-Demoulière, B., Dhonnchadha, B. N. & Hascöet, M. (2007) Animal models of anxiety in mice. Fundamental & Clinical Pharmacology 21:567–74. Available at: Scholar
Braniste, V., Al-Asmakh, M., Kowal, C., Anuar, F., Abbaspour, A., Tóth, M., Korecka, A., Bakocevic, N., Ng, L. G., Kundu, P., Gulyás, B., Halldin, C., Hultenby, K., Nilsson, H., Hebert, H., Volpe, B. T., Diamond, B. & Pettersson, S. (2014) The gut microbiota influences blood-brain barrier permeability in mice. Science Translational Medicine 6:263ra158. Available at: Scholar
Bravo, J. A., Forsythe, P., Chew, M. V., Escaravage, E., Savignac, H. M., Dinan, T. G., Bienenstock, J. & Cryan, J. F. (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences USA 108(38):16050–55. Available at: Scholar
Brown, R., Price, R. J., King, M. G. & Husband, A. J. (1990) Are antibiotic effects on sleep behavior in the rat due to modulation of gut bacteria? Physiology & Behavior 48:561–65.Google Scholar
Bruce-Keller, A. J., Salbaum, J. M. & Berthoud, H.-R. (2018) Harnessing gut microbes for mental health: Getting from here to there. Biological Psychiatry 83:214–23. Available at: Scholar
Bruce-Keller, A. J., Salbaum, J. M., Luo, M., Blanchard, E., Taylor, C. M., Welsh, D. A. & Berthoud, H.-R. (2015) Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biological Psychiatry 77:607–15. Available at: Scholar
Bucci, V. & Xavier, J. B. (2014) Towards predictive models of the human gut microbiome. Journal of Molecular Biology 426:3907–16. Available at: Scholar
Button, K. S., Ioannidis, J. P. A., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S. J. & Munafò, M. R. (2013) Power failure: Why small sample size undermines the reliability of neuroscience. Nature Reviews Neuroscience 14:365–76. Available at: Scholar
Cannon, W. B. (1909) The influence of emotional states on the functions of the alimentary canal. American Journal of the Medical Sciences 137:480–87.Google Scholar
Cannon, W. B. (1911) The mechanical factors of digestion. Edward Arnold.Google Scholar
Chedid, L. & Boyer, F. (1953) [Action of adrenaline on the effects of a bacterial endotoxin]. Comptes Rendus Des Seances de La Societe de Biologie et de Ses Filiales 147:1742–44. Available at: Scholar
Christian, L. M., Galley, J. D., Hade, E. M., Schoppe-Sullivan, S., Kamp Dush, C. & Bailey, M. T. (2015) Gut microbiome composition is associated with temperament during early childhood. Brain, Behavior, and Immunity 45:118–27. Availability at: Scholar
Clarke, G., Grenham, S., Scully, P., Fitzgerald, P., Moloney, R. D., Shanahan, F., Dinan, T. G. & Cryan, J. F. (2013) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Molecular Psychiatry 18(6):666–73. Available at: Scholar
Colquhoun, D. (2014) An investigation of the false discovery rate and the misinterpretation of p-values. Royal Society Open Science 1:140216. Available at: Scholar
Commons, K. G., Cholanians, A. B., Babb, J. A. & Ehlinger, D. G. (2017) The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chemical Neuroscience 8:955960. Available at: Scholar
Cowan, C. S. M., Hoban, A. E., Ventura-Silva, A. P., Dinan, T. G., Clarke, G. & Cryan, J. F. (2018) Gutsy moves: The amygdala as a critical node in microbiota to brain signaling. BioEssays 40:1700172. Available at: Scholar
Coyte, K. Z., Schluter, J. & Foster, K. R. (2015) The ecology of the microbiome: Networks, competition, and stability. Science 350:663–66. Available at: Scholar
Crumeyrolle-Arias, M., Jaglin, M., Bruneau, A., Vancassel, S., Cardona, A., Daugé, V., Naudon, L. & Rabot, S. (2014) Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 42:207–17. Available at: Scholar
Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T. G. & Cryan, J. F. (2014) Microbiota is essential for social development in the mouse. Molecular Psychiatry 19:146–48. Available at: Scholar
Desbonnet, L., Clarke, G., Traplin, A., O'Sullivan, O., Crispie, F., Moloney, R. D., Cotter, P. D., Dinan, T. G. & Cryan, J. F. (2015) Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour. Brain, Behavior, and Immunity 48:165–73. Available at: Scholar
de Theije, C. G., Wopereis, H., Ramadan, M., van Eijndthoven, T., Lambert, J., Knol, J., Garssen, J., Kraneveld, A. D. & Oozeer, R. (2014) Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain, Behavior, and Immunity 37:197206. Available at: Scholar
de Vos, W. M. & de Vos, E. A. J. (2012) Role of the intestinal microbiome in health and disease: From correlation to causation. Nutrition Reviews 70(S1):S4556. Available at: Scholar
Diaz Heijtz, R., Wang, S., Anuar, F., Qian, Y., Björkholm, B., Samuelsson, A., Hibberd, M. L., Forssberg, H. & Pettersson, S. (2011) Normal gut microbiota modulates brain development and behavior. Proceedings of the National Academy of Sciences USA 108:3047–52. Available at: Scholar
Dinan, T. G., Stanton, C. & Cryan, J. F. (2013) Psychobiotics: A novel class of psychotropic. Biological Psychiatry 74:720–26. Available at: Scholar
DiSalvo, D. (2017) Science is showing how gut bacteria affect the brain, but don't bother taking probiotics yet. Forbes, August 27. Available at: Scholar
Dupont, J. R., Jervis, H. R. & Sprinz, H. (1965) Auerbach's plexus of the rat cecum in relation to the germfree state. Journal of Comparative Neurology 125:1118. Available at: Scholar
Duvallet, C., Gibbons, S. M., Gurry, T., Irizarry, R. A. & Alm, E. J. (2017) Meta-analysis of gut microbiome studies identifies disease-specific and shared responses. Nature Communications 8:1784. Available at: Scholar
Eckburg, P. B., Bik, E. M., Bernstein, C. N., Purdom, E., Dethlefsen, L., Sargent, M., Gill, S. R., Nelson, K. E. & Relman, D. A. (2005) Diversity of the human intestinal microbial flora. Science 308:1635–38. Available at: Scholar
Eik-Nes, K. B. & Samuels, L. T. (1958) Metabolism of cortisol in normal and stressed dogs. Endocrinology 63:8288. Available at: Scholar
Eisen, J. A. (2017) Microbiomania and “overselling the microbiome.” The Tree of Life (blog). Available at: Scholar
Eisenstein, M. (2016) Microbiome: Bacterial broadband. Nature 533:S104106. Available at: Scholar
Ennaceur, A. (2014) Tests of unconditioned anxiety – Pitfalls and disappointments. Physiology & Behavior 135:5571. Available at: Scholar
Evans, D. G., Miles, A. A. & Niven, J. S. F. (1948) The enhancement of bacterial infections by adrenaline. British Journal of Experimental Pathology 29:2039. Available at: Scholar
Falony, G., Joossens, M., Vieira-Silva, S., Wang, J., Darzi, Y., Faust, K., Kurilshikov, A., Bonder, M. J., Valles-Colomer, M., Vandeputte, D., Tito, R. Y., Chaffron, S., Rymenans, L., Verspecht, C., De Sutter, L., Lima-Mendez, G., D'Hoe, K., Jonckheere, K., Homola, D., Garcia, R., Tigchelaar, E. F., Eeckhaudt, L., Fu, J., Henckaerts, L., Zhernakova, A., Wijmenga, C. & Raes, J. (2016) Population-level analysis of gut microbiome variation. Science 352(6285):560–64. Available at: Scholar
Fleming, A. (2017) Is your gut microbiome the key to health and happiness? Guardian, November 6. Available at: Scholar
Forsythe, P., Kunze, W. & Bienenstock, J. (2016) Moody microbes or fecal phrenology: What do we know about the microbiota-gut-brain axis? BMC Medicine 14:58. Available at: Scholar
Foster, J. A. & McVey Neufeld, K.-A. (2013) Gut-brain axis: How the microbiome influences anxiety and depression. Trends in Neurosciences 36(5):305–12. Available at: Scholar
Gareau, M. G., Wine, E., Rodrigues, D. M., Cho, J. H., Whary, M. T., Philpott, D. J., Macqueen, G. & Sherman, P. M. (2011) Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60:307–17. Available at: Scholar
Gastroenterology (1980) Notices: International symposium on the brain-gut axis. Gastroenterology 79(4):783.Google Scholar
Gevers, D., Kugathasan, S., Denson, L. A., Vázquez-Baeza, Y., Van Treuren, W., Ren, B., Schwager, E., Knights, D., Song, S. J., Yassour, M., Morgan, X. C., Kostic, A. D., Luo, C., González, A., McDonald, D., Haberman, Y., Walters, T., Baker, S., Rosh, J., Stephens, M., Heyman, M., Markowitz, J., Baldassano, R., Griffiths, A., Sylvester, F., Mack, D., Kim, S., Crandall, W., Hyams, J., Huttenhower, C., Knight, R. & Xavier, R. J. (2014) The treatment-naive microbiome in new-onset Crohn's disease. Cell Host & Microbe 15:382–92. Available at: Scholar
Goehler, L. E., Park, S. M., Opitz, N., Lyte, M. & Gaykema, R. P. A. (2008) Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: Possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain, Behavior, and Immunity 22:354–66. Available at: Scholar
Gold, N. I., Singleton, E., Macfarlane, D. A. & Moore, F. D. (1958) Quantitative determination of the urinary cortisol metabolites, “tetrahydro F,” “allo-tetrahydro F” and “tetrahydro E”: Effects of adrenocorticotropin and complex trauma in the human. Journal of Clinical Investigation 37:813–23. Available at: Scholar
Gonon, F., Bezard, E. & Boraud, T. (2011) Misrepresentation of neuroscience data might give rise to misleading conclusions in the media: The case of attention deficit hyperactivity disorder. PLoS ONE 6:e14618. Available at: Scholar
Gonon, F., Konsman, J.-P., Cohen, D. & Boraud, T. (2012) Why most biomedical findings echoed by newspapers turn out to be false: The case of attention deficit hyperactivity disorder. PLoS ONE 7:e44275. Available at: Scholar
Habibzadeh, F. (2013) Common statistical mistakes in manuscripts submitted to biomedical journals. European Science Editing 39:9294.Google Scholar
Haenel, H. (1961) Some rules in the ecology of the intestinal microflora of man. Journal of Applied Bacteriology 24:242–51. Available at: Scholar
Hanage, W. P. (2014) Microbiology: Microbiome science needs a healthy dose of scepticism. Nature 512:247–48. Available at: Scholar
Handelsman, J. (2004) Metagenomics: Application of genomics to uncultured microorganisms. Microbiology and Molecular Biology Reviews 68:669–85. Available at: Scholar
Handelsman, J., Rondon, M. R., Brady, S. F., Clardy, J. & Goodman, R. M. (1998) Molecular biological access to the chemistry of unknown soil microbes: A new frontier for natural products. Chemistry & Biology 5:R24549. Available at: Scholar
Hart, B. L. (1988) Biological basis of the behavior of sick animals. Neuroscience and Biobehavioral Reviews 12:123–37. Available at: Scholar
Hemmings, S. M. J., Malan-Müller, S., van den Heuvel, L. L., Demmitt, B. A., Stanislawski, M. A., Smith, D. G., Bohr, A. D., Stamper, C. E., Hyde, E. R., Morton, J. T., Marotz, C. A., Siebler, P. H., Braspenning, M., Van Criekinge, W., Hoisington, A. J., Brenner, L. A., Postolache, T. T., McQueen, M. B., Krauter, K. S., Knight, R., Seedat, S. & Lowry, C. A. (2017) The microbiome in posttraumatic stress disorder and trauma-exposed controls: An exploratory study. Psychosomatic Medicine 79:936–46. Available at: Scholar
Hill, C., Guarner, F., Reid, G., Gibson, G. R., Merenstein, D. J., Pot, B., Morelli, L., Canani, R. B., Flint, H. J., Salminen, S., Calder, P. C. & Sanders, M. E. (2014) The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews Gastroenterology & Hepatology 11:506–14. Available at: Scholar
Hodoval, L. F., Morris, E. L., Crawley, G. J. & Beisel, W. R. (1968) Pathogenesis of lethal shock after intravenous staphylococcal enterotoxin B in monkeys. Applied Microbiology 16:187–92. Available at: Scholar
Homberg, J. R. (2013) Measuring behaviour in rodents: Towards translational neuropsychiatric research. Behavioural Brain Research 236:295306. Available at: Scholar
Hooks, K. B. & O'Malley, M. A. (2017) Dysbiosis and its discontents. mBio 8:e01492-17. Available at: Scholar
Hsiao, E. Y., McBride, S. W., Hsien, S., Sharon, G., Hyde, E. R., McCue, T., Codelli, J. A., Chow, J., Reisman, S. E., Petrosino, J. F., Patterson, P. H. & Mazmanian, S. K. (2013) Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155:1451–63. Available at: Scholar
Huang, R., Wang, K. & Hu, J. (2016) Effect of probiotics on depression: A systematic review and meta-analysis of randomized controlled trials. Nutrients 8:483. Available at: Scholar
Human Microbiome Project Consortium (2012) Structure, function and diversity of the healthy human microbiome. Nature 486(7402):207–14. Available at: Scholar
Jabr, F. (2017) Probiotics are no panacea. Scientific American 317:2627. Available at: Scholar
Jeppsson, B., James, J. H., Hummel, R. P., Brenner, W., West, R. & Fischer, J. E. (1983) Increased blood-brain transport of tryptophan after portacaval anastomoses in germ-free rats. Metabolism: Clinical and Experimental 32:48. Available at: Scholar
Jiang, H., Ling, Z., Zhang, Y., Mao, H., Ma, Z., Yin, Y., Wang, W., Tang, W., Tan, Z., Shi, J., Li, L. & Ruan, B. (2015) Altered fecal microbiota composition in patients with major depressive disorder. Brain, Behavior, and Immunity 48:186–94. Available at: Scholar
Johnson, K. V.-A. & Foster, K. R. (2018) Why does the microbiome affect behaviour? Nature Reviews Microbiology 16:647–55. Available at: Scholar
Kelly, J. R., Allen, A. P., Temko, A., Hutch, W., Kennedy, P. J., Farid, N., Murphy, E., Boylan, G., Bienenstock, J., Cryan, J. F., Clarke, G. & Dinan, T. G. (2017) Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (jb-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain, Behavior, and Immunity 61:5059. Available at: Scholar
Kim, D., Hofstaedter, C. E., Zhao, C., Mattei, L., Tanes, C., Clarke, E., Lauder, A., Sherrill-Mix, S., Chehoud, C., Kelsen, J., Conrad, M., Collman, R. G., Baldassano, R., Bushman, F. D. & Bittinger, K. (2017a) Optimizing methods and dodging pitfalls in microbiome research. Microbiome 5:52. Available at: Scholar
Kirk, R. G. (2012) “Life in a germ-free world”: Isolating life from the laboratory animal to the bubble boy. Bulletin of the History of Medicine 86:237–75. Available at: Scholar
Kleiman, S. C., Watson, H. J., Bulik-Sullivan, E. C., Huh, E. Y., Tarantino, L. M., Bulik, C. M. & Carroll, I. M. (2015) The intestinal microbiota in acute anorexia nervosa and during renourishment: Relationship to depression, anxiety, and eating disorder psychopathology. Psychosomatic Medicine 77:969–81. Available at: Scholar
Knight, R., Vrbanac, A., Taylor, B. C., Aksenov, A., Callewaert, C., Debelius, J., Gonzalez, A., Kosciolek, T., McCall, L.-I., McDonald, D., Melnik, A. V., Morton, J. T., Navas, J., Quinn, R. A., Sanders, J. G., Swafford, A. D., Thompson, L. R., Tripathi, A., Xu, Z. Z., Zaneveld, J. R., Zhu, Q., Caporaso, J. G. & Dorrestein, P. C. (2018) Best practices for analysing microbiomes. Nature Reviews Microbiology 16(7):410–22. Available at: Scholar
Kristensen, N. B., Bryrup, T., Allin, K. H., Nielsen, T., Hansen, T. H. & Pedersen, O. (2016) Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: A systematic review of randomized controlled trials. Genome Medicine 8(1):52. Available at: Scholar
Leclercq, S., Matamoros, S., Cani, P. D., Neyrinck, A. M., Jamar, F., Stärkel, P., Windey, K., Tremaroli, V., Bäckhed, F., Verbeke, K., de Timary, P. & Delzenne, N. M. (2014) Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proceedings of the National Academy of Sciences USA 111:E448593. Scholar
Lepage, P., Leclerc, M. C., Joossens, M., Mondot, S., Blottière, H. M., Raes, J., Ehrlich, D. & Doré, J. (2013) A metagenomic insight into our gut's microbiome. Gut 62:146–58. Available at: Scholar
Liu, R. T. (2017) The microbiome as a novel paradigm in studying stress and mental health. American Psychologist 72(7):655–67. Available at: Scholar
Lyte, M. (1993) The role of microbial endocrinology in infectious disease. Journal of Endocrinology 137:343–45. Available at: Scholar
Lyte, M. (2011) Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics. BioEssays 33:574–81. Available at: Scholar
Lyte, M. & Ernst, S. (1992) Catecholamine induced growth of gram negative bacteria. Life Sciences 50:203–12. Available at: Scholar
Lyte, M., Varcoe, J. J. & Bailey, M. T. (1998) Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation. Physiology & Behavior 65:6368. Available at: Scholar
Magnusson, K. R., Hauck, L., Jeffrey, B. M., Elias, V., Humphrey, A., Nath, R., Perrone, A. & Bermudez, L. E. (2015) Relationships between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience 300:128–40. Available at: Scholar
Mayer, E. A., Knight, R., Mazmanian, S. K., Cryan, J. F. & Tillisch, K. (2014) Gut microbes and the brain: Paradigm shift in neuroscience. Journal of Neuroscience 34(46):15490–96. Available at: Scholar
Mayer, E. A., Tillisch, K. & Gupta, A. (2015) Gut/brain axis and the microbiota. Journal of Clinical Investigation 125:926–38. Available at: Scholar
Mazmanian, S. K., Round, J. L. & Kasper, D. L. (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–25. Available at: Scholar
McKean, J., Naug, H., Nikbakht, E., Amiet, B. & Colson, N. (2017) Probiotics and subclinical psychological symptoms in healthy participants: A systematic review and meta-analysis. Journal of Alternative and Complementary Medicine 23:249–58. Available at: Scholar
McNulty, N. P., Yatsunenko, T., Hsiao, A., Faith, J. J., Muegge, B. D., Goodman, A. L., Henrissat, B., Oozeer, R., Cools-Portier, S., Gobert, G., Chervaux, C., Knights, D., Lozupone, C. A., Knight, R., Duncan, A. E., Bain, J. R., Muehlbauer, M. J., Newgard, C. B., Heath, A. C. & Gordon, J. I. (2011) The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Science Translational Medicine 3:106r a106. Scholar
Messaoudi, M., Lalonde, R., Violle, N., Javelot, H., Desor, D., Nejdi, A., Bisson, J.-F., Rougeot, C., Pichelin, M., Cazaubiel, M. & Cazaubiel, J.-M. (2011) Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. British Journal of Nutrition 105:755–64. Available at: Scholar
Metchnikoff, É. (1908) Études sur la flore intestinale. Putréfaction intestinale. Annales de l'Institut Pasteur 22:930–55.Google Scholar
Molendijk, M. L. & de Kloet, E. R. (2015) Immobility in the forced swim test is adaptive and does not reflect depression. Psychoneuroendocrinology 62:389–91. Available at: Scholar
Momozawa, Y., Deffontaine, V., Louis, E. & Medrano, J. F. (2011) Characterization of bacteria in biopsies of colon and stools by high throughput sequencing of the V2 region of bacterial 16S rRNA gene in human. PLoS ONE 6:e16952. Available at: Scholar
Moran, N. A. & Sloan, D. B. (2015) The hologenome concept: Helpful or hollow? PLoS Biology 13:e1002311. Available at: Scholar
Mormède, P., Andanson, S., Aupérin, B., Beerda, B., Guémené, D., Malmkvist, J., Manteca, X., Manteuffel, G., Prunet, P., van Reenen, C. G., Richard, S. & Veissier, I. (2007) Exploration of the hypothalamic-pituitary-adrenal function as a tool to evaluate animal welfare. Physiology & Behavior 92:317–39. Available at: Scholar
Neufeld, K., Kang, N., Bienenstock, J. & Foster, J. A. (2011a) Effects of intestinal microbiota on anxiety-like behavior. Communicative & Integrative Biology 4:492–94. Available at: Scholar
Neufeld, K., Kang, N., Bienenstock, J. & Foster, J. A. (2011b) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterology and Motility 23:255–64, e119. Available at: Scholar
Ng, Q. X., Peters, C., Ho, C. Y. X., Lim, D. Y. & Yeo, W.-S. (2017) A meta-analysis of the use of probiotics to alleviate depressive symptoms. Journal of Affective Disorders 228:1319. Available at: Scholar
Nguyen, T. L. A., Vieira-Silva, S., Liston, A. & Raes, J. (2015) How informative is the mouse for human gut microbiota research? Disease Models & Mechanisms 8:116. Available at: Scholar
Nishino, R., Mikami, K., Takahashi, H., Tomonaga, S., Furuse, M., Hiramoto, T., Aiba, Y., Koga, Y. & Sudo, N. (2013) Commensal microbiota modulate murine behaviors in a strictly contamination-free environment confirmed by culture-based methods. Neurogastroenterology and Motility 25:521–e371. Available at: Scholar
Ohland, C. L., Kish, L., Bell, H., Thiesen, A., Hotte, N., Pankiv, E. & Madsen, K. L. (2013) Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome. Psychoneuroendocrinology 38:1738–47. Available at: Scholar
Olesen, S. W. & Alm, E. J. (2016) Dysbiosis is not an answer. Nature Microbiology 1:16228. Available at: Scholar
Olle, B. (2013) Medicines from microbiota. Nature Biotechnology 31:309–15. Available at: Scholar
O'Mahony, S. M., Clarke, G., Dinan, T. G. & Cryan, J. F. (2017) Early-life adversity and brain development: Is the microbiome a missing piece of the puzzle? Neuroscience 342:3754. Available at: Scholar
O'Mahony, S. M., Marchesi, J. R., Scully, P., Codling, C., Ceolho, A.-M., Quigley, E. M. M., Cryan, J. F. & Dinan, T. G. (2009) Early life stress alters behavior, immunity, and microbiota in rats: Implications for irritable bowel syndrome and psychiatric illnesses. Biological Psychiatry 65:263–67. Available at: Scholar
O'Malley, M. A. & Skillings, D. J. (2018) Methodological strategies in microbiome research and their explanatory implications. Perspectives on Science 26:239–65. Available at: Scholar
Park, A. J., Collins, J., Blennerhassett, P. A., Ghia, J. E., Verdu, E. F., Bercik, P. & Collins, S. M. (2013) Altered colonic function and microbiota profile in a mouse model of chronic depression. Neurogastroenterology and Motility 25:733–e575. Available at: Scholar
Perez-Burgos, A., Wang, B., Mao, Y.-K., Mistry, B., McVey Neufeld, K.-A., Bienenstock, J. & Kunze, W. (2013) Psychoactive bacteria Lactobacillus rhamnosus (JB-1) elicits rapid frequency facilitation in vagal afferents. American Journal of Physiology. Gastrointestinal and Liver Physiology 304:G21120. Scholar
Perez-Muñoz, M. E., Arrieta, M.-C., Ramer-Tait, A. E. & Walter, J. (2017) A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: Implications for research on the pioneer infant microbiome. Microbiome 5:48. Available at: Scholar
Persky, H., Hamburg, D. A., Basowitz, H., Grinker, R. R., Sabshin, M., Korchin, S. J., Herz, M., Board, F. A. & Heath, H. A. (1958) Relation of emotional responses and changes in plasma hydrocortisone level after stressful interview. AMA Archives of Neurology and Psychiatry 79:434–47. Available at: Scholar
Purves, D., Augustine, G. J., Fitzpatrick, D., Katz, L. C., LaMantia, A.-S., McNamara, J. O. & Williams, S. M., eds. (2001) Neuroscience. Sinauer Associates.Google Scholar
Qualliotine, D., DeChatelet, L. R., McCall, C. E. & Cooper, M. R. (1972) Effect of catecholamines on the bactericidal activity of polymorphonuclear leukocytes. Infection and Immunity 6:211–17. Available at: Scholar
Quigley, E. M. M. (2016) Leaky gut – Concept or clinical entity? Current Opinion in Gastroenterology 32:7479. Available at: Scholar
Quigley, E. M. M. (2017) Gut microbiome as a clinical tool in gastrointestinal disease management: Are we there yet? Nature Reviews Gastroenterology & Hepatology 14:315–20. Available at: Scholar
Rao, M. & Gershon, M. D. (2016) The bowel and beyond: The enteric nervous system in neurological disorders. Nature Reviews Gastroenterology & Hepatology 13:517–28. Available at: Scholar
Renaud, M. & Miget, A. (1930) Rôle favorisant des perturbations locales causées par l'adrénaline sur le développement des infections microbiennes. Comptes Rendus des Séances de la Société de Biologie et de ses Filiales 103:1052–54.Google Scholar
Romijn, A. R., Rucklidge, J. J., Kuijer, R. G. & Frampton, C. (2017) A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. Australian and New Zealand Journal of Psychiatry 51:810–21. Available at: Scholar
Rosen, C. E. & Palm, N. W. (2017) Functional classification of the gut microbiota: The key to cracking the microbiota composition code. BioEssays 39:1700032. Available at: Scholar
Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., Challis, C., Schretter, C. E., Rocha, S., Gradinaru, V., Chesselet, M.-F., Keshavarzian, A., Shannon, K. M., Krajmalnik-Brown, R., Wittung-Stafshede, P., Knight, R. & Mazmanian, S. K. (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell 167:1469–80.e12. Available at: Scholar
Sampson, T. R. & Mazmanian, S. K. (2015) Control of brain development, function, and behavior by the microbiome. Cell Host & Microbe 17:565–76. Available at: Scholar
Savage, D. C. (2001) Microbial biota of the human intestine: A tribute to some pioneering scientists. Current Issues in Intestinal Microbiology 2:115.Google Scholar
Schloss, P. D. (2018) Identifying and overcoming threats to reproducibility, replicability, robustness, and generalizability in microbiome research. mBio 9:e00525-18. Available at: Scholar
Schluter, J. & Foster, K. R. (2012) The evolution of mutualism in gut microbiota via host epithelial selection. PLoS Biology 10:e1001424. Available at: Scholar
Severance, E. G., Yolken, R. H. & Eaton, W. W. (2016) Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: More than a gut feeling. Schizophrenia Research 176:2335. Available at: Scholar
Shade, A. (2017) Diversity is the question, not the answer. ISME Journal 11:16. Available at: Scholar
Shanahan, F. & Quigley, E. M. M. (2014) Manipulation of the microbiota for treatment of IBS and IBD – Challenges and controversies. Gastroenterology 146:1554–63. Available at: Scholar
Sherwin, E., Dinan, T. G. & Cryan, J. F. (2018) Recent developments in understanding the role of the gut microbiota in brain health and disease. Annals of the New York Academy of Sciences 1420:525. Available at: Scholar
Slashinski, M. J., McCurdy, S. A., Achenbaum, L. S., Whitney, S. N. & McGuire, A. L. (2012) “Snake-oil,” “quack medicine,” and “industrially cultured organisms”: Biovalue and the commercialization of human microbiome research. BMC Medical Ethics 13:28. Available at: Scholar
Slykerman, R. F., Hood, F., Wickens, K., Thompson, J. M. D., Barthow, C., Murphy, R., Kang, J., Rowden, J., Stone, P., Crane, J., Stanley, T., Abels, P., Purdie, G., Maude, R., Mitchell, E. A. & Probiotic in Pregnancy Study Group. (2017) Effect of Lactobacillus rhamnosus HN001 in pregnancy on postpartum symptoms of depression and anxiety: A randomised double-blind placebo-controlled trial. EBioMedicine 24:159–65. Available at: Scholar
Smith, P. A. (2015) Can the bacteria in your gut explain your mood? New York Times, June 23. Available at: Scholar
Steenbergen, L., Sellaro, R., van Hemert, S., Bosch, J. A. & Colzato, L. S. (2015) A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain, Behavior, and Immunity 48:258–64. Available at: Scholar
Stephenson, M. & Rowatt, E. (1947) The production of acetylcholine by a strain of Lactobacillus plantarum. Journal of General Microbiology 1:279–98. Available at: Scholar
Stilling, R. M., Bordenstein, S. R., Dinan, T. G. & Cryan, J. F. (2014) Friends with social benefits: Host-microbe interactions as a driver of brain evolution and development? Frontiers in Cellular and Infection Microbiology 4:147. Available at: Scholar
Stilling, R. M., Dinan, T. G. & Cryan, J. F. (2016) The brain's Geppetto – microbes as puppeteers of neural function and behaviour? Journal of Neurovirology 22:1421. Available at: Scholar
Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X.-N., Kubo, C. & Koga, Y. (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. Journal of Physiology 558(1):263–75. Available at: Scholar
Surana, N. K. & Kasper, D. L. (2017) Moving beyond microbiome-wide associations to causal microbe identification. Nature 552:244–47. Scholar
Swiergiel, A. H. & Dunn, A. J. (2007) Effects of interleukin-1β and lipopolysaccharide on behavior of mice in the elevated plus-maze and open field tests. Pharmacology, Biochemistry, and Behavior 86:651–59. Available at: Scholar
Sze, M. A. & Schloss, P. D. (2016) Looking for a signal in the noise: Revisiting obesity and the microbiome. mBio 7:e01018-16. Available at: Scholar
Thompson, A. (2017) Is gut bacteria linked to autism? Pathogens in the stomach alter the brain's development and may increase the risk of condition. Daily Mail, August 25. Available at: Scholar
Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B., Guyonnet, D., Legrain-Raspaud, S., Trotin, B., Naliboff, B. & Mayer, E.A. (2013) Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 144(7):1394–401.Google Scholar
Toda, M., Morimoto, K., Nagasawa, S. & Kitamura, K. (2004) Effect of snack eating on sensitive salivary stress markers cortisol and chromogranin a. Environmental Health and Preventive Medicine 9:27. Available at: Scholar
Tsavkelova, E. A., Botvinko, I. V, Kudrin, V. S. & Oleskin, A. V. (2000) Detection of neurotransmitter amines in microorganisms with the use of high-performance liquid chromatography. Doklady Biochemistry: Proceedings of the Academy of Sciences of the USSR, Biochemistry Section 372:115–17. Available at: Scholar
Turnbaugh, P. J., Bäckhed, F., Fulton, L. & Gordon, J. I. (2008) Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host & Microbe 3:213–23. Available at: Scholar
Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R. & Gordon, J. I. (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–31. Available at: Scholar
Vidgen, B. & Yasseri, T. (2016) P-values: Misunderstood and misused. Frontiers in Physics 4:6. Available at: Scholar
Wang, H., Lee, I.-S., Braun, C. & Enck, P. (2016) Effect of probiotics on central nervous system functions in animals and humans: A systematic review. Journal of Neurogastroenterology and Motility 22:589605. Available at: Scholar
Wang, J., Dourmashkin, J. T., Yun, R. & Leibowitz, S. F. (1999) Rapid changes in hypothalamic neuropeptide y produced by carbohydrate-rich meals that enhance corticosterone and glucose levels. Brain Research 848:124–36. Available at: Scholar
Wang, Y. & Kasper, L. H. (2014) The role of microbiome in central nervous system disorders. Brain, Behavior, and Immunity 38:112. Available at: Scholar
Weiss, S., Van Treuren, W., Lozupone, C., Faust, K., Friedman, J., Deng, Y., Xia, L. C., Xu, Z. Z., Ursell, L., Alm, E. J., Birmingham, A., Cram, J. A., Fuhrman, J. A., Raes, J., Sun, F., Zhou, J. & Knight, R. (2016) Correlation detection strategies in microbial data sets vary widely in sensitivity and precision. ISME Journal 10:1669–81. Available at: Scholar
Worth, A. R., Lymbery, A. J. & Thompson, R. C. A. (2013) Adaptive host manipulation by Toxoplasma gondii: Fact or fiction? Trends in Parasitology 29:150–55. Available at: Scholar
Zaneveld, J. R., McMinds, R. & Vega Thurber, R. (2017) Stress and stability: Applying the Anna Karenina principle to animal microbiomes. Nature Microbiology 2:17121. Available at: Scholar
Zeiss, C. J. & Johnson, L. K. (2017) Bridging the gap between reproducibility and translation: Data resources and approaches. ILAR Journal 58:13. Available at: Scholar
Zimmer, C. (2014) Our microbiome may be looking out for itself. New York Times, August 14. Available at: Scholar
Zmora, N., Zilberman-Schapira, G., Suez, J., Mor, U., Dori-Bachash, M., Bashiardes, S., Kotler, E., Zur, M., Regev-Lehavi, D., Brik, R. B., Federici, S., Cohen, Y., Linevsky, R., Rothschild, D., Moor, A. E., Ben-Moshe, S., Harmelin, A., Itzkovitz, S., Maharshak, N., Shibolet, O., Shapiro, H., Pevsner-Fischer, M., Sharon, I., Halpern, Z., Segal, E. & Elinav, E. (2018) Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell 174(6):1388–405. Available at: Scholar

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