Bacterial infection causes stress-induced memory dysfunction in mice

Gareau, Mélanie G; Wine, Eytan; Rodrigues, David M; Cho, Joon Ho; Whary, Mark T; Philpott, Dana J; MacQueen, Glenda; Sherman, Philip M

doi:10.1136/gut.2009.202515

Cited by 909Gut microbiota and healthGastrointestinal motility and disordersProbiotics and Fermented Foods

Bacterial infection causes stress-induced memory dysfunction in mice

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Gareau, Mélanie G, Wine, Eytan, Rodrigues, David M, Cho, Joon Ho, Whary, Mark T, Philpott, Dana J, MacQueen, Glenda, Sherman, Philip M·2011·Gut

DOI 10.1136/gut.2009.202515

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Abstract

BACKGROUND: The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. OBJECTIVE: To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. METHODS: Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. RESULTS: No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. CONCLUSIONS: The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.

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Studies in germ-free animals showed that the brain is affected in the absence of microbiota.
“Firstly, studies in germ-free (GF) animals showed that the brain is affected in the absence of microbiota (see Table 2) (Clarke et al., 2013;Diaz Heijtz et al., 2011;Gareau et al., 2011;Hegstrand and Hine, 1986;Neufeld et al., 2011;Sudo et al., 2004).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Gareau et al., 2011
Microbes are crucially involved in regulating hippocampal-dependent memory function.
“In addition, these animals exhibit altered BDNF expression in the hippocampus (Bercik et al., 2011a;Diaz Heijtz et al., 2011;Gareau et al., 2011), which as stated earlier has an important role in synaptic plasticity and cognition (Baj et al., 2013;Lu et al., 2014;Neufeld et al., 2011), suggesting a crucial involvement of microbes in regulating hippocampal-dependent memory function.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Gareau et al., 2011
GF mice exhibit altered BDNF expression in the hippocampus.
“In addition, these animals exhibit altered BDNF expression in the hippocampus (Bercik et al., 2011a;Diaz Heijtz et al., 2011;Gareau et al., 2011), which as stated earlier has an important role in synaptic plasticity and cognition (Baj et al., 2013;Lu et al., 2014;Neufeld et al., 2011), suggesting a crucial involvement of microbes in regulating hippocampal-dependent memory function.”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Gareau et al., 2011
GF mice exhibit an impaired ability to remember a familiar object when presented with a novel object.
“It has been shown that GF mice exhibit an impaired ability to remember a familiar object when presented with a novel object (Gareau et al., 2011;Luk et al., 2018), as well as impaired working memory in remembering a familiar environment in the spontaneous alternation task (Gareau et al., 2011).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Gareau et al., 2011
An increasing body of preclinical and human evidence demonstrates that the microbiota-gut-brain axis plays important roles in the development and maintenance of various components of cognition.
“An increasing body of preclinical and human evidence demonstrates that the MGB axis plays important roles in the development and maintenance of various components of cognition (191, 362, 375).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [362]

The introduction of pathogenic bacteria reduced cognitive abilities and heightened anxiety-like behaviors.
“The introduction of pathogenic bacteria reduced cognitive abilities and heightened anxiety-like behaviors (362, 363).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [362]
The memory deficit from C. rodentium plus acute stress was prevented by daily administration of a Lactobacillus sp. probiotic combination before infection.
“This deficit was prevented by daily administration of a Lactobacillus sp. probiotic combination before infection.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [362]
Gareau et al. demonstrated impaired short-term recognition and working memory in 5- to 6-week-old germ-free mice when compared to conventionally reared counterparts.
“Gareau et al. demonstrated impaired short-term recognition and working memory in 5 to 6-week-old germ-free mice when compared to conventionally reared counterparts (362).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [362]
In the absence of microbes, germ-free mice exhibit deficits in learning, memory formation and recognition, and social and emotional behaviors.
“Studies in germ-free mice have shown that, in the absence of microbes, the brain is markedly affected, exhibiting deficits in learning, memory formation and recognition, and social and emotional behaviors (58, 123, 124, 362).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [362]
Germ-free mice present with social cognitive deficits, which may be associated with biochemical changes such as decreased hippocampal BDNF and c-FOS expression.
“Germ-free mice present with social cognitive deficits, which may be associated with biochemical changes, such as decreased hippocampal BDNF and c-FOS expression, important in memory (124, 362, 376, 377).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [362]
Administration of C. rodentium combined with acute stress led to memory dysfunction in young adult germ-free mice.
“Administration of C. rodentium, combined with acute stress, led to memory dysfunction in young adult germ-free mice (362).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [362]
Germ-free mice demonstrate a lack of memory in the T-maze test and novel object test in situations with or without stress.
“For example, Gareau et al. demonstrated a lack of memory in germ-free mice in the T-maze test and novel object test in situations with or without stress (362).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [362]
Rodents lacking all gut bacteria from birth have memory deficits and behavioral abnormalities compared to animals with normal gut microbiota.
“These studies show that rodents lacking all gut bacteria from birth (germ-free animals) have memory deficits28 and behavioral abnormalities29, 30 when compared to animals with normal gut microbiota.”
From The relation between cesarean birth and child cognitive development (2017) · cites this paper as [28]
These cognitive deficits in rodents can be corrected through colonization of the intestine via a fecal transplant from the control group, but only if it occurs early in life.
“Interestingly, these cognitive deficits in rodents can be corrected through the colonization of the intestine via a fecal transplant from the control group, but only if it occurs early in life.”
From The relation between cesarean birth and child cognitive development (2017) · cites this paper as [28]

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Eaton, K., Friedman, D., Francis, G. J., et al. (2008) · Infection and Immunity · doi:10.1128/iai.01626-07 · Cited by 88 · see citing works
Risk of Irritable Bowel Syndrome After an Episode of Bacterial Gastroenteritis in General Practice: Influence of Comorbidities
Ruigómez, A., Rodríguez, L. A. G., & Panés, J. (2007) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2007.02.008 · Cited by 84 · see citing works
Consequences of Citrobacter rodentium infection on enteroendocrine cells and the enteric nervous system in the mouse colon
O’Hara, J. R., Skinn, A. C., MacNaughton, W. K., Sherman, P. M., & Sharkey, K. A. (2005) · Cellular Microbiology · doi:10.1111/j.1462-5822.2005.00657.x · Cited by 82 · see citing works
Self-citation
CD4+-T-Cell Effector Functions and Costimulatory Requirements Essential for Surviving Mucosal Infection with Citrobacter rodentium
Bry, L., Brigl, M., & Brenner, M. (2006) · Infection and Immunity · doi:10.1128/iai.74.1.673-681.2006 · Cited by 81 · see citing works
The effects of acute and chronic administration of corticosterone on rat behavior in two models of fear responses, plasma corticosterone concentration, and c-Fos expression in the brain structures
Skórzewska, A., Bidziński, A., Lehner, M., Turzyńska, D., Wisłowska-Stanek, A., Sobolewska, A., Szyndler, J., Maciejak, P., Taracha, E., & Płaźnik, A. (2006) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2006.10.001 · Cited by 74 · cited 1× · see citing works
“conditioned fear test.(51) Furthermore, the hippocampus is highly responsive to glucocorticoids.”
Background
Hippocampal c-fos is necessary for long-term memory of a socially transmitted food preference
Countryman, R. A., Kaban, N. L., & Colombo, P. J. (2005) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2005.07.005 · Cited by 73 · cited 1× · see citing works
“in the CA1 region of the hippocampus. c-Fos expression is necessary for the consolidation of non-spatial hippocampus-dependent memory, as demonstrated in rats using a socially transmitted food preference model.”
Method
Lactobacillus helveticusandBifidobacterium longumtaken in combination reduce the apoptosis propensity in the limbic system after myocardial infarction in a rat model
Girard, S.-A., Bah, T. M., Kaloustian, S., Lada-Moldovan, L., Rondeau, I., Tompkins, T. A., Godbout, R., & Rousseau, G. (2009) · British Journal of Nutrition · doi:10.1017/s0007114509990766 · Cited by 70 · cited 1× · see citing works
“Probiotics also have extra-intestinal effects, such as prevention of myocardial infarctinduced apoptosis in the limbic region of the brain.(39) To determine the mechanism of action of microbe-induced memory deficits, the hippocampus was studied.”
Background
Decrease in non-selective, non-sustained attention induced by a chronic visceral inflammatory state as a new pain evaluation in rats
Millecamps, M., Etienne, M., Jourdan, D., Eschalier, A., & Ardid, D. (2004) · Pain · doi:10.1016/j.pain.2003.12.028 · Cited by 69 · cited 1× · see citing works
“Previous studies in rats with colitis indicate that altered memory is observed in association with inflammation-induced visceral pain.”
Background
Selective affective biasing in recognition memory in the irritable bowel syndrome.
Gomborone, J., Dewsnap, P., Libby, G., & Farthing, M. J. G. (1993) · Gut · doi:10.1136/gut.34.9.1230 · Cited by 67 · cited 1× · see citing works
“Furthermore, patients with IBS have a bias in recognition memory, similar to subjects with depression.(60) Administration of probiotics ameliorates colonic disease resulting from C rodentium infection(24) 26 and in models of psychological stress.”
Background
Updates on treatment of irritable bowel syndrome
Hammerle, C. W., & Surawicz, C. M. (2008) · World Journal of Gastroenterology · doi:10.3748/wjg.14.2639 · Cited by 64 · cited 1× · see citing works
“The brain–gut axis is important for maintaining normal gut function, with alterations in the axis implicated in both IBS and chronic inflammatory bowel diseases.”
Background
Probiotics Prevent Death Caused byCitrobacter rodentiumInfection in Neonatal Mice
Gareau, M. G., Wine, E., Reardon, C., & Sherman, P. M. (2009) · The Journal of Infectious Diseases · doi:10.1086/648614 · Cited by 59 · cited 2× · see citing works
“Trends towards changes were also seen in the C rodentiuminfected, placebo-treated group, suggesting a potential prebiotic effect, as has been described previously.(26) Probiotics also have extra-intestinal effects, such as prevention of myocardial infarctinduced apoptosis in the limbic region of the brain.”
BackgroundResultSelf-citation
Apoptosis Signal-Regulating Kinase 1 Regulates Colitis and Colitis-Associated Tumorigenesis by the Innate Immune Responses
Hayakawa, Y., Hirata, Y., Nakagawa, H., Sakamoto, K., Hikiba, Y., Otsuka, M., Ijichi, H., Ikenoue, T., Tateishi, K., Akanuma, M., et al. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.11.015 · Cited by 57 · cited 1× · see citing works
“CFU (colony forming units) killed at 14 days after infection) compared with DSS (40-fold increase compared with controls; 3% DSS killed at 10 days following initiation of the chemical challenge).”
Background
The effect of the chemical composition of maize plant lignin on the digestibility of maize stalk in the rumen of cattle
Cymbaluk, N. F., Gordon, A. J., & Neudoerffer, T. S. (1973) · British Journal of Nutrition · doi:10.1079/bjn19730071 · Cited by 57 · see citing works
Role of the Brain-Gut Axis in the Pathophysiology of Crohn’s Disease
Stasi, C., & Orlandelli, E. (2008) · Digestive Diseases · doi:10.1159/000116774 · Cited by 54 · cited 1× · see citing works
“The brainegut axis is important for maintaining normal gut function, with alterations in the axis implicated in both IBS and chronic inflammatory bowel diseases.(47) 48 Bidirectional effects, including bacterial influence on the HPA axis,(21) have prompted the study of the modulating effect of infections on behaviour.”
Background
Corticosterone Effects on BDNF mRNA Expression in the Rat Hippocampus During Morris Water Maze Training
Schaaf, M. J. M., Sibug, R. M., Duurland, R., Fluttert, M., Oitzl, M. S., de Kloet, E. R., & Vreugdenhil, E. (1999) · Stress · doi:10.3109/10253899909001121 · Cited by 51 · cited 1× · see citing works
“Morris water maze training causes an increase in corticosterone levels, but hippocampal BDNF is resistant to these changes—suggesting that stress alone is not sufficient to cause altered learning and memory.”
Background
Individual responses to novelty are associated with differences in behavioral and neurochemical profiles
Antoniou, K. M., Papathanasiou, G., Papalexi, E., Hyphantis, T. N., Nomikos, G. G., Spyraki, C., & Papadopoulou‐Daifoti, Z. (2007) · Behavioural Brain Research · doi:10.1016/j.bbr.2007.10.010 · Cited by 50 · cited 1× · see citing works
“34 Memory was assessed as the frequency to explore object #2 during the testing phase (object #2B), compared with the new object #3.(34) An exploration ratio was calculated (exploration ratio 1⁄4 freq.”
Method
Neonatal endotoxin exposure modifies the acoustic startle response and circulating levels of corticosterone in the adult rat but only following acute stress
Walker, F. R., Knott, B., & Hodgson, D. M. (2008) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2007.12.006 · Cited by 49 · cited 1× · see citing works
“Similarly, administration of bacterial endotoxin in neonatal rats results in altered anxiety-like behaviour in adult rats, but only after exposure to restraint stress.(56) Previous studies in rats with colitis indicate that altered memory is observed in association with inflammation-induced visceral pain.”
Background
Holeboard discrimination learning in mice
Kuc, K. A., Gregersen, B., Gannon, K. S., et al. (2006) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2005.00168.x · Cited by 45 · cited 1× · see citing works
“Novel object test Various strains of mice, including C57BL/6 and Swiss Webster exhibit similar characteristics for spatial working and reference memory.(30) The novel object test represents a test for dorsal hippocampal function based on the tendency of mice to investigate a novel object, rather then a familiar one.”
Background
Correlating Efficacy in Rodent Cognition Models with in Vivo 5-Hydroxytryptamine1A Receptor Occupancy by a Novel Antagonist, (R)-N-(2-Methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)-cyclohexane Carboxamide (WAY-101405)
Hirst, W., Andree, T., Aschmies, S., et al. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.133082 · Cited by 38
Transgenic overexpression of interleukin-1 receptor antagonist in the CNS influences behaviour, serum corticosterone and brain monoamines
Oprica, M., Zhu, S., Goiny, M., Pham, T. M., Mohammed, A. H. S., Winblad, B. G., Bartfai, T., & Schultzberg, M. (2004) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2004.07.006 · Cited by 32 · cited 1× · see citing works
“Corticosterone HPA axis activation was assessed by measuring levels of serum corticosterone.(42) Blood was collected by cardiac puncture at sacrifice, immediately placed on ice, centrifuged and serum isolated and frozen at 208C, until further analysis.”
Method
Irritable Bowel Syndrome
Schofield, P. F., Haboubi, N. Y., & Martin, D. F. (1993) · Springer eBooks · doi:10.1007/978-1-4471-3456-5_14 · Cited by 4 · see citing works

Flagged first, then by citations

2 of the 71 references couldn’t be matched to a known paper.

Sorted by citations

The Microbiota-Gut-Brain Axis
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286 · see citing works
Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour
Cryan, J. F., & Dinan, T. G. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3346 · Cited by 4,572 · see citing works
Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve
Bravo, J. A., Forsythe, P., Chew, M. V., Escaravage, E., Savignac, H. M., Dinan, T. G., Bienenstock, J., & Cryan, J. F. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102999108 · Cited by 3,888 · see citing works
“infected mice (34) as well as cognitive abilities in humans (35).”
Background
The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.
(2015) · PubMed Central · Cited by 2,540 · see citing works
Gut–brain axis: How the microbiome influences anxiety and depression
Foster, J. A., & McVey Neufeld, K.-A. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2013.01.005 · Cited by 2,460 · see citing works
Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism
Zheng, P., Zeng, B., Zhou, C., Liu, M., Fang, Z., Xu, X., Zeng, L., Chen, J., Fan, S., Du, X., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.44 · Cited by 2,023 · see citing works
Serotonin, tryptophan metabolism and the brain-gut-microbiome axis
O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G., & Cryan, J. F. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.027 · Cited by 2,012 · see citing works
The interplay between the intestinal microbiota and the brain
Collins, S. M., Surette, M., & Bercik, P. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2876 · Cited by 1,611 · see citing works
The central nervous system and the gut microbiome
Sharon, G., Sampson, T. R., Geschwind, D. H., & Mazmanian, S. K. (2016) · Cell · doi:10.1016/j.cell.2016.10.027 · Cited by 1,513 · see citing works
“If the gut microbiome can so profoundly impact the immune system, why would its influence not reach the nervous system? Indeed, germ-free (GF) mice, devoid of all associated microorganisms, exhibit increased risk-taking behaviors and hyperactivity, while also displaying learning and memory deficits compared to convent…”
BackgroundInfluential
Gut/brain axis and the microbiota
Mayer, E. A., Tillisch, K., & Gupta, A. (2015) · Journal of Clinical Investigation · doi:10.1172/jci76304 · Cited by 1,503 · see citing works
“Increased basal or stimulated HPA axis activity (measured as blood corticosterone or ACTH levels) was reported in GF Swiss-Webster and BALB/c mice (38, 40, 72), while a probiotic-induced reduction of corticosterone levels was observed in normal mice (42).”
Influential
Gut microbes and the brain: paradigm shift in neuroscience
Mayer, E. A., Knight, R., Mazmanian, S. K., Cryan, J. F., & Tillisch, K. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.3299-14.2014 · Cited by 1,033 · see citing works
The microbiome-gut-brain axis: from bowel to behavior
Cryan, J. F., & O’Mahony, S. M. (2011) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2010.01664.x · Cited by 990 · see citing works
Estrogen–gut microbiome axis: Physiological and clinical implications
Baker, J. M., Al‐Nakkash, L., & Herbst‐Kralovetz, M. M. (2017) · Maturitas · doi:10.1016/j.maturitas.2017.06.025 · Cited by 1,024 · see citing works
“Germ free mice have been shown to have reduced working memory compared to conventionally colonized controls [99].”
Background
From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways
Rogers, G. B., Keating, D. J., Young, R. L., Wong, M.-L., Licinio, J., & Wesselingh, S. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.50 · Cited by 969 · see citing works
Brain-gut-microbe communication in health and disease
Grenham, S., Clarke, G., Cryan, J. F., & Dinan, T. G. (2011) · Frontiers in Physiology · doi:10.3389/fphys.2011.00094 · Cited by 952 · see citing works
Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis
Jenkins, T., Nguyen, J., Polglaze, K., & Bertrand, P. (2016) · Nutrients · doi:10.3390/nu8010056 · Cited by 904 · see citing works
“Mice infected with an enteric pathogen exhibited working memory dysfunction [115], and socially-associated behavioural impairment [116] but only after acute water stress.”
Background
Microbiota is essential for social development in the mouse
Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T. G., & Cryan, J. F. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.65 · Cited by 866 · see citing works
The Gut Microbiota and Alzheimer’s Disease
Jiang, C., Li, G., Huang, P., Liu, Z., & Zhao, B. (2017) · Journal of Alzheimer's Disease · doi:10.3233/jad-161141 · Cited by 852 · see citing works
“A study by Savignac et ) [41] prevent the drop in hippocampal BDNF expression prevent stress-induced memory deﬁcits in C. rodentium -infected mice B. longum 1714 [59] need further investigation improve the ability of learning and memory in an anxious mouse B. breve 1205 [59] need further…”
Influential
Microbiota-Brain-Gut Axis and Neurodegenerative Diseases
Quigley, E. M. M. (2017) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-017-0802-6 · Cited by 804 · see citing works
Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration
Dinan, T. G., & Cryan, J. F. (2017) · The Journal of Physiology · doi:10.1113/jp273106 · Cited by 813 · see citing works
“In the hippocampus, the changes in Bdnf levels documented are inconsistent with some studies reporting an increase (Neufeld et al. 2011), whereas most others show a decrease in expression (Sudo et al. 2004; Diaz Heijtz et al. 2011; Gareau et al. 2011; Clarke et al. 2013).”
BackgroundResult
The role of microbiome in central nervous system disorders
Wang, Y., & Kasper, L. H. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.12.015 · Cited by 803 · see citing works
“GF animals displayed increased stress and impaired cognition (Gareau et al., 2011; Sudo et al., 2004).”
Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour
Desbonnet, L., Clarke, G., Traplin, A., O’Sullivan, O., Crispie, F., Moloney, R. D., Cotter, P. D., Dinan, T. G., & Cryan, J. F. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.04.004 · Cited by 760 · see citing works
“Similar deficits are reported in GF mice in the presence and absence of stress (Gareau et al., 2011).”
BackgroundResult
Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis
Ma, Q., Xing, C., Long, W., Wang, H. Y., Liu, Q., & Wang, R. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1434-3 · Cited by 752 · see citing works
“GF mice that are devoid of associated microflora exhibit neurological deficiencies in learning, memory, recognition, and emotional behaviors [11, 12].”
Background
The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice
Zheng, P., Zeng, B., Liu, M., Chen, J., Pan, J., Han, Y., Liu, Y., Cheng, K., Zhou, C., Wang, H., et al. (2019) · Science Advances · doi:10.1126/sciadv.aau8317 · Cited by 704 · see citing works
Kynurenine pathway metabolism and the microbiota-gut-brain axis
Kennedy, P. J., Cryan, J. F., Dinan, T. G., & Clarke, G. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.07.002 · Cited by 724 · see citing works
“Preclinical studies utilising various strategies including GF and GI infection models (Gareau, 2014; Gareau et al., 2011), antibiotic treatment (Desbonnet et al., 2015; Fröhlich et al., 2016) dietary manipulation (Li et al., 2009; Ohland et al., 2013) and probiotic treatment (Davari et al., 2013;…”
Method
Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication
Fröhlich, E. E., Farzi, A., Mayerhofer, R., Reichmann, F., Jačan, A., Wagner, B., Zinser, E., Bordag, N., Magnes, C., Fröhlich, E., et al. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.02.020 · Cited by 720 · see citing works
“The current findings thus add to the emerging concept that factors emanating from the gut microbiota impact on cognitive performance (Gareau et al., 2011; Neufeld et al., 2011; Farzi et al., 2012; Davari et al., 2013; Gareau, 2014; Desbonnet et al., 2015).”
BackgroundMethodInfluential
Altered Microbiomes Distinguish Alzheimer’s Disease from Amnestic Mild Cognitive Impairment and Health in a Chinese Cohort
Liu, P., Wu, L., Peng, G., Han, Y., Tang, R., Ge, J., Zhang, L., Jia, L., Yue, S., Zhou, K., et al. (2019) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2019.05.008 · Cited by 669 · see citing works
Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress
Liang, S., Wang, T., Hu, X., Luo, J., Li, W., Wu, X., Duan, Y., & Jin, F. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.09.033 · Cited by 651 · see citing works
“Moreover, hippocampus neurogenesis regulation was also connected with gut microbiota (Gareau et al., 2011).”
Background
Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior
Luczynski, P., McVey Neufeld, K.-A., Oriach, C. S., Clarke, G., Dinan, T. G., & Cryan, J. F. (2016) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw020 · Cited by 632 · see citing works
“, 2011) and a decrease in expression (Sudo et al., 2004; Gareau et al., 2011; Heijtz et al., 2011; Clarke et al., 2013).”
BackgroundInfluential
Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats
Ait-Belgnaoui, A., Durand, H., Cartier, C., Chaumaz, G., Eutamene, H., Ferrier, L., Houdeau, E., Fioramonti, J., Bueno, L., & Theodorou, V. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.03.024 · Cited by 612 · see citing works
“rodentium was not associated with behavioral abnormalities, exposure to an acute stress of previously infected mice during infection or after bacterial clearance is associated with memory dysfunction (Gareau et al., 2011).”
Background
Brain-Derived Neurotrophic Factor in Alzheimer’s Disease and Its Pharmaceutical Potential
Gao, L., Zhang, Y., Sterling, K., & Song, W. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00279-0 · Cited by 606 · see citing works
Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology
Dinan, T. G., & Cryan, J. F. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.03.007 · Cited by 577 · see citing works
“…bowel syndrome who have an exaggerated ACTH and cortisol response to CRH infusion (Dinan et al., 2006) together with an altered microbiota (Grenham et al., 2011 Although the bulk of research to date has focused on the impact of the microbiota on CNS function, there is also research to…”
Influential
Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats
Crumeyrolle-Arias, M., Jaglin, M., Bruneau, A., Vancassel, S., Cardona, A., Daugé, V., Naudon, L., & Rabot, S. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.01.014 · Cited by 581 · see citing works
Beneficial psychological effects of a probiotic formulation ( Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers
Messaoudi, M., Violle, N., Bisson, J.-F., Desor, D., Javelot, H., & Rougeot, C. (2011) · Gut Microbes · doi:10.4161/gmic.2.4.16108 · Cited by 574 · see citing works
“Since NMDA receptors in the hippocampus are implicated in long-term memory consolidation,(5) these results are in good accordance with those of a study which recently demonstrated memory impairments in such germ-free mice.(6) Interestingly, similar brain modifications have also been described in animals following stre…”
Result
Collective unconscious: How gut microbes shape human behavior
Dinan, T. G., Stilling, R. M., Stanton, C., & Cryan, J. F. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.02.021 · Cited by 571 · see citing works
“Using a similar model Gareau et al. (2011) found that feeding a Lactobacillus spp. reduced corticosterone levels.”
Method
Specialized metabolites from the microbiome in health and disease
Sharon, G., Garg, N., Debelius, J., Knight, R., Dorrestein, P. C., & Mazmanian, S. K. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.016 · Cited by 544 · see citing works
Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis
Westfall, S., Lomis, N., Kahouli, I., Dia, S. Y., Singh, S. P., & Prakash, S. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2550-9 · Cited by 548 · see citing works
“rodentium infection was prevented by daily probiotic treatment [162]”
Background
The microbiome and host behavior
Vuong, H. E., Yano, J. M., Fung, T. C., & Hsiao, E. Y. (2017) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-072116-031347 · Cited by 537 · see citing works
“Compared to SPF controls, GF mice exhibited decreased working memory behavior in the novel object recognition task (Gareau et al. 2011).”
Background
Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532 · see citing works
Probiotic Supplementation Improves Cognitive Function and Mood with Changes in Gut Microbiota in Community-Dwelling Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial
Kim, C.-S., Cha, J., Sim, M., Jung, S., Chun, W. Y., Baik, H. W., & Shin, D.-M. (2020) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaa090 · Cited by 551 · see citing works
“Several studies demonstrated that gut dysbiosis correlates with reduced expression of BDNF, which alters cognitive function and triggers anxiety-like behavior in germ-free animals (45,46), supporting a role of BDNF in the gut–brain axis.”
Background
Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice
De Palma, G., Lynch, M. D. J., Lu, J., Dang, V. T., Deng, Y., Jury, J., Umeh, G., Miranda, P. M., Pigrau Pastor, M., Sidani, S., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf6397 · Cited by 505 · see citing works
“Recent demonstrations of the ability of the intestinal microbiota in mice to influence brain development (9), neurochemistry (10), and cognitive (11) and emotive (12) functions have prompted consideration of a microbiota gut-brain axis (13).”
Background
Adult hippocampal neurogenesis is regulated by the microbiome
Ogbonnaya, E. S., Clarke, G., Shanahan, F., Dinan, T. G., Cryan, J. F., & O’Leary, O. F. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.12.023 · Cited by 491 · see citing works
Neuropeptide, Y, peptide YY and pancreatic polypeptide in the gut-brain axis
Holzer, P., Reichmann, F., & Farzi, A. (2012) · Neuropeptides · doi:10.1016/j.npep.2012.08.005 · Cited by 501 · see citing works
“longed memory dysfunction (Gareau et al., 2011).”
Brain gut microbiome interactions and functional bowel disorders
Mayer, E. A., Savidge, T., & Shulman, R. J. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.02.037 · Cited by 496 · see citing works
Mild cognitive impairment has similar alterations as Alzheimer's disease in gut microbiota
Li, B., He, Y., Ma, J., Huang, P., Du, J., Cao, L. H., Wang, Y., Xiao, Q., Tang, H., & Chen, S. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.07.002 · Cited by 480 · see citing works
Antibiotics, gut microbiota, and Alzheimer’s disease
Angelucci, F., Cechova, K., Amlerova, J., & Hort, J. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1494-4 · Cited by 454 · see citing works
Role of the intestinal microbiome in health and disease: from correlation to causation
de Vos, W. M., & de Vos, E. A. (2012) · Nutrition Reviews · doi:10.1111/j.1753-4887.2012.00505.x · Cited by 440 · see citing works
Neuropeptides and the Microbiota-Gut-Brain Axis
Holzer, P., & Farzi, A. (2014) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4939-0897-4_9 · Cited by 451 · see citing works
“At the behavioural level, germ-free animals exhibit reduced anxiety in three [43,58,59] but one study [60].”
HPA Axis in the Pathomechanism of depression and schizophrenia: new therapeutic strategies based on its participation
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Authors: Gareau, M. G., Wine, E., Rodrigues, D. M., Cho, J. H., Whary, M. T., Philpott, D. J., MacQueen, G., & Sherman, P. M.
Affiliations: Hospital for Sick Children (CA)
University of Alberta (CA)
University of Toronto (CA)
Massachusetts Institute of Technology (US)
University of Calgary (CA)
Corresponding author: Sherman, Philip M
ORCID: Gareau, Mélanie G
Wine, Eytan
Rodrigues, David M
Philpott, Dana J
MacQueen, Glenda
Sherman, Philip M
Venue: Gut
Publisher: BMJ
Published: 2010-10-21
Volume: 60
Issue: 3
Pages: 307-317
ISSN: 0017-5749 (ISSN-L)
1468-3288
DOI: 10.1136/gut.2009.202515
OpenAlex: W2170856053
Cited by: 909
References: 71
Citations by year: 2026: 19 · 2025: 53 · 2024: 72 · 2023: 60 · 2022: 94 · 2021: 91 · 2020: 113 · 2019: 79 · 2018: 73 · 2017: 62 · 2016: 60 · 2015: 36 · 2014: 41 · 2013: 22 · 2012: 17
FWCI: 7.17
Type: journal article
Language: en
Open access: green
hdl.handle.net
Licence: cc-by-nc
Locations: Gut (publishedVersion)
PubMed (publishedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
HighWire Press Open Archive (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
Keywords: enteric bacterial infection, Citrobacter rodentium, gut microbiota, germ-free mice, non-spatial memory, anxiety, water avoidance stress, probiotics, gut-brain axis, acute stress
MeSH terms: Animals, Anxiety, Behavior, Animal, Colon, Corticosterone, Enterobacteriaceae Infections, Feces, Female, Germ-Free Life, Hippocampus, Hyperplasia, Memory Disorders, Mice, Inbred C57BL, Stress, Psychological, Cytokines, Proto-Oncogene Proteins c-fos, Inflammation Mediators, Brain-Derived Neurotrophic Factor, Probiotics, Citrobacter rodentium, Mice

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Bacterial infection causes stress-induced memory dysfunction in mice

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