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What do experimental animal models of mood disorders tell clinicians about influence of probiotics on the gut-brain axis?

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Fig. 1

Selected grip points of probiotic therapy in relation to the brain-gut axis. Effect of probiotics on intestinal barrier function. Based on Borchers et al. 2009 [13], Kuśmierska and Fol 2014 [14], Liu et al. 2015 [82], Mennigen et al. 2009 [81], Raoult et al. 2008 [69], Sanders et al. 2007 [47] and 2009 [61]
Selected grip points of probiotic therapy in relation to the brain-gut axis. Effect of probiotics on intestinal barrier function. Based on Borchers et al. 2009 [13], Kuśmierska and Fol 2014 [14], Liu et al. 2015 [82], Mennigen et al. 2009 [81], Raoult et al. 2008 [69], Sanders et al. 2007 [47] and 2009 [61]

Studies using animal models and tests to assess the probiotic influence on the animals' mood

Probiotic influence on depressive behavior in animal models and tests
Publication Animal model / test Probiotics Results and clinical implications
Abildgaard et al. [67] FST Powder consisting of a mixture of the following bacterial strains: Bifidobacterium bifidum W23, B. lactis W52, Lactobacillus acidophilus W37, L. brevis W63, L. casei W56, Lactobacillus salivarius W24, L. lactis W19, L. lactis W58 FST confirmed that HFD aggravates depressive behavior of Flinders Sensitive Line (FSL) rats compared to Sprague-Dawley rats. Protected activity of probiotics against the pro-depressive influence of High Fat Diet was confirmed. No such impact was noticed in FSL rats in control group. A strong link between depressive mood and cerebral T cell populations was demonstrated. Antidepressant effect of probiotics has been connected with higher level of T cell–related cytokines created by peripheral blood mononuclear cells, which reduced the production of some monocyte-derived cytokines: IL-6 and TNF-alpha. In this way the immunomodulatory role of probiotics has once again been proved.
Abildgaard et al. [66] FST Powder consisting of a mixture of the following bacterial strains: Bifidobacterium bifidum W23, B. lactis W52, Lactobacillus acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, L. lactis W19, L. lactis W59 Probiotic mixture reduced depressive rat behavior regardless of diet. The use of probiotics has influenced the structure of cytokine creation by stimulating blood mononuclear cells. Probiotics influenced hippocampal expression by lowering the level of HPA-axis control factors (Crh-r1, Crh-r2 and Mr). Moreover, probiotics have increased the level of plasma metabolites, such as indolo-3-propionic acid, that may play a neuroprotective role. The above results show commitment to probiotics as a possible approach to treating depression and should be further tested in clinical trials of depressed patients.
Desbonnet et al. [57] FST Bifidobacteria infantis 35624 In rats, probiotic administration resulted in a significant decrease in proinflammatory cytokine concentrations (IFN-gamma, TNF-alpha and IL-6 and IL-10) in comparison with the control group. Moreover, the probiotic increased the content of tryptophan and its metabolite kynurenic acid. Additionally, it was found that in the group given the probiotic, there was a reduced 5-hydroxyindoleacetic acid – a product of 5-HT metabolism – in the frontal cortex and reduced 3,4-dihydroxyphenylacetic acid – a dopamine metabolite – in the cortex of the almond body. These results prove antidepressive features of Bifidobacteria infantis.
Desbonnet et al. [58] FST Bifidobacteria infantis 35624 The paradigm of rat maternal separation models (MS), proven in stress-related studies, was used. Adult MS animals were treated chronically with Bifidobacteria or citalopram. Probiotic treatment, slightly less than citalopram, has led to stabilization of the immune response, inversion of behavioral deficits, and recovery of basic noradrenaline levels in the brain stem. Such results indicate clear significance of Bifidobacteria in the functioning of neurons and indicate that probiotics may play a larger therapeutic role in depressive disorders.
McVey Neufeld et al. [55] TST Lactobacillus rhamnosus JB-1 The ability of fluoxetine and Lactobacillus rhamnosus JB-1TM, in weakening the depressive behavior in different mice strains, varying in the degree of expression of anxiety behavior (BALB/c and Swiss Webster), was compared. The results confirm the antidepressant effect of the probiotic in the BALB/c mice. It is justified to investigate the antidepressant effect of L. rhamnosus JB-1 in mood disorder patients and to confirm further interrelations of the host genotype with changes of intestinal microbiota that could affect behavioral responses.
Ait-Belgnaoui et al. [71] CUMS, Water Avoidance Stress (WAS) Lactobacillus helveticus R0052, Bifidobacterium longum R0175 Probiotic administration limited plasticity deficits and neurogenesis caused by chronic stress and decreased HPA axis tension and autonomic nervous system activity in response to stress (measurement of cortisone and catecholamine). Probiotics also improved intestinal barrier integrity. These benefits were not observed for another probiotic species – L. salivarus.
Bercik et al. [79] Light-dark preference test, PA Lactobacillus rhamnosus NCC4007, Bifidobacterium longum NCC3001 Probiotic influence on the behavior and brain biochemistry in Trichuris muris–infected mice was studied. T. muris infection resulted in mild to moderate colonic inflammation and behavior similar to anxiety. T. muris-infected mice treated with B. longum had alleviated anxiety behavior; in case of L. rhamnosus this effect was not observed. The anxiolytic B. longum effect on behavior probably is largely independent of an immunomodulatory effect and kynurenine pathway (circulating cytokines and kynurenine remained increased). Complete normalization of hippocampal BDNF levels suggests that B. longum effect involved no inflammatory, neural, or metabolic pathways.
Bercik et al. [7] PA Bifidobacterium longum NCC3001 Positive anxiety relief effect of B. longum NCC3001 caused by chronic enteritis depended on the integrity of the vagus nerve. Probably, the anxiolytic effect of the probiotic is transmitted through vagal track coming either at the level of the ENS or directly on vagal afferent endings in the intestine. B. longum NCC3001 can have a therapeutic potential, especially for patients with chronic intestinal and associated mental disorders.
Bharwani et al. [54] LDT, Social behavior tests Lactobacillus rhamnosus (JB-1) Effect of oral administration of Lactobacillus rhamnosus JB-1 strain on behavioral deficiencies and systemic immunological changes resulting from chronic psychosocial stress exposition was studied. Treatment of single strain of bacteria reduced anxiety behavior caused by stress and acted to prevent gaps in social interaction with specific groups, but did not affect the avoidance of aggressors after social failure. The study confirmed that although the intestinal microbiota system is complex, exposure to L. rhamnosus JB-1 could protect against certain stress-induced behavior and systemic immunological changes.
Messaoudi et al. [56] Defensive marble burying Lactobacillus helveticus R0052, Bifidobacterium longum R0175 Anxiolytic activity in rats combining L. helveticus R0052 and B. longum R0175 has been confirmed. Subsequent study confirmed that the intestinal microflora plays a role in stress, anxiety, and depression, probably through the enteric nervous system as well as centrally, and may show positive psychological results in healthy volunteers.
Ohland et al. [53] Barnes maze Lactobacillus helveticus ROO52′ with normal and Western-style diet The objective of the study was to examine the differences in the modulating effect of probiotics, which varies depending on the diet and genotype of the mouse (wild type (WT) and IL-10 deficient (IL-10−/−) 129/SvEv mice). The capacity of L. helveticus to modulate changes in the expression of intestinal microbiota and cytokine or anxiety disorders depended on genotype and diet. Western-style diet had a negative effect on anxiety and memory, related to inflammation, which was prevented by probiotic administration. The results suggest that the type of diet ingested by the host and lack or occurrence of active infection can significantly alter the probiotic's ability to modify function and physiological behavior.
Arseneault-Bréard et al. [45] FST, PA Lactobacillus helveticus R0052, Bifidobacterium longum R0175 The effect of administration of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 on depressive behavior in rats after myocardial infarction has been tested. The administration of probiotics prevented the loss of intestinal barrier integrity and prevented the development of depressive behaviors after myocardial infarction, which may be an interesting hypothesis for further clinical studies.
Bravo et al. [10] Stress-induced hyperthermia (SIH), FST, EPM Lactobacillus rhamnosus (JB-1) Administration of Lactobacillus rhamnosus JB-1 to mice for 4 weeks attenuated an anxiolytic effect and the HPA/corticosterone response to stress, and caused specific changes in mRNA for GABA-A and -B receptor subtypes in specific CNS areas. These changes were coherent with the activities of GABA by itself, the dominant inhibitory neurotransmitter in the brain, and importantly are greatly withdrawn by subdural vagotomy. Once again, the function of probiotics in the two-way communication of the GBA was confirmed.
Gareau et al. [52] CUMS, WAS, LDT, NOR, T-Maze test Lactobacillus helveticus R0052, Lactobacillus rhamnosus R0011 Exposure to a stressor in the form of WAS, i.e., a model of psychological stress, which allows for the detection of changes in colorectal physiology after only 1h of exposure) resulted in a noticeable growth of serum corticosterone level, reduced by administration of probiotics, versus placebo. The administration of probiotics prevented memory disorders, which occurred in infected animals under WAS. Normalization of the microbiota can prevent behavioral abnormalities.
Liang et al. [68] SPT, EPM Lactobacillus helveticus NS8 Studies have confirmed a positive effect of L. helveticus NS8 on chronic behavioral and cognitive deficits caused by stress, similar or higher to those of citalopram administered to the sample group. The probiotic administration positively influenced the level of neurotransmitters, adrenocorticotropic hormone and decreased the level of corticosterone caused by chronic stress. The results indicate the antidepressive influence of L. helveticus NS8 in group of rats subjected to chronic restraint depression and potential support of probiotic therapy in treatment of stress and other types of depression.
Liu et al. [63] FST, EPM Lactobacillus plantarum PS128 Administering Lactobacillus plantarum to GF mice significantly improved locomotion and anxiety-like behavior, but did not significantly affect depression-like behavior. Moreover, changes in behavior were related to an increase in the level of monoamine neurotransmitters in the striatum. Such results indicate that everyday probiotic consumption may improve anxiety behavior and may support a mitigation of neuropsychiatric disorders.
Savignac et al. [50] SIH, Defensive marble burying, EPM, TST, FST Bifidobacterium longum 1714, Bifidobacterium breve 1205 The study compared the effect of different Bifidobacteria strains on the mood of BALB/c mice and compared them with the effect of antidepressant (escitalopram). Probiotics and escitalopram decreased anxiety (marble burying), but only B. longum 1714 reduced SIH. B. breve 1205 reduced anxiety and B. longum 1714 induced antidepressant behavior. However, there were no differences in corticosterone concentration between individual groups. The results suggest probiotic supplementation might have a positive impact on stress-related disorders of the cerebral-intestinal axis, which opens up new possibilities in the field of neurogastroenterology.
Gilbert et al. [8] FST, PA Lactobacillus helveticus R0052, Bifidobacterium longum R0175 A study objective was to compare the effect of a diet rich in PUFA n-3 or a combination of the probiotics Lactobacillus helveticus R0052 and Bifidobacterium longum R0175, administered to rats after myocardial infarction. The administration of probiotics and/or with a high n-3 PUFA diet, after the start of reperfusion, reduced the amount of proinflammatory cytokines in the general circulation, reduced apoptosis within the limbic system, and inhibited the manifestation of depressive behavior. This may be relevant for further research on probiotics in the context of weakening depression-like behaviors observed after myocardial infarction.
Tian et al. [2] FST, sucrose preference test, PA Bifidobacterium longum subsp. infantis E41, Bifidobacterium breve M2CF22M7 The effect of B. longum subsp. infantis E41 and B. breve M2CF22M7 on depressive behavior and cognition in mice was studied. Bacteria decreased depressive behavior and increased levels of 5-hydroxytryptophan and neurotrophic factor in the brain. In addition, M2CF22M7 decreased serum corticosterone levels. The positive effect of probiotics on stress-induced microbiosis was confirmed. The antidepressant action of Bifidobacterium longum E41 and B. breve M2CF22M7 in mice indicates the need for further studies on the influence of these probiotic strains on the treatment of mood and memory disorders.
Trudeau et al. [80] FST, PA Bifidobacterium longum R0175 Lactobacillus helveticus R0052, Lactobacillus salivarius HA-118 Antidepressant effects of probiotics administered to rats 14 days before causing myocardial infarction were studied. The results did not confirm the effect of probiotics on infarction range. A positive effect of B. longum on both socialization and depression-like behavior was confirmed. Additionally, this bacterial strain weakened Caspase-3 activation and reduced the amount of proinflammatory cytokines. In case of two Lactobacillus strains, only for L. salivarius was a significant effect on learning and memory confirmed. Study results may be relevant in the context of previous studies on the influence of combination of different strains (B. longum R017 and L. helveticus R0052) on depression after myocardial infarction. The antidepressant effect is associated with Bifidobacterium longum.
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Life Sciences, Molecular Biology, Microbiology and Virology, Medicine, Basic Medical Science, Immunology