The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat

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Abstract

It is becoming increasingly apparent that probiotics are important to the health of the host. The absence of probiotic bacteria in the gut can have adverse effects not only locally in the gut, but has also been shown to affect central HPA and monoaminergic activity, features that have been implicated in the aetiology of depression. To evaluate the potential antidepressant properties of probiotics, we tested rats chronically treated with Bifidobacteria infantis in the forced swim test, and also assessed the effects on immune, neuroendocrine and central monoaminergic activity. Sprague-Dawley rats were treated for 14 days with B. infantis. Probiotic administration in naive rats had no effect on swim behaviours on day 3 or day 14 following the commencement of treatment. However, there was a significant attenuation of IFN-γ, TNF-α and IL-6 cytokines following mitogen stimulation (p < 0.05) in probiotic-treated rats relative to controls. Furthermore, there was a marked increase in plasma concentrations of tryptophan (p < 0.005) and kynurenic acid (p < 0.05) in the bifidobacteria-treated rats when compared to controls. Bifidobacteria treatment also resulted in a reduced 5-HIAA concentration in the frontal cortex and a decrease in DOPAC in the amygdaloid cortex. The attenuation of pro-inflammatory immune responses, and the elevation of the serotonergic precursor, tryptophan by bifidobacteria treatment, provides encouraging evidence in support of the proposition that this probiotic may possess antidepressant properties. However, these findings are preliminary and further investigation into the precise mechanisms involved, is warranted.

Introduction

The remarkable convergence of research strategies in the diverse fields of psychiatry, gastroenterology and neuroscience that has occurred in recent years has been pivotal in advancing our understanding of psychiatric illness and the overlap that often exists between gastrointestinal (GI) and mood disorders. As a consequence, treatment approaches to certain psychiatric illnesses have considerably improved. In particular, irritable bowel syndrome (IBS), that is acknowledged to be associated with both psychosocial and GI disturbances (Levy et al., 2006) and is often accompanied by depressive symptoms (Whitehead, 2007), has benefited from an interactive approach. Although the existence of a mutual interaction between the brain and the GI system, organs that are functionally very different, seems unlikely, the emerging body of literature presents compelling evidence for the existence of a “brain–gut axis” (BGA), and suggests that not only can the brain affect gut function, but that the gut, by both direct and indirect mechanisms, can also induce changes in the CNS (Shanahan, 1999, Wakefield, 2002, Mayer et al., 2006). This bi-directional communication is particularly relevant during stress (Tache and Bonaz, 2007), and in stress-related disorders such as depression (Logan and Katzman, 2005). Nevertheless, to date, antidepressant treatments have not addressed this facet of depressive illness.

Clinical antidepressant treatment has undergone remarkable improvement since the initial introduction of the tricyclic antidepressants (TCA) and monoamine oxidase inhibitors (MAOI). The side-effect profiles of these earlier treatments have significantly improved with the introduction of the selective serotonin re-uptake inhibitors (Vaswani et al., 2003), and the more recent emergence of the serotonin and noradrenaline re-uptake inhibitors (Papakostas et al., 2007). Nevertheless, outstanding clinical needs still exist for the treatment of depression (Kennedy, 2006), and improved therapeutic strategies are required, particularly in terms of addressing treatment-resistant depression and additional co-morbid painful physical conditions such as GI discomfort.

The gut microflora is composed of micro-organisms that can be classified as pathogenic, neutral or beneficial to the host. The latter group of bacteria, also known as probiotic bacteria, generally predominates in the healthy gut. The word “Probiotic”, is derived from Greek, meaning “for life”, and probiotics have been defined as “living micro-organisms that contribute to intestinal microbial balance and have the potential to improve the health of their human host” (Fuller, 1991). Although probiotics have been a part of human micro-ecology for millennia, they are less prevalent in westernised societies today, probably as a result of a combination of factors including the over-emphasis placed on hygiene, the prevalent use of antibiotic therapy and the increased stresses associated with current lifestyles. In recent years, their important contribution toward the health of the host has become increasingly apparent. Data provided by studies in germ-free animals dramatically emphasize the importance of a healthy microflora for the normal development and maintenance of intestinal immune homeostasis. The absence of micro-organisms in the GIT of mice has been shown to reduce the number of Peyer’s patches and IgA-producing B-cells in the lamina propria relative to healthy controls, whereas the introduction of microbes reverses these effects (reviewed by Cebra et al. (1998)). Interestingly, germ-free mice also show evidence of an overactive HPA axis and diminished monoaminergic activity (Sudo, 2006) suggesting that microbial colonization can have a long-lasting impact on central systems, systems that have been implicated in the psychopathology of depression. One of the most common species of probiotics is the bifidobacteria. Shortly after birth, up to 90% of the bacteria found in the infant GIT is composed of bifidobacteria (Harmsen et al., 2000), and in the adult they still make up approximately 3–5% of the microflora (Harmsen et al., 2002). This particular probiotic has been shown to be effective in inhibiting LPS-induced inflammation, by blocking NF-κB activation (Riedel et al., 2006). Furthermore, in inflammatory disorders such as IBS, treatment with bifidobacteria normalises the imbalance that exists between pro-inflammatory and anti-inflammatory cytokines in this disorder (O’Mahony et al., 2005). As the balance between anti- and pro-inflammatory cytokines has also been shown to have an important role in the pathophysiology of depression (Mayer et al., 2006), it seems reasonable to hypothesize that probiotics may possess antidepressant properties. Indeed, the potential benefits of probiotics as an adjuvant therapy in depression have recently been discussed (Logan and Katzman, 2005). What is more, a recent study has demonstrated a beneficial effect of chronic probiotic treatment on mood in healthy subjects (Benton et al., 2007).

In addition to effects on the immune system, probiotics have also been shown to improve carbohydrate malabsorption (Sherman, 2004), which in turn has been associated with both the early signs of depression (Ledochowski et al., 2000) and reduced tryptophan levels (Ledochowski et al., 1999). The possibility exists that treatment with probiotics may elicit its beneficial effect on mood by increasing levels of the serotonin-precursor, tryptophan, and consequently elevating serotonin availability.

The objective of this study was to assess the potential antidepressant properties of the probiotic, Bifidobacteria infantis. This was achieved by measuring behaviours in the forced swim test (FST), a well-established model in the evaluation of pharmacological antidepressant activity (Cryan et al., 2005). Furthermore, as the biological effects of bifidobacteria are initiated at the level of the gut, whereas pathological abnormalities of depressive illness predominantly originate in the brain, any potential antidepressant effects of this treatment are likely to be mediated via the three major interacting pathways that comprise the BGA, the neuroendocrine, immune, and neuronal (ANS) systems. Therefore, to assess the effects of chronic probiotic treatment on the neuroendocrine system, the expression of vasopressin (AVP) and corticotrophin-releasing factor (CRF) in the hypothalamus, in addition to basal plasma corticosterone concentrations, were quantified. Peripheral blood cytokines were analysed to determine if immune parameters were affected by probiotics. Finally to establish whether bifidobacteria treatment altered neurotransmitter activity, monoamine concentrations in various brain regions as well as peripheral levels of tryptophan and its metabolites were also measured.

Section snippets

Animals and housing

Twenty adult male Sprague-Dawley rats, weighing between 200 and 250 g, were bred in our animal facility. All rats were singly housed in standard polycarbonate cages (25 × 38 × 26 cm) 10 days prior to the commencement of experiments to allow rats to habituate to the new housing conditions. Rat chow and water were available ad libitum throughout the procedures. Twelve rats were assigned to the bifidobacteria treatment group (n = 12) and there were eight control rats (n = 8). Rats treated with bifidobacteria

Body weight gain

Bifidobacteria treatment significantly altered body weights during the first and second week. At the end of the first week, the mean body weight gain was significantly reduced in the probiotic-treated group relative to non-treated rats, where the latter group gained a mean weight of 30.8 ± 7.0 g as opposed to only 3.33 ± 5.8 g in the bifidobacteria-treated group (t(18) = 2.99, p < 0.01). In contrast on day 14 of treatment, rats receiving bifidobacteria gained a greater amount of weight when compared to

Discussion

In recent years there is a growing body of literature emphasizing the importance of probiotics to the health of the gut, and their effectiveness in treating the symptoms of GI disorders. However, to the best of our knowledge, this is the first study to assess the potential effects of probiotic therapy on the brain and systems associated with depression.

Conflict of interest statement

All the authors declare that they have no conflicts of interest with respect to this study or its publication.

Contributors

Dr. Lieve Desbonnet organised the study, carried out the experimental analyses and the interpretation of data, and wrote the manuscript. Prof. Timothy G. Dinan supervised the performance of the experiments and contributed to the experimental design. Dr. Lillian Garrett played a substantial role in the harvesting and dissection of tissue samples. Gerard Clarke contributed to the HPLC data collection and analysis. Prof. John Bienenstock provided valuable advice throughout the study. All authors

Role of funding source

Funding for this study was provided by a HEA research grant, and also in part by Science Foundation Ireland in the form of a centre grant (Alimentary Pharmabiotic Centre), by the Health Research Board (HRB), and the Wellcome Trust. These sponsors had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Acknowledgement

We are grateful to Dr. Paul Scully and Dr. Siobhain O’Mahony for their technical assistance in this study. We would also like to thank Dr. John Cryan for his contributions to aspects of the experimental design.

References (69)

  • M. Maes et al.

    Increased neutering and interferon-γ secretion and lower availability of l-tryptophan in major depression: further evidence for an immune response

    Psychiatry Research

    (1994)
  • M. Maes et al.

    The monocyte-T-lymphocyte hypothesis of major depression

    Psychoneuroendocrinology

    (1995)
  • M. Maes et al.

    The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway

    International Immunopharmacology

    (2005)
  • A.M. Myint et al.

    Th1, Th2, and Th3 cytokine alterations in major depression

    Journal of Affective Disorders

    (2005)
  • A.-M. Myint et al.

    Kynurenine pathway in major depression: evidence of impaired neuroprotection

    Journal of Affective Disorders

    (2007)
  • L. O’Mahony et al.

    Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles

    Gastroenterology

    (2005)
  • L.R. Orlando et al.

    The role of group I and group II metabotropic glutamate receptors in modulation of striatal NMDA and quinolinic acid toxicity

    Experimental Neurology

    (2001)
  • G.I. Papakostas et al.

    Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents

    Biological Psychiatry

    (2007)
  • K. Schröcksnadel et al.

    Monitoring tryptophan metabolism in chronic immune activation

    Clinica Chimica Acta

    (2006)
  • A. Sluzewska et al.

    Indicators of immune activation in depression

    Psychiatry Research

    (1996)
  • R.S. Smith

    The macrophage theory of depression

    Medical Hypotheses

    (1991)
  • C. Song et al.

    The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression

    Journal of Affective Disorders

    (1998)
  • B.N. Srikumar et al.

    The involvement of cholinergic and noradrenergic systems in behavioural recovery following oxotremorine treatment to chronically stressed rats

    Neuroscience

    (2006)
  • N. Sudo

    Stress and gut microbiota: does postnatal microbial colonization programs the hypothalamic-pituitary–adrenal system for stress response?

    International Congress Series

    (2006)
  • E.H. Turner et al.

    Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan

    Pharmacology and Therapeutics

    (2006)
  • M. Vaswani et al.

    Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review

    Progress in Neuropsychopharmacology and Biological Psychiatry

    (2003)
  • Y. Xu et al.

    Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats

    Pharmacology Biochemistry and Behavior

    (2005)
  • M. Yoshioka et al.

    Effects of conditioned fear stress on 5-HT release in the rat prefrontal cortex

    Pharmacology Biochemistry and Behavior

    (1995)
  • J. Amat et al.

    Medial prefrontal cortex determines how stressor controllability affects behaviour and dorsal raphe nucleus

    Nature Neuroscience

    (2005)
  • D. Benton et al.

    Impact of consuming a milk drink containing a probiotic on mood and cognition

    European Journal of Clinical Nutrition

    (2007)
  • S.T. Bland et al.

    Stressor-controllability modulates stress-induced dopamine and serotonin efflux in the medial prefrontal cortex

    Neuropsychopharmacology

    (2003)
  • L. Capuron et al.

    Cytokines and depression: the need for a new paradigm

    Brain Behavior and Immunity

    (2003)
  • J.J. Cebra et al.

    Development and maintenance of the gut-associated lymphoid tissue (GALT): the roles of enteric bacteria and viruses

    Developmental Immunology

    (1998)
  • M.Y. Chung et al.

    Regional differences in the levels of bioorganic amines and their metabolites in rat brain after tricyclic antidepressant treatments

    Yonsei Medical Journal

    (1993)
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