Abstract
The term probiotic is derived from the Greek meaning ‘for life’ and the first formal description of a probiotic was provided by the Nobel laureate Metchnikoff in 1908, based on his observation that individuals who lived in a certain region of Bulgaria had a longer lifespan than their fellow citizens, a fact which he attributed to the regular ingestion of a fermented milk product [1]. The current accepted definition of a probiotic is a live organism that, when ingested in adequate amounts, exerts a health benefit. In recent years many products have appeared on health food store and supermarket shelves which are labelled probiotic. Due to a widespread lack of uniform regulation extravagant claims for their effectiveness have proliferated. Fortunately, from a consumer perspective, times are changing and regulatory agencies around the world have begun to cast a forensic and skeptical eye on probiotics and their claims. What evidence, if any, is there to indicate that probiotics might have psychotropic actions or benefit in patients with depression?
Probiotics are a broad heterogeneous group of microbes and the most commonly used are lactic acid bacteria and non-pathogenic yeasts. Very few of the plethora of ‘probiotic’ preparations marketed today fulfil the definition of a probiotic [2]. They may not contain live organisms or have not been adequately tested to ensure that the organisms will survive in the conditions (e.g. room temperature) or for the length of time (days, weeks, or months) that is claimed. They may not confer a health benefit because either they have never been tested in humans or because what studies have been performed have been grossly inadequate or even negative.
In contrast to the relative paucity of high-quality clinical data, considerable information on the basic functions of probiotics and their interactions with the host has been generated from cutting edge basic science laboratories. Indeed, a series of studies have recently been published focusing on the impact of putative probiotics on the central nervous system and behaviour.
Preclinical studies
Major depression is a stress-related disorder and over the past two decades well-tolerated antidepressants have emerged. However, not all patients respond to antidepressants and some patients are averse to pharmacological interventions, while access to cognitive behaviour therapy is not always readily available. From a biological perspective it is known that depressed patients frequently have hypothalamic-pituitary-adrenal (HPA) alterations such as elevated cortisol levels in plasma, elevated corticotropin releasing hormone (CRH) levels in the cerebrospinal fluid and a failure to suppress cortisol in response to dexamethasone challenge [3]. Antidepressants treatment is accompanied by reversal of these abnormalities. That microbes can influence the functioning of the HPA is demonstrated by the fact that germ-free mice with a sterile gastrointestinal tract have an overactive HPA in response to stress. This hyper-response of the HPA is reversed by mono-association with a single organism, Bifidobacterium infantis, which is a predominant bacterium in the infant gut and a commonly used probiotic organism [4]. Furthermore, in germ free animals the levels of noradrenaline (NA) and 5-hydroxy tryptamine (5-HT) in the cortex and hippocampus are significantly reduced [5]. Thus, preclinical data clearly show that commensal bacteria have the capability of altering not only the HPA axis but key neurotransmitters thought to be of relevance in the aetiology of depression.
Desbonnet et al. [6] assessed the potential benefits of the probiotic Bifidobacterium infantis in the rat maternal separation (MS) model of depression, a paradigm that has proven to be of value in the study of antidepressant effects. MS adult rat offspring were chronically treated with bifidobacteria or the selective serotonin reuptake inhibitor citalopram and subjected to the forced swim test (FST) to assess motivational state. Cytokine concentrations in stimulated whole blood samples, monoamine levels in the brain, and central and peripheral HPA measures were also analysed. MS reduced swim behaviour and increased immobility in the FST, decreased NA content in the brain, and enhanced peripheral interleukin (IL)-6 release and amygdala corticotropin-releasing factor mRNA levels. Probiotic treatment resulted in normalization of the immune response, reversal of behavioural deficits, and restoration of basal NA concentrations in the brainstem. These findings point to an influential role for bifidobacteria in neural function, and suggest that probiotics may have broader therapeutic applications than previously considered. Further support for this view is provided by the series of studies by Lyte and his colleagues [7–10]. They have shown that oral administration of the pathogen Campylobacter jejuni, in subclinical doses, which were too low to elicit overt immune activation, resulted in anxiety-like behaviour in mice. They also reported that areas of brainstem activation, most notably the nucleus tractus solitarius and lateral parabrachial nucleus, participate in neural information processing that lead to autonomic, neuroendocrine and behavioural responses. These experiments support the view that the gut microbiota may be involved in the modulation, not only of the central nervous system, but also, and consequently, behaviour [11].
Clinical studies
That patients with major depression have a pro-inflammatory phenotype with increased levels of pro-inflammatory cytokines is now generally accepted [12]. Elevations in plasma IL-6 and tumour necrosis factor alpha (TNF-alpha) are those most consistently demonstrated [13]. It is now clear from both animal and human studies that certain probiotic bacteria have an anti-inflammatory capacity with the ability to alter a pro-inflammatory phenotype [14]. This has, however, yet to be shown in patients with major depression but has been demonstrated in patients with irritable bowel syndrome [14].
In a recent double-blind, placebo-controlled, randomized parallel group study volunteers received either the probiotic combination Lactobacillus helveticus R0052 and Bifidobacterium longum or placebo for 30 days and were assessed by the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and the measurement of 24 hour urinary free cortisol levels [15]. Daily administration of probiotic combination significantly reduced psychological distress in volunteers, as measured by the HSCL-90 scale, the HADS and by the CCL. Furthermore, urinary free cortisol levels were significantly reduced by the probiotics. This is the first demonstration of a probiotic influencing the HPA in humans.
Another study by Benton et al. [16] found that the consumption of a probiotic-containing yoghurt improved mood. A total of 132 physically healthy subjects with a mean age 61.8 years, volunteered in response to local media coverage; 124 completed the trial. For a 3 week period, either a probiotic-containing milk drink or a placebo was consumed daily. Mood and cognition were measured at baseline and after 10 and 20 days of consumption. When the third with the lowest baseline mood were considered, they selectively responded by reporting themselves as happy rather than depressed after taking the probiotic.
In a study of patients with chronic fatigue syndrome, subjects were treated three times daily with Lactobacillus casei strain Shirota (LcS) or a placebo with identical taste and appearance [17]. Overall there was a significant improvement in anxiety among those taking the active LcS compared to the placebo, providing further support for the view that a probiotic may have psychotropic effects.
Conclusions
Logan and Katzman [18] first proposed the use of probiotics as adjunct therapy in the management of depression. Since then there has been an accumulation of data from both clinical and preclinical studies supporting the view that probiotics may have a role in the treatment of depression. It is, however, certain that not all probiotics are the same, and while some may have an impact on neurotransmitters and behaviour, others will not [19]. After all, they each have a unique genome with varying capacities to produce neuroactive substances. Certainly, for some patients probiotics would be far more acceptable than the current use of SSRIs and other antidepressants. However, before any firm conclusions can be drawn, properly powered studies comparing an appropriate probiotic with an antidepressant and placebo and rigorously assessing the impact of a probiotic as adjunctive therapy to conventional antidepressants need to be conducted.