Probiotics in the treatment of depression:
science or science fiction?
Timothy G. Dinan, Eamonn M. Quigley

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 definotion 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 definotion
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 flui
and a failure to suppress cortisol in response to dexamethasone
challenge [3]. Antidepressants treatment is
accompanied by reversal of these abnormalities. That
microbes can inflsence 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,
Bifi dobacterium 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 Bifi dobacterium 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 bifidobacter  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 (TNFalpha)
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 Bifi dobacterium 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 signifi cantly reduced psychological distress
in volunteers, as measured by the HSCL-90 scale, the
HADS and by the CCL. Furthermore, urinary free cortisol
levels were signifi cantly reduced by the probiotics.
This is the fi rst 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

Conclusions
Logan and Katzman [18] fi rst 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