1. NATUROPATHIC DOCTOR NEWS & REVIEWFebruary 2014
also other central nervous system (CNS)
molecules that are implicated in the
pathophysiology of depression. Desbonnet
et al3
showed that Bifidobacteria infantis
could modulate tryptophan metabolism,
suggesting that the normal gut microflora
can influence the precursor pool for serotonin
(5-HT), a major neurotransmitter of the
brain-gut axis and mood. Furthermore, by
investigating behavior and brain mRNA
expression of genes implicated in anxiety and
stress reactivity, another study4
found that
germ-free mice exhibited decreased serotonin
receptor 1A (5HT1A) expression, which
normally binds 5-HT, in the hippocampus.
This research suggests that probiotics can
affect mood chemistry and susceptibility to
anxiety and depression at the CNS level.
Probiotics not only affect mood and
anxiety behavior in the long term, but also
acutely; in fact, such behavior is observed
as early as 7 to 8 hours after infecting mice
with a gut pathogen.5
Possible mechanisms
may be via the vagus nerve and enteric
nervous system (ENS), as well as various
inflammatory cytokines and hormones.6
It
is interesting to note that stress is at the root
cause of these physiological changes seen
in anxiety. Chronic stress overload can lead
to both gastrointestinal and mood disorders
by disrupting the microflora balance.7
Yet,
depression itself will also reduce one’s
ability to cope with any sort of stress, and
so the vicious cycle continues. The brain-
gut axis is even more evidenced by the fact
that 50% of irritable bowel disease (IBD)
patients also present with mood disorders.8
Similarly, there have been positive results
using antidepressants to treat IBD.9
Hence,
the animal data suggests a bidirectional
communication between the gut and the
brain. The type of stress will be unique to
each individual, and naturopathic doctors
have an important role to play in helping
patients identify it.
Human Clinical Trials
Clinical research has demonstrated evidence
for probiotics as a preventive and adjuvant
therapy for improving general mental
health in both patients with stress-related
psychiatric conditions and healthy subjects.
The most recent research was presented at a
conference session given by Tillisch in 2012.10
Tillisch discussed evidence that demonstrated
diminished brain arousal in healthy women
while taking probiotics and performing
emotional tasks over a 4-week period (see
Table 1). The diminished connectivity of the
amygdala-centered network within the cortex
suggests a role for probiotic supplementation
in manipulating brain activity.
Messaoudi et al performed 2 double-
blind studies in 2011 examining the effect
of probiotics on stress reactions. In the first
study,11
healthy subjects with low stress
were divided into probiotic and placebo
groups. After 30 days, participants in the
probiotic group showed improvements
in mood, as measured through various
stress scales, as well as lower urinary free
cortisol (see Table 1). Messaoudi’s follow-up
study12
further showed that even the least
stressed subjects benefited from probiotics,
as measured by lower scores on anxiety and
depression scales, as well as sub-categories
of “obsessive compulsive” and “paranoid-
ideation.” Findings demonstrated the
broad effect of microflora on the body and
to modulate synaptophysin and PSD-95
protein – both signs of synaptic maturation
– in the striatum of the forebrain during
the sensitive period of synaptogenesis. If
applicable to humans, there may be long-
term consequences of developing mood
disorders in adulthood if the infant gut
flora is compromised. The prenatal period,
specifically up to 6 weeks of age, is critical
for this type of programming because of
the ability of the microflora to modulate its
development.1
Probiotic supplementation
may potentially be able to reverse the
excess HPA-axis responsiveness and the
associated anxiety-like behavior.
Commensal bacteria not only have
the ability to influence the HPA axis, but
relationship between the gut microflora and
neurological function.
Animal Studies
One animal study1
showed that germ-
free mice (gnotobiotic mice that have
not been naturally colonized by
microorganisms) exhibited an increased
hypothalamic-pituitary-adrenal (HPA)-axis
responsiveness to stress during adulthood.
The mice had decreased sensitivity to
the negative feedback of glucocorticoids,
resulting in elevated adrenocorticotropic
hormone (ACTH) and corticosterone
levels – a stressful state resembling anxiety.
Heijtz et al2
further demonstrated that the
gut microflora of germ-free mice was able
Polina Kapoustina,
Phillip Rouchotas, ND, MSc
The role of the gut in treating psychiatric
conditions is not always considered,
but current research on the use of probiotics
in depression and related mood disorders
has gained traction, both as an adjuvant
therapy and a preventative measure. This
research gives naturopathic physicians a
strong foundation to present to their patients
and educate them on how the health of their
guts directly impacts the health of their
minds and vice versa, encouraging them to
be mindful of the mind-body connection.
This review evaluates the current evidence
and possible mechanisms explaining the
S t u d e n t S c h o l a r s h i p – 1 s t
P l a c e R e s e a r c h R e v i e w
Probiotics and Psychiatry
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2. NATUROPATHIC DOCTOR NEWS & REVIEWFebruary 2014
markers such as inflammatory cytokines.
Yet, it is important to note that with
probiotics there is no risk of addiction or
memory impairment, as is the case with
psychoactive drugs, making a strong case
for including probiotics in the protocol for
anxiety and depression. Although plenty
of questions remain, the benefit of using
probiotics to treat behavior disorders is
becoming increasingly more apparent.
Naturopathic medicine has a critical role
to play in implementing this evidence
in clinical practice, as we integrate our
understanding of stress-induced disease
and the mind-body connection.
mind. Hence, probiotic supplementation
can have positive behavioral effects, even
in a healthy population. Benton et al13
also
conducted research on healthy subjects
in England, investigating the effect of
probiotics specifically on mood and memory.
The supplementation influenced mood in
subjects with the lowest baseline mood, with
no improvement in memory (see Table 1).
Rao et al14
were the only investigators
examining a population with a specific
diagnosis, in this case chronic fatigue
syndrome (CFS), in which over 50% of
patients present with anxiety. Mental health
conditions and “functional somatic disorders”
like CFS have higher incidence in developed
countries. This may be due to a changing
microbial environment in these countries,
leading to an elevation of inflammatory
cytokines, which at even low levels can
produce anxiety and depression in otherwise
healthy adults, as mentioned above.13
Rao found that after 8 weeks, there was a
significant decrease in anxiety among those
taking probiotics (see Table 1). It is interesting
to note that there was a consequential rise
in probiotic strains in the stool that were not
supplemented in the subjects, indicating
improvements in overall gut health.14
This body of research suggests that
the brain-gut links proposed in animal
studies are validated clinically. The action
of gut microflora on the HPA axis and
CNS messaging may indeed explain the
radically positive results on mood, anxiety,
and stress in the human studies outlined
here. However, it is important to distinguish
between direct and indirect consequences of
probiotic supplementation in the studies. An
example of an indirect effect on the CNS or
ENS would be improved bowel movements
due to the probiotic, which research has
shown leads to improved mood.15
We
cannot assume that probiotics directly
affect the CNS, although animal studies do
suggest possible mechanisms.
In all of the studies discussed here,
probiotic supplementation produced none
of the side effects that would be expected
with conventional antidepressants. Further
investigation into dosing and probiotic
strain is needed. Some of the research used
a dairy beverage for delivering the probiotic
formulations. It would be interesting to
see the effects of higher-dose, pill-form
probiotics. Moreover, most studies were
done on healthy subjects, rather than
patients with mental health diagnoses.
Baseline mood was not always measured
at the beginning of the study. To properly
evaluate the results, it’s important to know
if the subjects may have already been happy
Benton13
did indeed divide subjects into 3
categories, according to baseline mood in
the first 4 days of the study, using POMS
scores. Overall, probiotics produce positive
results on mood and anxiety in a healthy
population, and may indeed be an option
for adjuvant or preventative therapy.
Conclusion
We are on the cusp of a surge in research
on probiotic applications in psychiatry.
There are still trials to be done on
populations with more serious mental
health conditions, including identification of
the proper flora strain(s) and dose for each
condition; nonetheless, we are continually
realizing the vital role of the gut on CNS
functions. Future studies should evaluate
the coadministration of probiotics with
psychotropic drugs on a larger sample size,
taking into account baseline physiological
S t u d e n t S c h o l a r s h i p – 1 s t
P l a c e R e s e a r c h R e v i e w
Table 1. Effects of Probiotic Supplementation on Depression,
Anxiety, Stress, and Mood – Human Trials
Reference Method Outcome
Tillisch; 201310
RCT; 36 healthy women, ages 18–55 years
125 g BID, 4 weeks
Probiotic yogurt with Bifidobacterium lactis,
Lactobacillus bulgaricus, Streptococcus
thermophilus, and Lactococcus lactis
OR non-fermented dairy OR no beverage
Assessed with blood flow assessments (fMRI)
while performing emotional tasks
Probiotic group showed lower
brain reactivity to an emotional
task (p=0.004), compared to
non-fermented dairy group and
no beverage group.
The probiotics group showed
decreased connectivity of an
amygdala-centered network
with the insula, dorsal
striatum, and lateral prefrontal
cortex.
Messaoudi;
201111
RCT; 25 subjects with urinary free cortisol
levels <50 ng/mL at baseline (article addendum
to study below), aka less-stressed subjects
Lactobacillus helveticus and Bifidobacterium
longum (3 x109
cfu)
OR Placebo
Subjects assessed with the Hopkins Symptom
Checklist (HSCL-90), the Hospital Anxiety and
Depression Scale (HADS), the Perceived Stress
Scale (PSS), and 24-hour urinary free cortisol
Anxiety and depression scores
significantly improved, as
in the general population.
Three other sub-scores
also improved: “obsessive
compulsive,” “anxiety,” and
“paranoid-ideation.” No side
effects. Good safety profile.
Messaoudi;
201112
RCT; 66 healthy subjects
Once daily, 30 days
Lactobacillus helveticus and Bifidobacterium
longum (1.5 g; 3 x109
cfu) OR Placebo
Subjects assessed with the HSCL-90, the
HADS, the PSS, the Coping Checklist (CCL), and
24-hour urinary free cortisol
Overall decrease in the
scales measuring anxiety and
depression, due to decrease
in somatization and anger-
hostility. Improvement in
mood: significantly reduced
psychological distress in
volunteers (p<0.05). No group
differences were observed in
the PSS.
Urinary free cortisol levels
were significantly reduced by
the probiotics (p<0.05).
Benton; 200713
RCT; 124 physically healthy subjects, mean age
of 62 years
Once daily, 3 weeks
Milk drink with Lactobacillus casei Shirota
(6.5 x 109
cfu)
OR Placebo
Mood (questionnaire-based POMS) and
cognition (Wechsler Memory Scale) measured
at baseline and after 10 and 20 days of
supplementation
Mood: Probiotics failed
to influence mood in 5/6
POMS mood dimensions, but
significance in the bottom third
with the lowest baseline mood.
Memory: Placebo group
demonstrated better recall
compared to probiotic group.
Rao; 200914
Pilot RCT; 39 patients with chronic fatigue
syndrome (CFS)
Once daily, 8 weeks
Lactobacillus casei Shirota (24 billion cfu)
OR Placebo
Patients provided stool samples and were
assessed with the Beck Depression and
Beck Anxiety Inventories before and after the
intervention.
A significant decrease in
anxiety among those taking
the active LcS compared to
the placebo (p = 0.01); no
statistically significant changes
in depression.
A 73.7% increase in
Bifidobacteria and
Lactobacillus in treated group
(vs 37.5% Bifidobacteria
and 43.8% Lactobacillus in
placebo group)
(RCT – Randomized, controlled trial; fMRI – functional magnetic resonance imaging;
POMS – Profile of Mood States)
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colonization programs the hypothalamic-pitutary-
adrenal system for stress response in mice. J Physiol.
2004;558(Pt 1):263-275.
2. Diaz Heijtz R, Wang S, Anuar F, et al. Normal gut
microbiota modulates brain development and behavior.
Proc Natl Acad Sci USA. 2011;108(7):3047-3052.
3. Desbonnet L, Garrett L, Clarke G, et al. The probiotic
Bifidobacteria infantis: an assessment of potential
antidepressant properties in the rat. J Psychiatr Res.
2008;43(2):164-174.
4. Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced
anxiety-like behavior and central neurochemical
change in germ-free mice. Neurogastroenterol Motil.
2011;23(3): 255-264.
5. Goehler LE, Park SM, Opitz N, et al. Campylobacter
jejuni infection increases anxiety-like behavior in
the holeboard: possible anatomical substrates for
viscerosensory modulation of exploratory behavior.
Brain Behav Immun. 2008;22(3):354-366.
6. Graff LA, Walker JR, Bernstein CN. Depression and
anxiety in inflammatory bowel disease: a review of
comorbidity and management. Inflamm Bowel Dis.
2009;15(7):1105-1118.
7. Logan A, Katzman M. Major depressive disorder:
probiotics may be an adjuvant therapy. Med
Hypotheses. 2005;64(3):533-538.
8. O’Mahony SM, Marchesi JR, Scully P, et al. Early life
stress alters behavior, immunity, and microbiota in rats:
implications for irritable bowel syndrome and psychiatric
illnesses. Biol Psychiatry. 2009;65(3):263–267.
9. Goodhand JR, Greig FI, Koodun Y, et al. Do
antidepressants influence the disease course in
inflammatory bowel disease? A retrospective case-
matched observational study. Inflamm Bowel Dis.
2012;18(7):1232-1239.
10. Tillisch K, Labus J, Kilpatrick L, et al. Consumption of
fermented milk product with probiotic modulates brain
activity. Gastroenterology. 2013;144(7):1394-1401.
11. Messaoudi M, Lalonde R, Violle N, et al. Assessment of
psychotropic-like properties of a probiotic formulation
(Lactobacillus helveticus R0052 and Bifidobacterium
longum R0175) in rats and human subjects. Br J Nutr.
2011;105(5):755-764.
12. Messaoudi M, Violle N, Bisson JF, et al. Beneficial
psychological effects of a probiotic formulation
(Lactobacillus helveticus R0052 and Bifidobacterium
longum R0175) in healthy human volunteers. Gut
Microbes. 2011;2(4):256-261.
13. Benton D, Williams C, Brown A. Impact of consuming
a milk drink containing a probiotic on mood and
cognition. Eur J Clin Nutr. 2007;61(3):355-361.
14. Rao AV, Bested AC, Beaulne TM, et al. A randomized,
double-blind, placebo-controlled pilot study of a
probiotic in emotional symptoms of chronic fatigue
syndrome. Gut Pathog. 2009;1(1):6.
15. Logan A, Katzman M. Major depressive disorder:
probiotics may be an adjuvant therapy. Med
Hypotheses. 2005;64(3):533-538.
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Polina Kapoustina is a 3rd- year
student at the Canadian College for
Naturopathic Medicine (CCNM). She is
the founder of the CCNM Pediatrics Club
(www.pediatricsclub.com) and served as
the VP Communications 2012-2013 in
the National Medical Student Association
(NMSA). She is also the Eastern Current
representative at CCNM. Polina loves the outdoors and
adventure sports. She is passionate about naturopathic
medicine and can’t wait to start helping people get well!
Philip Rouchotas MSc, ND has been a practicing
naturopathic doctor since 2004. His areas of clinical
focus include metabolic disorders (diabetes, high blood
pressure, elevated cholesterol, overweight/obesity),
autoimmune conditions (arthritis, IBD, chronic migraine,
asthma, eczema, psoriasis, lupus), and psychiatric con-
cerns (depression, bipolar, anxiety, ADHD, insomnia,
schizophrenia). Philip serves as an associate professor at
the Canadian College of Naturopathic Medicine, respon-
sible for assimilation and delivery of the second-year cur-
riculum in clinical nutrition. He is also the editor-in--chief
of Integrated Healthcare Practitioners, a peer-reviewed
journal reaching naturopathic doctors, chiropractors, and
medical doctors across Canada. Philip graduated from
CCNM in 2004, preceded by an honours undergraduate
degree in nutritional sciences and a masters degree in
nutritional sciences, both from the University of Guelph.
16