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Nutritional Neuroscience
An International Journal on Nutrition, Diet and Nervous System
ISSN: 1028-415X (Print) 1476-8305 (Online) Journal homepage: https://www.tandfonline.com/loi/ynns20
Psychobiotics as treatment for anxiety,
depression, and related symptoms: a systematic
review
Kristen S. Smith, Michael W. Greene, Jeganathan Ramesh Babu & Andrew D.
Frugé
To cite this article: Kristen S. Smith, Michael W. Greene, Jeganathan Ramesh Babu & Andrew
D. Frugé (2019): Psychobiotics as treatment for anxiety, depression, and related symptoms: a
systematic review, Nutritional Neuroscience, DOI: 10.1080/1028415X.2019.1701220
To link to this article: https://doi.org/10.1080/1028415X.2019.1701220
Published online: 20 Dec 2019.
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REVIEW
Psychobiotics as treatment for anxiety, depression, and related symptoms: a
systematic review
Kristen S. Smith , Michael W. Greene , Jeganathan Ramesh Babu and Andrew D. Frugé
Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL, USA
ABSTRACT
Objective: Altering the gut microflora may produce health benefits in individuals suffering from
mood disorders. The purpose of this review was to evaluate the efficacy of probiotics, prebiotics,
or synbiotics as a potential treatment for symptoms of depression, anxiety, and stress (as
psychobiotics).
Methods: Google Scholar, PubMed, PsychINFO, and Web of Science were utilized to identify and
evaluate studies through October 31, 2019. Studies were included if subjects were evaluated for
altered mood or stress levels at start of the study and consumed probiotics, prebiotics, and/or
synbiotics for intervention.
Results: Search results yielded 142 articles, while only 12 studies met all inclusion criteria. Nine of
the 12 studies identified evaluated the efficacy of various probiotic strains, while only two evaluated
synbiotics and one evaluated prebiotics. Six out of 12 studies found probiotics to reduce depression,
while two studies found probiotics to reduce anxiety.
Discussion: Translational research in this field is limited and further investigation of the efficacy of
psychobiotics in mood disorders is warranted.
KEYWORDS
Depression; anxiety; stress;
mood disorders;
psychobiotics; prebiotics;
probiotics; synbiotics
Introduction
Depression and anxiety both rank in the top five mental
and physical conditions that affect Americans [1]. One in
five US adults will be clinically depressed [2], and sub-
sequently have impaired quality of life during their life-
time [3]. Anxiety, a comorbidity accompanying
depression [4], and its treatment cost $29.1 billion
annually in personal health care expenditure in the US
[5]. Severity of both anxiety and depression are highly
influenced by stress [6]. These three conditions are
often intertwined. Watson and Clark described the tri-
partite model of depression and anxiety, where an inde-
pendent stressor could have positive affectivity or
negative affectivity on the severity of depression and/or
anxiety [4]. Negative stress stimuli in life may cause wor-
sening of depression and anxiety by increased negative
affectivity, while the opposite is true for positive stress
stimuli. Stress, whether negative or positive, is an unwa-
vering aspect of life, and there are physiological mechan-
isms to cope with normal levels of stress. However,
disease and illness arise when coping mechanisms
become overwhelmed [7]. Developing novel therapeutic
methods for treatment of these mood disorders, as well
as exacerbation from outside stressors, is necessary to
moderate the burden of these comorbid conditions.
Among new therapy techniques, modifying intestinal
microbiota and gut health has become increasingly pop-
ular. Specifically, the bidirectional interaction of the
microbiome with the nervous system via the gut-brain
axis (GBA) and its role in mood disorders is gaining
interest. Through multiple pathways, gut microbiota
may modulate human host health [8]. The first pathway
of communication between the gut microbiome and the
brain is through immunoregulation. Microbiota interact
with immune cells and the lymphatic system to affect
cytokine production, inflammation, and immune
response [9]. The second method of interaction is via
the vagus nerve, which connects the brain to the entire
gastrointestinal tract [10]. Sensory neurons are exposed
to gut microbiota, and these interactions regulate release
of gut hormones and affect intestinal motility. Further-
more, metabolites produced by dietary components
and bacteria interactions signal via the vagus nerve and
directly affect brain function, sleep, stress response, and
hormone release [11–13]. The third means of communi-
cation is the neuroendocrine pathway, as the intestine is
home to various types of enteroendocrine cells and is the
largest endocrine organ in the body [9]. Host-microbial
metabolic interactions may regulate neurotransmitter
synthesis and availability. Most related with depression
© 2019 Informa UK Limited, trading as Taylor & Francis Group
CONTACT Kristen S. Smith kss0034@auburn.edu Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, 101E PSB, 260 Lem
Morrison Drive, Auburn, AL 36849, USA
NUTRITIONAL NEUROSCIENCE
https://doi.org/10.1080/1028415X.2019.1701220
and anxiety, the tryptophan-kynurenine pathway is sig-
nificantly influenced by gut microbiota [14]. This is the
opposing pathway for the conversion of tryptophan to
serotonin, and serotonin deficiency was once thought
to lead to development of depression and anxiety due
to its mood-regulatory function [15]. Unfortunately,
this monoamine transporter blockade theory does not
illustrate the full depression picture. Recent research
has revealed synaptic plasticity [16], neurogenesis [17],
and discovery of N-methyl-D-aspartate (NMDA) recep-
tor antagonists [18] play a greater role in mood regu-
lation. The gut microbiome has been implicated in
shaping of neural networks, most notably restored hip-
pocampal neurogenesis in germ-free (GF) mice upon
the administration of probiotics [19].
The GBA is greatly influenced by the relative diver-
sity/alleged health of the gut microbiome. Evidence
from multiple studies indicates depression and anxiety
symptoms are transferrable when mice undergo fecal
microbiota transplants from depressed or anxious
humans or animals [20–22]. However, conflicting evi-
dence exists for GF mice and their response to stressors.
Clarke et al. found anxiolytic behaviors in GF mice under
anxiety-inducing circumstances [23], while Crumeyr-
olle-Arias et al. report increased anxiety-like behaviors
in GF rats [24]. Differences in species may account for
conflicting results, however, further research is war-
ranted to investigate gut-microbiome influences and
actions within human subjects.
Although the exact mechanism is unknown, there is a
link between the gut and mood disorders. Psychosocial
factors, such as quality of life or well-being, are greatly
influenced by gut function and there is a strong corre-
lation between psychosocial factors and gastrointestinal
disorders [25]. Furthermore, chronic stress can predict
clinical outcomes and worsen severity of symptoms in
patients with Irritable Bowel Syndrome (IBS) [26]. Elev-
ated stress, anxiety, and depression are linked to intestinal
dysbiosis [27] and mood disorders are disproportionately
high in patients with functional gut disorders [28,29].
Functional gut disorders, as well as Chronic Fatigue Syn-
drome (CFS) are frequently comorbid with stress,
depression, and anxiety due to altered expressions and
interactions between the gut and central nervous system
(CNS) [30]. The relationship between functional gut dis-
orders and comorbidities of mood disorders may be
explained by the influence of gut microbiota and their
metabolites. Understanding the interplay of these dis-
orders could aid in the treatment and comprehension
of functional gut disorders and, more importantly,
mood disorders in relation to the microbiome.
Communication along the GBA can be modified
through the administration of probiotics and prebiotics.
Probiotics are defined as consumed microorganisms that
beneficially contribute to host gut microbial flora [31].
Prebiotics are chemical compounds/nutrients that influ-
ence gut microbiome composition by feeding specific
bacterial species [31]. Most common prebiotics include
fructooligosaccahrides (FOS) and galactooligosacchar-
ides (GOS), as these are dietary fibers with well-estab-
lished impact on intestinal flora [32]. A combination of
probiotics and prebiotics are called ‘synbiotics’[31]. Cer-
tain bacterial species are researched specifically for their
benefits to host’s mental health, such as Bifidobacterium
longum (B. longum) and Lactobacillus helveticus
(L. helveticus). Both of these species have aided in
decreasing gastrointestinal discomfort in stress-affected
individuals [33], and improving emotional behavior in
mice and psychological outcomes in healthy humans
[34]. B. longum reduced anxious and depressive beha-
viors in mice [35], and reduced anxiety and stress
response in healthy volunteers [36]. When ingested in
adequate amounts, these strains may provide beneficial
changes in psychosocial factors and symptoms in indi-
viduals suffering from psychiatric disorders, and be
aptly identified as psychobiotics [37].
Administration of probiotics and prebiotics, as psy-
chobiotics, for treatment of depression and anxiety was
first suggested by Logan and Katzman in 2005 [38],
while the use of bacteria (lactic acid bacillus) to treat mel-
ancholic symptoms related to constipation in hospital
patients was investigated in 1910 [39]. Among the exist-
ing studies, many portray conflicting results, and almost
all of these studies evaluating psychological distress are
completed in healthy human subjects [40–43]. While
this area of research is valid and merits exploration,
the focus of this review is to evaluate the efficacy of psy-
chobiotic administration in human subjects to affect
symptoms of depression, anxiety, or elevated stress.
Methods
PubMed, Google Scholar, Web of Science, and Psy-
chINFO were searched using combinations of the follow-
ing terms to compile current research investigating
efficacy of probiotics or prebiotics to reduce mood dis-
order-related symptoms: ‘probiotics,’‘prebiotics,’‘syn-
biotics,’‘mood disorders,’‘anxiety,’‘depression,’
‘stress,’and ‘gut-brain axis.’Search results were limited
to publications in English from the earliest date available
to 31 October 2019. An example of the full electronic
search strategy used in PubMed is provided in Appendix
A. Inclusion criteria were set a priori as follows: (1)
human subjects were evaluated; (2) intervention of pro-
biotics, prebiotics, or synbiotics was studied; (3) subjects
were chosen for levels of depression, anxiety, or stress
2K. S. SMITH ET AL.
prior to study (4) studies were required to evaluate effects
of probiotics, prebiotics, or synbiotics on mood-disor-
dered human subjects. Exclusion criteria were: (1) sys-
tematic reviews or meta-analyses; (2) subjects with
unaltered mental health; or (3) no reported intervention
including probiotics, prebiotics, or synbiotics. Although
systematic reviews and meta-analyses were excluded,
references therein were examined to complete accurate
search for studies with probiotics in human subjects
with altered mental health. This systematic literature
review was conducted in accordance with PRISMA rec-
ommendations [44].
Studies were graded to assess quality using a pre-
viously validated instrument, the Downs and Black
checklist for quality of studies (Quality Index, QI) [45].
There are several scoring tools, however, this instrument
considered differences in non-randomized and random-
ized studies and was determined to be most relevant.
Briefly, the 27-item checklist contains 5 subscales:
reporting (9 items), external validity (3 items), bias (7
items), confounding (6 items), and power (1 item).
These subscales allowed for overall assessment of the
profile of the study, as well as particular methodological
strengths and weaknesses, which is a major limitation of
other scoring systems. The power subscale on the orig-
inal Downs and Black checklist has been modified,
since half of the studies scored did not conduct any
power analysis. Therefore, a study received 1 point if a
power analysis was conducted. Using this modified QI,
each study receives a total score with 28 possible points;
a value indicating maximum study quality. To aid in
comparison of QI scores, a previously used qualitative
categorization was employed (≥20: very good; 15–19:
good; 11–14 fair; ≤10: poor) [46,47].
Results
Following a keyword search and elimination of excluded
studies, 142 articles were found to discuss psychobiotics
and mental health. Figure 1 describes search results in
full detail. Of these 142 articles, 12 studies were identified
that met inclusion criteria for this review. Table 1
describes detailed findings and QI score of each study.
Briefly, 9 out 12 studies administered probiotics with
various strains to study subjects, 1 study provided pre-
biotics, and 2 studies used synbiotics. Six studies
observed decreased depression scores or related symp-
toms following psychobiotic administration. Two of
the 12 studies observed a reduction in anxiety symptoms,
and one study reported improved general condition and
decreased stress response following probiotic consump-
tion. Five studies found no differences in either anxiety
or depression symptoms compared to placebo groups.
Based on QI scoring system, the average study quality
score was 21.2 ± 6.12 and subscale scores can be seen in
Table 1. Six of the 12 studies were qualitatively categor-
ized as very good, whereas 5 were good and 1 was fair. Of
the 3 studies exclusively investigating stress symptoms, 2
were rated as good and 1 rated fair quality. The only
study examining anxiety was rated as good quality,
with a score of 15. Four of the five studies evaluating psy-
chobiotic effects exclusively in depression symptoms
were rated as very good quality, while one was rated
good. The two studies looking at both anxiety and
depression scored as very good and good quality, while
the sole study investigating all three conditions was
rated very good quality.
Three studies evaluated probiotic consumption in
individuals with elevated stress. The first study, con-
ducted by Gruenwald et al., explored the effects of a pro-
biotic multivitamin compound, consisting of
Lactobacillus acidophilus (L. acidophilus),Bifidobacter-
ium bifidum (B. bifidum), and B. longum, on an individ-
ual’s ability to cope with stress. Adults with moderate to
intense exhaustion, based on the Psychological-Neuro-
logical Questionnaire (PNQ), consumed the probiotic
multivitamin capsule daily with their breakfast meal
for 6 months. At baseline, and months 2, 4, and 6, par-
ticipants completed the List of Adjectives (Eigenschafts-
wörterliste; EWL), and reported infections or
gastrointestinal disturbances; EWL scoring is split into
two subcategories, negative condition and positive con-
dition. Over the course of the 6-month intervention, par-
ticipants improved their positive condition sub-score
and decreased their negative condition sub-score,
accumulating to an overall 40.7% improvement in
stress-coping abilities. Respiratory infections and other
infections, as well as gastrointestinal disturbances
decreased over the 6-month trial (29% and 91%, respect-
ively) [48]. Gruenwald and colleagues demonstrated a
probiotic multivitamin compound may be effective in
decreasing stress and exhaustion in adults with moderate
to intense exhaustion, although this study did not
employ a placebo or control group for comparison.
Students under academic examination stress display
disturbances in cytokine regulation, altered immunoglo-
bulin levels, and lymphocyte function [49,50] and often
are studied as models of psychological stress. Marcos
et al. investigated the effects of a fermented milk drink
with probiotics using this model of psychological stress
in students. The fermented probiotic milk contained
Lactobacillus delbrueckii bulgaricus,Streptococcus sali-
varius thermophilus, and Lactobacillus casei (L. casei).
Participants were randomized to consume either semi-
skimmed milk (control) or fermented milk containing
yogurt cultures (probiotic), and instructed to consume
NUTRITIONAL NEUROSCIENCE 3
the milk with their morning meal. The study lasted 6
weeks split into two phases: Phase 1 lasted three weeks
prior to the examination period, and Phase 2 was the
three weeks of the examination period. Anxiety levels
were measured using the Speilberger state-trait anxiety
inventory (STAI) at baseline and completion of study.
Blood samples were collected from participants and
tested for routine biochemistry, pro-inflammatory cyto-
kines, and immunological lymphocyte production. Both
state-anxiety and trait-anxiety increased from beginning
to end of study, which was expected due to design of
study and nature of examination stress. No significant
differences were observed between probiotic and placebo
groups on anxiety measures (21.65 ± 5.09 vs. 19.14 ± 3.67
for control). However, lymphocyte production was
increased in the probiotics group from baseline to com-
pletion of study, while the placebo group showed a
decreased production. The probiotic group also showed
maintenance of CD-56 cells (17.29 ± 17.27), where a
decline in these natural killer cells was seen in the pla-
cebo group (−51.97 ± 21.33). This study demonstrates
the efficacy of a fermented milk product to modulate
immune responses in students under academic
examination stress and may reduce the risk of acute ill-
ness while under or after stressful situations [7].
Stress plays an important role in gastrointestinal func-
tion. Diop et al. conducted a randomized, double-blind,
placebo-controlled trial in 75 volunteers with stress
symptoms. Subjects were randomized to receive either
a probiotic capsule (containing L. acidophilus and
B. longum) or placebo daily for 3 weeks. Stress-induced
symptoms were assessed using a 62-item questionnaire
evaluating physical and psychological discomforts and
disturbances. Over the 3 week trial, gastrointestinal
symptoms of abdominal pain and nausea/vomiting sig-
nificantly decreased in the probiotics group compared
to the control (−2.59 vs. −0.34, and −0.82 vs. 0.77,
respectively). Probiotic supplementation did not signifi-
cantly alter mood symptoms induced by stressful life
events. While probiotic consumption may alleviate
stress-induced gastrointestinal symptoms, findings
from this study do not support the hypothesis that pro-
biotics modify mood symptoms in chronically stressed
individuals [33].
Another study utilizing a potential psychobiotic
aimed to relieve anxiety symptoms and was conducted
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of article screening, selection,
and elimination.
4K. S. SMITH ET AL.
Table 1. Summary of results from research evaluating effects of psychobiotics on mood disorder conditions.
Study authors
and year
Objective Subjects Intervention (compound/microbes) Variables measured ResultsQI scores*
STRESS
Diop et al
(2008)
Investigate effects of probiotic
supplement on stress-induced
psychological and gastrointestinal
symptoms.
75 volunteers with 2 or
more symptoms of
stress
3-week intervention: probx capsule
containing L. acidophilus and
B. longum; or placebo
Stress-induced symptoms (gastrointestinal and
psychological)
Stress-induced abdominal pain and nausea/
vomiting was significantly reduced following
consumption of probiotics. Psychological
symptoms were not altered.
Reporting: 7
External Validity:
0
Bias: 5
Confounding: 3
Power: 0
Total: 15
Gruenwald
et al. (2002)
Effects of probiotic multivitamin in
stress control and immune
function.
42 adults with
moderate to intense
exhaustion and
stress
6-month intervention: Multivitamin
capsule containing probx:
L. acidophilus,B. bifidum,B. longum
Improvement in Stress/Exhaustion (via EWL);
number and severity of infections and GI
disturbances
General condition improved, with changes due to
increase positive condition and decrease in
negative condition. Number of infections and GI
disturbances were reduced.
Reporting: 10
External Validity:
1
Bias: 3
Confounding: 1
Power: 0
Total: 15
Marcos et al
(2004)
Evaluate effect of milk containing
probiotics on immune system and
anxiety levels in University
students.
155 college-aged
students under
examination stress
6-week intervention: 200 mL of
fermented milk containing
L. delbrueckii bulgaricus,Streptococcus
salivarius thermophilus, and L. casei; or
200 mL semi-skimmed milk
Anxiety levels (STAI), blood hematology, blood
biochemistry, serum cortisol, lymphocyte
production, and cytokine production
Level of anxiety increased in both groups from
baseline to study end. Increase in absolute
lymphocyte number and maintenance of CD-56
immune cells was observed in probx group.
Reporting: 4
External Validity:
1
Bias: 4
Confounding: 3
Power: 0
Total: 12
ANXIETY
Yang et al
(2016)
Determine effects of probiotic
treatment to reduce pre-surgical
anxiety in laryngeal cancer
patients
30 laryngeal cancer
patients with pre-
surgery anxiety; 20
healthy volunteers
3-week intervention: probx capsule
containing Clostridium butyricum;or
placebo
Anxiety score (HAMA), CRF levels, morning and
evening heartbeat during surgery waiting
period
Probx administration significantly reduced anxiety
scores pre-surgery. Placebo group showed an
increase in heartbeat, but the probx group
maintained steady heartbeat throughout surgery
waiting period. CRF levels did not fluctuate in
probx group, but increased in placebo group.
Reporting: 6
External Validity:
2
Bias: 4
Confounding: 3
Power: 0
Total: 15
DEPRESSION
Akkasheh
et al. (2016)
Determine effects of probiotic
intake in patients with MDD on
symptoms of depression and
metabolic status.
40 patients with Major
Depressive Disorder
(MDD)
8-week intervention:
Probx capsule containing L. acidophilus,
L. casei, and B. longum; or placebo
Depressed mood (via BDI); FPG; insulin
metabolism; lipid concentrations; hs-CRP; total
antioxidant capacity; GSH levels
Probx significantly decreased BDI scores, decreased
oxidative damage (increased GSH), decreased
serum insulin levels and insulin resistance,
decreased hs-CRP levels
Reporting: 10
External Validity:
3
Bias: 6
Confounding: 6
(Continued)
NUTRITIONAL NEUROSCIENCE 5
Table 1. Continued.
Study authors
and year
Objective Subjects Intervention (compound/microbes) Variables measured ResultsQI scores*
Power: 1
Total: 26
Ghorbani
et al. (2018)
Efficacy of symbiotic
supplementation in treatment
therapy of moderate depression.
40 outpatient adults
with clinically
diagnosed moderate
depression
6-week intervention: Synbx capsule
containing L. casei, L. acidophilus,
L. bulgarigus, L. rhamnosus, B. breve,
B. longum,Streptococcus thermophilis,
and 100 mg FOS; or placebo
Response to depression therapy (HAM-D) Synbx group significantly reduced HAM-D scores
Reporting: 9
External Validity:
2
Bias: 6
Confounding: 5
Power: 1
Total: 23
Kazemi et al
(2019)
Evaluate and compare effect of
supplementation with prebiotics
and probiotics on depression
symptoms and tryptophan
metabolism.
110 adults with mild to
moderate
depression
8-week intervention: Probx containing
L. helveticus and B. longum; or prebx
containing GLOS; or placebo
Depression severity (BDI); serum kynurenine/
tryptophan ratio; serum tryptophan/BCAAs ratio
Probx significantly decreased BDI score, kynurenine/
tryptophan ratio. Prebx significantly decreased
tryptophan/BCAAs ratio.Reporting: 11
External Validity:
3
Bias: 7
Confounding:6
Power: 1
Total: 28
Romijn et al
(2017)
Determine effectiveness of probiotic
as primary treatment in low mood
individuals.
79 adults with mild to
moderate
depression
8-week intervention: probx capsule with
L. helveticus; or placebo
Depression and anxiety symptoms (MADRS, iCGI,
QIDS-SR, DASS-42), functionality (GAF), IBS
symptoms (IBS-SSS), hs-CRP, IL-1β, IL-6, TNF-α,
vitamin D, BDNF
Blood biomarkers and psychological outcomes were
not affected by probx intervention. Higher vitamin
D levels increased mood improvement in probx
group. Probx group had significantly more severe
IBS symptoms compared to placebo.
Reporting: 11
External Validity:
3
Bias: 7
Confounding: 6
Power: 1
Total: 28
Talbott et al
(2019)
Determine microbiome changes
and psychological mood state
following symbiotic
administration.
32 ‘healthy stressed’
individuals
1-month intervention: synbx supplement
containing L. helveticus R0052;
B. longum R0175; L. rhamnosus R0011;
GOS, and phytonutrients
Psychological factors related to mood state: POMS Increase in Lactobacillus and Bifidobacterium (‘good’
bacteria) populations. Increased global mood
scores and vigor (+25%; +44%, respectively) and
decrease in mood state subscales (tension,
depression, anger, fatigue, and confusion).
Reporting: 4
External Validity:
0
Bias: 7
Confounding: 4
Power: 0
Total: 15
ANXIETY AND DEPRESSION
Pinto-Sanchez
et al (2017)
Evaluate effects of B. longum
bacteria supplementation on
anxiety and depression in IBS
patients.
44 IBS patients with
mild to moderate
depression scores
6-week intervention: powdered probx
containing B. longum; or placebo
Anxiety and depression scores (HAD), IBS global
adequate relief, IBS symptoms, somatization,
quality of life, changes in brain activation
patterns, inflammatory biomarkers,
neurotransmitters, stool microbiota, urine
metabonomic
Probx group significantly decreased HAD scores and
depression levels, and increased quality of life
scores, but had no effect on anxiety levels or IBS
symptoms. Probx reduced responses to negative
emotional stimuli. Stool microbiota, inflammatory
biomarkers, and neurotransmitters were similar
between placebo and probx groups.
Reporting: 11
External Validity:
3
Bias: 6
Confounding: 6
Power: 1
Total: 27
(Continued)
6K. S. SMITH ET AL.
Table 1. Continued.
Study authors
and year
Objective Subjects Intervention (compound/microbes) Variables measured ResultsQI scores*
Rao et al
(2009)
Determine efficacy of probiotic
administration in symptoms of
depression and anxiety in patients
with CFS
35 CFS patients 8-week intervention: probx powder
containing L. casei; or placebo
Anxiety and depression scores (BDI, BAI), stool
microbiota profiles
Probx group increased total Lactobacillus and
Bifidobacterium in fecal samples. Probx groups
also showed significant improvement in anxiety
scores, but not in depression scores.
Reporting: 6
External Validity:
3
Bias: 5
Confounding: 5
Power: 0
Total: 19
STRESS, ANXIETY, AND DEPRESSION
Chahwan
et al. (2019)
Determine effect of probiotic
supplement consumption on
depressive symptoms.
71 participants with
mild to severe
depression
8-week intervention: probx sachet
containing B. bifidum, B. lactis,
Lactobacillus acidophilus, L. brevis,
L. casei, L. salivarius,andLactococcus
lactis; or placebo
Depression scores (MINI; BDI; DASS-21; LEIDS-r),
anxiety scores (BAI) dietary questionnaire, stool
sample analysis, client satisfaction
questionnaire
Probx group significantly reduced cognitive
reactivity compared to placebo. No significant
differences in microbiota, BDI, BAI, or DASS scores
between groups.
Reporting: 11
External Validity:
1
Bias: 6
Confounding: 5
Power: 1
Total: 24
Abbreviations: B.: Bifidobacterium, BAI: Beck Anxiety Inventory, BCAAs: Branched-chain amino acids, BDI: Beck Depression Inventory, BDNF: Brain-derived neurotrophic factor, CRF: Corticotropin-releasing factor, DASS:
Depression, Anxiety, Stress Scale, EWL: List of Adjectives, FFQ: Food frequency questionnaire, FOS: Fructooligosaccharide, FPG: Fasting Plasma Glucose, GLOS: Galactooligosaccharide, GSH: Glutathione, HAD: Hospital Anxiety
and Depression scale, HAMA: Hamilton rating scale for anxiety, HAM-D: Hamilton rating scale for depression, hs-CRP: high sensitivity C-reactive protein, IBS: Irritable Bowel Syndrome, IL-1β: Interleukin-1β, IL-6: Interleukin-6, L.:
Lactobacillus, LEIDS-r: Leiden Index of Depression Sensitivity-revised, MINI: Mini International Neuropsychiatric Interview, POMS: Profile of Mood States, Prebx: Prebiotics, Probx: Probiotics, STAI: State-Trait Anxiety Inventory,
Synbx: Synbiotics, QI: Quality Index, TNF-α: Tumor necrosis factor-alpha.
*Quality Index Score based on 28-point system; ≥20: very good; 15–19: good; 11–14 fair; ≤10: poor.
NUTRITIONAL NEUROSCIENCE 7
by Yang et al. in laryngeal cancer patients [51]. Partici-
pants were stratified by healthy or needing-surgery and
then randomized to receive a placebo, probiotic, or no
intervention. Patients receiving a probiotic or placebo
were instructed to consume the capsule twice daily
for 2 weeks. Probiotic capsules contained Clostridium
butyricum. The Hamilton Anxiety Scale was used to
evaluate patients’anxiety about surgery at baseline
and the day before the operation. Blood samples were
collected from all participants at baseline and 1 day
prior to surgery. Heartbeat was recorded twice daily,
morning and evening. Within the cancer patients, the
probiotic intervention showed no fluctuation in circu-
lating corticotropin-releasing factor (CRF) levels, how-
ever, the placebo and no intervention group increased
CRF levels from baseline to 1 day prior to surgery.
Among healthy controls, there was no differences in
CRF levels across the time points. Placebo and no
intervention groups increased heartbeat throughout
the duration of the study, whereas probiotic adminis-
tration in patients kept their heartbeats steady. Com-
pared to placebo, anxiety scores significantly
decreased in the probiotic intervention group (19.8
baseline score vs. 10.2 study end score). Anxiety scores
did not differ among healthy controls [51]. This study
demonstrated the effectiveness of probiotic adminis-
tration on reducing pre-surgery stress in laryngeal can-
cer patients.
The aforementioned study in laryngeal cancer
patients was the only study to exclusively investigate
anxiety symptoms. The following four studies explored
depression as another mood disorder potentially effected
by psychobiotic consumption. Romijn et al. investigated
the potential benefits of probiotic species, L. helveticus,
and B. longum in human subjects with mild to moder-
ately low mood scores, evaluated by self-reported screen-
ing questionnaires. During this 8-week randomized-
controlled, double-blind trial, participants received pla-
cebo or probiotic powder to consume once daily.
Researchers investigated changes in mood, stress,
anxiety, IBS symptoms, and levels of serum pro-inflam-
matory cytokines, brain-derived neurotrophic factor,
and plasma Vitamin D levels. Romijn et al. found no sig-
nificant differences in depression, anxiety, stress, or
mood between probiotic and placebo groups. Although
there were also no significant differences in blood bio-
markers, plasma vitamin D levels were found to moder-
ate treatment effect. Within the probiotic group, those
with high Vitamin D levels at baseline displayed greater
improvement in mood and functioning than those with
low Vitamin D levels [52]. Although this study indicates
these probiotic strains may not influence mood or
depression symptoms, future research should be
conducted to evaluate the effects on subjects with more
severe depression symptoms.
Current treatment may be effective in reducing
depression, although combined effects with synbiotics
may provide optimal benefits from treatment therapies.
Ghorbani et al. integrated current depression treatment
drugs (Fluoxetine) in combination with a synbiotic. Syn-
biotic capsules contained L. casei, L. acidophilus, Lacto-
bacillus bulgarigus, Lactobacillus rhamnosus,
Bifidobacterium breve,B. longum,Streptococcus thermo-
philis, and 100 mg FOS. Following completion of a 4-
week fluoxetine-only treatment, patients with moderate
depression were given two daily capsules of either a syn-
biotic or placebo for 6 weeks. Depression severity was
measured using the Hamilton Rating for Depression
(HAM-D). As both treatment arms were receiving fluox-
etine, both decreased HAM-D scores. However, treat-
ment with synbiotic significantly decreased depression
scores in the final 3 weeks of the trial (−19.25 ± 1.71 vs
−17.75 ± 2.05 in placebo group) [53]. This study indi-
cates beneficial effects of adjuvant depression therapy
of probiotics with fluoxetine.
In a randomized, double-blind, placebo-controlled
trial by Akkasheh et al., effects of probiotic adminis-
tration was explored in patients diagnosed with major
depressive disorder. Patients either consumed the pro-
biotic (L. acidophilus, L. casei, and B. longum) or placebo
daily throughout the 8 week study. Depression scores
were based on BDI questionnaire completion. After
intervention, the probiotic group showed significantly
reduced depression scores (−5.7 vs. −1.5 change in
BDI scores) and oxidative stress (glutathione level
increase of 1.8 ± 83.1 vs −106.8 ± 190.7 µmol/L in pla-
cebo). Patients receiving the probiotics also decreased
serum insulin and hs-CRP levels significantly compared
to the placebo group [54]. Akkasheh et al. demonstrated
efficacy of probiotic administration on depression symp-
toms, as well as oxidative stress, in patients suffering
from major depressive disorder (MDD).
The pathophysiology of depression involves the dis-
turbance and dysbiosis of the gut microbiome. Kazemi
et al. conducted a randomized, placebo-controlled,
double-blind trial to evaluate an intervention of probio-
tics and prebiotics in patients diagnosed with MDD on
depression symptoms and neurotransmitter metabolites.
Patients were randomized to one of three groups (pro-
biotic, prebiotic, or placebo) and asked to consume sup-
plement prior to a meal every day for 2 months.
Probiotics included L. helveticus and B. longum, while
the prebiotics contained GLOS. At baseline and end of
study visits, blood samples, BDI questionnaire, and
anthropometrics were collected. BDI scores were signifi-
cantly decreased by the end of study in the probiotic
8K. S. SMITH ET AL.
group compared to placebo group (9.1 vs 15.55 ending
BDI score), however, the prebiotic group showed a
decrease, though non-significant, in BDI scores com-
pared to placebo and probiotic groups (14.14 vs 15.55;
14.14 vs 9.1, respectively). The probiotic group also
showed a significant decrease in kynurenine/tryptophan
ratio compared to the placebo group (Cohen’sDeffect
size 0.51). Both the prebiotic group and the probiotic
group displayed a significant change in tryptophan/iso-
leucine ratio (ES d: 0.41 and 0.34 in probiotic and pre-
biotic respectively) [55]. This randomized controlled
trial suggests probiotics may be beneficial in the treat-
ment of MDD by decreasing depression scores and
increasing availability of tryptophan for synthesis of
serotonin.
The final study investigating depression symptoms
following psychobiotic consumption was conducted by
Talbott et al. [56]. Investigators recruited 32 healthy
individuals with ‘moderate’levels of psychological stress
and randomized them to either a symbiotic supplement
(n= 21) or placebo control (n= 11). The symbiotic
included L. helveticus R0052, B. longum R0175, and
L. rhamnosus R0011 strains, as well as prebiotic GOS,
and some phytonutrients. Participants were instructed
to consume supplement daily for 1 month. Stool samples
and questionnaires were collected at pre- and post-inter-
vention time-points. Following supplementation admin-
istration, the symbiotic group showed increased
populations of ‘good’bacteria (+28% Lactobacillus and
+30% Bifidobacterium increase in genera). Furthermore,
the symbiotic group showed improved global mood
scores (+25%) and decreased subscale scores in
depression (−55%), anger (−54%), fatigue (−64%), ten-
sion (−45%), and (−43%) confusion scores compared
to the placebo group. This study implies possible persis-
tant changes in mood state through microbiome
modulation.
Uncontrolled stress may manifest into cognitive dys-
function and sleep disturbances, potentially leading to
CFS development [57]. Approximately half of patients
diagnosed with CFS meet the criteria for an anxiety dis-
order or major depressive disorder, and 97% of CFS
patients report neuropsychological disturbances [30].
Rao et al. randomized patients with CFS to receive either
a placebo or lactic acid probiotic strain, L. casei strain
Shirota (LcS). Participants were instructed to consume
placebo or probiotic after each main meal, for the dur-
ation of the 8-week trial. Participants provided stool
samples and completed self-reported questionnaires
(Beck Depression Inventory (BDI), Beck Anxiety Inven-
tory (BAI)) at baseline and end of 8-week intervention
period. In the probiotics group, 73.7% of subjects dis-
played an increase in both fecal Lactobacillus and
Bifidobacteria (vs. 43.8% and 37.5% for placebo group,
respectively), although the increase in Lactobacillus was
expected due to high levels of this genus in the probiotic
sachets. CFS patients are known to have lower levels of
Bifidobacteria, and this genus is associated with a healthy
colonic environment [58] through increasing tryptophan
levels and modifying dopamine and serotonin metab-
olism [59]. Furthermore, the probiotic group demon-
strated a significant decrease in BAI scores from
baseline to follow-up compared to the placebo group
(increase of 8.415 total score). No significant differences
in BDI scores were observed in either group [60]. This
pilot study by Rao et al. indicates potential anxiety-redu-
cing effects of administration of the probiotic species
L. casei.
Patients with IBS display altered gut-brain communi-
cation [61], leading to psychiatric comorbidities such as
depression and anxiety. In a randomized, placebo-con-
trolled, double-blind study, Pinto-Sanchez et al. investi-
gated the effects of a probiotic strain, B. longum
NCC3001, in patients suffering from IBS and mild to
moderate depression or anxiety. Screening assessment
was completed 4 weeks prior to start of study, and sub-
jects provided stool, urine, and blood samples, as well
as functional magnetic resonance imaging (fMRI), Bir-
mingham IBS scale, and self-reported anxiety and
depression questionnaire (Hospital Anxiety and
Depression scale). Subjects were then randomized to
receive 6 weeks of B. longum probiotic or placebo at
baseline visit, where the same biological samples and
questionnaires were collected, in addition to Patient
Health Questionnaire (PHQ-15), STAI, and Short
Form Health Survey (SF-36). Throughout duration of
study, Birmingham IBS scale was completed weekly,
and HAD was completed at week 3. Following com-
pletion of the 6-week intervention, participants provided
the same biological samples and questionnaires as base-
line visit. A follow-up visit was completed 4 weeks post-
intervention for collection of questionnaires. At week 6, a
significant number of subjects decreased depression
scores by 2 or more points in the probiotic group com-
pared to the placebo group (14 of 22 patients vs 7 of
22 patients), and a significant increase in quality of life
scores. Administration of the probiotic also significantly
reduced responses to negative emotional stimuli in var-
ious areas of the brain, compared to placebo. Depression
scores were still significantly reduced at the week 10 fol-
low-up visit in the probiotic group. No significant differ-
ences were seen in serum pro-inflammatory biomarkers
or neurotransmitters and neurotrophins between groups
[62]. Pinto-Sanchez et al. demonstrated the probiotic
B. longum reduces depression scores, but not anxiety,
through altered emotional processing in multiple brain
NUTRITIONAL NEUROSCIENCE 9
areas, and may be effective in modifying disordered gut-
brain communication in IBS patients.
Most recently, Chahwan et al., investigated the effects
of probiotics on depressive symptoms in participants
with mild to severe depression. This was the only study
found to discuss psychobiotic effects on anxiety,
depression, and stress. Participants with mild to severe
depression were randomized to consume either a placebo
or probiotic capsule (containing B. bifidum, Bifidobacter-
ium lactis, L. acidophilus, Lactobacillus brevis, L. casei,
Lactobacillus salivarius, and Lactococcus lactis) twice
daily for 8 weeks. Levels of depression, stress, and anxiety
were measured using Mini International Neuropsychia-
tric Interview (MINI; clinician administered), BDI,
BAI, Depression, Anxiety, Stress Scale (DASS-21), Lei-
den Index of Depression Sensitivity-Revised (LEIDS-
R). Participants also provided stool samples and dietary
information (in the form of Food Frequency Question-
naire and brief list of typical foods consumed). Four
weeks after completion of the intervention, participants
completed these questionnaires again for follow-up ana-
lyses. No significant differences were observed in BDI,
BAI, DASS-21, or MINI scores between probiotics and
placebo groups, with the same being true between par-
ticipants with mild or severe depression. One-month fol-
low-up revealed no significant differences in depression
or anxiety self-report measures. However, participants
in the probiotics groups were more likely to move
from sub-clinical depression diagnosis to no diagnosis
of depression from pre to follow-up (z=−3.29, p=
0.00) and post to follow-up (z=−2.64, p= 0.00). The
probiotic group also demonstrated a significant decrease
in cognitive reactivity, based on LEIDS-R scores, com-
pared to the placebo group (mean = 55.24 ± 21.64 vs.
61.22 ± 13.86, respectively). No differences were found
between probiotic group and placebo group for alpha
diversity or beta diversity. Furthermore, when compared
to the non-depressed control group, participants with
depression showed no differences in alpha diversity
and beta diversity. Relative abundance showed no differ-
ences at any taxonomic level between both placebo and
probiotic groups, and depressed and non-depressed par-
ticipants [63]. Although no changes were observed
during microbiota analysis between groups, probiotics
were still effective in reducing cognitive reactivity in par-
ticipants with depression. These results demonstrate the
ability of probiotics to influence change in cognitive pat-
terns associated with depression.
Discussion
The studies reviewed herein present evidence in support
of psychobiotics in the treatment of elevated stress,
anxiety, or depression. Probiotics were discovered over
a century ago [64], however, the use of psychobiotics
for treatment of mood disorders is a young field of
research [37]. Nine of the studies discussed were pub-
lished within the last 10 years, and seven of those nine
reduced either depression or anxiety through adminis-
tration of psychobiotics, while one lowered cognitive
reactivity to sad mood after psychobiotic consumption.
These results are consistent with other literature sup-
porting use of probiotics or prebiotics to improve
psychological factors, such as depressive symptoms,
anxiety, or stress response [34,42,65] in healthy human
volunteers. Current research is limited on studies con-
ducted in humans currently suffering from mood dis-
orders. Further investigation with the focus on patients
currently experiencing altered mental conditions is
warranted.
Our findings in the current review correspond with
results from a similar meta-analysis conducted by Liu
et al., which support efficacy for probiotics in
depression and anxiety [66]. Comparable to the present
study, these results had generally small pooled effects,
the largest of which were seen in probiotics and
depression. However, the review by Liu et al. differs
from the present study. First, it included only controlled
clinical trials, whereas the present review included non-
controlled trials in addition to controlled clinical trials.
Second, inclusion criteria encompassed studies with
healthy human subjects. Furthermore, the present
review included studies utilizing synbiotics and multivi-
tamin treatment conditions in addition to prebiotics
and probiotics.
Depression is characterized with persistent, low-grade
inflammation [67]. Gut bacteria interact with immune
cells and the lymphatic system to modulate cytokine pro-
duction and immune response, altering systemic inflam-
mation [9]. Three of the studies within reported
improved immune system function or reduced inflam-
mation in individuals consuming psychobiotic com-
pounds. Two of these studies reported decreased
depression scores, however, the third did not assess
depression throughout the study [7,54,62]. Introducing
beneficial bacteria is known to reduce systemic inflam-
mation and improve immune response [68]. These
results suggest a potential mechanism through which
psychobiotics may relieve depression symptoms by mod-
erating immune response and inflammation levels via
the GBA. The GBA is also influenced by neurotransmit-
ter production, although none of these studies reported
altered neurotransmitter levels.
Prevalence of depression and anxiety is on the rise
[1,69], and psychological stress remains a constant
aspect of human life. Therefore, developing effective,
10 K. S. SMITH ET AL.
easily accessible treatment options is necessary to over-
come the burden of these conditions. Current treatment
options can be expensive and cause unpleasant side
effects such as dry mouth, constipation, difficulty operat-
ing a car, and sexual dysfunction [70]. Conversely, pro-
biotics and prebiotics offer limited side effects that are
often attenuated after consistent consumption [71]. Con-
sumption of these compounds can also lead to other
benefits, such as reduced gastrointestinal disturbances,
reduced inflammation, and increased immune response
[7,33,54,68]. As previously reported, psychobiotics may
provide benefit when used in conjunction with current
antidepressant medications [53]; further investigation
is needed. Patients discontinuing antidepressant use
have been known to experience withdrawal symptoms
[72]. If psychobiotics were deemed efficacious, patients
may require less time on antidepressant medications
and therefore decrease their symptoms of withdrawal.
Results from the study by Ghorbani and colleagues
showed improvement in depression severity following
adjuvant administration of psychobiotics with standard
fluoxetine treatment. Although decreased depression
severity was seen in both groups receiving fluoxetine
treatment, the symbiotic groups assumedly obtained
additional health benefits [73]. Administration of these
psychobiotics could potentially alleviate comorbidities
or other ailments, leading to comprehensive treatment
approaches. Although current research is impressive,
more questions have arisen than answers. Future
research is needed and should attempt to cohesively
address the unanswered questions to provide more hom-
ogeneity and reproducibility. Improved homogeneity
will provide the scientific foundation for statistical and
clinical investigation of psychobiotic efficacy.
This review and the articles herein have limitations.
Due to the heterogeneity in interventions, participants,
design and methods, and outcomes and measures across
the studies, we were unable to conduct a meta-analysis
and comprehensively assess the efficacy of psychobiotics.
The studies described used various criteria and question-
naires to measure and evaluate changes in symptoms of
depression, anxiety, or stress. These studies also provided
bacteria in various selections and combinations to study
subjects. These inconsistencies weaken the conclusions,
but on the other hand also provide multiple methods
and approaches for future research in this field. Another
limitation is small study sizes and various locations
around the world. These studies were conducted in
North America, Iran, New Zealand, and across Europe
and Asia, which limits generalizability, but may explain
some differences and variations in results. Various cri-
teria and qualifications were used to recruit participants,
and ranged from elevated stress to MDD patients.
Furthermore, the majority of studies conducted analyses
on non-clinical populations. Few studies collected data
on adherence or compliance of psychobiotic interven-
tion, and none reported this adherence data in manu-
scripts or in other published work. Unknown
adherence of the intervention limits attribution of results
to psychobiotic consumption. Finally, few studies
reported compositional changes in the gut or fecal
microbiota. Gut microbes vary between individuals,
and may have affected the response of subjects to treat-
ment interventions.
Although this review is with limitations, the studies
and results discussed herein offer supporting evidence
for psychobiotics in treatment of mood disorders.
Probiotics and prebiotics reduced anxiety scores in
adults with CFS and pre-surgery laryngeal cancer
patients and relieved depression symptoms in MDD,
andmildtomoderatedepression.Stressandimmune
responses were improved following psychobiotic
intervention in stressed adults and university students.
Psychobiotics offer potential alternative treatment
options in mood disorders and their accompanying
symptoms.
Further research into the effects of these psychobiotics
on mood disorders and stress-induced symptoms is war-
ranted to relieve the ever-growing burden of depression
and anxiety in our society.
Disclosure statement
No potential conflict of interest was reported by the authors.
Notes on contributors
Kristen S. Smith, Department of Nutrition, Dietetics, and Hos-
pitality Management, Auburn University, Auburn, AL, USA.
Michael W. Greene, Department of Nutrition, Dietetics, and
Hospitality Management, Auburn University, Auburn, AL,
USA.
Jeganathan Ramesh Babu, Department of Nutrition, Dietetics,
and Hospitality Management, Auburn University, Auburn,
AL, USA.
Andrew D. Frugé, Department of Nutrition, Dietetics, and
Hospitality Management, Auburn University, Auburn, AL,
USA.
ORCID
Kristen S. Smith http://orcid.org/0000-0002-8845-0609
Michael W. Greene http://orcid.org/0000-0002-6443-8269
Jeganathan Ramesh Babu http://orcid.org/0000-0002-3719-
932X
Andrew D. Frugé http://orcid.org/0000-0001-9119-1380
NUTRITIONAL NEUROSCIENCE 11
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Appendices
Appendix A. Full electronic search strategy for PubMed and adapted for other databases, as appropriate
(((((((‘probiotics’[MeSH Terms] OR ‘probiotics’[All Fields]) OR (‘prebiotics’[MeSH Terms] OR ‘prebiotics’[All Fields])) OR (‘syn-
biotics’[MeSH Terms] OR ‘synbiotics’[All Fields])) AND (‘mood disorders’[MeSH Terms] OR (‘mood’[All Fields] AND ‘disor-
ders’[All Fields]) OR ‘mood disorders’[All Fields])) OR (‘anxiety’[MeSH Terms] OR ‘anxiety’[All Fields])) OR (‘depressive
disorder’[MeSH Terms] OR (‘depressive’[All Fields] AND ‘disorder’[All Fields]) OR ‘depressive disorder’[All Fields] OR ‘depres-
sion’[All Fields] OR ‘depression’[MeSH Terms])) OR (‘Stress’[Journal] OR ‘stress’[All Fields])) AND (gut-brain[All Fields] AND
(‘axis, cervical vertebra’[MeSH Terms] OR (‘axis’[All Fields] AND ‘cervical’[All Fields] AND ‘vertebra’[All Fields]) OR ‘cervical
vertebra axis’[All Fields] OR ‘axis’[All Fields]))
Appendix B. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist of
content included in systematic review
Section/topic # Checklist item
Reported on
page #
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study
eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results;
limitations; conclusions and implications of key findings; systematic review registration number.
2
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 3–6
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants,
interventions, comparisons, outcomes, and study design (PICOS).
6
METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g. Web address), and, if
available, provide registration information including registration number.
N/a
Eligibility criteria 6 Specify study characteristics (e.g. PICOS, length of follow-up) and report characteristics (e.g. years
considered, language, publication status) used as criteria for eligibility, giving rationale.
6
Information sources 7 Describe all information sources (e.g. databases with dates of coverage, contact with study authors
to identify additional studies) in the search and date last searched.
6
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that
it could be repeated.
21
Study selection 9 State the process for selecting studies (i.e. screening, eligibility, included in systematic review, and,
if applicable, included in the meta-analysis).
20
Data collection process 10 Describe method of data extraction from reports (e.g. piloted forms, independently, in duplicate)
and any processes for obtaining and confirming data from investigators.
N/a
(Continued)
14 K. S. SMITH ET AL.
Continued.
Section/topic # Checklist item
Reported on
page #
Data items 11 List and define all variables for which data were sought (e.g. PICOS, funding sources) and any
assumptions and simplifications made.
6–7
Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of
whether this was done at the study or outcome level), and how this information is to be used in
any data synthesis.
6–7
Summary measures 13 State the principal summary measures (e.g. risk ratio, difference in means). N/a
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including
measures of consistency (e.g. I
2
) for each meta-analysis.
N/a
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g. publication bias,
selective reporting within studies).
6
Additional analyses 16 Describe methods of additional analyses (e.g. sensitivity or subgroup analyses, meta-regression), if
done, indicating which were pre-specified.
N/a
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons
for exclusions at each stage, ideally with a flow diagram.
20
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g. study size, PICOS, follow-
up period) and provide the citations.
17–19
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item
12).
17–19
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data
for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
17–19
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of
consistency.
N/a
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 17–19
Additional analysis 23 Give results of additional analyses, if done (e.g. sensitivity or subgroup analyses, meta-regression
[see Item 16]).
N/a
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider
their relevance to key groups (e.g. healthcare providers, users, and policy makers).
15–16
Limitations 25 Discuss limitations at study and outcome level (e.g. risk of bias), and at review-level (e.g. incomplete
retrieval of identified research, reporting bias).
17
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for
future research.
16
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g. supply of data); role of
funders for the systematic review.
N/a
From: Moher [44].
NUTRITIONAL NEUROSCIENCE 15
