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

A review of dietary and microbial connections to

depression, anxiety, and stress

Andrew M. Taylor & Hannah D. Holscher

To cite this article: Andrew M. Taylor & Hannah D. Holscher (2020) A review of dietary and
microbial connections to depression, anxiety, and stress, Nutritional Neuroscience, 23:3, 237-250,
DOI: 10.1080/1028415X.2018.1493808

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A review of dietary and microbial connections
to depression, anxiety, and stress
Andrew M. Taylor1, Hannah D. Holscher 1,2

1
Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, USA, 2Division of
Nutritional Sciences, University of Illinois, Urbana, IL, USA

Objective: Pre-clinical evidence suggests that the gastrointestinal microbiota contributes to mood and
behavior disorders. Among humans, diet quality and patterns, which also impact the gastrointestinal
microbiota, have been linked to depression, anxiety, and stress. This review summarizes findings from
clinical studies using dietary intervention to improve depression, anxiety, or stress and the role the
gastrointestinal microbiota may have in these disorders.
Methods: A literature search was conducted using the keywords microbiome, microbiota, depression,
anxiety, stress, diet, dietary pattern, diet quality, fiber, prebiotics, probiotics, and mood.
Results: Mood was improved by enhancing diet quality. Fructooligosaccharide and galactooligosaccharide
improved anxiety and depression in participants consuming ≥ 5 g/day. Additionally, bifidobacteria were
enriched in subjects consuming ≥ 5 g/day. Probiotic consumption improved psychological or biological
measures of depression, anxiety, or stress in individuals predisposed to a mood disorder. Probiotics
suppressed biological markers of stress in healthy individuals in a strain-dependent manner.
Discussion: High-quality diets, prebiotics, and probiotics may beneficially affect mood. Habitual diets rich in
dietary fiber and omega-3-polyunsaturated fatty acids may be linked to reduced risk of developing symptoms
of depression, anxiety, and stress; however, additional studies are necessary. Certain probiotics may
enhance mood, but their influence on the gastrointestinal microbiota requires further investigation.
Keywords: Microbiome, Probiotics, Prebiotics, Fiber, Microbiota, Mood, Diet quality

Introduction gastrointestinal tract via the gut-brain axis is presum-

There is increasing evidence that the gastrointestinal
microbiota influences human health, and metabolic,
gastrointestinal, and psychological diseases.1–3 Pre-
clinical and clinical evidence suggest that the gastroin-
testinal microbiota influence mood and behavior,
including depression, anxiety, and stress.4,5 Similarly,
diet, eating behaviors, and consumption of fiber
and prebiotic fibers affect the composition and
metabolic functions of the human gastrointestinal
microbiota.6–11 Clinical research has revealed diet
quality, as well as specific dietary components and
dietary supplements aid in prevention or treatment
of symptoms of depression, anxiety, and stress.
Specifically, high diet quality, prebiotic fiber consump-
tion, and probiotic supplements reduced anxiety
symptoms and had anti-depressant effects in
humans.12–15 The exact role the gastrointestinal micro-
biota play in the development of mental disorders is
still being elucidated, but its involvement in bidirec-
tional communication between the brain and
Correspondence to: Hannah D. Holscher, University of Illinois, 260 Edward
R. Madigan Laboratory 1201 W. Gregory Dr., Urbana, IL, USA. Email:
hholsche@illinois.edu
ably a fundamental link between the microbiota and
mood disorders. Delineating the relationship between
diet, the gastrointestinal microbiota, and mental
health is important for future applications of diet
therapy for the treatment of depression, anxiety, and
stress.
Herein, we review and discuss dietary and microbial
factors that may influence the symptoms of
depression, anxiety, and stress. The primary focus of
this article is on the outcomes from dietary interven-
tion trials conducted in human subjects.
Gut microbiota and mood
The brain-gut-microbiota axis is a bidirectional com-
munication network that allows gastrointestinal
microbes to convey information to the brain, and for
the brain to communicate with the gastrointestinal
tract. The mechanisms by which microbes affect
mood in humans are not fully known, but pre-clinical
studies have demonstrated that the gut microbiota
plays an important role in mental health.5,16–18 For
example, depression symptoms have been transferred
via fecal microbiota transplant from depressed

© 2018 Informa UK Limited, trading as Taylor & Francis Group

DOI 10.1080/1028415X.2018.1493808 Nutritional Neuroscience 2020 VOL. 23 NO. 3 237
Taylor and Holscher A review of dietary and microbial connections to depression, anxiety, and stress
humans to rodents.17,19 The gut microbiota of
depressed individuals have been compared to healthy
individuals and alterations at several taxonomic
levels were reported.17 Notably, differences in the
dominant phyla, Bacteroidetes, Firmicutes, and
Actinobacteria, were observed,17,20 but the relative
abundances of these phyla were not consistent
between the two studies. Jiang et al. reported increased
relative abundances of Bacteroidetes and
Actinobacteria, among others, and decreased relative
abundances of Firmicutes. Zheng et al. similarly
reported higher relative abundances of
Actinobacteria; however, Bacteroidetes were lower,
and no differences were observed in Firmicutes.17,20
Others have reported that Bacteroidetes is positively
associated with depression.21 These conflicting
results may, in part, be explained by a lack of control
for diet as the aforementioned studies did not collect
dietary data. As diet influences the gut microbiota,7,22
it may be contributing to the lack of consistency
among trials.
To understand the mechanisms and impact the gut
microbiota have on mood, additional clinical trials
are needed. Future studies should examine the role
habitual dietary intake and dietary components have
in altering gut microbiota of individuals with mood
disorders. As we will discuss, dietary intervention has
been reported to improve mood. However, human
dietary interventions trials investigating the gut micro-
biota as a mediator of mood improvement are lacking.
Diet quality and mood: observational studies
Observational studies provide evidence linking poor
diet quality to depression, while good diet quality
has been connected to a reduced risk of
depression.23–26 Recently, a nine-year prospective
cohort study reported a lower risk of depression for
subjects in the highest tertile of diet quality compared
to the lowest tertile.24 The Mediterranean diet has also
been associated with a reduced risk of depression
among participants with high and moderate adherence
to the Mediterranean diet pattern.27 Interestingly, the
Mediterranean diet, and other dietary patterns rich
in fruits and vegetables, have been shown to benefi-
cially impact the gut microbiota.27,28 Dietary patterns
aimed at reducing diet inflammatory potential have
been also connected to a reduced risk of
depression.29–34 Dietary recommendations to reduce
the risk of depression include increasing the intake of
fruits, vegetables, fish, whole-grains, legumes, and
olive oil, in conjunction with reducing the consump-
tion of highly refined grains, red meat, fried foods,
and sweets.35
The Mediterranean diet pattern has been connected
to a reduced risk of depression,36–38 presumably by
altering pro-inflammatory mechanisms.39,40 The risk
238 Nutritional Neuroscience 2020 VOL. 23 NO. 3
of developing depression has been linked to diets
with high inflammatory potential, i.e. energy-dense
foods, high-fat and high-sugar, refined grains, and
alcohol.32–34 The inflammatory potential of a diet
can be measured using a dietary index, e.g. Dietary
Inflammatory Index, which categorizes an individual’s
diet on a continuum ranging from maximally anti-
inflammatory to maximally inflammatory.29,32,34 The
Mediterranean diet pattern has a low inflammatory
potential.41
Systematic reviews and meta-analyses investigating
the relationship between diet quality and depression
have reported a relationship between measures of
diet quality and depression.25,36,38,42 However,
additional clinical intervention trials are needed to
determine if there is a causal role of dietary factors
on depression.
Dietary components
The habitual intake of specific food groups has been
associated with stress and depression. Specifically,
sweets and fast-food are consumed more frequently
in stressed and depressed individuals.43,44 Contrarily,
fruits and vegetables are consumed less frequently by
depressed individuals.43–46
Interestingly, the intake of dietary fiber derived from
fruits and vegetables, but not total, soluble, or insoluble
fiber intake, has been reported to be inversely related to
depression symptoms.47,48 Dietary fibers comprise the
cell walls of fruits and vegetables and are resistant to
digestion by human enzymes, e.g. pectins, gums, and
fructans, but may be metabolized by microbial
enzymes in the gastrointestinal tract.49,50 Thus, these
dietary fibers can be fermented by resident microbes,
resulting in the production of short-chain fatty acids
(SCFA).51 SCFA, especially butyrate, play a crucial
role in regulating intestinal epithelial barrier integrity
by providing energy to intestinal epithelial cells and
microbes, and by stimulating the secretion of gluca-
gon-like peptides 1 and 2.52 Glucagon-like peptides 1
and 2 decrease the permeability of intestinal epithelial
cells.52 Inadequate dietary fiber intake deprives
microbes of a nutrient source and decreases butyrate-
producing bacteria.27 To compensate, secreted mucus
glycoproteins may be used by microbes as an alternative
energy source,53 eroding the colonic mucus barrier, and
compromising intestinal barrier protection. A
reduction in butyrate-producing bacteria may also
compromise intestinal barrier protection.54,55
Accordingly, an increase in permeability allows the
translocation of lipopolysaccharides, a component of
the outer membrane of gram-negative bacteria and
pro-inflammatory stimulus, into systemic circulation.56
Lipopolysaccharides play a significant role in chronic
low-grade inflammation, a phenomenon known as
endotoxemia.56 Inflammation is characteristic of
 Taylor and Holscher
depression.57 Thus, SCFAs may indirectly influence
mood by modulating intestinal permeability and sys-
temic lipopolysaccharide circulation.
In addition to providing a source of dietary fiber,
fruits and vegetables are rich sources of antioxidants.
Antioxidants play an important role in protecting
cells from oxidative and nitrosative stress (ONS).
ONS can damage cellular lipids, proteins, and DNA
and cause cell death.58 ONS can also activate transcrip-
tion factors, e.g. NF-κB, that lead to the expression of
inflammatory cytokines.59,60 ONS and inflammation
have been observed in depressed individuals.61,62
Dietary fiber and antioxidants are often consumed in
low abundances in individuals following an unhealthy
eating pattern.63 Antioxidants, e.g. polyphenols, may
reach the large intestine in association with dietary
fiber, and become dissociated when fiber is metabolized
by colonic microbiota.64,65 Extraction, metabolization,
and absorption of polyphenols from dietary fiber in the
gastrointestinal tract are dependent on bacterial
enzymes. Additionally, polyphenolics can modulate
the gastrointestinal microbiota66,67 and act as antimi-
crobial or anti-inflammatory compounds.68–70 Thus,
the elevated ONS and inflammation observed in
depressed subjects may partially be explained by
inadequate dietary intake of antioxidants.
Diet quality and mood: clinical trials
Clinical trials investigating the efficacy of dietary inter-
ventions to treat depression, anxiety, and stress have
reported improvements in mood and behavior, and ben-
eficial changes in biological markers (See Table 1). A
common characteristic among diets improving mood
was high unsaturated fatty acid or fiber intake.
The Mediterranean dietary pattern has been
associated with a reduced risk of depression and has a
low inflammatory potential.30–34 Recently, the
Mediterranean diet with fish oil supplementation
(900 mg/d docosahexaenoic acid and 200 mg/day eico-
sapentaenoic acid) improved mental health and quality
of life scores in subjects with depression.71 This
6-month dietary intervention prescribed daily consump-
tion of fish oil capsules, bi-weekly workshops that
instructed participants on how to prepare and cook
meals adhering to the Mediterranean diet pattern, a
supply of food items specific to the recipes discussed
during the workshops, and additional food items includ-
ing extra-virgin olive oil, vegetables, fruit, canned
legumes, canned tomatoes, canned tuna, and mixed
nuts. Following three months of treatment, participants
no longer attended bi-weekly workshops, but continued
consuming fish oil supplements until the end of the trial.
The control group did not receive any training or fish oil
capsules but did attend ‘social workshops’ every two
weeks. The social workshops consisted of various activi-
ties including playing games and book discussions, but
A review of dietary and microbial connections to depression, anxiety, and stress
did not include any nutrition or dietary advice or food
items. Mental health outcomes were assessed by
Depression, Anxiety, and Stress Scale (DASS) scores,
Positive and Negative Affect Scale scores, and
Assessment of Quality of Life-8D scale scores. After
three months of participation in the study, the
Mediterranean diet and control group improved all out-
comes from baseline. However, the Mediterranean diet
group’s DASS – Depression subscale scores and
Assessment of Quality of Life-Mental health scores
showed a greater improvement over the course of the
study compared to the control group (1.68 and 1.52
times, respectively). No changes to outcomes from three
months to six months were reported, despite similar
Mediterranean diet scores between the two groups.
Adherence to a diet to reduce depression symptoms
and nutritional counseling reduced symptoms of
depression in subjects with major depression.12 Jacka
and colleagues utilized nutritional counseling to
provide support for diet quality and improve
Montgomery–Asberg Depression Rating scale scores.
They reported reductions in depression symptoms fol-
lowing personalized dietary support and counseling.12
The foundation of the treatment diet was modeled
after the traditional Mediterranean diet, but also fol-
lowed the recommendations of the Australian dietary
guidelines and the Greek dietary guideline and was
termed the ‘ModiMed’ diet. For a thorough descrip-
tion of the ModiMed diet see reference.72 Briefly, the
ModiMed diet recommended daily intakes of whole-
grains (5–8 servings), vegetables (6 servings), fruits
(3–5 servings), reduced-fat and unsweetened dairy
(2–3 servings), extra-virgin olive oil (60 mL), and
nuts (1 serving) and weekly consumptions of legumes
(3–4 servings), lean red meat (3–4 servings), fish rich
in oil (≥2 servings), poultry (2–3 servings), eggs (≤6
eggs), and limit additional foods to <3, e.g. fast-
food, sweets, 2 alcoholic beverages, etc. Notably, the
ModiMed diet provided >20% of total energy from
monounsaturated fatty acids and daily dietary fiber
intake was approximately 50 g/day. The recommen-
dation of 3–4 servings of lean red meat was substan-
tiated by reports linking weekly intake of lean red
meat outside the range of 3–4 servings to a greater like-
lihood of depressive and anxiety disorders and the
richness of nutrients hypothesized to play a protective
role in many mental illnesses, e.g. iron, zinc, and
vitamin B12.72
Brinkworth et al. conducted a 1-year dietary inter-
vention implementing a high carbohydrate/low-fat
diet or a low carbohydrate/high-fat diet and reported
reductions in Beck Depression Inventory scores and
improvements to Profile of Mood States scores from
both diets.73 The low carbohydrate/high-fat diet
limited carbohydrates to 14% of total kilocalories
and set the daily intake of fat at 58% of total energy;
Nutritional Neuroscience 2020 VOL. 23 NO. 3 239
Taylor and Holscher A review of dietary and microbial connections to depression, anxiety, and stress

Table 1 Clinical intervention trials investigating diet quality and mood

Mood
Behavior assessment Behavioral
Reference studied Population tool Design Intervention Duration outcome
12
Depression, Moderate to MADRS, Randomized Diet Support 12 Diet may
Anxiety, Mood, severe POMS, parallel group, (personalized weeks provide an
Well-being and depressed HADS, CGI-I, single blind, nutritional counseling efficacious
self-efficacy males and WHO-5 N=67; sessions and advice; treatment for
females CON=34, e.g. motivational common mental
TRT=33 interviewing, goal disorders.
setting, and mindful
eating.)
71
Depression Depressed DASS, AQoL, Randomized, Fish oil supplement 6 DASS
males and PANAS single blind (900 mg DHA/ day months depression
females N=152; and 200 mg EPA/ subscale
CON=77, day) and 3 months of improved
TRT=75 Mediterranean diet- greater than
style cooking control and
workshops AQoL and
PANAS
improved from
baseline
73
Psychosocial Obese, POMS, BDI, Randomized Low Carb and High 1 year Improved
health T2DM SAI N=115; Carb diet, exercise 3x quality of life
TRT1=58, week measures,
TRT2=57 mood state in
both diet
groups
77
Depression, Healthy POMS, CES- Randomized, Low-glycemic load 4 weeks HGL resulted in
Anxiety, Mood, weight, D crossover, (<125 glycemic 38% higher
Well-being and overweight, controlled load/d) and high- score for
Self-efficacy and obese feeding N=82 glycemic load diet depressive
male and (>250 glycemic symptoms on
females load/d) the CES-D;
Overweight/
obese had 40%
higher scores
on CES-D scale
74
Anxiety, Healthy, POMS Randomized, Oleic acid:Palmitic 3 weeks Reduced anger
Depression, normal, double-blind, acid; (40.29 g/100 hostility scores
and Mood overweight, crossover g:30.95 g/ 100 g,
State and obese N=32 respectively)
BMI Or (4.59 g/100
g:74.80 g/100 g,
respectively
75
Depression Healthy, CES-D, BAI Randomized, Omega-3- 12 Reduced
and Anxiety medical double-blind, polyunsaturated fatty weeks anxiety scores,
students parallel group acids (2.5 g/ depression
N=68; day;2085mg scores were
CON=34 eicosapentaenoic unaffected
TRT=34 acid and 348 mg/day
docosahexaenoic
acid)

AQoL, Assessment of Quality of Life; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; CES-D, Center for
Epidemiological Studies; CGI-I, Clinical Global Impression – Improvement; COPE, Copenhagen Burnout Inventory; DASS,
Depression, Anxiety, and Stress Scale; DHA, Docosahexaenoic Acid; EPA, Eicosapentaenoic Acid; HADS, Hospital Anxiety and
Depression Scale; MADRS, Montgomery–Asberg Depression Rating Scale; OSI, Occupational Stress inventory; PANAS, Positive and
Negative Affect Scale; POMS, Profile of Mood States; PSS, Perceived Stress Scale; SAI, Spielberger State Anxiety Inventory; WHO-5,
World Health Organization Well-being Scale; RCT, Randomized, Controlled Trial; CON, Control group; TRT, Treatment Group; T2DM,
Type 2 Diabetes Mellitus; LC, Low Carbohydrate Diet; HC, High Carbohydrate Diet

unsaturated fatty acids comprised 51% (38% monoun-
saturated fatty acids; 13% polyunsaturated fat
(PUFA)) of this group’s diet. Diets rich in unsaturated
fatty acids, especially long-chain PUFAs may have
anti-depressant effects on depressed individuals.39,40
Similarly, the high carbohydrate/low-fat diet group’s
fat consumption was primarily comprised of unsatu-
rated fatty acids.
Similar results were reported in a clinical trial that
investigated the effect of saturated fatty acid:unsatu-
rated fatty acid ratio on mood and behavior.74 The
saturated fatty acid, palmitic acid, and monounsatu-
rated fatty acid, oleic acid, were given to participants
at a ratio of either high palmitic acid:low oleic acid
or high oleic acid:low palmitic acid. All food was pro-
vided to the subjects during the intervention.74

240 Nutritional Neuroscience 2020 VOL. 23 NO. 3

 Taylor and Holscher
Utilizing the Profile of Mood States questionnaire,
Kien et al. reported a reduction in subscale scores
related to anger-hostility among subjects receiving
high oleic acid compared to high palmitic acid treat-
ment. In men, high oleic acid treatment corresponded
with a decrease in total mood disturbance.
The supplementation of omega-3-PUFAs may also
confer mental health benefits, although mixed results
have been reported.75,76 Kiecolt-Glaser and colleagues
compared omega-3 PUFAs to a placebo mimicking
the saturated:monounsaturated:polyunsaturated fatty
acid ratio consumed by US adults. Compared to con-
trols, subjects in the treatment group exhibited a 14%
reduction in lipopolysaccharide-stimulated pro-
inflammatory cytokine interleukin-6 (IL-6) and a
20% reduction in anxiety symptoms. Additionally,
they reported n-6 PUFA:n-3 PUFA ratio as a slightly
stronger predictor of anxiety scores and lipopolysac-
charide-stimulated IL-6 production with increasing
n-6 PUFA:n-3 PUFA ratio associated with increased
anxiety scores and lipopolysaccharide-stimulated IL-
6 production.75
In 2016, Breymeyer et al. reported differences in
mood between a high-glycemic load diet and low-glyce-
mic load diet.77 The dietary fiber content of the low-gly-
cemic load diet and high-glycemic load diet were 55 and
28 g/day, respectively.77,78 The investigators reported
lower mean vigor/activity scores, a subscale of the
Profile of Mood States questionnaire, during the high-
glycemic load diet compared to the low-glycemic load
diet. Moreover, participants consuming a high-glyce-
mic load diet reported higher Profile of Mood States
subscale scores, fatigue/inertia and total mood disturb-
ance, indicative of lower subjective energy and less
mood stability. Clinical Epidemiological Studies
Depression Scale scores were 38% higher when a
high-glycemic load diet was consumed compared to
when a low-glycemic load diet was consumed.77 The
results suggest glycemic load impacts subjective
mood. Specifically, high-glycemic load diets may
decrease subjective energy perception, while reducing
mood stability.
The improvement in Beck Depression Inventory
scores and total mood disturbance scores may be
related to the high unsaturated fatty acid content of the
treatments.73,74 Unsaturated fatty acids may improve
depression symptoms by reducing systemic inflam-
mation.79 Unsaturated fatty acids are involved in mul-
tiple signaling pathways, and their inhibition of pro-
inflammatory cytokines may be related to the thera-
peutic effects exerted by unsaturated fatty acid consump-
tion.76,80 Individuals with depression have been shown to
have high concentrations of circulating pro-inflamma-
tory cytokines.81 Additionally, saturated fatty acids can
elicit an inflammatory response by acting on pro-inflam-
matory receptors, e.g. toll-like receptor 4.82
A review of dietary and microbial connections to depression, anxiety, and stress
Dietary fat intake can also influence the gastrointes-
tinal microbiota and inflammation, see reference83 for
a more thorough review. Briefly, dietary fat intake
stimulates the secretion of bile acids. Bile acids that
reach the large intestine have an antimicrobial effect
on resident microbes. Gram-negative bacteria, a
primary source of lipopolysaccharides, tend to be
more tolerant of bile acids compared to gram-positive
bacteria. Thus, high dietary fat intake may reduce
total bacterial numbers in the large intestine,84 while
the proportion of gram-negative bacteria are
enhanced, increasing a major source of lipopolysac-
charides. However, it is important to note that the
direct effect dietary fats have on the gut microbiota
is still not well known, largely due to the incorporation
of fat at the expense of carbohydrates, a major source
of energy for microbes, in study diets.
The evidence provided from clinical trials suggests
diet quality impacts mood. It should also bring atten-
tion to dietary fiber and n-3-PUFAs consumption.
The relationship between fiber and mood is less
explored than n-3-PUFAs. However, both may
improve mood by reducing systemic inflammation.
Intervention trials are needed to determine if fiber con-
sumption contributes to changes in mood and if the
food source of fiber or the isolated fiber by itself
affects mood.
Prebiotic fibers and gastrointestinal microbiota
A prebiotic is a substrate that is selectively utilized by
host microorganisms conferring a health benefit to
the host.85 Most prebiotics are fibers, however, it is
not a prerequisite for being considered a prebiotic. As
research continues, it is likely that additional dietary
components, such as polyphenols, may be recognized
as prebiotics.85 Prebiotics are present within foods,
e.g. onions, chicory root, and wheat, or taken in a pur-
ified form as a dietary supplement. Prebiotics may
attenuate disease by promoting the growth of beneficial
microbes and/or reducing pathogenic microbes.9,86,87
Prebiotics have demonstrated psychobiotic effects in
human clinical trials. Psychobiotic describes a bacteria
or source of support for bacteria that beneficially affects
the relationship between the microbiota and brain.88
Commonly studied prebiotics for mood and behavior
improvement include fructooligosaccharides and
galactooligosaccharides.89 Both prebiotics have
demonstrated the ability to enhance Bifidobacterium
in humans.9,90–92 Although, the bifidogenic effect may
be dose-dependent, requiring ≥5.0 g/day to enhance
bifidobacteria.93–95 Bifidobacteria may promote
health benefits by producing B vitamins, antioxidants,
and polyphenols;96,97 and aiding immune system func-
tion by inducing the production of immunoglobu-
lins.49,97 Additionally, bifidobacteria contribute to the
production of lactate and acetate, which can be utilized
Nutritional Neuroscience 2020 VOL. 23 NO. 3 241
Taylor and Holscher A review of dietary and microbial connections to depression, anxiety, and stress

by other bacteria in the gastrointestinal microbial com-

Increased Bifidobacterium in both

Increased Bifidobacterium; 7.0 g/

munity to produce butyrate, a phenomenon known as

CON, Control Group; ECM, Emotional Categorization and Memory; ETB, Emotional Procession Task; FERT, Facial Expression Recognition Task; FOS, Fructooligosaccharide; FT, Fructooligosaccharide
cross-feeding.98 This production of SCFA also provides

Microbiota Outcome

Bacteroides:Prevotella ratio
day of prebiotic decreased
a benefit to the host by suppressing pathogenic
microbes by the inherent decrease in pH with increasing

placebo and control

SCFA concentrations.98,99

Treatment; GOS, Galactooligosaccharide; GT, Galactooligosaccharide Treatment; HADS, Hospital Anxiety and Depression Scale; IBS, Irritable Bowel Syndrome; scFOS, Short-chain
Prebiotics and mood: clinical trials
Three randomized controlled trials (Table 2) reported

n/a
improvements in mood or behavior following the con-
sumption of prebiotic fibers, fructooligosaccharides,

Improved anxiety and depression

Increased attentional vigilance to

galactooligosaccharides, or trans-galactooligosacchar-

Behavioral Outcome
ides.15,100,101 Fructooligosaccharides and trans-galac-

information following BGOS

negative versus positive
tooligosaccharides supplemented at 5.0 and 7.0 g/
day, respectively, induced changes to the gastrointesti-

Improved anxiety
supplementation.
nal microbiota, along with improvements in
mood.15,101
Silk et al. examined the ability of trans-galactooligo-
saccharide to relieve symptoms of irritable bowel syn-
drome and improve mood.15 Patients receiving
7.0 g/day of trans-galactooligosaccharide reported

Duration

4 weeks

3 weeks

weeks
significantly lower scores on the Hospital Anxiety

12
and Depression Scale-Anxiety subscale compared
to baseline. Trans-galactooligosaccharide enhanced
Intervention

(5.0 g/day)

(5.5 g/day)

7.0 g/day)
Bifidobacterium spp. and reduced Clostridium perfrin-
(Dose)

FOS or
gens subgroup histolyticum, Bacteroides/Prevotella
scFOS

(3.5 or
BGOS

TGOS
ratio, and Eubacterium rectale/Clostridium coccoides.
Similar results have been reported following fruc-
tooligosaccharide consumption. A study investigating
placebo-controlled, parallel-

placebo-controlled, parallel
Randomized, double-blind,

Randomized, double-blind,

the efficacy of 5 g/day fructooligosaccharide to treat

placebo-controlled N=79;

Randomized Control Trial,

irritable bowel syndrome symptoms reported a

arm N=45; CON=15,
TRT1=15, TRT2=15
Design

decrease in Hospital Anxiety and Depression Scale-

CON=38. TRT=41

Fructooligosaccharide; TGOS, Trans-galactooligosaccharide; TRT, Treatment Group;

Anxiety subscale scores.101 Moreover, fructooligosac-
charide consumption increased fecal bifidobacteria.
crossover

In 2015, Schmidt et al. assessed the effects of

Table 2 Clinical intervention trials investigating prebiotics and mood

N=44

Bimuno® galactooligosaccharide and fructooligosac-

charides on salivary cortisol levels and emotional pro-
cessing.100 They reported anxiolytic-like effects and
Assessment

decreased waking salivary cortisol concentrations and

FERT, ECM
Mood

Tool

attentional vigilance to negative versus positive stimuli

HADS

HADS

in subjects receiving Bimuno® galactooligosaccharide

treatment. No differences in salivary cortisol were
reported for the fructooligosaccharide treatment.100
Population

patients

patients
Healthy

The anxiolytic and anti-depressant effects demon-

adults

strated in these trials are not well-understood and

IBS

IBS

additional studies are needed to confirm the anxiolytic

Anxiety, and Stress
Behavior Studied

and anti-depressant effects of specific prebiotics. One

Depression and

explanation for the changes in mood may be related to

Depression,
Personality,

the bifidogenic effect from fructooligosaccharide and

galactooligosaccharide supplementation. Prebiotics fer-
Anxiety

Anxiety

mented by microbes in the gastrointestinal tract produce

metabolites, like SCFA, that may enhance and help regu-
Reference

late immune system function.102,103 Dysregulation of the

immune system may disrupt homeostasis, altering critical
101

100

feedback mechanism, e.g. cortisol production.

15

242 Nutritional Neuroscience 2020 VOL. 23 NO. 3

 Taylor and Holscher
Cortisol, a glucocorticoid hormone, has widespread
effects and is involved in several mechanisms of
homeostasis and adaption to stressors, such as
glucose metabolism, immune system regulation, and
inflammation. A key regulator of cortisol production
is the hypothalamic–pituitary–adrenal (HPA) axis.104
The HPA axis primarily regulates cortisol output
through negative feedback mechanisms, but stressors,
e.g. inflammation and psychological stress, can
bypass these control mechanisms and increase HPA
axis activity resulting in increased cortisol production.
Chronic exposure to stressors cause over-suppression
of the immune system, increased circulating pro-
inflammatory cytokines, and increased risk of develop-
ing anxiety and depression.104,105 Gastrointestinal
microbiota may mediate HPA activity by modulating
immune responses to stressors.106
Probiotics and mood
Probiotics, defined as live microorganisms that when
consumed in adequate amounts confer health
benefits to the host,107 have demonstrated benefits
to mental health (Table 2). Probiotics are inherent
in many fermented foods, e.g. yogurt, sauerkraut,
and kefir, and are commercially available as dietary
supplements. Probiotic consumption can promote
gastrointestinal microbiome functions, including
inhibition of pathogenic species, epithelial barrier
integrity, and modulation of immune response.108,109
Probiotics, specifically, Lactobacillus spp. and
Bifidobacterium spp., are typically representative of
only a small proportion of the human gastrointestinal
microbial community but have been associated with
improvements in mental health. A probiotic strain
may affect mood by direct or indirect interaction
with the central nervous system, modulation of
immune response, and inhibition of opportunistic
pathogens.110
Gastrointestinal microbes can interact with the
central nervous system directly or indirectly through
the synthesis of neurotransmitters, e.g. serotonin, and
metabolites that interact with hormone receptors in
the large intestine; SCFA activate GPR43 on L-cells
stimulating the release of glucagon-like peptide-1.
Serotonin and its precursor, tryptophan, can be pro-
duced by microbes in the gastrointestinal tract and
may influence the concentration of serotonin in the
brain.111,112 Low levels of serotonin in the brain have
been associated with depressed mood. The influence
microbially derived neurotransmitters have on psycho-
physiology is still being researched, but modulation of
neurotransmission of the enteric nervous system may
contribute to the release of gut hormones linked to
mood and behavior.88
A review of dietary and microbial connections to depression, anxiety, and stress
Probiotics and mood: clinical trials
Studies investigating the effect of single-strain probio-
tics on mood have reported improvements in humans,
Table 3. For example, Bifidobacterium longum species
may promote improvements in mental health. B.
longum strains have been shown to reduce stress113
and depression scores.114 Additionally, Messaoudi
and colleagues reported decreased Hospital Anxiety
and Depression Scale scores in participants consuming
a probiotic comprised of B. longum R0175 and
Lactobacillus helveticus R0052.115
Clinical trials investigating L. casei Shirota have
reported reductions in anxiety scores116 and biomarkers
of stress in subjects consuming the probiotic.117,118 L.
casei Shirota consumption reduced anxiety scores in
individuals suffering from chronic fatigue syndrome.
In a cohort of medical students preparing for an
exam, where self-reported stress increased as the exam
approached, consumption of L. casei Shirota sup-
pressed stress-response genes. Additionally, salivary
cortisol was elevated in the placebo-treatment, but not
in subjects consuming probiotic treatment, as the
exam approached. However, these findings were not
replicated in healthy individuals. Benton et al. reported
null findings following the consumption of a milk-drink
containing L. casei Shirota in healthy adults. Thus, L.
casei Shirota may suppress stress and anxiety rather
than reducing it.116–119
It is also important to note that the probiotic effects
of bacteria are strain dependent. For example, two
different strains of Lactobaccilus, L. rhamnosus JB-1
and L. rhamnosus HN001, were used in separate
studies. Kelly and colleagues administered L. rhamno-
sus JB-1 to healthy adult men and women and
reported no differences in physiological or psychologi-
cal measures of stress.120 Conversely, women consum-
ing L. rhamnosus HN001 from ∼15 weeks gestation to
6 months post-partum reported lower depression and
anxiety scores compared to placebo.121
Multi-strain probiotics have also demonstrated the
ability to improve mood (see Table 3) in
healthy115,122–124 and diseased125 populations.
Although many of the multi-strain probiotics
improved mood, outcome measurements were not
consistent when probiotics containing the same
species of bacteria were consumed. For example,
Steenberg et al. investigated a probiotic containing
B. bifidum, L. acidophilus, and L. casei among
others, and reported no changes to Beck Depression
Inventory scores.123 Contrarily, Akkakesh et al.
reported a reduction in Beck Depression Inventory
scores following the consumption of a probiotic con-
taining the same three bacterial species.125 These con-
flicting results may partially be explained by the
differences in study populations, as Akkakesh and
Nutritional Neuroscience 2020 VOL. 23 NO. 3 243
Taylor and Holscher A review of dietary and microbial connections to depression, anxiety, and stress
colleagues studied the probiotics affect on subjects suf-
fering from major depressive disorder. Moreover, the
dose of probiotic administered in the study conducted
by Steenberg et al was lower than the dose prescribed
by Akkakesh et al. To fully understand the effects pro-
biotics have on mood, additional intervention studies
need to be conducted in healthy and diseased popu-
lations and the prescribed dosages of the probiotic
and strain should be similar to past studies.
Limitations of clinical trials
Diet quality
A limitation of dietary trials is that adherence to a pre-
scribed dietary pattern is frequently measured by self-
reported diet records or self-reported questionnaires.
Self-reported diet records may not accurately reflect
the amount of food consumed by a participant result-
ing in under- or overestimated values. It is also not
always possible, or is very difficult, to blind partici-
pants and/or researchers to nutritional treatments,
which may bias results. In addition, the impact
dietary changes have on the gastrointestinal micro-
biota was not measured by any of the clinical trials
investigating diet quality and mood in this review.
Thus, we can only speculate on the role gastrointesti-
nal microbiota played in the mood and behavioral
changes.
Prebiotics
Fructooligosaccharides and galactooligosaccharides
demonstrated anxiolytic effects when 5.0 g/day or
more was consumed. However, only one study was
conducted in healthy adults.100 The other two studies
reported findings from patients with irritable bowel
syndrome.15,101 Many of the trials reviewed also
lacked participant dietary information. Additional
studies in healthy populations are needed to translate
these results to the general population.
Probiotics
A majority of the studies investigating the effects of
probiotics on mood and behavior reported improve-
ments. However, few studies analyzed the gastrointes-
tinal microbiota. Also, to better understand an
individual strain’s therapeutic effect, additional
studies with single-strain probiotics need to be con-
ducted as the utility of a probiotic may depend on
the strain. Investigating the gastrointestinal microbiota
will also provide insight into the adaptions occurring
in the gastrointestinal ecosystem following probiotic
consumption. Microbiota analyses may help differen-
tiate responders versus non-responders to probiotic
treatment in future studies.
Summary of findings
Consumption of high-quality diets reduced
depression, anxiety, and stress symptoms in clinical
244 Nutritional Neuroscience 2020 VOL. 23 NO. 3
trials, especially when intervention diets were rich in
n-3-PUFAs and fiber.73,78 Furthermore, fiber from
fruits and vegetables was associated with reduced like-
lihood of depression symptoms, irrespective of total
fiber intake.47 This may partially be explained by the
high concentrations of antioxidants within fruits.
Fiber and antioxidants may synergistically benefit
gut health by enriching bifidobacteria and reducing
inflammation.
Galactooligosaccharide and fructooligosaccharide
consumption had anxiolytic and anti-depressive
effects on subjects with irritable bowel syndrome.15,101
When they were administered to healthy women,
galactooligosaccharides induced anxiolytic effects in
the participants. Notably, a reduction in waking corti-
sol was reported in a healthy cohort of women, but no
significant reduction in anxiety scores was observed in
self-reported questionnaires.100 Although specific pre-
biotics have displayed psychobiotic properties, due to
the very limited evidence available, additional clinical
intervention studies are needed before they can be
accepted as anxiolytic or anti-depressive.
The clinical trials investigating probiotics revealed
certain probiotics were efficacious as therapeutic
agents for the treatment of depression, anxiety, and
stress. Both physiological biomarkers and psychologi-
cal symptoms were relieved or suppressed following
the consumption of probiotics. Specifically, B.
longum and L. casei Shirota may have therapeutic
effects for individuals suffering from mood disorders.
Conclusions
Reports from dietary interventions provide evidence
that there is a link between diet quality and mood.
Yet, the directionality of these relationships still
needs to be discerned. To accomplish this, longitudinal
studies and clinical trials need to be conducted and
biological markers of disease need to be recorded.
The efficacy of prebiotics to treat mood disorders is
less certain due to a paucity of studies investigating
prebiotics effect on mood. Regarding the gastrointesti-
nal microbiota, altered microbiota composition has
been reported in depressed individuals20 and specific
microbes have been associated with depression,21 but
an insufficient amount of clinical data is currently
available to causatively link the gastrointestinal micro-
biota to depression, anxiety, and stress in humans.
Additional well-designed dietary intervention trials
targeting the interconnection of diet quality, dietary
components, and the gastrointestinal microbiota are
required. Identifying the microbial species residing in
the gastrointestinal tract will help progress our under-
standing of their involvement in mood disorders.
Nevertheless, microbiota compositional data has a
limited capacity to characterize microbiome function-
ality. Thus, additional multi-omics technologies are
 Table 3 Clinical intervention trials investigating probiotics and mood

Mood
Behavior Assessment Intervention
Reference Studied Population Tool Design (Dose) Duration Behavioral Outcome Microbiota Outcome
114
Depression IBS patients, Mild HADS, STAI Randomized, double- Bifidobacterium longum 6 weeks Reduced depression but Null
and Anxiety to moderate blind, placebo-controlled NCC3001 not anxiety
anxiety and/or N=44; (1×1010 cfu/day)
depression CON=22 TRT=22
113
Depression, Healthy males CSS Crossover, placebo- Bifidobacterium longum 1714 4 weeks Reduced stress and n/a
Anxiety, Stress controlled (1×109 cfu/day) improved memory
N=22
115
Depression, Healthy adults HADS, PSS Randomized, double- Lactobacillus helveticus R0052, 30 days Decrease in cortisol n/a
Anxiety, Stress, blind, placebo-controlled, Bifidobacterium longum R0175 values, Decrease in
Coping parallel group (3×109 cfu/day) HADS-D scores
Strategies N=55;
CON=29, TRT=26

Taylor and Holscher

118
Anxiety and Healthy adult STAI Randomized, double- Lactobacillus casei Shirota 8 weeks Treatment did not reduce n/a
Stress medical students blind, placebo-controlled, (100×1011 cfu/day) anxiety scores. Salivary
parallel group cortisol levels were
N=149 significantly lower in the
treatment group
compared to placebo.
117
Stress Healthy adult STAI Randomized, double- Lactobacillus casei Shirota 8 weeks Maintained salivary Alpha-diversity was
(100×1011 cfu/day)

A review of dietary and microbial connections to depression, anxiety, and stress

medical students blind, placebo-controlled, cortisol levels from maintained;
parallel group baseline in the treatment Bacteroidaceae family
N=47 group; a twofold increase was significantly lower
in expression of stress- before the exam
response genes in compared to placebo
placebo compared to
Nutritional Neuroscience

treatment
116
Depression Chronic fatigue BDI, BAI Randomized, double- Lactobacillus casei Shirota 8 weeks Reduced anxiety scores Lactobacillus and
and Anxiety syndrome patients blind, placebo-controlled, (24×109 cfu/day) compared to control Bifidobacterium
pilot study increased from baseline
N=35
119
Mood Healthy adults POMS Randomized, double- Lactobacillus casei Shirota 3 weeks No effects n/a
blind, placebo-controlled, (65×109 cfu/day)
parallel group
N=124
126
Anxiety and IBS, HADS, STAI Double-blind, placebo- Lactobacillus gasseri CP2305 12 weeks Improved sleep quality, n/a
2020

Stress undergraduate controlled, parallel group (1×1010 cfu/day) normalized bowel habits
medical students N=69; under stressful situations
CON=35, TRT=34
VOL.

Continued
23
NO.
3
245
246

Taylor and Holscher

Table 3 Continued
Nutritional Neuroscience

Mood
Behavior Assessment Intervention
Reference Studied Population Tool Design (Dose) Duration Behavioral Outcome Microbiota Outcome

A review of dietary and microbial connections to depression, anxiety, and stress

121
Depression Pregnant women EPDS, STAI 1
Randomized, double- Lactobacillus rhamnosus HN001 ∼15 weeks Lower post-partum n/a
and Anxiety through post- blind, placebo-controlled (1×109 cfu/day) gestation+6 depression and anxiety
partum N=380 months post- scores compared to
CON=187 partum control
TRT=193
2020

120
Depression, Healthy males MINI, SECPT Randomized, placebo- Lactobacillus rhamnosus JB-1 8 weeks No effects Null
Anxiety, and controlled, crossover (1×109 cfu/day)
Stress N=29
125
Major MDD BDI Randomized, double- Lactobacillus acidophilus, 8 weeks Reduced BDI scores n/a
VOL.

Depressive blind, placebo-controlled Lactobacillus casei,

23

Disorder N=40; Bifidobacterium bifidum

CON=40, TRT=40 (2×109 cfu/day of each bacteria)
124
Depression Healthy adults DASS Randomized, Double- Probiotic yogurt: Lactobacillus 6 weeks Improved DASS scores n/a
NO.

blind, placebo-controlled acidophilus LA5, Bifidobacterium with either probiotic

3

N=70; lactis BB12 treatment

CON=20, TRT1=25, (1x107 cfu/day of each
TRT2=25 bacteria); Conventional Yogurt:
Streptococcus thermophilus and
Lactobacillus bulgaricus;
Probiotic capsule: Lactobacillus
casei
(3×103 cfu/day),
L. acidophilus
(3×107 cfu/day),
L. rhamnosus
(7×109 cfu/day),
L. bulgaricus
(5×108 cfu/day),
Bifidobacterium breve
(2×1010 cfu/day,
B. longum
(1×109 cfu/day),
S. thermophilus (3×108 cfu/day)
123
Reactivity to Healthy adults LEIDS-r, BDI-II Randomized, triple-blind, Bifidobacterium bifidum W23, 4 weeks Reduced overall cognitive n/a
Sad Mood parallel group Bifidobacterium lactis W52, reactivity to sad mood
N=40; Lactobacillus acidophilus W37,
CON=20, TRT=20 Lactobacillus brevis W63,
Lactobacillus casei W56,
Lactobacillus salivarius W24,
and Lactococcus lactis (W19
and W58)
(5×109 cfu/day)
Continued
 Taylor and Holscher A review of dietary and microbial connections to depression, anxiety, and stress

needed to develop an understanding of mechanisms

BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; BDI-II, Beck Depression Inventory II; cfu, colony-forming unit; CON, Control Group; CSS, Cohen Perceived Stress Scale; DASS, Depression
Microbiota Outcome
and pathways the microbiota may alter.

Anxiety and Stress Scale; EDPS, Edinburgh Postnatal Depression Scale; HADS, Hospital Anxiety and Depression Scale; IBS, Irritable Bowel Syndrome; LEIDS-r, Leiden Index of Depression Sensitivity;
MINI, Mini International Neuropsychiatric Interview; POMS, Profile of Mood State; PSS, Perceived Stress Scale; SECPT, Socially Evaluated Stress Pressor Test; STAI, State-trait Anxiety Inventory; TRT,
Disclaimer statements
Contributors Both authors wrote and approved the
final manuscript.
Null

Funding This work was supported by the USDA

National Institute of Food and Agriculture, Hatch
related to emotional and
Behavioral Outcome

Activity in brain regions

sensational processes

project under Grant number 1009249.

Conflicts of interest The authors report no conflict of
were affected

interest.
Ethics approval Not applicable.

ORCID
Hannah D. Holscher http://orcid.org/0000-0003-
Duration

4918-2426
4 weeks

These details describe the clinical intervention trial. The mental health outcomes were assessed, retrospectively, 6–12 months post-partum.

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