Current Opinion in Psychiatry

The Gut Microbiome and Diet in

Psychiatry: Focus on Depression
Sarah Dash, Gerard Clarke, Michael Berk, Felice N. Jacka
Disclosures
Curr Opin Psychiatry. 2015;28(1):1-6.

Abstract and Introduction

Abstract
Purpose of review With depressive disorders the leading source of disability
globally, the identification of new targets for prevention and management is
imperative. A rapidly emerging field of research suggests that the
microbiomegutbrain axis is of substantial relevance to mood and behaviour.
Similarly, unhealthy diet has recently emerged as a significant correlate of and
risk factor for depression. This review provides evidence for the gut
microbiota as a key factor mediating the link between diet and depressive
illness.
Recent findings The development of new technologies is affording a better
understanding of how diet influences gut microbiota composition and activity
and how this may, in turn, influence depressive illness. New interventions are
also suggesting the possible utility of pre and probiotic formulations and
fermented food in influencing mental health.
Summary Although in its early stages, the emerging field of research focused
on the human microbiome suggests an important role for the gut microbiota in
influencing brain development, behaviour and mood in humans. The
recognition that the gut microbiota interacts bidirectionally with other
environmental risk factors, such as diet and stress, suggests promise in the
development of interventions targeting the gut microbiota for the prevention
and treatment of common mental health disorders.

Introduction
The naturally occurring 'commensal' bacteria that exist symbiotically with our
bodies are estimated to number 100 trillion in the human gut alone.[1] The gut
microbiome the community of bacteria and their genetic material living in
the gut is often referred to as a virtual organ.[2,3] Much of the early microbiota
research was subject to the limitations of culturing technology, restricting our
understanding of bacterial composition and functioning. More recently, the
development and use of new metagenomic and molecular technologies has
afforded detailed insights into the important role of microbiota in human
health and disease.[46] These new insights have, in turn, pointed to the
pathophysiological role of the gut microbiota in diverse disorders from atopy
to depression. The recognition that the gut microbiota interacts with other
environmental risk factors, such as stress and diet, suggests promise in the
development of interventions targeting the gut microbiota for the prevention
and treatment of disease. In this review, we address the evidence linking the
gut microbiome to the recently established associations between dietary intake
in humans and the prevalence of or risk for depressive illness [25,7,8] and highlight
new possibilities and implications for the prevention and treatment of
depressive disorders arising from this evidence.

Determinants and Role of Gut Microbiota

The influence of the gut microbiome extends across multiple physiological
domains. For example, bacterial colonization of the intestine is considered
essential for the development of the immune system[9] as well as the regulation
of gastrointestinal motility and maintenance of gut barrier function. [4] The
diverse functional repertoire of the gut microbiota has seen it classified in
terms of both a metabolic organ[10] and an endocrine organ[11] in addition to its
key role in immune system development. [12] The understanding of the gut
microbiota as a primary driver of host development and physiology [13] now
extends to key features of brain and behaviour.[14] The microbial composition
of an individual begins to establish itself at birth [15] and can vary depending on
infant delivery method and feeding.[16,17] The gut microbiome stabilizes in the
first few years of life[18] but continues to be influenced by age, genetics,[19]
geography,[20] medication use[21,22] and, most relevant to this review, diet.[23]

Diet and Mental Health

There have been a rapidly increasing number of observational studies
documenting cross-sectional and prospective associations between habitual
diet quality and the prevalence of risk for depression. These associations have

been consistently observed in adults, adolescents and children across a

multitude of different countries and cultures.[24] A recent systematic review and
meta-analysis, including results from 13 observational studies, concluded that
a healthy diet is significantly associated with a reduced odds for depression
[odds ratio (OR) 0.84; 95% confidence interval (95% CI) 0.760.92; P <
0.001].[25] Similarly, a meta-analysis of 22 studies investigating the protective
effects of adherence to a Mediterranean-style diet on brain diseases
demonstrated that higher adherence was associated with a reduced risk for
depression (relative risk 0.68, 95% CI 0.540.86), as well as cognitive decline.
[7]
Moreover, increased consumption of unhealthy, sugar and fat-rich foods is
related to an increased risk of psychological symptomatology in children and
adolescents.[8] Of particular note are results from two new, large, cohort studies
suggesting an independent role for early life nutritional exposures in
influencing the mental health of offspring.[26,27] These observational studies are
supported by two recent trials that indicate the efficacy of dietary
improvement as a strategy for the prevention of depression. [28,29] Although this
field is still evolving, treatment trials are currently underway.[30] The focus is
now turning to the explication of biological pathways that may mediate this
now-established association, foremost being the gut microbiota.

Microbiota and Mental Health

Bested et al. [31] provide an intriguing overview of the long history of
investigation into the 'gutbrain' axis, including the first suggestions in the
1800s that systemic disease, including mental health disorders, could be
rooted in intestinal 'self-infective' processes and that increasing rates of
melancholia may be a by-product of urban and western civilization, possibly
mediated by dietary habits and toxins arising from the gastrointestinal tract.
The evidence that the gut microbiota influences brain and behaviour is now
rapidly expanding and is a view that has started to gain traction in the
literature.[14,32,33] This is largely due to compelling preclinical evidence that the
gut microbiota can influence behaviours of relevance to anxiety [34,35,36,37] and that
manipulation of the gut microbiota with specific probiotics [38,39] or with
antibiotics[40,41] can influence depression-like behaviours. The microbiota likely
recruits the gutbrain axis to exert effects at the level of the central nervous
system (CNS).[42] This is a reciprocal relationship, with the CNS moderating,
for example, gut motility and secretion. [43] Both humoral and neural
mechanisms are plausible, with the role of the vagus nerve in particular
receiving much attention.[38]

Independent studies have now confirmed that an anxious phenotype can be

transferred via the gut microbiota.[44,45] Moreover, it appears that both prenatal
and early-life stress, both risk factors for psychopathology, engender
potentially deleterious gut microbiota alterations that can manifest during
critical neurodevelopmental periods and that may persist into adulthood. For
example, Bailey et al.[46] monitored gut bacteria colonization in infant monkeys
whose mothers were either undisturbed or stressed during pregnancy, finding
marked changes in microflora concentrations in the offspring of stressed
mothers. Certainly, the animal data suggest that early colonization of gut
microbiota influences the programming of the stress response system in
offspring.[47] Moreover, preclinical studies have shown that both early life
stress and surgically induced depression produce alterations in the gut
microbiota.[48,49] Adverse early life exposures are related to the stress response
and the risk for mental disorders in offspring; [50] thus, the understanding that
prenatal and early life stress modulates the microbial composition of the gut in
infants suggests implications for the vulnerability to mental disorders in
children. It is worth noting that the adult gut microbiome appears to be
resilient and begins recovery immediately after disruption,[51] although the
impact of very early life or repeated antibiotic use on the microbiome can be
pervasive and long-lasting.[52]
Given the ability of the gut microbiota to influence serotonin and its precursor,
tryptophan,[53] regulate the stress response[54,55] and modulate cognition[56,57] and
behaviour,[58,59] the potential importance of the gut microbiota to psychiatry in
general and to depression specifically is apparent. Microbiome alterations are
evident in irritable bowel syndrome (IBS), a functional gastrointestinal
disorder with significant psychiatric comorbidity.[60] However, only one
preliminary study has specifically examined microbiome alterations in
depression and, although some correlations were established, the overall
species richness and diversity was not different to healthy controls. [61] More
detailed studies are now warranted to interrogate this intriguing proposition.
Recent indications that certain probiotic formulations can both produce
beneficial psychological effects in healthy populations[62] and modulate brain
activity in an imaging study[63] underline the importance of such a venture.

Leaky Gut
Beyond metabolism, microbial balance influences the protective epithelial gut
barrier. The integrity of the mucosal gut barrier is maintained by tight
junctions that control the flow of molecules between the gastrointestinal tract
and bloodstream.[64] Compromised integrity of the epithelial barrier has been

termed 'leaky gut' and this condition has been associated with a wide range of
intestinal and systemic diseases, including allergies, autoimmune disorders,
asthma, IBD and, speculatively, to mental health,[65,66] although it is important
to note that most data are correlational at this stage.[67]
One consequence of intestinal permeability, or leaky gut, is the increase in
circulating bacteria-derived lipopolysaccharide (LPS), which triggers both an
immunological and inflammatory response characterized by increased
systemic pro-inflammatory cytokines.[68] Inflammation is suggested as a
causative factor in depression[69] and it is notable that elevated serum levels of
IgM and IgA against Gram-negative enterobacteria-derived LPS are elevated
in chronic depression.[70] Moreover, bacterial translocation across the gut wall
induces an autoimmune response to serotonin that is associated with fatigue
and illness behaviour.[71] A novel animal model of depression has been
developed on the basis of this model whereby chronic LPS administration
induces the behavioural phenotype of depression and is reversed by
antidepressants.[72] Relevant to this review, intestinal permeability is promoted
by high-fat diets.[73]

Microbiota and Diet

The gut microbiota is central in metabolism, breaking down dietary
components of foods to fuel energy generation.[74] Metabolism of dietary
components supports energy production, signalling and homeostatic functions.
A previous study[75] postulated that modern modifications to diet and
subsequent changes to the gut microbiota are responsible for the increasing
rate of inflammatory disease such as cardiovascular disease, rheumatoid
arthritis and depression. The Mediterranean diet, a gold standard healthy
eating model, can have a beneficial effect on the host microbiota, and in turn,
on host health and wellness.[76]
Carbohydrate consumption, particularly of dietary fibre, is an important
determinant of microbial composition and results in short chain fatty acid
(SFCA) production, promoting a shift towards different types of 'beneficial'
bacteria and inhibiting the proliferation of 'bad' bacteria.[77] Dietary fibre
provides substrates for bacterial fermentation that results in the SCFAs acetate,
propionate and butyrate; these are mediators of the colonic inflammatory
response.[78] A recent trial placed 10 healthy volunteers on either a 'plant-based'
or 'animal-based' diet, showing rapid (5-day) change in the function profile of
the gut.[79] Poor quality or 'western' diets, particularly low in nondigestible
fibre, lessen microbial diversity and support fewer antipathogenic bacteria. [20]
A recent review suggests that microbiota may even affect eating behaviour by

eliciting cravings for foods that fuel bacterial fitness, but not necessarily host
health, and that increased microbial diversity may limit bacterial control over
dietary choices.[80]
Microbial exposure and long-term, habitual diets are shown to be one of the
strongest influences on gut microbial composition, determining an individual
'enterotype'.[81] Data from studies examining the effect of dietary modification
on microbial composition are beginning to emerge, with evidence that the
consumption of complex carbohydrates, plant-based foods/fruits and
vegetables[81,82] and fermented food[83] influence microbial composition,
synthesis of anti-inflammatory SCFAs and host health. Conversely, high-fat
diets trigger microbial dysbiosis, intestinal permeability and inflammation, [73]
with behavioural disruptions that are independent of obesity.[44]
In a landmark study, De Filippo et al.[20] saw significant differences in gut
microbial composition between African children consuming a 'traditional' diet
compared with European children eating a 'Western'-style diet. In this study,
African children on a plant-based diet had greater microbial diversity and had
anti-inflammatory bacteria that were functionally absent in the European
children consuming a Western-style diet. In support of this finding, Wu et al.
[81]
found that diets higher in fat and lower in fibre were associated with more
Bacteroidetes and Actinobacteria in healthy volunteers. Conversely, a healthy
diet, high in fibre and low in fat, was characterized by the phyla Firmicutes
and Proteobacteria. These bacterial ratios are important in determining pro
and anti-inflammatory balance in the gut. The authors then conducted a
controlled feeding study with 10 of the healthy individuals, who followed
either a high-fat/low-fibre or a low-fat/high-fibre diet for 10 days. Phenotypal
microbiota composition was noted to change quite quickly; however,
microbial enterotype remained constant over the 10 days.[81] This suggests that
longer-term dietary change may be required to make lasting, significant
changes to gut health. Concordantly, reviewers Power et al.[84] reported that
levels of dominant phyla of bacteria in the gut are diet-dependant and may be
specifically related to the type of nondigestible carbohydrate consumed.
However, relationships between diet and bacteria might be dependent on
individual factors and people may have different responses to dietary change.
More data are needed to understand the complex ways in which dietary
patterns influence gut microbiota composition and activity, with the ultimate
objective aimed at achieving precise changes in the gut microbiota
composition that can lead to improved mental health.[85]

Opportunities for Prevention and

Treatment
The gut may be a feasible focus for prevention and treatment interventions. As
before, the gut microbiota appears to have a reciprocal and regulatory
relationship with the stress response system. [47,49,86] However, the disruptive
impact of stress on the gut has been prevented and even partially reversed by
probiotic administration in animal studies.[87] Dietary manipulation, including
the consumption of prebiotics (fermented dietary ingredients including
fructans and oligosaccharides) and fermented foods, result in specific changes
in the activity of the gastrointestinal microbiota and may provide a feasible
means of intervention to address depression and other disorders. [83] In
considering the role of diet in gut health, it should be acknowledged that a
healthy diet will often coexist with other health behaviours, such as exercise, [88]
that also promote microbial health.

Conclusion, Discussion, Future Direction

With depression currently one of the leading causes of global disease burden,
[89]
the imperative to develop effective prevention and treatment strategies is
clear. The gut microbiome has been implicated as an important health
determinant relevant to both physical and mental health. The emerging
literature from this nascent field suggests that the recently established
association between diet quality and depressive disorders[90] is likely to be, at
least partly, mediated by the gut microbiota. Depressive symptoms prompt the
increased consumption of high-fat, sugary foods, [91] although the long-term
impact of these dietary habits is noxious.[92] Microbial changes perpetuated by
poor diet may drive and exacerbate depressive symptoms. On the contrary,
dietary improvement has been shown to prevent depression.[29,93] As a readily
accessible and effective tool for modifying microbial composition, diet may
provide a more acceptable alternative to drug therapy with unpleasant side
effects, particularly in patients with milder symptoms of depression. This
provides an important target for the prevention and treatment of common
mental disorders.[24]
It is important to bear in mind that the field is in its early stages and has not
yet been able to comprehensively identify and describe the composition of a
'healthy' gut, nor the full functional capacity of most bacterial phyla.
Importantly, microbial composition seems to be individualized; overall,
microbiome function can vary greatly between persons, yet different
microbiome compositions between individuals can also have the same range

of functions. Advances in analytical technology will continue to shed light on

this rapidly developing field of investigation. Although early probiotic and
dietary research provides support for diet as a possible target for microbial
modification and in turn, the alleviation of mental health symptoms, there is a
clear need for more high quality research, including randomized controlled
trials, to investigate the effectiveness and feasibility of mental health
improvement as a function of microbial modulation. Although pre and
probiotics (whose presence is transient and dependant on continued
consumption) offer tantalising promise for efficacy in psychiatry, holistic
dietary changes may be necessary to promote long-term improvements in
health.

References
1.

Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and
depression. Trends Neurosci 2013; 36:305312.

2.

Zhu B, Wang X, Li L. Human gut microbiome: the second genome of human body. Protein Cell
2010; 1:718725.

3.

O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep 2006; 7:688693.

4.

Grenham S, Clarke G, Cryan JF, et al. Brain-gut-microbe communication in health and disease.
Front Physiol 2011; 2:94.

5.

Fraher MH, O'Toole PW, Quigley EM. Techniques used to characterize the gut microbiota: a guide
for the clinician. Nat Rev Gastroenterol Hepatol 2012;9:312322.
*A comprehensive and accessible recent review detailing the methodological advances in the
assessment of the gut microbiota.

6.

Lepage P, Leclerc MC, Joossens M, et al. A metagenomic insight into our gut's microbiome. Gut
2013; 62:146158.

7.

Psaltopoulou T, Sergentanis TN, Panagiotakos DB, et al. Mediterranean diet, stroke, cognitive
impairment, and depression: a meta-analysis. Ann Neurol 2013; 74:580591.
* An important overview of the favourable effects of the Mediterranean diet on the occurrence of
stroke, cognitive impairment and depression.

8.

O'Neil A, Quirk SE, Housden SL, et al. The relationship between diet and mental health in children
and adolescents: a systematic review. Am J Public Health 2014; 104:e31e42.

9.

Battersby AJ, Gibbons DL. The gut mucosal immune system in the neonatal period. Pediatr Allergy
Immunol 2013; 24:414421.

10. Guinane CM, Cotter PD. Role of the gut microbiota in health and chronic gastrointestinal disease:
understanding a hidden metabolic organ. Therap Adv Gastroenterol 2013; 6:295308.
11. Clarke G, Stilling RM, Kennedy PJ, et al. Minireview: gut microbiota: the neglected endocrine
organ. Mol Endocrinol 2014; 28:12211238.

12. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune
system. Science 2012; 336:12681273.
13. Sommer F, Backhed F. The gut microbiota masters of host development and physiology. Nat Rev
Microbiol 2013; 11:227238.
** An outstanding overview of the critical importance of the gut microbiota in human physiology.
14. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and
behaviour. Nat Rev Neurosci 2012; 13:701712.
** A field-defining review that provides the framework for future studies charting the impact of the
gut microbiota at the level of the CNS.
15. Dominguez-Bello MG, Costello EK, Contreras M, et al. Delivery mode shapes the acquisition and
structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S
A 2010; 107:1197111975.
16. Cho CE, Norman M. Cesarean section and development of the immune system in the offspring. Am J
Obstet Gynecol 2013; 208:249254.
* An important review exploring the relationship mode of delivery and development of the immune
system.
17. Fallani M, Young D, Scott J, et al. Intestinal microbiota of 6-week-old infants across Europe:
geographic influence beyond delivery mode, breast-feeding, and antibiotics. J Pediatr Gastroenterol
Nutr 2010; 51:7784.
18. Clarke G, O'Mahony S, Dinan TG, et al. Priming for health: gut microbiota acquired in early life
regulates physiology, brain and behaviour. Acta Paediatr 2014; 103:812819.
19. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography.
Nature 2012; 486:222227.
20. De Filippo C, Cavalieri D, Di Paola M, et al. Impact of diet in shaping gut microbiota revealed by a
comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A 2010;
107:1469114696.
21. Dethlefsen L, Huse S, Sogin ML, et al. The pervasive effects of an antibiotic on the human gut
microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 2008; 6:e280.
22. Davey KJ, Cotter PD, O'Sullivan O, et al. Antipsychotics and the gut microbiome: olanzapineinduced metabolic dysfunction is attenuated by antibiotic administration in the rat. Transl Psychiatry
2013; 3:e309.
* An important paper which demonstrates that metabolic side effects of antipsychotic medication can
be mediated by the gut microbiota.
23. Claesson MJ, Jeffery IB, Conde S, et al. Gut microbiota composition correlates with diet and health
in the elderly. Nature 2012; 488:178184.
24. Jacka FN, Mykletun A, Berk M. Moving towards a population health approach to the primary
prevention of common mental disorders. BMC Med 2012; 10:149.
25. Lai JS, Hiles S, Bisquera A, et al. A systematic review and meta-analysis of dietary patterns and
depression in community-dwelling adults. Am J Clin Nutr 2014; 99:181197.

26. Jacka FN, Ystrom E, Brantsaeter AL, et al. Maternal and early postnatal nutrition and mental health
of offspring by age 5 years: a prospective cohort study. J Am Acad Child Adolesc Psychiatry 2013;
52:10381047.
* A notable demonstration that early nutritional exposures influence behavioural and emotional
outcomes in the offspring.
27. Steenweg-de Graaff J, Tiemeier H, Steegers-Theunissen RP, et al. Maternal dietary patterns during
pregnancy and child internalising and externalizing problems. The Generation R Study. Clin Nutr
2014; 33:115121.
28. Sanchez-Villegas A, Martinez-Gonzalez MA, Estruch R, et al. Mediterranean dietary pattern and
depression: the PREDIMED randomized trial. BMC Med 2013; 11:208.
29. Stahl ST, Albert SM, Dew MA, et al. Coaching in healthy dietary practices in at-risk older adults: a
case of indicated depression prevention. Am J Psychiatry 2014; 171:499505.
30. O'Neil A, Berk M, Itsiopoulos C, et al. A randomised, controlled trial of a dietary intervention for
adults with major depression (the 'SMILES' trial): study protocol. BMC Psychiatry 2013; 13:114.
31. Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probiotics and mental health: from
Metchnikoff to modern advances: part I: autointoxication revisited. Gut Pathog 2013; 5:5.
32. Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 2011;
12:453466.
33. Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nat
Rev Microbiol 2012; 10:735742.
34. Diaz Heijtz R, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and
behavior. Proc Natl Acad Sci U S A 2011; 108:30473052.
35. Crumeyrolle-Arias M, Jaglin M, Bruneau A, et al. Absence of the gut microbiota enhances anxietylike behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 2014;
42:207217.
* An important study using germ-free rats that further confirms the importance of the gut microbiota
in brain and behaviour.
36. Clarke G, Grenham S, Scully P, et al. The microbiome-gut-brain axis during early life regulates the
hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 2013; 18:666673.
** Together with refs [34,37], this study links the gut microbiota to alterations in neurotransmitters
and neurotrophic factors in the brain as well as alterations in anxiety-like behaviour.
37. Neufeld KM, Kang N, Bienenstock J, et al. Reduced anxiety-like behavior and central
neurochemical change in germ-free mice. Neurogastroenterol Motil 2011; 23:255264.
38. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior
and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A
2011; 108:1605016055.
39. Desbonnet L, Garrett L, Clarke G, et al. Effects of the probiotic Bifidobacterium infantis in the
maternal separation model of depression. Neurscience 2010; 170:11791188.
40. Mello BS, Monte AS, McIntyre RS, et al. Effects of doxycycline on depressivelike behavior in mice
after lipopolysaccharide (LPS) administration. J Psychiatr Res 2013; 47:15211529.

* An interesting study which shows that doxycline in addition to minocycline, both of which are
from the same class of antibiotic, can potentially modulate depressivelike behaviours.
41. Molina-Hernandez M, Tellez-Alcantara NP, Perez-Garcia J, et al. Antidepressant-like actions of
minocycline combined with several glutamate antagonists. Prog Neuropsychopharmacol Biol
Psychiatry 2008; 32:380386.
42. Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain-gut-enteric
microbiota axis. Nat Rev Gastroenterol Hepatol 2009; 6:306314.
43. Mayer EA, Naliboff B, Munakata J. The evolving neurobiology of gut feelings. Prog Brain Res
2000; 122:195206.
44. Bruce-Keller AJ, Salbaum JM, Luo M, et al. Obese-type gut microbiota induce neurobehavioral
changes in the absence of obesity. Biol Psychiatry 2014. doi: 10.1016/j.biopsych.2014.07.012. [Epub
ahead of print].
** Taken together with ref [45], these studies independently verify that relevant behaviours can be
transferred via gut microbiota transplants.
45. Bercik P, Denou E, Collins J, et al. The intestinal microbiota affect central levels of brain-derived
neurotropic factor and behavior in mice. Gastroenterology 2011; 141:599609.
46. Bailey MT, Lubach GR, Coe CL. Prenatal stress alters bacterial colonization of the gut in infant
monkeys. J Pediatr Gastroenterol Nutr 2004; 38:414421.
47. Sudo N, Chida Y, Aiba Y, et al. Postnatal microbial colonization programs the hypothalamicpituitary-adrenal system for stress response in mice. J Physiol 2004; 558 (Pt 1):263275.
48. Park AJ, Collins J, Blennerhassett PA, et al. Altered colonic function and microbiota profile in a
mouse model of chronic depression. Neurogastroenterol Motil 2013; 25:733-e575.
* An interesting preclinical study highlighting the potential links between the gut microbiota and
depression.
49. O'Mahony SM, Marchesi JR, Scully P, et al. Early life stress alters behavior, immunity, and
microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol
Psychiatry 2009; 65:263267.
50. Lewis AJ, Galbally M, Gannon T, et al. Early life programming as a target for prevention of child
and adolescent mental disorders. BMC Med 2014; 12:33.
51. Relman DA. The human microbiome: ecosystem resilience and health. Nutr Rev 2012; 70 (Suppl
1):S2S9.
52. Sommer MO, Dantas G. Antibiotics and the resistant microbiome. Curr Opin Microbiol 2011;
14:556563.
53. O'Mahony SM, Clarke G, Borre YE, et al. Serotonin, tryptophan metabolism and the brain-gutmicrobiome axis. Behav Brain Res 2014. doi: 10.1016/j.bbr.2014.07.027. [Epub ahead of print].
54. Moloney RD, Desbonnet L, Clarke G, et al. The microbiome: stress, health and disease. Mamm
Genome 2014; 25:4974.
55. Dinan TG, Cryan JF. Regulation of the stress response by the gut microbiota: implications for
psychoneuroendocrinology. Psychoneuroendocrinology 2012; 37:13691378.

56. Gareau MG, Wine E, Rodrigues DM, et al. Bacterial infection causes stressinduced memory
dysfunction in mice. Gut 2011; 60:307317.
57. Li W, Dowd SE, Scurlock B, et al. Memory and learning behavior in mice is temporally associated
with diet-induced alterations in gut bacteria. Physiol Behav 2009; 96:557567.
58. Desbonnet L, Clarke G, Shanahan F, et al. Microbiota is essential for social development in the
mouse. Mol Psychiatry 2014; 19:146148.
* One of the first preclinical studies to demonstrate an effect of the gut microbiota on social
behaviour.
59. Ohland CL, Kish L, Bell H, et al. Effects of Lactobacillus helveticus on murine behavior are
dependent on diet and genotype and correlate with alterations in the gut microbiome.
Psychoneuroendocrinology 2013; 38:17381747.
60. Mayer EA, Savidge T, Shulman RJ. Brain-gut microbiome interactions and functional bowel
disorders. Gastroenterology 2014; 146:15001512.
61. Naseribafrouei A, Hestad K, Avershina E, et al. Correlation between the human fecal microbiota and
depression. Neurogastroenterol Motil 2014; 26:11551162.
62. Messaoudi M, Violle N, Bisson JF, et al. Beneficial psychological effects of a probiotic formulation
(Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers.
Gut microbes 2011; 2:256261.
63. Tillisch K, Labus J, Kilpatrick L, et al. Consumption of fermented milk product with probiotic
modulates brain activity. Gastroenterology 2013; 144:13941401.
** A pivotal study demonstrating an effect of probiotic consumption on brain activity in healthy
humans.
64. Hollander D. Intestinal permeability, leaky gut, and intestinal disorders. Curr Gastroenterol Rep
1999; 1:410416.
65. Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol 2012; 42:7178.
66. Maes M. The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress
(IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol
Lett 2008; 29:287291.
67. Odenwald MA, Turner JR. Intestinal permeability defects: is it time to treat? Clin Gastroenterol
Hepatol 2013; 11:10751083.
68. Qin L, WuX, Block ML, et al. Systemic LPS causes chronic neuroinflammation and progressive
neurodegeneration. Glia 2007; 55:453462.
69. Berk M, Williams LJ, Jacka FN, et al. So depression is an inflammatory disease, but where does the
inflammation come from? BMC Med 2013; 11:200.
70. Maes M, Kubera M, Leunis JC, et al. Increased IgA and IgM responses against gut commensals in
chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect
Disord 2012; 141:5562.
71. Maes M, Ringel K, Kubera M, et al. In myalgic encephalomyelitis/chronic fatigue syndrome,
increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and
bacterial translocation. J Affect Disord 2013; 150:223230.

72. Kubera M, Curzytek K, Duda W, et al. A new animal model of (chronic) depression induced by
repeated and intermittent lipopolysaccharide administration for 4 months. Brain Behav Immun 2013;
31:96104.
73. Kim KA, Gu W, Lee IA, et al. High fat diet-induced gut microbiota exacerbates inflammation and
obesity in mice via the TLR4 signaling pathway. PLoS One 2012; 7:e47713.
74. Nieuwdorp M, Gilijamse PW, Pai N, et al. Role of the microbiome in energy regulation and
metabolism. Gastroenterology 2014; 146:15251533.
75. Maslowski KM, Mackay CR. Diet, gut microbiota and immune responses. Nat Immunol 2011; 12:5
9.
76. Del Chierico F, Vernocchi P, Dallapiccola B, et al. Mediterranean diet and health: food effects on gut
microbiota and disease control. Int J Mol Sci 2014; 15:1167811699.
77. Scheppach W, Luehrs H, Menzel T. Beneficial health effects of low-digestible carbohydrate
consumption. Br J Nutr 2001; 85 (Suppl 1):S23S30.
78. Kaczmarkczyk MM, Miller MJ, Freund GG. The health benefits of dietary fiber: beyond the usual
suspects of type 2 diabetes mellitus, cardiovascular disease and colon cancer. Metabolism 2012;
61:10581066.
79. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut
microbiome. Nature 2014; 505:559563.
** An important study highlighting a role for diet in modulation of the gut microbiome.
80. Alcock J, Maley CC, Aktipis CA. Is eating behavior manipulated by the gastrointestinal microbiota?
Evolutionary pressures and potential mechanisms. BioEssays 2014; 36:940949.
81. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial
enterotypes. Science 2011; 334:105108.
82. Albenberg LG, Wu GD. Diet and the intestinal microbiome: associations, functions, and implications
for health and disease. Gastroenterology 2014; 146:15641572.
83. Selhub EM, Logan AC, Bested AC. Fermented foods, microbiota, and mental health: ancient practice
meets nutritional psychiatry. J Physiol Anthropol 2014; 33:2.
84. Power SE, O'Toole PW, Stanton C, et al. Intestinal microbiota, diet and health. Br J Nutr 2014;
111:387402.
85. Hamaker BR, Tuncil YE. A perspective on the complexity of dietary fiber structures and their
potential effect on the gut microbiota. J Mol Biol 2014. doi: 10.1016/j.jmb.2014.07.028. [Epub ahead
of print].
86. Knowles SR, Nelson EA, Palombo EA. Investigating the role of perceived stress on bacterial flora
activity and salivary cortisol secretion: a possible mechanism underlying susceptibility to illness.
Biol Psychol 2008; 77:132137.
87. Zareie M, Johnson-Henry K, Jury J, et al. Probiotics prevent bacterial translocation and improve
intestinal barrier function in rats following chronic psychological stress. Gut 2006; 55:15531560.
88. Clarke SF, Murphy EF, O'Sullivan O, et al. Exercise and associated dietary extremes impact on gut
microbial diversity. Gut 2014. doi: 10.1136/gutjnl-2013-306541. [Epub ahead of print].
* This study demonstrates that exercise might have an effect on the gut microbiota.

89. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and
substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 2013;
382:15751586.
90. Jacka FN, Kremer PJ, Leslie ER, et al. Associations between diet quality and depressed mood in
adolescents: results from the Australian Healthy Neighbourhoods Study. Aust N Z J Psychiatry 2010;
44:435442.
91. Whitaker KM, Sharpe PA, Wilcox S, et al. Depressive symptoms are associated with dietary intake
but not physical activity among overweight and obese women from disadvantaged neighborhoods.
Nutr Res 2014; 34:294301.
92. Jacka FN, Sacks G, Berk M, et al. Food policies for mental and physical health. BMC Psychiatry
2014; 14:132.
93. Sanchez-Villegas A, Martinez-Gonzalez MA. Diet, a new target to prevent depression? BMC Med
2013; 11:3.