Translational Psychiatry www.nature.

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REVIEW ARTICLE OPEN

Role of diet and its effects on the gut microbiome in the

pathophysiology of mental disorders
1✉
J. Horn1, D. E. Mayer2, S. Chen3 and E. A. Mayer

© The Author(s) 2022

There is emerging evidence that diet has a major modulatory influence on brain-gut-microbiome (BGM) interactions with important
implications for brain health, and for several brain disorders. The BGM system is made up of neuroendocrine, neural, and immune
communication channels which establish a network of bidirectional interactions between the brain, the gut and its microbiome.
Diet not only plays a crucial role in shaping the gut microbiome, but it can modulate structure and function of the brain through
these communication channels. In this review, we summarize the evidence available from preclinical and clinical studies on the
influence of dietary habits and interventions on a selected group of psychiatric and neurologic disorders including depression,
cognitive decline, Parkinson’s disease, autism spectrum disorder and epilepsy. We will particularly address the role of diet-induced
microbiome changes which have been implicated in these effects, and some of which are shared between different brain disorders.
While the majority of these findings have been demonstrated in preclinical and in cross-sectional, epidemiological studies, to date
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there is insufficient evidence from mechanistic human studies to make conclusions about causality between a specific diet and
microbially mediated brain function. Many of the dietary benefits on microbiome and brain health have been attributed to anti-
inflammatory effects mediated by the microbial metabolites of dietary fiber and polyphenols. The new attention given to dietary
factors in brain disorders has the potential to improve treatment outcomes with currently available pharmacological and non-
pharmacological therapies.

Translational Psychiatry (2022)12:164 ; https://doi.org/10.1038/s41398-022-01922-0

INTRODUCTION life for compromised brain function have long been known [8, 9].
Psychiatric disorders have traditionally been considered diseases While the great majority of studies to date has focused on dietary
of the brain, with little role of the body or individual organs in components such as amino acids and micronutrients that are
their pathophysiology. Exceptions to this brain-focused approach completely absorbed in the proximal small intestine, there has
have been pre-scientific concepts in Traditional Chinese Medicine, been a growing interest in food molecules that are too large to be
Ayurvedic Medicine, and Hippocratic Medicine, all of which absorbed intact in the proximal gut, and whose absorption largely
attributed a significant role of the body, in particular the digestive relies on metabolism by the gut microbiota in the distal small
system and diet, in modulating mental processes. Modern intestine and colon. The health benefit of these non-absorbable
psychosomatic medicine has posited that stress, emotional, and dietary components is crucially dependent on the composition
cognitive factors can influence body functions. and functions of the gut microbiome.
Early evidence suggesting a role of altered gut to brain The exponential progress in microbiome science following the
signaling in anxiety, depression, and autism spectrum disorder Human Microbiome Project [10] and some of the paradigm
(ASD) have come from clinical anecdotal observations in patients challenging results from early rodent studies about the influence
with these diagnoses and associated GI manifestations. In many of of the gut microbiome on emotion-like behavior and brain
these studies, psychiatric conditions were viewed as co-morbid biochemistry have introduced the concept of the BGM axis (or
conditions to the primary diagnosis of a gut disorder. In addition, a better BGM system) playing a role in many psychiatric disorders
number of large epidemiological studies have implicated dietary [11–13]. While these pioneering studies had a major influence on
factors in some of these disorders [1–5], both in terms of risk our understanding of the role of gut microbes in mammalian
factors [6] as well as potential therapies [2, 5, 7]. However, none of behavior, few of their findings have been translatable into the
these studies have been able to establish a causative role of the diagnosis or treatment of human psychiatric disorders to [12].
gut or dietary factors in psychiatric disease to date. However, as diet has a major influence on human gut microbial
composition and function, the notion that diet in addition to
Diet can affect the brain via multiple mechanisms direct effect of macro and micronutrients on the brain could play a
The importance of sufficient macro- and micronutrients for normal causative role in gut microbiome alterations with impacts on
brain development and the role of nutrient deficiencies early in human emotional and cognitive function, has become an exciting

1
G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los
Angeles, CA, USA. 2MayerInterconnected, LLC, Los Angeles, CA, USA. 3University of California, San Francisco, CA, USA. ✉email: emayer@ucla.edu

Received: 19 July 2021 Revised: 22 March 2022 Accepted: 29 March 2022

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Table 1. Evidence for the effect of dietary interventions on brain disorders.
Disorder Dietary intervention therapies
Depression Epidemiological, interventional studies, and meta-analysis of RCTs revealed that intervention with a largely plant-
based diet can reduce depressive symptoms compared to control conditions (Jacka et al., 2017; Parletta et al., 2019;
Sanchez-Villegas et al., 2013). A large population-based study found a positive correlation between Coprococcus
and Dialister with quality of life, and a depletion of these taxa in treatment-free depression. Participants with low
relative abundance of Bacteroides showed lower quality of life scores and higher prevalence of depression (Valles-
Colomer et al., 2019).
Anxiety Meta-analysis of 11 RCTs from 2270 individuals showed no overall effect of dietary interventions on anxiety
compared with control conditions (g = 0.100, 95% CI = − 0.036 to 0.235, p = .148, Q = 18.5, I2 = 46.1). As with
depression outcomes, some studies using mostly (>75%) female participants observed significant positive effects
on anxiety from dietary interventions (n = 6, n = 965, g = 0.211, 95% CI = 0.09 to 0.34, p = 0.001), whereas those
with predominantly male participants observed non-significant negative effects (g = −0.19, 95% CI = − 0.42 to
0.04, p = 0.107) (Firth et al., 2019).
Parkinson’s Disease The MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet consisting of higher consumption
of berries and green leafy vegetables than the traditional Mediterranean diet resulted in a significantly lower risk
for parkinsonism as well as a slower rate of PD symptom progression relative to controls in a study with 706
participants of an age range between 59 and 97. The group on a Mediterranean diet showed a significant
reduction in parkinsonism progression when compared to the control group (Agarwal et al., 2018).
Alzheimer’s Disease Early-stage clinical studies show positive causal evidence for a ketogenic diet to improve cognitive function in
those with AD despite the heterogeneity of interventional dietary studies. However, there is a paucity of evidence
supporting an effect of a ketogenic diet on the prevention of AD development, an area of potential future research
(Krikorian et al., 2012; Henderson et al., 2009, Ota et al., 2019; Reger et al., 2004; Taylor et al., 2018; Neth et al., 2020;
Morrison et al., 2020; Fortier et al., 2019). The NUAGE dietary intervention trial showed that adherence to a
Mediterranean diet was associated with increased abundance of butyrate producing taxa, which were negatively
associated with inflammatory markers and positively associated with enhanced cognition (Ghosh et al., 2019).
Supplementation with probiotics for 12 weeks induced a significant improvement in Mini- Mental State
Examination score (Akbari et al., 2016).
Autism Spectrum Disorder Various small, low quality dietary intervention studies have shown improvement in several domains compared to
control groups, such as communication, social interaction, inattention, and hyperactivity (Cade et al., 2000;
Knivsberg et al., 2002; Elder et al., 2006; Whiteley et al., 2010; Adams et al., 2018; Grimaldi et al., 2018). Metabolic
and endocrine pathways have been observed to be different in ASD individuals compared to healthy controls
(Needham et al., 2021; Emond et al., 2013). No strong causal evidence for diet-induced therapeutic microbiome
changes. MTT was associated with a significant sustained decrease in GI symptoms and ASD symptoms, and
favorable changes in the abundance of certain beneficial bacterial taxa (Kang et al., 2017; Kang et al., 2019).
Epilepsy Meta-analysis of 10 RCTs found weak positive evidence of seizure reduction of the dietary intervention groups
relative to the control groups (McGill et al., 2018). A case-control study demonstrated a 50% reduction in seizures
in children with DRE after one week of being on the ketogenic diet, associated with decreased levels of several
microbial taxa (Xie et al., 2017). Another ketogenic dietary intervention study showed no significant change in
alpha diversity but diminished relative abundance of the butyrate producing taxa bifidobacteria, E. rectale, and
Dialister and increase of E. coli (Lindefelt et al., 2019). In children treated with a ketogenic diet for six months, a
decrease of Firmicutes and Actinobacteria and increased levels of Bacteroidetes were observed. The subgroup with
increased abundance of Alistipes, Clostridiales, Lachnospiraceae, Ruminococcaceae, and Rikenellaceae had a less than
50% reduction in seizures compared to other subgroups (Zhang et al., 2018).
Eating Disorders High adherence to a Mediterranean diet in 11.1% of 1472 subjects at high risk for binge eating disorder was
associated with decreased development of the disorder (Bertoli et al., 2015). A study with 11,800 women with
either anorexia nervosa or bulimia nervosa showed evidence for a potential inverse association between a
Mediterranean dietary pattern and both eating disorders (Leone et al., 2018). Significant differences in the relative
abundance of certain gut microbiota have been observed in anorexia nervosa (Kleiman et al., 2015; Morita
et al., 2015).
ADHD In a study with 100 children randomly assigned to either the dietary or the control group, the ADHD rating scale
score between baseline and the first phase of the dietary intervention was significantly lower in the group
following a restricted elimination diet compared to the control group (Pelsser et al., 2017).The beta diversity of the
gut microbiome of ADHD participants was different than in the control group, even though the changes of
individual bacterial taxa were different (Aarts et al., 2017; Prehn-Kristenen et al., 2018).

research topic in psychiatry, and the term Nutritional Psychiatry A growing number of interventional and mechanistic studies have
has been proposed [11, 14, 15]. confirmed a beneficial effect of a mostly plant-based diet, high in
Nutritional psychiatry is a relatively new field of research that fiber and polyphenols, on mental health.
has developed from revolutionary preclinical observations and a In this review, we will first discuss the emerging science about
series of large, cross-sectional, epidemiological studies, linking diet the bidirectional communication within the BGM system, and then
with different aspects of mental health, and from the insights review the existing animal and human literature supporting a role
gained from microbiome science which has provided a link for diet and supplements in influencing the brain, psychiatric
between diet, microbial function, and brain health. Converging pathophysiology, and symptoms. We will focus on a limited and
results from these studies support a potential role of diet, and a non-exhaustive number of mechanisms which have been impli-
possible beneficial role of particular dietary interventions in cated in several brain disorders, and which illustrate different ways
different brain disorders, including, but not limited to depression, by which diet-related gut microbial molecules, metabolites and
cognitive decline, and Alzheimer’s disease (AD), ASD, and certain mechanisms can affect the brain, in particular short chain fatty
forms of epilepsy (for a complete list of such disorders, see Table 1). acids, tryptophan (Trp) metabolites, bile acid (BA) metabolites, and

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immune-mediated processes. From the large number of psychiatric norepinephrine and likely other neurotransmitters released from
disorders which have been associated with diet and the postsynaptic sympathetic terminals has been reported [18].
microbiome, we have limited the discussion to those disorders Evidence for a similar release of stress-induced serotonin from
for which sufficient scientific evidence from preclinical and clinical enterochromaffin cells into the gut lumen has been reported, with
studies is available to suggest a causative role. We will point out some microbes exhibiting a serotonin transporter in their cell
the paucity of well controlled longitudinal, interventional clinical membranes [19]. The functional consequences of this luminally
studies (RCTs), which identify a causality between a specific diet, or released serotonin (as well as other signaling molecules stored in
supplements, and a psychiatric disorder. We will also discuss specialized gut cells) remains to be determined.
potential future implications of Nutritional Psychiatry, such as the
proposed role of diagnostic testing of the gut microbiome to Neuroendocrine communication channel
identify targets for personalized treatments and will discuss the Many microbes produce metabolites from dietary components
potential for integrative approaches combining dietary interven- (complex carbohydrates, amino acids), bodily secretions (BAs,
tions, pharmacotherapy, and cognitive behavioral approaches. estrogens), or chemical substances, so called xenobiotics (includ-
ing pesticides and some medications). Many of these metabolites
The brain gut microbiome system have been shown to influence brain structure and function in
Emerging evidence supports a model of bi-directional commu- preclinical studies [20, 21].
nication between the central nervous system (CNS), the gut, and Gut microbes communicate with a variety of cells of the
its microbiome, collectively referred to as the BGM system (Fig. 1). gastrointestinal endocrine system [22]. Enteroendocrine cells
As discussed throughout this review, a number of dietary effects (EECs) are interspersed in the gut epithelium and contain
on the brain are mediated by the BGM system, and a general important signaling molecules, including key orexigenic (ghrelin)
knowledge of this system is required to better understand many and anorexigenic (NPY, PYY) hormones which can act locally on
aspects of dietary modulation of the brain. The gut microbiome the vagus nerve as neurotransmitters, or reach the CNS via the
has been shown to interact with the brain primarily through three systemic circulation in an endocrine fashion [12]. The interaction
interacting pathways, namely neuronal, endocrine, and immunor- of such hormones in the periphery and in the hypothalamus play
egulatory [12, 16]. In turn, the CNS can directly influence the a key role in the regulation of appetite and satiety [23] and a
composition and function of the gut microbiota through the dysregulation of these signaling systems has been implicated in
autonomic nervous system [17]. This top-down modulation can obesity and food addiction [24]. Enteroendocrine and enterochro-
occur indirectly via regulation of gastrointestinal (GI) motility and maffin cells (ECCs) form close synaptic connections with certain
transit, mucus secretion and permeability of the intestinal barrier, vagal afferent fibers through cell extensions called neuropods
and luminal release of neurotransmitters. In addition, direct [25, 26]. While these gut hormones are also released into the
modulation of gut microbial gene expression and function by systemic circulation and reach the brain directly, these synaptic
connections function in the rapid relay of a nutrient and other
signals from the gut to the brain.
Brain Connectome The essential amino acid Trp is a precursor to serotonin, as well
as to other important metabolites in neuroendocrine signaling
(Fig. 2). Specific gut microbiota play a critical role in the
Central nervous system Interactions of multiple gut and modulation of Trp into various metabolites, which include but
microbe derived molecules are not limited to kynurenine, indoles, and tryptamine [19, 27, 28].
Trp metabolites are important contributors to neuroendocrine and
Microbe-derived Gut-derived molecules neuroimmune mechanisms as they can act on the CNS either
neuroactive molecules
• Neuronal through the bloodstream or via vagal afferent signaling [18].
• Immune
• Neuroendocrine The great majority of the body’s serotonin (95%) is produced
Food and stored in ECCs and plays an important role in modulating the
activity of the enteric nervous system and in signaling to the brain
via different subtypes of vagal afferents which form synaptic
Microbe-derived molecules contacts with ECCs [29]. Microbial metabolites (SCFAs and BAs)
have been shown to stimulate the production and release of
Gut microbiota Gut-derived molecules serotonin by ECCs [19]. By regulating the serotonergic system, gut
ANS modulation
microbes can directly influence their environment [18]. While
• Motility serotonergic neurons located in the brainstem show widespread
• Secretion projections to the brain and are well-known to play an important
Gut Microbiome • Permeability Gut Connectome
• Microbiome role in modulating vital functions such as sleep, food intake, mood
regulation and pain, gut-based serotonin plays an important role
Fig. 1 The influence of food on the brain gut microbiome system. in gastrointestinal motility and secretion [12]. Germ-free mice
The brain connectome, gut connectome and microbiome make up
the 3 hubs in the larger BGM network. All hubs are linked by have been demonstrated to have half the amount of serotonin
bidirectional connections with multiple feedback loops generating a when compared to mice with a normal gut microbiome [28].
non-linear system. Different components of food influence the Another Trp metabolite is kynurenine, the synthesis of which is
brain, the gut and the gut microbiome via different communication modulated by Lactobacillus taxa (Marin et al., 2017). Lactobacilli
channels. Dietary components can influence the gut directly and produce hydrogen peroxide, a reactive oxygen species which
reach the brain after absorption in the small intestine. In addition, normally suppress host kynurenine metabolism by inhibiting the
diet can influence gut microbial composition and diversity, and after expression of the enzyme indoleamine-2,3-dioxygenase (IDO1).
microbial metabolism can modulate the gut connectome. Some of IDO1 plays part in the synthesis of kynurenine from Trp in the GI
the microbial derived molecules are absorbed and reach the brain tract (Schwarcz et al., 2012). In a rodent model of chronic variable
via the systemic circulation and/or the vagus nerve (see Fig. 2)
Similarly, the brain can modulate the microbiome directly through stress, the stress-induced reduction of Lactobacillus decreased
the effect of neuroactive substances released into the gut lumen hydrogen peroxide-mediated inhibition of IDO1, resulting in an
affecting gene expression and behavior of microbes, or indirectly via increased synthesis of kynurenine from Trp, (Valladares et al., 2013,
alterations of the gut microbial environment. Modified with Vujkovic-Cvijin, 2015). In these studies, higher kynurenine
permission from Martin et al., 2018. concentrations in the brain were correlated with increased

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Indoles
Dependent on
Gut Microbes
Microbiota
Trp TnaB
Vagal/spinal
signals to CNS TnaA
ANS modulation
of gut function
Serotonin and ECCs
Modulated by Indole
Gut Microbes
Luminal 5-HT release
and uptake
Dietary
Indole
tryptophan

Microbiota
SCFA, 2º BAs
Tryptophan
Spore forming Clostridiales

Kynurenin
Modulated by Tryptophan Serotonin
Gut Microbes Indoxyl-sulfate
H2O2
Lactobacilli IDO1 Indole Indole aldehyde
Quinolinic acid acetic acid
Kynurenine
Anthranilic acid
Skatole Tryptanthrin
Tryptamine
Kynurenic acid

Fig. 2 Gut microbes generate neuroactive metabolites from tryptophan. The essential amino acid Tryptophan is the precursor for a number
of neuroactive signaling molecules including serotonin, kynurenine and indoles. Whereas microbes only play a modulatory role in the
generation of serotonin and kynurenine, the synthesis of indoles is fully dependent on gut microbial metabolism. The relative abundance of
the 3 metabolites is dependent on tryptophan intake, on the relative abundance of involved microbial taxa and on stress induced input from
the autonomic nervous system. Modified with permission from Martin et al., 2018.

depression-like behavior which was reduced by the administration

of Lactobacillus [30]. Kynurenine, which can pass the blood-brain Diet-Derived Microbe-Derived
barrier, has been shown to produce neuroinflammation and Polysaccharides Cell wall components
neurodegeneration, which have also been reported in AD and Polyphenols
Amino acids
depression [31].
A third group of Trp metabolites are indoles, which are solely Host-Derived De Novo
produced by gut microbes. Indoles are precursor molecules to Primary bile acids Biosynthetic precursors
many compounds that are critical for brain health and function Steroid hormones Xenobiotics
and have been detected in the GI tract, brain, and the systemic
circulation [32]. While many indoles are known to positively
Microbial Signals
influence both systemic and intestinal homeostasis [20], preclinical
studies have demonstrated that some indole metabolites may also
exert negative effects on brain health, such as causing depression- Secondary Bile Acids

Active Hormone
Short-chain fatty acids

• Simple phenols
Microorganism-
associated
molecular patterns
Toxins

like behavior [33]. While gut microbes play only a modulatory role Metabolites • Estrogens (MAMS, LPS)

•
in both serotonin and kynurenine production from Trp, the indole •
•
Neurotransmitters
Indoles
Polyamines
pathway is completely microbe dependent, as only certain • Phenols

microbes possess the enzyme tryptophanase required for their Fig. 3 Four sources for gut microbial signaling molecules. Gut
production from Trp [34]. Indoles are further metabolized in the microbial signaling molecules are derived from at least 4 different
liver and are precursor molecules to many compounds that are sources: Diet-derived, microbe-derived, host-derived and newly
critical for brain health and function. They have been detected in synthesized molecules. Chemical transformation of these molecules
the GI tract, brain, and the systemic circulation [32]. One such results in a vast number of signaling molecules which can influence
metabolite, indoxyl sulfate, may play part in the pathophysiology not only cells in the gut (immune, nerve, endocrine cells), but
of several brain disorders, including ASD, AD, and depression [12]. following dissemination throughout the body are able to modulate
In summary, the interactions of gut microbes with dietary all organs, including the brain. Certain diet-derived microbial
metabolites have neuroactive effects on the central and autonomic
tryptophan leading to the generation of multiple neuroactive nervous system, while microbial cell wall components can activate
metabolites, some of which have been implicated in several brain the immune system by interacting with TLRs. Some microbial
disorders, clearly shows the intricate connection between diet, the metabolites (in particular the SCFA butyrate) exert anti-inflammatory
gut and certain gut microbes, and brain diseases. effects. Modified with permission from Needham et al., 2020.

The immune communication channel

Lipopolysaccharides (LPS) and microbe associated molecular and CNS inflammation. The gut microbiome can influence central
patterns (MAMPs) contained in the cell wall of gram-negative immune activation through direct activation of the gut based
microbes can interact locally with receptors on enteric neurons or immune system and trigger pro- and anti-inflammatory systemic
vagal afferents (so called toll-like receptors or TLRs), with cells of immune responses [35]. The involvement of neuroinflammatory
the gut-based immune system, or exert their effects distally and neurodegenerative mechanisms related to the BGM system
throughout the body, including the brain. Many studies have which may play a role in various brain disorders has recently been
investigated the complex interactions between the gut microbiota reviewed (Fig. 3) [13].

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While cell wall components of gut microbes play an important metabolic endotoxemia results from a compromised gut barrier
role in neuroinflammation, other microbes play an important role (“leaky gut”), allowing contacts between gut microbial cell wall
in preventing and counteracting immune activation in the gut. components and Toll-like receptors on dendritic cells, or after
Ackermansia strains are involved in the regulation of the intestinal translocation of intact microbes and activation of other cells in the
mucus layer, an important component of the gut barrier. Another gut-associated immune system. An increase in microbial taxa with
group of microbial metabolites, in particular short chain fatty acids anti-inflammatory function, such as Faecalibacterium prausnitzii (F.
(SCFAs) exert powerful anti-inflammatory effects. SCFAs, in prausnitzii), Eubacterium rectale (E. rectale), E. hallii, and Rumino-
particular butyrate, are produced by a limited number of gut coccus bromii (R. bromii), contributes to a reduction in metabolic
microbes through fermentation of complex carbohydrates, such endotoxemia [41]. Dietary factors that increase the relative
as resistant starch. This group of beneficial microbes include the abundance of these anti-inflammatory and other health-
taxa Faecalibacterium prausnitzii (F. prausnitzii), Eubacterium rectale promoting bacteria include prebiotics such as oligosaccharides
(E. rectale), E. hallii, and Ruminococcus bromii (R. bromii) [36]. They and polyphenols some of which have prebiotic-like effects [42].
mediate their anti-inflammatory effects (Topping et al. 2001; Prebiotics are defined as substrates which benefit host health
Russell et al. 2011) by promoting TH1 cell mediated IL-10 because they are utilized by health-promoting microorganisms
production via G-protein coupled receptors 43 (GPR43). In [43]. One of the main effect of prebiotics is to increase the relative
addition, butyrate has also been shown to downregulate the abundance and activity of gut microbial taxa involved in the
expression of genes involved in inflammatory pathways in non- metabolism of complex carbohydrates into SCFAs [44]. Several
inflamed intestinal tissue [37]. clinical studies have shown the beneficial effects of a diet rich in
There is a close link between immune activation in the gut and prebiotics on the diversity and richness of the gut microbiome,
neuroinflammation in the brain, as the gut microbiome can and on the reduction of systemic immune activation [6, 45]. Such
directly influence the maturation and functioning of microglia in Mediterranean-like diets can promote healthy brain function as
the CNS as part of the immunoregulatory pathways. Microglia demonstrated in a variety of dietary intervention trials in
make up the majority of immune cells in the brain, and gut depression and in cognitive decline [1–3, 6].
bacteria play an important role in their proper functioning. In a If supported by controlled longitudinal intervention studies,
rodent study, germ-free mice had a decreased number of mature such a dietary approach combined with pharmacological and
microglia in various brain areas when compared to mice with a behavioral interventions holds significant promise as a new
normal microbiome [38]. Another study with germ-free mice therapeutic comprehensive approach for psychiatric disorders,
found functional defects in microglia and as a result observed utilizing knowledge discovered in the novel field of Nutritional
heightened levels of proinflammatory cytokines IL-1B, IL-6, and Psychiatry [14].
TNF-alpha [39], indicating an impairment in immune function.
Interestingly, impairments in microglia function were reversed by Diet and neuroactive metabolites
administration of SCFAs [38]. Dysregulation of microglia and gut A healthy diet may change the synthesis and secretion of
microbial dysbiosis have been implicated in several psychiatric neuroactive metabolites by gut microbes, which affects brain
disorders, such as anxiety, depression, neurodegenerative dis- function and health. As discussed under neuroendocrine path-
orders, such as Parkinson’s and multiple sclerosis, and neurode- ways of the last section, 95% of the body’s serotonin is produced
velopmental disorders, such as ASD. in the gut by ECCs and enteric nerve cells with help of the
In summary, the close link between inflammatory signals microbiome [19]. The gut microbiome influences serotonin
originating in the gut in response to certain diets, in particular production and secretion as a direct result of the food we eat
the Standard American Diet, and the crucial role of the gut (in particular the amount of Trp), as diet modulates microbial
microbiota in the generation of both pro- and anti-inflammatory composition [46]. A higher Trp concentration in the gut leads to
signals emphasize the important, but incompletely understood increased serotonin synthesis in ECCs [18, 47]. In a rodent study, it
interactions between diet, the gut microbiome, and brain diseases. was found that mice without an enteric microbiome had only half
the amount of serotonin in the circulation when compared to
Diet and brain health mice with normal gut microbiota [48]. Stimulation of ECCs by
In view of the key role that diet plays in the composition, richness, microbes or intestinal contents moving through the gastrointest-
and function of the gut microbiome, and in view of the existence inal tract trigger the secretion of serotonin onto vagal sensory
of multiple close communication between the microbiome and nerve endings and into the circulation and gut lumen [19]. This
the brain via a network of interacting gut brain communication stimulation of the vagus nerve can result in signal relay to
channels, it has become clear that the interactions of diet and the emotion-regulating brain areas [49]. In the CNS, serotonin
microbiota plays a crucial role in brain structure and function produced and stored in the raphe nuclei as well as vagal signals
throughout the lifespan in multiple ways. While early (“first generated by release of serotonin from ECCs is crucial to the
thousand days”) effects of nutrition on the developing brain have regulation of sleep, appetite, pain sensitivity and mood [18].
long been known, chronic dietary influences on the adult and
aging brain have received increasing attention, in the context of Diet and micronutrients
cognitive decline, AD and Parkinson’s disease. Alterations in this Specific micronutrients such as omega-3 fatty acids and zinc may
influence on the brain as a result of unhealthy diets, or the have an important effect on brain development and function
opportunity to use gut microbiome targeted dietary interventions independent of the gut microbiome [50]. Nutritional research has
as a therapeutic approach have become the focus of Nutritional moved away from focusing on single nutrients because they are
Psychiatry. There are several ways in which diet promotes healthy never consumed in an isolated manner in real life [14]. Rather, a
brain structure and function, which include reduction and diet made up of a variety of different nutritious foods has been
prevention of metabolic endotoxemia, neuroactive metabolites, shown to have the most beneficial effect on both physical and
and essential micronutrients. mental health [11]. Nutrients derived from diet, such as vitamins,
minerals, poly-unsaturated fats, and amino acids support healthy
Diet and metabolic endotoxemia brain function [51–55]. Many of these nutrients serve as cofactors
A number of preclinical and clinical studies have demonstrated a for enzymes, supporting for example the synthesis of neurotrans-
link between the Standard American diet (SAD), and an increase in mitters, myelination, cell signaling, and metabolic pathways [56]. A
markers of systemic immune activation, a phenomenon referred few specific nutrients have been intensely studied in their anti-
to as metabolic endotoxemia [37, 40], As reviewed elsewhere [12], depressant effect such as omega-3 fatty acids, folate, s-adenosyl-

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methionine, inositol, and vitamins B3, B6, and C and may be even unhealthy dietary patterns and poorer mental health, as well as
beneficial if supplemented but only if adjunctive to a gut-healthy for good-quality diet and better mental health in children and
diet [50, 51, 57]. A high ratio of omega-6 to omega-3 fatty acids adolescents. However, in the cross-sectional studies included in
can contribute to a pro-inflammatory state due to the inflamma- this systematic review, no conclusions about causality of diet and
tory properties of AA-produced eicosanoids and anti-inflammatory mental health can be drawn, and the authors discussed several
properties of EPA-produced eicosanoids [58]. Furthermore, low factors that could have influenced the results. One is the
omega-3 fatty acid ingestion has been reflected in mental possibility that subjects with internalizing disorders or symptoms
diseases such as depression [59]. eat more unhealthy foods (“comfort foods”) as a form of self-
In summary, a healthy diet rich in fiber, polyphenols and medication. Another possibility is the influence of early eating
micronutrients has been shown to exert a positive effect on gut habits and nutritional intake on brain development. And there is
microbial composition, a reduction of metabolic endotoxemia and evidence that a nutrient-poor diet may lead to nutrient
neuroinflammation, and has been associated with improvements deficiencies, which have been associated with mental health
in brain health. Fiber has been associated with improved brain issues [67, 68]. Consuming folate, zinc and magnesium is inversely
health and function in a variety of small-scale observational and associated with depressive disorders, whereas omega-3 fatty acids
interventional studies [60]. Serotonin production and release in are inversely related to anxiety disorders.
the enteric nervous system is greatly influenced by dietary choices Systemic immune activation has been implicated in the
as well, with the amounts of complex carbohydrates and pathophysiology of depression [69]. Diets associated with meta-
tryptophan contained in the diet being the most important bolic endotoxemia, such as the SAD, may have a direct impact on
factors. Certain dietary micronutrients such as zinc, omega-3 fatty various biological systems related to depression. Several studies
acids, folate, and B vitamins may further influence brain that have reported strong correlations between mental well-being
development and function, the lack of which can result in mental and reported happiness, and a healthy diet high in fresh fruits and
dysfunction and contribute to the development of brain disorders. vegetables [52–55]. Several reviews and meta-analyses have also
backed this association. An analysis of four cohorts and nine cross-
Diet, the BGM system and brain disorders sectional studies showed that a reduced likelihood of depression
Diet-related alterations in BGM system interactions have been was associated with a higher intake of fruit, vegetables, fish and
implicated in several psychiatric and neurological disorders whole grains [70]. A meta-analysis consisting of eight cohort
summarized in Table 1. In the following, we will discuss a limited studies and one case control, linked a reduced risk of depression
number of these disorders for which significant clinical evidence with adherence to the Mediterranean diet [71].
supports such a relationship. One of the first intervention studies performed to date, the
SMILES trial, involved a 12-week, parallel-group, single-blind
Diet and depression randomized controlled trial (RCT) in 33 female and male
Depression (major depressive disorder, MDD, or clinical depres- participants with moderate to severe depression. Participants
sion) has been increasing in prevalence, in particular in younger were randomized to receive either dietary support or social
age groups [61]. Traditional therapies consist of centrally acting support. Dietary intervention incorporated personalized dietary
medications often in combination with cognitive behavioral advice and nutritional counseling, including motivational inter-
strategies or other psychological strategies. viewing, goal setting, and mindful eating to support adherence to
There have been a number of recent studies demonstrating that the recommended diet [72]. Social support incorporated a
patients with MDD have an altered gut microbiome when ‘befriending’ protocol following the same visit schedule and
compared to healthy controls [62, 63], although the nature of length as the dietary support [2]. Results of the study confirmed
the dysbiosis in each of the studies varies, has not identified a that the dietary intervention caused a statistically significant
consistent microbial biomarker, and causality between gut decrease of depression symptoms compared to the conventional
dysbiosis and clinical symptoms of depression has not been therapy alone, indicating that an adjuvant dietary intervention,
established. A recent large fecal microbiome population study likely involving modulation of the gut microbiome, may be an
using data from the Flemish Gut Flora Project investigated the effective treatment approach for depression.
correlation between gut microbiota composition, symptoms of While two recent RCTs confirmed the benefits of
depression, and indicators of quality of life. The study found a Mediterranean-style diet on depression [1, 3], a diet supplemented
negative correlation between measures of physical functioning with omega-3 fatty acids, selenium, vitamin D, and calcium in the
and the bacterial species Flavonifractor. The bacterial taxa MooDFOOD randomized controlled trial did not reduce major
Coprococcus and Dialister were found to be positively associated depression episodes in overweight or obese adults with subsyn-
with quality of life and depleted in treatment-free depression. The dromal depressive symptoms [73, 74]. However, accounting for
participants with low relative abundance of Bacteroides showed only subjects who complied over 12 months, a supplemented diet
lower quality of life scores and higher prevalence of depression. may be preventive in depression onset.
Furthermore, the GABA and Tryp metabolism pathways were The PREDIMED randomized trial is the largest dietary interven-
enriched in gut health associated microbiota, indicating a tion study to date, including 7,447 participants between 55 and 80
potential role of gut microbes in these pathways [64]. years old, over a time period of 8 years. The primary endpoint of
Several studies have also shown that transferring the micro- the study was a reduction of mortality in participants at high risk
biome of a depressed individual into a healthy rodent (without or for cardiovascular disease. The two intervention groups were put
with suppressed gut microbiota) can induce depressive-like on a traditional Mediterranean diet, one supplemented with nuts
behaviors in the murine recipient, suggesting the possibility of a and the other supplemented with olive oil, whereas the control
causal role for the microbiota in the pathophysiology of group was put on a low-fat diet. While the primary endpoint was
depression [63, 65]. In view of the important influence of diet reached before the study ended, in a secondary analysis of the
on the gut microbiome, and the association of gut microbiome study results, the researchers assessed whether the dietary
changes on depression-like behaviors, diet has emerged as a intervention decreased the risk for depression. Even though not
potential treatment strategy for depression (Table 1). A systematic statistically significant, the average risk for depression for the
review looked at twelve epidemiological studies to determine intervention group was 20% lower. However, in the subset of
whether an association exists between diet quality and patterns in patients with type-2 diabetes, the risk for depression was 40%
mental health in children and adolescents [66]. The study found lower in the intervention group when compared to the control
evidence for a statistically significant relationship between group, which was found to be statistically significant. In addition

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7
to the demonstrated benefit for patients with chronic heart will modulate the gut microbiome in a way that promotes healthy
disease, as well as a subset with depression, this study suggests an ageing. Results of this study showed that dietary adherence to a
interconnectedness of two very prevalent chronic diseases: Mediterranean diet was correlated with specific bacterial taxa
cardiovascular disease and mental illness [3]. which were negatively associated with inflammatory markers and
The HELFIMED study directly investigated the effects of dietary also positively associated with markers of low frailty. Furthermore,
intervention on self-reported depression. Over a 6-month inter- the researchers performed a microbiome ecosystem network
vention period, self-reported depressed subjects were put on a analysis which showed that butyrate producing bacterial taxa
Mediterranean-style diet with fish oil and received nutritional (including the taxa Eubacterium, Feacalibacterium, Blautia and
coaching and cooking classes for enabling maximal dietary unclassified Clostridiales) which were enriched as a result of the
adherence. To account for potential anti-depressive, non-diet dietary intervention are more central than those taxa that are
related effects of nutritional coaching, the control group received associated with increased inflammation and reduced cognition,
social support. The results of this study indicated a significant hence frailty.
reduction in depression, which directly correlated with increased A higher diet quality in adult life has been associated with a
adherence to the Mediterranean diet over 3-months as well as reduced risk of cognitive decline [82]. Moreover, the intake of
6-months. Further interesting findings of the study were the polyphenols in the elderly has been associated with improved
association between decreased depressive symptoms with a cognitive abilities [83, 84]. Another study showed that a
decreased ratio of omega-6 fatty acids to omega-3 fatty acids [1]. Mediterranean diet supplemented with olive oil and nuts was
In summary, the benefits of a largely plant-based diet in associated with improved cognitive function in an older popula-
depression summarized above is likely to include anti- tion [85]. The observed associations of polyphenol rich diets
inflammatory effects mediated by increased production of SCFAs (which require gut microbes to metabolize into absorbable
and polyphenols, an improvement of intestinal permeability and a components) with cognitive function in humans are consistent
resulting reduction in metabolic endotoxemia. Additional benefits with earlier preclinical study results [86].
from increased consumption of omega-3 fatty acids and trace In summary, evidence from preclinical, epidemiological, and a
minerals may relieve the deficiency of certain important nutrients limited number of intervention studies supports the concept that
for mood and overall brain health. a largely plant-based diet, like the Mediterranean diet is conducive
to improved cognition, and a reduction in cognitive decline. These
Diet and cognitive decline clinical benefits are associated with a reduction in levels of certain
Alzheimer’s disease (AD) is a progressive neurodegenerative secondary BAs, alterations in brain structure, and positive changes
disease which currently affects over 40 million people worldwide in gut microbial composition.
[74]. The disease is characterized by memory loss and a loss of
executive function of the brain and can be comorbid with Ketogenic diet and cognitive decline
depression, anxiety, and insomnia [75]. Several clinical studies have shown a positive effect of a ketogenic
Various theories exist about the biochemical mechanisms diet on patients with AD or mild cognitive impairment (MCI),
underlying AD. Biomarkers for AD include the protein aggregates consistent with preclinical results [87–91] (Table 1).
amyloid-beta (Aβ) and tau, which are suggested to undergo Consistent with earlier, preclinical findings [89–94], several
disposition in the CNS as part of the pathophysiology [76]. clinical studies showed that diets that can induce high blood
Brainstem regions like the N. solitarius and the locus coeruleus ketone levels improved cognition and memory in those with AD,
receive vagal input, emphasizing a potential neural link between with emerging evidence for those with MCI [4, 95–99].
the gut microbiome and brain areas that are affected by AD as In AD patients or patients with MCI, a ketogenic diet was
shown in postmortem studies [77]. Neuroinflammation as a associated with improvements in cognitive ability as assessed by
precursor of cognitive impairment which also depends on the the Alzheimer’s Disease Assessment Scale – Cognitive Subscale
composition of the gut microbiome, has previously been (ADAS-cog) [96], improved verbal memory after 6 weeks on the
associated with AD [78]. AD patients have been found to low carbohydrate diet [95], significantly improved executive
demonstrate decreased levels of systemic primary BAs and function [98] and alterations in relative abundance of gut
enhanced levels of distinct secondary BAs (the product of gut microbes such as increased Enterobacteriaceae, Akkermansia,
microbial metabolism) when compared to healthy controls, which Slackia, Christensenellaceae and Erysipelotriaceae abundance, and
are directly correlated with impairments in cognitive functioning decreased Bifidobacterium and Lachnobacterium, in association
and brain glucose mechanism [79]. As bile acid synthesis is with improved AD biomarkers [99]. Several clinical pilot studies
crucially dependent on dietary factors, and as secondary bile are additionally confirmed the positive effect of a medium chain
exclusively generated by certain gut microbes, these findings triglyceride (MCT) diet on ADAS-cog outcomes in adults with mild-
suggest a possible role of diet and the gut microbiome in the to-moderate AD, with observations of an acute improvement on
observed alterations in the ratio between primary and secondary the ADAS-cog [100], a long-term significant improvement in
BAs. Secondary BA levels were associated with the progression of immediate and delayed logical memory and digit-symbol coding
AD symptoms from mild to severe, with higher levels of secondary test [4], and an improvement in the ADAS–cog, Memory
BAs being correlated with worse cognitive function [79]. In Composite Score, and episodic memory, language, executive
another study that compared the metabolic profiles of AD, function, and processing speed [97, 101].
patients to those of healthy controls found the BA deoxycholic In summary, evidence from both preclinical and early-stage
acid to be a part of the characteristic metabolites in early clinical studies suggests a therapeutic benefit of a ketogenic diet
diagnosis of AD [80]. A study by Nho et al. found a correlation in improving cognitive function in particular in patients with
between specific BAs and changes in brain structure and advanced AD despite the heterogeneity of interventional dietary
cerebrospinal fluid (CSF) biomarkers, suggesting that the gut- studies. However, there is a paucity of evidence supporting the
liver-brain axis plays part in cognitive decline characteristic for effect of a ketogenic diet on the prevention of AD development or
AD [81]. All of these data strongly suggest a link between the gut in the treatment of MCI, an area of ongoing research.
microbiota and the development of AD.
The NUAGE dietary intervention is a one-year trial across 5 Diet and autism spectrum disorder
European countries investigating the influence of a healthy diet Autism Spectrum Disorder (ASD) is characterized by impaired
on frailty in pre-frail subjects [6] (Table 1). The premise of this social communication and persistent repetitive behavior present
study with 612 participants held that adopting a high-quality diet in early development and significantly interfering with proper

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social functioning [102]. Over the past decade and a half, the casein-free diet may produce positive effects on symptomatology
prevalence of ASD has been increasing dramatically with ASD and severity in some ASD patients, as well as improvements in
affecting one in 54 children in the United States today [103]. ASD comorbid GI problems. However, due to the small sample size and
is often comorbid with gastrointestinal symptoms, anxiety and the lack of blinding and randomization in most of these studies,
immune dysregulation [104]. The GI symptoms often associated dietary interventions in the treatment of ASD remain to be further
with ASD include diarrhea, abdominal pain and discomfort, gastric researched in well-controlled, large-scale trials. Such studies
reflux, and alterations in bowel habits [105, 106]. should also evaluate the potential role of diet induced changes
As risk genes predisposing for the development of ASD have in gut microbial function in symptom improvement.
not changed during the past decades, various environmental risk
factors including diet and environmental toxins have been Ketogenic diet in epilepsy
implicated in its etiology. Several pre-clinical and clinical studies Although epilepsy is a treatable condition with 1–3% prevalence,
found increased levels of inflammatory markers in the systemic 30% of patients continue to have drug‐resistant epilepsy (DRE), or
circulation of ASD individuals when compared to neurotypical recurrent seizure activity despite taking multiple antiepileptic
controls, such as increased IL-1B [107, 108] and heightened drugs [124]. The pathophysiology has not been fully elucidated,
systemic TNF-alpha [108–110]. Evidence for increased intestinal but intestinal dysbiosis has been implicated, thus making
permeability has been reported in postmortem analysis of ASD ketogenic diet a potential therapy that can exert antiepileptic
individuals [111]. These observations together with the common effects due to changes in the microbiota. A landmark study in
comorbidity of GI symptoms and anxiety strongly suggest that gut mouse models of epilepsy showed that a ketogenic diet protected
dysbiosis may be part of the underlying pathophysiology of ASD. against refractory epileptic seizures only in mice that were
A number of clinical studies [112–115] are consistent with colonized with certain gut microbiota compared to mice treated
preclinical findings [116–118] in demonstrating altered gut with antibiotics [125]. The underlying mechanism involved a
microbial composition and function in ASD patients and suggest- change in microbial abundances, leading to a decline in the
ing a potential role of the gut microbiome in ASD pathophysiology. synthesis of GABA in the periphery while increasing GABA in the
Several small-scale dietary intervention studies have investi- CNS to exert antiseizure effects.
gated diet as a treatment option for ASD (Table 1). An open-label Emerging studies in patients with epilepsy have begun to
study in 70 children with ASD investigated the effects of a 12- elucidate the change in the gut microbiota after being treated
month dietary intervention consisting of a gluten-free, casein-free with a ketogenic diet (Table 1). An initial metanalysis of 10 RCTs on
diet and found improvement for 81% of the participants after the ketogenic diet and drug-resistant epilepsy in children and one
three months [119]. A 12-week, double-blind, cross-over study of a RCT in adults found evidence for a small reduction in seizures
gluten-free, casein-free diet in 14 children with ASD did not report between treated and untreated groups. However, the study was
significant differences between the groups but benefits observed limited given the rate of attrition and short follow-up time frame
by parents which were not identified by the testing were reported of 6 months or less [126].
[120]. A randomized, placebo-controlled, single-blind study in 54 Some studies have evaluated the effect of a ketogenic diet on
children investigated how dietary intervention over a 12-month gut microbial composition. In six patients with DRE and glucose
period affects communication, which was evaluated with the transporter type 1 deficiency syndrome who followed the
Autism Diagnostic Observation Schedule (ADOS). The results ketogenic diet for three months, reverse transcription polymerase
reported were significant improvements in communication in the chain reaction analysis of the fecal microbial profiles showed no
dietary intervention group when compared to the control group. change in Firmicutes or Bacteroides while showing a significant
Additionally, the parents who were not blinded for the study increase in Desulfovibrio spp, which is involved in gut mucosal
confirmed improved social interaction, inattention, and hyper- inflammation [127]. However, in a more recent study, shotgun
activity [121]. A more recent randomized, single-blind, controlled metagenomic DNA sequencing was applied to fecal samples from
study over a 12-month time period involved a comprehensive twelve children with DRE before and after three months on the
dietary intervention where a gluten-free, casein-free diet was ketogenic diet. While taxonomic and functional profiles were
supplemented with certain key nutrients. The researchers altered, alpha diversity did not change significantly during the
reported significant benefits in nonverbal intellectual ability, dietary intervention. Relative abundance of the butyrate produ-
greater improvement in ASD symptoms, and developmental age cing taxa bifidobacteria, E. rectale, and Dialister were significantly
in the dietary intervention group when compared to the control diminished during the intervention, while E. coli was increased
group [7]. Altogether, these studies suggest that ASD core [128]. A case‐control study on 14 children with DRE and 30 healthy
symptoms as well as associated comorbid conditions can be controls showed that a ketogenic diet for a week led to a 50%
improved through comprehensive dietary treatment interven- reduction in seizure frequency in infants, associated with
tions, the definite cause of which has yet to be identified and may decreased levels of Proteobacteri (Cronobacter) and increased
include but not be limited to changes in the gut microbiome. levels of beneficial Bacteroidetes taxa (Bifidobacterium, Bacteroides,
Microbial Transfer Therapy (MTT) has emerged as a promising and Prevotella) compared to baseline, correlating with suppression
treatment approach for ASD patients, wherein a microbiota of seizure activity [108]. A study of 20 children treated with a
transplant from a healthy donor is inserted into the patient. A ketogenic diet for six months showed different patterns of
study with ASD children undergoing MTT found a significant changes in microbiota abundance, with generally lower levels of
sustained decrease in both GI and ASD symptoms and confirmed Firmicutes and Actinobacteria and increased levels of Bacteroidetes
favorable changes in the abundance of certain beneficial bacterial [129]. There was also heterogenous patient outcomes, where a
taxa, including Bifidobacteria, Prevotella, and Desulfovibrio subgroup with increased abundance of butyrate producers
[113, 122]. These results strongly support the view that the gut (Alistipes, Clostridiales, Lachnospiraceae, Ruminococcaceae, and
microbiome plays a pathophysiological role in ASD. Additionally, Rikenellaceae) had a less than 50% reduction in seizures compared
this study indirectly suggest that dietary manipulation of the gut to other subgroups.
microbiome may exert a therapeutic effect mediated by gut When viewed together, there is emerging but mixed clinical
microbes. Reported studies about therapeutic benefits of fecal evidence tying the ketogenic diet to changes in the gut
microbial transfer in patient populations for other psychiatric microbiota and improvements in seizure activity in subsets of
conditions have recently been reviewed with mixed results [123]. patients. Given the dysbiosis that is a consequence of the
In summary, dietary interventions as assessed in these small- ketogenic diet, empirical trials of pre- or probiotics may be
scale, poorly controlled clinical studies suggest that a gluten-free, considered in conjunction with a ketogenic diet in children with

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9
DRE, and longer-term RCTs are needed to assess the feasibility, unaccounted for. Future studies may use metabolomics (“Fodo-
including side effects. mics”) to objectively determine the dietary habits of study
participants [131, 132].
Challenges A major unresolved question is the disease specificity of altered
Published studies collectively show possible therapeutic benefits gut microbial signaling mechanisms. As discussed in this review,
from nutritional interventions in chronic brain disorders, an there appears to be a limited number of such mechanisms, which
important step in an area which has not seen major advances in have been identified in different brain disorders, including but not
the development of novel medications [130]. However, several limited to immune signals, anti-inflammatory mechanisms
challenges remain before the role of diet in the treatment of (SCFAs), tryptophan metabolites, and secondary bile acids. Even
depression, anxiety, cognitive decline, epilepsy, AD and ASD is though comprehensive assessment of gut microbial functions is
firmly established (summarized in Table 2). While a growing list of not available for all disorders to date, it is plausible that a relatively
findings observed in animal models of these diseases strongly limited number of such signaling mechanisms in genetically
suggest a causative role of the gut microbiome and indirectly diet vulnerable individuals plays a role in such different disorders as
in behavioral and biological alterations, the translatability of ASD, depression, AD and MDD. Consistent with this hypothesis are
preclinical findings into human psychiatric diseases has been reported findings from the American Gut Project showing that
challenging in part due to heterogeneity of human study individuals who reported a mental disorder such as depression,
populations, interindividual differences in genetic vulnerability, schizophrenia, post-traumatic stress disorder (PTSD) or bipolar
confounding environmental factors and considerable differences disorder had more in common with other people with mental
in structure and function between the human and mouse brain. In disorders, in terms of the bacteria makeup of their gut
addition to the challenges to clearly identify a causative role of the microbiomes, than they did with their mentally healthy pairs.
gut microbiome, high quality reports about diet-induced normal- This observation held true in both U.S. and UK populations as well
ization of disease-associated dysbiosis which result in behavioral as in males and females [133].
improvements are largely missing. Detailed and standardized
characterization of the gut microbial composition down to the Clinical implications and future directions
strain level, and functional characterization using shotgun Until an objective therapeutic benefit of specific dietary interven-
metagenomics, meta-transcriptomics and metabolomics has only tions has clearly been established, practical implications are
been used in a minority of recent studies. Information about the largely limited to the general recommendation of a healthy,
benefits of certain diets largely comes from cross sectional, largely plant-based diet similar to the traditional Mediterranean
epidemiological studies. These studies have primarily shown a diet which has clearly been shown to be associated with an
benefit of a largely plant based diet in slowing cognitive decline increased abundance of diverse and rich gut microbiome species
[6, 85], or in being associated with a lower rate of depression [1–3]. with a high abundance of anti-inflammatory SCFA producers,
However, there is a paucity of high quality, randomized controlled including F. prausnitzii, E. rectale, Roseburia and A. mucinophilia
clinical trials, and with the exception of a few studies in (Table 3). As discussed extensively in this review, systemic low
depression, cognitive decline and in intractable epilepsy, there is grade immune activation due to increased gut permeability and
relatively little evidence to date that such dietary interventions reduced abundances of SCFA producers appears to be a shared
show a significant therapeutic benefit. The implementation and feature of several common chronic brain disorders and increasing
control of a standardized diet over long periods of time is the prevalence of butyrate producing microbes in the gut should
challenging. The assessment of dietary habits in most studies has be a general therapeutic strategy. High quality RCT demonstrating
relied on questionnaire data which have been notoriously benefits beyond adherence to such a “microbiome-friendly” diet
unreliable. Furthermore, in the reviewed publications, the way by the intake of supplements in the form of pre, pro- or
diet was measured using different questionnaires and interviews postbiotics (substances produced through and released by the
varied greatly between each study, leaving many variables metabolic activity of the microbiome) are currently not available,

Table 2. Challenges in Nutritional Psychiatry.

Challenges
Poor translatability of preclinical findings into human psychiatric diseases due to heterogeneity of human study populations, confounding
environmental factors and significant interspecies differences in brain structure and function.
Paucity of high quality RCT showing diet-induced normalization of disease-associated dysbiosis causally related to clinical improvements.
Detailed and standardized characterization of the gut microbiome down to the strain level, and functional characterization using shotgun
metagenomics, meta-transcriptomics and metabolomics has only been used in a minority of recent studies.
Methodological limitations in assessing dietary habits using questionnaires and interviews
Implementation of and adherence to a standardized diet over long periods of time has been challenging.

Table 3. Future directions in Nutritional Psychiatry.

Clinical implications/future directions
Until an objective’s therapeutic benefits of specific dietary interventions have clearly been established, effective treatments are limited to the
general recommendation of a healthy, largely plant-based diet with high variety of fruit and vegetables, or a ketogenic diet in some instances.
Results from high quality RCTs demonstrating benefits beyond adherence to a largely plant based (“microbiome-friendly”) diet by the intake of
supplementary pre-, pro- or postbiotics are currently not available.
Potential therapeutic benefits of fecal microbial transplants in brain disorders, mimicking such effects previously reported in animal models, and in
human C difficile colitis has generally not been successful, with the exception of an uncontrolled study in ASD (Kang et al., 2017; Kang et al; 2019).
Confirmation of these findings in an RCT is essential before recommending in as an effective treatment for ASD. Reported studies about
therapeutic benefits of fecal microbial transfer in patient populations for other psychiatric conditions have recently been reviewed with mixed
results (Chinna Meyyappan et al., 2020).

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ACKNOWLEDGEMENTS Reprints and permission information is available at http://www.nature.com/
EAM was supported by NIH grants R01 DK048351, R01 DK064539 and P30DK041301. reprints
We thank Cathy Liu for her outstanding editorial support.
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AUTHOR CONTRIBUTIONS
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