TYPE Review

PUBLISHED 09 February 2024

DOI 10.3389/fnut.2024.1337889

Gut microbiota, nutrition, and

OPEN ACCESS mental health
EDITED BY
Andrea K. Boggild,
University of Toronto, Canada
Gia Merlo 1*, Gabrielle Bachtel 2 and Steven G. Sugden 3
REVIEWED BY Department of Psychiatry, New York University Grossman School of Medicine and Rory Meyers
1

Maria Elisa Caetano-Silva, College of Nursing, New York, NY, United States, 2 Lake Erie College of Osteopathic Medicine, Erie, PA,
University of Illinois at Urbana-Champaign, United States, 3 Department of Psychiatry, The University of Utah School of Medicine, Salt Lake City,
United States UT, United States
Ornella Cominetti,
Nestlé Research Center, Switzerland
The human brain remains one of the greatest challenges for modern medicine,
*CORRESPONDENCE
Gia Merlo yet it is one of the most integral and sometimes overlooked aspects of medicine.
[email protected] The human brain consists of roughly 100 billion neurons, 100 trillion neuronal
RECEIVED 14November 2023 connections and consumes about 20–25% of the body’s energy. Emerging
ACCEPTED 24 January 2024 evidence highlights that insufficient or inadequate nutrition is linked to an
PUBLISHED 09 February 2024
increased risk of brain health, mental health, and psychological functioning
CITATION
compromise. A core component of this relationship includes the intricate
Merlo G, Bachtel G and Sugden SG (2024)
Gut microbiota, nutrition, and mental health. dynamics of the brain-gut-microbiota (BGM) system, which is a progressively
Front. Nutr. 11:1337889. recognized factor in the sphere of mental/brain health. The bidirectional
doi: 10.3389/fnut.2024.1337889 relationship between the brain, gut, and gut microbiota along the BGM
COPYRIGHT system not only affects nutrient absorption and utilization, but also it exerts
© 2024 Merlo, Bachtel and Sugden. This is an
substantial influence on cognitive processes, mood regulation, neuroplasticity,
open-access article distributed under the
terms of the Creative Commons Attribution and other indices of mental/brain health. Neuroplasticity is the brain’s capacity
License (CC BY). The use, distribution or for adaptation and neural regeneration in response to stimuli. Understanding
reproduction in other forums is permitted,
neuroplasticity and considering interventions that enhance the remarkable
provided the original author(s) and the
copyright owner(s) are credited and that the ability of the brain to change through experience constitutes a burgeoning area
original publication in this journal is cited, in of research that has substantial potential for improving well-being, resilience,
accordance with accepted academic
and overall brain health through optimal nutrition and lifestyle interventions.
practice. No use, distribution or reproduction
is permitted which does not comply with The nexus of lifestyle interventions and both academic and clinical perspectives
these terms. of nutritional neuroscience emerges as a potent tool to enhance patient
outcomes, proactively mitigate mental/brain health challenges, and improve
the management and treatment of existing mental/brain health conditions
by championing health-promoting dietary patterns, rectifying nutritional
deficiencies, and seamlessly integrating nutrition-centered strategies into
clinical care.

KEYWORDS

brain-gut-microbiota axis, neuroplasticity, mental health, brain health, nutritional

psychiatry, lifestyle psychiatry

1 Introduction
The complex interplay between the foods we eat and how our brains react to nutrition
highlights the interconnectedness of daily lifestyle habits and the health of the brain, mind,
and body. Understanding the relationship between food and its impact on mental/brain health,
in conjunction with the reciprocal influence of mental/brain health on whole-body health,
including gut health, and daily lifestyle habits, such as dietary choices, requires a
transdisciplinary approach that incorporates the fields of psychiatry, psychology, neuroscience,
nutrition, and lifestyle medicine (1–4). This review will explore the significant impact of
nutrition on brain health, mental well-being, and cognitive functioning. It will highlight the

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emerging role of lifestyle interventions and nutritional neuroscience serotonin. Currently, this has been expanded to include
in proactively improving patient outcomes and managing mental/ norepinephrine and dopamine as well. Second is the biorhythm
brain health conditions. theory, which centers on sleep disruption and altercations within the
The brain has the greatest metabolic demands (approximately REM sleep and deep sleep patterns. A dysfunctional sleep rhythm
20–25% of the body’s total energy consumption) of any human organ alters the natural circadian rhythm that is regulated within the nucleus
(5). Additionally, optimal brain health requires various nutrients, suprachiasmaticus (SCN), It is hypothesized that the altered circadian
including carbohydrates, essential fatty acids, proteins, vitamins, and rhythm within the SCN contributes to mood dysregulation patterns
minerals (6, 7). Glucose derived from carbohydrates is the primary throughout the day.
source of energy for the brain. Essential fatty acids (e.g., omega-3 fatty Third is the neuro-endocrine hypothesis. Thyroid levels,
acids, omega-6 fatty acids) play a critical role in maintaining the particularly, hypothyroidism has been linked with the onset of
integrity of structures in the brain, as well as promoting the synthesis depressive symptoms (17). Changes in thyroid hormones have been
and functioning of neurotransmitters and components of the immune linked with serotonin insufficiency (18). As will be discussed in more
system (8). Finally, amino acids found in protein foods, including detail, dysregulation within the HPA, particularly higher levels of
tryptophan, tyrosine, histidine, and arginine, are also utilized by the cortisol have been linked with altercations of the circadian rhythm,
brain to produce neurotransmitters and neuromodulatory compounds hippocampus, and limbic system, which may account for changes of
(9). Research surrounding the link between nutrition and mental/ emotions seen in depression. Individuals with depression also as a
brain health issues has transitioned from an initial focus on nutrient whole have higher levels of cortisol in the mornings and evenings
deficiencies that manifested observable psychiatric and/or compared to non-depressed individuals (19). The fourth is the neuro-
neurological symptoms in clinical settings (i.e., the lack of thiamine immune hypothesis, which also will be discussed in more detail. The
and the potential development of Wernicke syndrome) to a HPA axis and the immune system are significantly interconnected,
prioritization of research inquiries aiming to better understand the and changes with cortisol levels can greatly impact the immune
implications of comprehensive dietary patterns on human well-being system. Changes within neurohormones or other triggers cause the
in the context of both health and disease (4). release of neurotrophic factors, like BDNF, regulatory cytokines, etc.,
Evidence in the burgeoning fields of lifestyle psychiatry and which have been linked with changes in the hippocampus, limbic
nutritional neuroscience has made it increasingly evident that diet is system, SCN and have been linked with depression. Finally, the fifth
not only a matter of physical sustenance but also a fundamental factor is the kindling hypothesis, which states that the actual illness causes
influencing cognitive abilities, emotional states, and risk of or cell death and reinforces depressive symptoms with progressive
protection against mental health issues and/or brain illnesses (4, 10– worsening symptoms.
13). This bidirectional relationship challenges the historical silos of In the 2021 review, Marx et al., show dietary patterns, commonly
nutrition and neuroscience, emphasizing the need for transdisciplinary known as the Western Diet or Standard American Diet, which are
collaboration to unravel the intricacies of how the foods we consume high in saturated fats, refined carbohydrates and ultra-processed
shape the functioning of our brains and, in turn, how the state of our foods, can create many of the Loonen and Ivanona hypotheses (16,
brains influences our dietary choices. 20). A systematic analysis of the Global Burden of Disease Study
assessing the health effects of dietary risks in 195 countries from 1990
to 2017 found that diet-related risk factors were responsible for
2 Intersection of nutrition and mental approximately one-fourth of all deaths among adults and almost
health one-fifth of all disability-adjusted life years among adults (21).
Particularly concerning is the increasing consumption of UPF. Prior
The intersection between nutrition and mental health is an to COVID-19 pandemic, the typical U.S. diet consisted of about 60%
emerging area of research interest. For the purpose of this paper, UPF. The consumption patterns were consistent between gender and
we will focus on depression since the data is more complete and race (22), and the global consumption of UPF has increased in the
depression is projected to be one of the top health concerns by 2030 post-pandemic era (23). UPF contains excessively high levels of
(14). Despite growing medications and therapeutics, the negative refined sugars, saturated fat, trans-fat, caffeine, and sodium, with
impact of depression continues to grow as reflected by the increase in regards to both overall macro- and micronutrient content and energy
disability-adjusted life-years (DALYs), years lived with disability density, as well as very low levels of dietary fiber.
(YLDs), and years of life lost (YLLs) (15).

2.2 Ultra-processed food and

2.1 Five theories of neuropathology of neuropathology
depression
In an attempt to categorize food content, the NOVA food
In their 2016 review, Loonen and Ivanona postulated five theories classification system was developed, which categorizes food into four
regarding the neuropathology of depression (16). First is the well subgroups: 1) unprocessed and minimally processed foods, 2)
known monoamine theory. The majority of psychotropic medications processed culinary ingredients, 3) processed foods, and 4) ultra-
that have FDA approval for the treatment of depression (e.g., selective processed food (UPF), which are defined as “food substances of no or
serotonin reuptake inhibitors, serotonin-norepinephrine reuptake rare culinary use” (24, 25). A 2021 meta-analysis from Lane et al. of
inhibitors, or tricyclic acids) modulate serotonin, as such, the over 345,000 individuals noted that higher rates of UPF predicted an
monoamine theory links the origins of depression to deficits of increased risk of subsequent mental health symptoms (26). In a

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cross-section design of 10,359 participants, Hecht et al. showed that of life and continues to diversify throughout life. Evidence indicates
individuals who consumed primarily NOVA4, had an odds ratio for that microbiota bacteria have undergone a co-evolutionary process
developing depression (OR: 1.81; 95% CI 1.09, 3.02). They had a risk alongside humans and engage in bidirectional physiological
ratio for being more mentally unhealthy (RR: 1.22; 95% CI 1.18, 1.25). interactions with our bodily systems (42). It is estimated that the
Finally, they were also significantly less likely to report zero mentally ratio of microbial cells to human cells in the body is approximately
unhealthy days (OR: 0.60; 95% CI 0.41, 0.88) (27). A potential one-to-one, which points to the significance of microbiota in
explanation may be how a diet rich in UPF leads to dysregulated facilitating processes that support human flourishing across the
neuroimmune responses (28), increased neuroinflammation (29, 30), lifespan. There are three primary pathways through which the gut
and altercations within the neuroendocrine system (29). microbiota interacts with the brain along the BGM system,
including neuroimmune, neuroendocrine, and vagus nerve
pathways (37).
2.3 Ultra-processed food and the gut

People suffering from mental illness consume more UPF (30) and 3.2 BGM system-neuroimmune pathway
people who consume more UPF are prone to develop mental illness
(31, 32). Apart from the neuroinflammatory contribution of mental Dietary habits play a huge role in maintaining a healthy gut
illness on the microbiota, diets high in UPF promote low-grade microbiota (3), which inturn plays a key role in modulating the
inflammation, affecting the microbiota (29). In a recent meta-analysis immune system. Diets rich in dietary fibers, not UPFs, activate
conducted by Nikolova et al. (33), 34 studies comprising more than microbial enzymes within certain bacteria (Bifidobacterium,
1,500 individuals with mental health illness were evaluated and Lactobacillus, Lachnospiraceae, Blautia, Coprococcus, Roseburia, and
showed a pattern of microbiota among mental illness diagnoses, Faecalibacterium) are able to break down complex carbohydrates (43),
which were depleted of pyruvate-producing bacteria. It is important via a fermentation, into short-chain fatty acids (SCFA), namely
to note that this shift in microbial diversity, which affects the acetate, propionate, and butyrate (3). These SCFA have a wide range
absorption of key amino acids and adversely affects brain health of host activities, including metabolism, cell differentiation, gene
(34, 35). regulation (3, 44), and regulating anti-inflammatory and
The following sections delve into the current state of pro-inflammatory cytokines (45). Within the gut, SCFAs strengthen
understanding regarding these intersections, shedding light on the the epithelial barrier functions, which maintains an favorable
mechanisms through which nutrition influences mental well-being environment for commensal bacteria and inhibits pathogen’s
and offering insights into potential avenues for growth (44).
therapeutic interventions. Butyrate is metabolized into acetyl CoA, which is needed in
mitochondrial metabolism. It also plays a pivotal role in regulating
IL-10 receptors and maintaining the gut epithelial tight junctions (44).
3 The brain-gut-microbiota: the Without this, a change of the overall gut microbiota diversity can
developmental origins and a review develop, which may lead to a condition known as dysbiosis. The
growth of Enterobacteriaceae, especially Escherichia, Shigella, Proteus,
3.1 Developmental origins and Klebsiella can increase in enterotoxin levels (46), which leads to
dysbiosis. This pro-inflammatory microbial imbalance typically
The BGM system is a bidirectional communication network occurs in diets rich in UPFs, sodium, saturated fats, trans-fat, and
connecting the gastrointestinal system and the brain that has emerged refined sugar (47, 48). It is significant to note that dysbiosis can lead
as a focal point linking nutrition, health, and well-being (36, 37), to dysregulated immune responses that can contribute to chronic
particularly related to mental/brain health. The gut microbiota is a inflammation and have a wide range of negative health implications,
diverse community of microorganisms inhabiting the digestive tract including health challenges such as neuropsychiatric conditions and
that influences various aspects of brain function through the autoimmune diseases in which neuroinflammation is a key
production of neurotransmitters, immune signaling molecules, and contributing factor (49, 50).
metabolic substances (38). Dietary patterns alter the microbiota Specifically, chronic inflammation from the Enterobacteriaceae
composition of the gut (39). Strengthening the gut microbiota through can release lipopolysaccharide (LPS) from their own cells. Once
dietary interventions holds promise as a novel approach to ameliorate released within the gut, they impair gut-associated lymphoid tissue
mental/brain health symptoms, risk factors, and protective factors as (GALT), which includes the multi-follicular Peyer’s patches of the
the BGM system is a primary mechanistic channel through which the ileum, the numerous isolated lymphoid follicles (ILF) distributed
gut microbiota exert their effects on mental/brain health through along the length of the intestine, and the vermiform appendix (28).
nutrition-related pathways (4, 33). Additionally, the disruption of the immune system within the
The gut and brain are both derived from neural crest tissue enteric system will alter system immunity. Additional critical
during embryogenesis and influence each other during human consequences of LPS include: increases blood brain barrier
developmental processes as they integrate into the enteric nervous permeability, altering the microglia of the CNS as it promotes
system (40, 41). Microbes initially colonize the gastrointestinal tract gliosis and neuronal damage (51). Due to the breakdown of the
at the time of birth. A microbiota is a biological community that blood brain barrier, there is an increase of plasma proteins into the
forms when microorganisms live in a specific habitat and produce brain, particularly the component proteins, which can adversely
genetic material. The human microbiota develops after the first year affect synaptic pruning (52).

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Communication between the gut microbiota and the immune nerve, which is also composed of motor branches known as vagal
system occurs as part of the broader BGM system, rather than in efferents, sends signals from the brain to the gastrointestinal tract and
isolation. Bidirectional crosstalk between these two major biological other organs. Vagal motor signals can influence functions of the
systems happens in such a way that signals from the gut can affect the gastrointestinal tract like gut motility, the secretion of digestive
brain and vice versa. The immune system may send signals to the enzymes, and the modulation of immune responses in GALT (63).
brain when it detects inflammation in the gut, which can affect mood,
behavior, and cognitive function. There is evidence that this
bidirectional communication can contribute to the development or 4 Brain health, mental health, and
progression of neuropsychiatric conditions such as depression, wellness
anxiety, and as well as other mood disorders (47).
While mental health is known by both the public and scientific
community, it does not capture the importance of the concept of brain
3.3 BGM system-neuroendocrine pathway health. Brain health is defined by the WHO as the fostering of optimal
brain development, cognitive health, and well-being throughout the
The neuroendocrine pathway of the BGM system involves a entire lifespan (64). As such, brain health includes what is thought,
complex network of communication between the brain, the gut, and done, said, and felt. The lifespan continuum of brain health is also in
the endocrine system (37). In addition, the production of LPS has alignment with current evidence regarding neuroplasticity, the ability
been shown to activate the hypothalamic–pituitary–adrenal axis of the brain to adapt and escape previous genomic restrictions through
(HPA) (53). Heightened levels of cortisol can in turn change intestinal the formation and reorganization of synaptic connections.
permeability by activating interferon gamma, interleukin 6, Brain health includes the concepts of wellness, mental health, and
interleukin 1 beta, and tumor necrosis factor alpha (54), which alter brain health (65) (see Figure 1 for a representation of the relationship
the diversity of the gut microbiota, leading to dysbiosis (55), neuronal between wellness, mental health, and brain health). With this
damage within microglia and astrocytes, and depletion of framework in mind, it is important to note how dietary choices across
neurotrophic factors, like BDNF (56). Heightened levels of cortisol the lifespan have the potential to positively alter brain structure and
can affect brain function by decreasing prefrontal cortex activity, improve brain health or negatively impact it.
heightening amygdala fear response and decreasing functional
memory due to its negative hippocampal interactions.
Additionally, there is a growing body of literature that a number 5 Nutrition and brain changes across
of neurotransmitters that function as hormones are also mediated the lifespan
within the BGM axis. Serotonin, for example, is derived from the
essential amino acid tryptophan, which is absorbed within the The brain and body are exposed to a wide array of exogenous and
kynurenine pathway (34) and regulated through the gut microbiota endogenous stimuli that can impart various levels of functionality
(46, 55). Serotonin concentration within the brain can contribute to across biopsychosocial spheres of health, which determine both
the development and or progression of depression and anxiety (57). short- and long-term outcomes across the lifespan. A healthy early
Enterobacteriaceae have also been shown to be histamine producing life development of the BGM system helps prevent later disease
bacteria (58). Histamine has been linked with visceral gut development. Nutritional programming is the concept that key cells
hypersensitivity, increased gut permeability and altered gut motility within the body will be able to absorb nutrients or synthesize them
(59), and studies have linked depression to these heightened de novo in key periods of time to support early life development (66).
eosinophilic conditions (60). Multiple nutrients with epigenetic potential that are present in the
diet or produced via microbial metabolism in the human gut. The
B-complex vitamins, SCFAs, and polyphenols are among nutrients
3.4 BGM system-vagus nerve known to exert epigenetic effects on the host (67). Significant
synaptogenesis in the brain occurs simultaneous to diversification of
The vagal pathway of the BGM system involves the vagus nerve, gut bacteria during critical windows (68, 69). Critical windows are
the tenth cranial nerve, that plays a significant role in the bidirectional periods of development during which the phenotypic outcomes (e.g.,
transmission of signals between the brain and the gastrointestinal intelligence quotient) of an individual are remarkably sensitive to
tract. The vagus nerve extends from the brainstem into the abdomen interactions between environmental and genetic factors.
through the gastrointestinal tract and other organs, including the Environmental factors, such as diet, can significantly alter the
heart and lungs and transmits both sensory and motor signals developmental course of high-plasticity bodily systems, such as the
throughout the mesenteric organs. The sensory components of the central nervous system, cardiovascular system, gastrointestinal
vagus nerve called vagal afferents relay information from numerous system, and immune system (70). As such, within the nutritional
organs to the brain, including signals associated with the gut framework, nutrients need to be available for optimal
environment such as the presence of inflammation, gut distension, development (66).
nutrient availability, and gut hormones (i.e., leptin, ghrelin, glucagon-
like peptide 1, and insulin), and gut microbial metabolites (29, 61).
Bidirectional communication between the brain and gut relies on an 5.1 Fetal period
axis composed of 80% afferent and 20% efferent neurons (62). These
microbial sensory signals can convey information about the The fetal period is a key nexus period within the nutritional
composition and activity of the gut microbiota to the brain. The vagus framework. It is estimated that over half of the maternal energy

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FIGURE 1
Relationship between wellness, mental health, and brain health. Copyright 2023. From Lifestyle Psychiatry by Gia Merlo & Chris Fagundes. Reproduced
by permission of Taylor and Francis Group, LLC, a division of Informa plc.

available to the growing fetus during pregnancy is allocated to brain connectivity of neuronal networks in both white and gray matter,
development (71). The brain health, quality of life, and overall well- including regions of the brain consistent with improved outcomes
being of offspring are critically dependent on the trajectory of their related to cognitive and behavioral performance (80–83). Studies have
neurodevelopment, which begins prenatally (72, 73). An explanation not only revealed that levels of cognitive function of breast-fed
for the relationship between postnatal neurodevelopment and gut children are significantly higher than formula-fed children at six to
microbiota diversity may lie in their influence on each other’s twenty-three months of age, but also that this distinction in brain
maturation processes mediated through the BGM axis (74). performance persists over time as children age (84–86).
Diet plays a critical role in the development of the gut microbiota
in early life (75, 76). Research has demonstrated that the presence of
breast- or formula-feeding, as well as the timing of transition to solid 5.2 Early life
foods, are major drivers in shifting the gut microbiota to a more adult-
like composition (77). Gut microbiota composition varies between Early life eating patterns, which modulate and prime the gut
infants fed breast milk versus formula. The microbiota of breast-fed microbiota have been found to influence both short- and long-term
infants primarily consists of Bifidobacterium, Lactobacillus, and human health and disease, including brain health and heart disease
Staphylococcus (77, 78). Notably, the microbiota of formula-fed infants (87). Codagnone et al. (88) identified the gut microbiota as the fourth
is predominantly Clostridium, Anaerostipes, and Roseburia. Moreover, most significant element in the programming of brain health and
data indicates that the introduction of solid foods around 6 months of disease during early life, in addition to host genetics and prenatal and
age (within the critical neurodevelopmental window) in infants with postnatal environment. Adolescence is a critical period of
an immature gut microbiota can fortify their health by stimulating the neurodevelopment that coincides with maturing socially, cognitively,
growth of microbes typically present in the adult gut (79). Adult-like and improving executive function (89). Typical adolescent diets tend
gut microbiota are typically inclusive of Anaerostipes, Bacteroides, to be high in UPF, high in sugar containing foods and beverages, and
Bilophila, Clostridium, and Roseburia (77). low in fiber. Adolescent diets can contribute to mental health
It has also been noted that breast milk feeding and duration of symptoms, yet experts are still investigating the crossroads of a healthy
breastfeeding are positively associated with enhanced structural gut microbiota, a developing brain, and brain health (90).

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5.3 Adult life within the microglia. The intent of this section is not to provide a
definitive review of all possible implications but rather show
Composition of gut microbiota gradually shifts throughout the examples within the metabolic, immune, neuronal, and
lifespan and has been shown to play a role in the regulation of endocrine pathways.
age-related changes in cognitive function and immunity (91). It is of
significance to note that the current global burden of disease is mainly
caused by neuropsychiatric conditions and cardiovascular disease. 6.1 Neuronal cell count
Poor diet, which can induce dysbiosis, has been established as one of
the major contributing factors to the global burden of disease (92). Neurogenesis is a fundamental component of neuroplasticity, as
Individuals affected by neuropsychiatric conditions are also more well as the functional and structural processes related to brain health
likely to be affected by chronic conditions, such as cardiovascular homeostasis. The formation of new neuronal cells continues in the
diseases (93). Daily lifestyle choices, including healthy or unhealthy adult hippocampus throughout the course of the lifespan. The
eating patterns, can serve as protective factors or risk factors for the hippocampus is a region in the brain that modulates learning,
development and progression of neuropsychiatric conditions and memory, and mood and is extremely sensitive to environmental
chronic health conditions. stimuli, including diet (103). Evidence suggests that decreased
Individual differences in lifestyle-related factors, such as diet, neurogenesis contributes to cognitive impairment and
contribute to cognitive reserve and physical reserve. Cognitive reserve neuropsychological conditions, such as anxiety and depression (104,
is the brain’s adaptive capacity to be resilient against neural damage or 105). Zainuddin & Thuret suggest that nutrition can influence adult
age-related cognitive decline by efficiently using available brain hippocampal neurogenesis via four primary pathways, including
resources through pre-existing or compensatory processes (94). caloric intake, the nutritional content of meals, frequency of meals,
Physical reserve is the body’s capacity to maintain physical and texture of meals (106).
functionality in the setting of illness, injury, or age-related
physiological changes (95). Robust evidence indicates healthy eating
(96). The World Health Organization describes a healthy diet as an 6.2 Neuronal cell migration
eating pattern that is rich in fruits, vegetables, legumes, nuts, and
whole grains and restricted in refined sugar, salt, saturated fats, and Recent literature suggests that neuropsychiatric disorders and
trans-fats (97). A healthy diet has been found to be positively cognitive dysfunction are linked to damage induced by oxidative stress
correlated with cognitive reserve and cognitive function (98). on nuclear and mitochondrial DNA (107, 108). Oxidative stress is a
key pathway through which dietary factors affect neuronal cell
migration. Of note, reactive oxygen species (ROS) involved in
5.4 Elderly life pathways related to oxidative stress have been found to induce
epigenetic changes in aging processes of the brain (109), as oxidative
The gut microbiota composition again changes in this phase of damage has been recorded as a significant contributor to
adult life as the bacterial diversity decreases. Opportunistic bacteria, neurodegeneration (110). Increased production of free radical
like the Enterobacteriaceae family, increase in density (99). Animal production and inflammatory responses may occur when long-term
models have shown that higher concentrations of LPS in adults can exposure to prooxidant and proinflammatory metabolic factors
lead to increased blood brain permeability, tau hyperphosphorylation exceeds the capacity of bodily systems to protect against tissue injury
and additional neuroinflammation and may account for cognitive and mitochondrial damage (111). Long-standing excess in certain
deficits (100). In a cross-sectional study of 127 participants, Saji et al. nutritional components can induce a metabolic state of chronic,
found a correlation between LPS concentration and mild cognitive dysregulated, low-level inflammation often co-occurs with
impairment (odds ratio: 2.09, 95% confidence interval: 1.14–3.84, mitochondrial dysfunction (112).
p = 0.007) (101). Oxidative stress and damage can be caused by prooxidant foods,
which have been found to decrease antioxidant activity and increase
the production of ROS (113). The quality and quantity of various
6 BGM system and neuroplasticity macronutrients and micronutrients can interact with prooxidant or
antioxidant metabolic pathways (114). Data indicates that oxidative
Brain development is a process that occurs throughout the mechanisms inhibit the proliferation of precursor neurons, as well as
lifespan of the individual. After the initial fetal development, the migration, differentiation, and viability of new neuronal cells
which is driven by the actual genetics of the fetus, subsequent (115, 116).
development, also called neuroplasticity, is significantly driven by
environmental and epigenetic changes. Changes can provide
benefits or maladaptive effects that can lead to a spectrum of 6.3 Cell phenotypes
neuropsychiatric sequelae (102). In a recent review, Innocenti
identifies five potential targets of neuroplastic change: 1) neuronal The differentiation process of a neuron into somato-dendritic or
cell count, 2) neuronal cell migration, 3) differentiation of the axonal phenotypes engenders alterations in metabolic needs that vary
somatodendritic and axonal phenotypes, 4) formation of neuronal from those of precursor or stem neuronal cells and are mediated by
connections or pathways, and 5) cytoarchitectonic differentiation dietary nutrients (117). Differentiated mature neurons require higher

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levels of energy. The increased energy needs of the developing or microglial diversity in later life through these epigenetic
mature brain is bolstered through a metabolic shift from energy modifications (129).
primarily sourced from cytoplasmic aerobic glycolysis to neuronal
oxidative phosphorylation modulated by the mitochondria (117, 118).
It is important to note that the reprogramming of metabolic processes 7 Neuropsychiatric disorders affected
related to the oxidation, glycolysis, and mitochondria supports by food
neurogenesis and the functionality of differentiated neuronal cells by
promoting adequate epigenetic modulation of gene expression and As previously discussed, there is a bidirectional link between
increased signaling of neurotransmitters in both the central nervous metabolic aberrations and a diverse array of neuropsychiatric
system and across the BGM system. disorders (130–132). Approximately one in three individuals with a
chronic health condition are affected by co-occurring neuropsychiatric
condition (133, 134). Not surprisingly, the neuropsychiatric conditions
6.4 Neuronal connections most affected by dietary factors, anxiety and depression (135), are also
those most prevalent in the general population. Diet-related pathways
Increasing evidence substantiates that the both cognitive and for therapeutic targets include the BGM system, inflammation,
non-cognitive functions of the brain encoded in the human genome oxidative stress, mitochondrial dysfunction, epigenetics, the HPA axis,
are vulnerable to modification via epigenetic and epitranscriptomic and tryptophan-kynurenine metabolism (20), which address many of
mechanisms (119–122). The bidirectional relationship between food neural circuits implicated in depression (16).
and the BGM system can alter neuroplasticity through interactions As noted, depression continues to be one of the world’s most
with these epigenetic and epitranscriptomic pathways. Nutrient intake debilitating illnesses. World estimates have estimated the lifetime
can regulate gene expression that modulates learning, memory, and prevalence between 30 and 40% (136). It is not uncommon for
adaptive behaviors (123). Alternatively, neuroplastic changes in symptoms to last at least 1 year in duration (137). Depression is
learning, memory, and adaptive behaviors can alter gene expression comorbid with other neuropsychiatric illnesses (i.e., anxiety, cognitive
to promote different eating patterns. For instance, peptide hormones, impairment, post-traumatic stress disorder, substance use disorders)
such as ghrelin, leptin, and insulin, which are implicated in and chronic physical disorders (i.e., arthritis, asthma, cancer,
physiological processes surrounding hunger and satiety, utilize cardiovascular disease, chronic pain, chronic respiratory disorders,
nutrient sensing along the BGM system to modulate signals in the diabetes, hypertension, obesity) (138). Those with these comorbid
brain related to hunger, satiety, and food-induced reward (124). outcomes tend to have worse outcomes (137). As a result, individuals
Reception of these signals then shapes adaptive behaviors and with depressive disorders commonly develop a pattern of dysbiosis,
experiential learning and conditioning associated with food intake, showing higher concentrations of the Bacteroides species, a species
which can regulate mechanisms for the activation or repression of that alters the BGM system (139, 140).
certain genes (125). Historically, the treatment of choice for depression has been the
use of medications that modulate the uptake of serotonin (i.e.,
selective serotonin reuptake inhibitors). Many individuals, however,
6.5 Cytoarchitectonic differentiation have not received symptom relief from these remedies (141). Lessale
et al., conducted a meta analysis of 21 cross sectional studies and 20
Bioactive nutritional compounds may have the potential to longitudinal studies. Individuals were either adhering to the
restore quiescent capacity of microglia, which are cells that play a Mediterranean diet (MD), the Healthy Eating Index, the Alternative
vital role in neurodevelopment (e.g., neuronal proliferation, Healthy Eating Index, the Dietary Approaches to Stop Hypertension,
neuronal differentiation), brain health homeostasis, neuroplasticity, or the Dietary Inflammatory Index. Individuals on the MD had an
and injury response and repair mechanisms in the central nervous estimated relative risk of developing depression of 0.67 (5% CI 0.55–
system. Dysregulation of microglial cytoarchitectonic differentiation 0.82) (142). Firth et al. examined 16 randomized clinical controlled
has implications in neuroinflammation, cognitive deficits, trials (dietary interventions varied) comprising over 45,000
neuropsychiatric conditions, and chronic inflammatory diseases participants and noted that dietary interventions improved
(126). Cytoarchitectonic differentiation within the microglia depressive symptoms compared to controls (g = 0.275, 95% CI = 0.10
denotes the process of area-specific structural organization of these to 0.45, p = 0.002) (29). The SMILES study, a randomized control
nervous system-specific macrophage cells. Neuroinflammatory study, had study participants avoid UPF and fast food. The study
responses can be induced by microglial cells in response to immune showed that the number needed to improve depressive symptoms
signals from the periphery. Evidence has demonstrated that was 4.1 (143). A meta-analysis from 2018 of epidemiological studies
age-related alterations in the brain cause changes in microglial showed that every increase in 100 g of whole fruits or vegetables
morphology, as well as attenuated microglial functional capability corresponded with a 5% reduction risk of depression (144). Given
to regulate injury and repair processes through adequate these findings the Royal Australian and New Zealand College of
homeostatic shifts between anti-inflammatory and proinflammatory Psychiatrists recommend lifestyle changes, including diet and
states and migratory and clearance abilities (127). Epigenetic exercise, and therapy for mild and moderate forms of depression
modifications also change microglial functional profiles (128). Data (145). Similarly, the World Federation of Society for Biological
suggests that microglia exposed to different environmental factors Psychiatry has adopted a WFBP within its treatment
early in life, such as certain nutrients, may have implications in recommendations for depression (146).

Frontiers in Nutrition 07 frontiersin.org

Merlo et al. 10.3389/fnut.2024.1337889

8 Future directions related to the gut Psychiatry and adopt lifestyle guidelines within their
microbiota, nutrition, and mental mental recommendations.
health
Prior to the COVID-19 pandemic, it was estimated that 50% of Author contributions
the United States experienced loneliness (147). Following the
pandemic, the impact of loneliness has increased. More adolescents GM: Writing – original draft, Writing – review & editing. GB:
report loneliness and isolation and chronic illness. Although there Writing – original draft, Writing – review & editing. SS: Writing –
is not a direct correlation between isolation, chronic illness and original draft, Writing – review & editing.
mental health, those who experience isolation report having
increasing mental health symptoms (148). Based on world events,
social injustice, and worsening socioeconomic factors, it seems Funding
unlikely that these trends will reverse. Although it may seem trivial
in the wake of these factors to focus on the BGM system and The author(s) declare that no financial support was received for
nutrition, this effort may have more of a global impact. In addition the research, authorship, and/or publication of this article.
to the mental health symptoms as outlined, dietary choices are the
largest driver of chronic illness (21). The health industry promotes
protein as the optimal food ingredient to reverse these trends and Conflict of interest
overlooks the importance of fiber (43). As a result, less than 5% of
Americans are consuming an adequate dose of fiber (149), which The authors declare that the research was conducted in the
has been key in developing and maintaining a healthy BGM-system absence of any commercial or financial relationships that could
(3, 34, 150). be construed as a potential conflict of interest.
Traditionally, healthcare professionals receive very little evidence-
based nutrition didactics during their formal education (151). The
reasons vary from nutrition being a “soft science,” or there is “too Publisher’s note
much controversy over the nutrition literature,” or there is “only time
to teach what is on licensing exams.” To ensure that healthcare All claims expressed in this article are solely those of the authors
providers receive this vital training, licensure boards need to and do not necessarily represent those of their affiliated
incorporate questions regarding plant-based nutrition and the organizations, or those of the publisher, the editors and the
importance of the BGM system. Additionally, we encourage other reviewers. Any product that may be evaluated in this article, or
medical organizations to follow the Royal Australian and New Zealand claim that may be made by its manufacturer, is not guaranteed or
College of Psychiatrists and World Federation of Society for Biological endorsed by the publisher.

References
1. Merlo G, Vela A. Mental health in lifestyle medicine: a call to action. Am J Lifestyle 12. Firth J, Gangwisch JE, Borisini A, Wootton RE, Mayer EA. Food and mood: how
Med. (2021) 16:7–20. doi: 10.1177/15598276211013313 do diet and nutrition affect mental wellbeing? BMJ. (2020) 369:m2382. doi: 10.1136/bmj.
m2382
2. Marx W, Moseley G, Berk M, Jacka F. Nutritional psychiatry: the present state of
the evidence. Proc Nutr Soc. (2017) 76:427–36. doi: 10.1017/S0029665117002026 13. Morais LH, Schreiber HL 4th, Mazmanian SK. The gut microbiota-brain axis in
behaviour and brain disorders. Nat Rev Microbiol. (2021) 19:241–55. doi: 10.1038/
3. Berding K, Vlckova K, Marx W, Schellekens H, Stanton C, Clarke G, et al. Diet and
s41579-020-00460-0
the microbiota-gut-brain Axis: sowing the seeds of good mental health. Adv Nutr. (2021)
12:1239–85. doi: 10.1093/advances/nmaa181 14. Herselman MF, Bailey S, Bobrovskaya L. The effects of stress and diet on the
"brain-gut" and "gut-brain" pathways in animal models of stress and depression. Int J
4. Adan RAH, van der Beek EM, Buitelaar JK, Cryan JF, Hebebrand J, Higgs S, et al.
Mol Sci. (2022) 23:2013. doi: 10.3390/ijms23042013
Nutritional psychiatry: towards improving mental health by what you eat. Eur
Neuropsychopharmacol. (2019) 29:1321–32. doi: 10.1016/j.euroneuro.2019.10.011 15. GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden
of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis
5. Magistretti PJ, Allaman I. A cellular perspective on brain energy metabolism and for the global burden of disease study 2019. Lancet Psychiatry. (2022) 9:137–50. doi:
functional imaging. Neuron. (2015) 86:883–901. doi: 10.1016/j.neuron.2015.03.035 10.1016/S2215-0366(21)00395-3
6. Muth AK, Park SQ. The impact of dietary macronutrient intake on cognitive 16. Loonen AJ, Ivanova SA. Circuits regulating pleasure and happiness-mechanisms
function and the brain. Clin Nutr. (2021) 40:3999–4010. doi: 10.1016/j.clnu.2021.04.043 of depression. Front Hum Neurosci. (2016) 10:571. doi: 10.3389/fnhum.2016.00571
7. Suárez-López LM, Bru-Luna LM, Martí-Vilar M. Influence of nutrition on mental 17. Nuguru SP, Rachakonda S, Sripathi S, Khan MI, Patel N, Meda RT. Hypothyroidism
health: scoping review. Healthcare (Basel). (2023) 11:2183. doi: 10.3390/ and depression: a narrative review. Cureus. (2022) 14:e28201. doi: 10.7759/cureus.28201
healthcare11152183
18. Kirkegaard C, Faber J. The role of thyroid hormones in depression. Eur J
8. Yehuda S, Rabinovitz S, Mostofsky DI. Essential fatty acids and the brain: from Endocrinol. (1998) 138:1–9. doi: 10.1530/eje.0.1380001
infancy to aging. Neurobiol Aging. (2005) 26:98–102. doi: 10.1016/j.
19. Zajkowska Z, Gullett N, Walsh A, Zonca V, Pedersen GA, Souza L, et al. Cortisol
neurobiolaging.2005.09.013
and development of depression in adolescence and young adulthood - a systematic
9. van de Rest O, van der Zwaluw NL, de Groot LC. Literature review on the role of review and meta-analysis. Psychoneuroendocrinology. (2022) 136:105625. doi: 10.1016/j.
dietary protein and amino acids in cognitive functioning and cognitive decline. Amino psyneuen.2021.105625
Acids. (2013) 45:1035–45. doi: 10.1007/s00726-013-1583-0
20. Marx W, Lane M, Hockey M, Aslam H, Berk M, Walder K, et al. Diet and
10. Grosso G. Nutritional psychiatry: how diet affects brain through gut microbiota. depression: exploring the biological mechanisms of action. Mol Psychiatry. (2021)
Nutrients. (2021) 13:1282. doi: 10.3390/nu13041282 26:134–50. doi: 10.1038/s41380-020-00925-x
11. Gulas E, Wysiadecki G, Strzelecki D, Gawlik-Kotelnicka O, Polguj M. Can 21. GBD 2017 Diet Collaborators. Health effects of dietary risks in 195 countries,
microbiology affect psychiatry? A link between gut microbiota and psychiatric disorders. 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet.
Psychiatr Pol. (2018) 52:1023–39. doi: 10.12740/PP/OnlineFirst/81103 (2019) 393:1958–72. doi: 10.1016/S0140-6736(23)02839-8

Frontiers in Nutrition 08 frontiersin.org

Merlo et al. 10.3389/fnut.2024.1337889

22. Juul F, Parekh N, Martinez-Steele E, Monteiro CA, Chang VW. Ultra-processed 47. Barber TM, Valsamakis G, Mastorakos G, Hanson P, Kyrou I, Randeva HS, et al.
food consumption among US adults from 2001 to 2018. Am J Clin Nutr. (2022) Dietary influences on the microbiota-gut-brain Axis. Int J Mol Sci. (2021) 22:3502. doi:
115:211–21. doi: 10.1093/ajcn/nqab305 10.3390/ijms22073502
23. Dicken SJ, Batterham RL. Ultra-processed food: a global problem requiring a 48. Malesza IJ, Malesza M, Walkowiak J, Mussin N, Walkowiak D, Aringazina R, et al.
global solution. Lancet Diabetes Endocrinol. (2022) 10:691–4. doi: 10.1016/ High-fat, Western-style diet, systemic inflammation, and gut microbiota: a narrative
S2213-8587(22)00248-0 review. Cell. (2021) 10:3164. doi: 10.3390/cells10113164
24. Monteiro CA, Cannon G, Moubarac JC, Levy RB, Louzada MLC, Jaime PC. The 49. Mousa WK, Chehadeh F, Husband S. Microbial dysbiosis in the gut drives systemic
UN decade of nutrition, the NOVA food classification and the trouble with ultra- autoimmune diseases. Front Immunol. (2022) 13:906258. doi: 10.3389/
processing. Public Health Nutr. (2018) 21:5–17. doi: 10.1017/S1368980017000234 fimmu.2022.906258
25. Braesco V, Souchon I, Sauvant P, Haurogné T, Maillot M, Féart C, et al. Ultra- 50. Xu H, Liu M, Cao J, Li X, Fan D, Xia Y, et al. The dynamic interplay between the
processed foods: how functional is the NOVA system? Eur J Clin Nutr. (2022) gut microbiota and autoimmune diseases. J Immunol Res. (2019) 2019:1–14. doi:
76:1245–53. doi: 10.1038/s41430-022-01099-1 10.1155/2019/7546047
26. Lane MM, Davis JA, Beattie S, Gómez-Donoso C, Loughman A, O'Neil A, et al. 51. Yu LW, Agirman G, Hsiao EY. The gut microbiome as a regulator of the
Ultraprocessed food and chronic noncommunicable diseases: a systematic review and Neuroimmune landscape. Annu Rev Immunol. (2022) 40:143–67. doi: 10.1146/annurev-
meta-analysis of 43 observational studies. Obes Rev. (2021) 22:e13146. doi: 10.1111/ immunol-101320-014237
obr.13146
52. Veerhuis R, Nielsen HM, Tenner AJ. Complement in the brain. Mol Immunol.
27. Hecht EM, Rabil A, Martinez Steele E, Abrams GA, Ware D, Landy DC, et al. (2011) 48:1592–603. doi: 10.1016/j.molimm.2011.04.003
Cross-sectional examination of ultra-processed food consumption and adverse mental
53. Farzi A, Fröhlich EE, Holzer P. Gut microbiota and the neuroendocrine system.
health symptoms. Public Health Nutr. (2022) 25:3225–34. doi: 10.1017/
Neurotherapeutics. (2018) 15:5–22. doi: 10.1007/s13311-017-0600-5
S1368980022001586
54. Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J,
28. Mörbe UM, Jørgensen PB, Fenton TM, von Burg N, Riis LB, Spencer J, et al.
et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-
Human gut-associated lymphoid tissues (GALT); diversity, structure, and function.
analysis, and meta-regression. Lancet Psychiatry. (2015) 2:1002–12. doi: 10.1016/
Mucosal Immunol. (2021) 14:793–802. doi: 10.1038/s41385-021-00389-4
S2215-0366(15)00309-0
29. Firth J, Marx W, Dash S, Carney R, Teasdale SB, Solmi M, et al. The effects of
55. Rusch JA, Layden BT, Dugas LR. Signaling cognition: the gut microbiota and
dietary improvement on symptoms of depression and anxiety: a Meta-analysis of
hypothalamic-pituitary-adrenal axis. Front Endocrinol (Lausanne). (2023) 14:1130689.
randomized controlled trials. Psychosom Med. (2019) 81:265–80. doi: 10.1097/
doi: 10.3389/fendo.2023.1130689
PSY.0000000000000673
56. Calcia MA, Bonsall DR, Bloomfield PS, Selvaraj S, Barichello T, Howes OD. Stress
30. Tristan Asensi M, Napoletano A, Sofi F, Dinu M. Low-grade inflammation and
and neuroinflammation: a systematic review of the effects of stress on microglia and the
ultra-processed foods consumption: a review. Nutrients. (2023) 15:1546. doi: 10.3390/
implications for mental illness. Psychopharmacology. (2016) 233:1637–50. doi: 10.1007/
nu15061546
s00213-016-4218-9
31. Adjibade M, Julia C, Allès B, Touvier M, Lemogne C, Srour B, et al. Prospective
57. Pourhamzeh M, Moravej FG, Arabi M, Shahriari E, Mehrabi S, Ward R, et al. The
association between ultra-processed food consumption and incident depressive
roles of serotonin in neuropsychiatric disorders. Cell Mol Neurobiol. (2022) 42:1671–92.
symptoms in the French NutriNet-Santé cohort. BMC Med. (2019) 17:78. doi: 10.1186/
doi: 10.1007/s10571-021-01064-9
s12916-019-1312-y
58. Mou Z, Yang Y, Hall AB, Jiang X. The taxonomic distribution of histamine-
32. Chen X, Zhang Z, Yang H, Qiu P, Wang H, Wang F, et al. Consumption of ultra-
secreting bacteria in the human gut microbiome. BMC Genomics. (2021) 22:695. doi:
processed foods and health outcomes: a systematic review of epidemiological studies.
10.1186/s12864-021-08004-3
Nutr J. (2020) 19:86. doi: 10.1186/s12937-020-00604-1
59. Vanuytsel T, Bercik P, Boeckxstaens G. Understanding neuroimmune interactions
33. Nikolova VL, Smith MRB, Hall LJ, Cleare AJ, Stone JM, Young AH. Perturbations
in disorders of gut-brain interaction: from functional to immune-mediated disorders.
in gut microbiota composition in psychiatric disorders: a review and Meta-analysis.
Gut. (2023) 72:787–98. doi: 10.1136/gutjnl-2020-320633
JAMA Psychiatry. (2021) 78:1343–54. doi: 10.1001/jamapsychiatry.2021.2573
60. Ronkainen J, Aro P, Jones M, Walker MM, Agréus L, Andreasson A, et al.
34. Horn J, Mayer DE, Chen S, Mayer EA. Role of diet and its effects on the gut
Duodenal eosinophilia and the link to anxiety: a population-based endoscopic study.
microbiome in the pathophysiology of mental disorders. Transl Psychiatry. (2022)
Neurogastroenterol Motil. (2021) 33:e14109. doi: 10.1111/nmo.14109
12:164. doi: 10.1038/s41398-022-01922-0
61. Gómez-Pinilla F. Brain foods: the effects of nutrients on brain function. Nat Rev
35. Järbrink-Sehgal E, Andreasson A. The gut microbiota and mental health in adults.
Neurosci. (2008) 9:568–78. doi: 10.1038/nrn2421
Curr Opin Neurobiol. (2020) 62:102–14. doi: 10.1016/j.conb.2020.01.016
62. Bonaz B, Bazin T, Pellissier S. The Vagus nerve at the Interface of the microbiota-
36. Appleton J. The gut-brain Axis: influence of microbiota on mood and mental
gut-brain Axis. Front Neurosci. (2018) 12:49. doi: 10.3389/fnins.2018.00049
health. Integr Med (Encinitas). (2018) 17:28–32.
63. Larraufie P, Martin-Gallausiaux C, Lapaque N, Dore J, Gribble FM, Reimann F.
37. Chakrabarti A, Geurts L, Hoyles L, Iozzo P, Kraneveld AD, La Fata G, et al. The
SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci Rep.
microbiota-gut-brain axis: pathways to better brain health. Perspectives on what
(2018) 8:74. doi: 10.1038/s41598-017-18259-0
we know, what we need to investigate and how to put knowledge into practice. Cell Mol
Life Sci. (2022) 79:80. doi: 10.1007/s00018-021-04060-w 64. Brain health (2022). World Health Organization. Available at: https://www.who.
int/health-topics/brain-health#tab=tab_1
38. Dash S, Syed YA, Khan MR. Understanding the role of the gut microbiome in
brain development and its association with neurodevelopmental psychiatric disorders. 65. Brady KJS, Trockel MT, Khan CT, Raj KS, Murphy ML, Bohman B, et al. What do
Front Cell Dev Biol. (2022) 10:880544. doi: 10.3389/fcell.2022.880544 we mean by physician wellness? A systematic review of its definition and measurement.
Acad Psychiatry. (2018) 42:94–108. doi: 10.1007/s40596-017-0781-6
39. Yao S, Zhao Y, Chen H, Sun R, Chen L, Huang J, et al. Exploring the plasticity of
diet on gut microbiota and its correlation with gut health. Nutrients. (2023) 15:3460. doi: 66. Ratsika A, Codagnone MC, O'Mahony S, Stanton C, Cryan JF. Priming for life:
10.3390/nu15153460 early life nutrition and the microbiota-gut-brain Axis. Nutrients. (2021) 13:423. doi:
10.3390/nu13020423
40. Goldstein AM, Hofstra RM, Burns AJ. Building a brain in the gut: development of
the enteric nervous system. Clin Genet. (2013) 83:307–16. doi: 10.1111/cge.12054 67. Hullar MA, Fu BC. Diet, the gut microbiome, and epigenetics. Cancer J. (2014)
20:170–5. doi: 10.1097/PPO.0000000000000053
41. Sharkey KA, Mawe GM. The enteric nervous system. Physiol Rev. (2023)
103:1487–564. doi: 10.1152/physrev.00018.2022 68. Berardi N, Pizzorusso T, Maffei L. Critical periods during sensory development.
Curr Opin Neurobiol. (2000) 10:138–45. doi: 10.1016/S0959-4388(99)00047-1
42. Gordo I. Evolutionary change in the human gut microbiome: from a static to a
dynamic view. PLoS Biol. (2019) 17:e3000126. doi: 10.1371/journal.pbio.3000126 69. Meredith RM, Dawitz J, Kramvis I. Sensitive time-windows for susceptibility in
neurodevelopmental disorders. Trends Neurosci. (2012) 35:335–44. doi: 10.1016/j.
43. So D, Whelan K, Rossi M, Morrison M, Holtmann G, Kelly JT, et al. Dietary fiber
tins.2012.03.005
intervention on gut microbiota composition in healthy adults: a systematic review and
meta-analysis. Am J Clin Nutr. (2018) 107:965–83. doi: 10.1093/ajcn/nqy041 70. Hanson MA, Gluckman PD. Early developmental conditioning of later health and
disease: physiology or pathophysiology? Physiol Rev. (2014) 94:1027–76. doi: 10.1152/
44. Martin-Gallausiaux C, Marinelli L, Blottière HM, Larraufie P, Lapaque N. SCFA:
physrev.00029.2013
mechanisms and functional importance in the gut. Proc Nutr Soc. (2021) 80:37–49. doi:
10.1017/S0029665120006916 71. Ho A, Flynn AC, Pasupathy D. Nutrition in pregnancy. Obstet Gyanaecol Reprod
Med. (2016) 26:259–64. doi: 10.1016/j.ogrm.2016.06.005
45. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, et al. Regulation of
inflammatory responses by gut microbiota and chemoattractant receptor GPR43. 72. Tarry-Adkins JL, Ozanne SE. The impact of early nutrition on the ageing trajectory.
Nature. 461:1282–6. doi: 10.1038/nature08530 Proc Nutr Soc. (2014) 73:289–301. doi: 10.1017/S002966511300387X
46. Dicks LMT. Gut Bacteria and neurotransmitters. Microorganisms. (2022) 10:1838. 73. Rando OJ, Simmons RA. I'm eating for two: parental dietary effects on offspring
doi: 10.3390/microorganisms10091838 metabolism. Cell. (2015) 161:93–105. doi: 10.1016/j.cell.2015.02.021

Frontiers in Nutrition 09 frontiersin.org

Merlo et al. 10.3389/fnut.2024.1337889

74. Tognini P. Gut microbiota: a potential regulator of neurodevelopment. Front Cell Front Cell Infect Microbiol. (2020) 10:104. doi: 10.3389/fcimb.2020.
Neurosci. (2017) 11:25. doi: 10.3389/fncel.2017.00025 00104
75. Stewart CJ, Ajami NJ, O'Brien JL, Hutchinson DS, Smith DP, Wong MC, et al. 100. Wei S, Peng W, Mai Y, Li K, Wei W, Hu L, et al. Outer membrane vesicles enhance
Temporal development of the gut microbiome in early childhood from the TEDDY tau phosphorylation and contribute to cognitive impairment. J Cell Physiol. (2020)
study. Nature. (2018) 562:583–8. doi: 10.1038/s41586-018-0617-x 235:4843–55. doi: 10.1002/jcp.29362
76. Galazzo G, van Best N, Bervoets L, Dapaah IO, Savelkoul PH, Hornef MW, et al. 101. Saji N, Saito Y, Yamashita T, Murotani K, Tsuduki T, Hisada T, et al. Relationship
Development of the microbiota and associations with birth mode, diet, and atopic between plasma lipopolysaccharides, gut microbiota, and dementia: a cross-sectional
disorders in a longitudinal analysis of stool samples, collected from infancy through study. J Alzheimers Dis. (2022) 86:1947–57. doi: 10.3233/JAD-215653
early childhood. Gastroenterology. (2020) 158:1584–96. doi: 10.1053/j.gastro.2020.01.024
102. Innocenti GM. Defining neuroplasticity. Handb Clin Neurol. (2022) 184:3–18.
77. Bäckhed F, Roswall J, Peng Y, Feng Q, Jia H, Kovatcheva-Datchary P, et al. doi: 10.1016/B978-0-12-819410-2.00001-1
Dynamics and stabilization of the human gut microbiome during the first year of life.
103. Murphy T, Dias GP, Thuret S. Effects of diet on brain plasticity in animal and
Cell Host Microbe. (2015) 17:690–703. doi: 10.1016/j.chom.2015.04.004
human studies: mind the gap. Neural Plast. (2014) 2014:563160. doi:
78. Ihekweazu FD, Versalovic J. Development of the pediatric gut microbiome: impact 10.1155/2014/563160
on health and disease. Am J Med Sci. (2018) 356:413–23. doi: 10.1016/j.
104. Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal
amjms.2018.08.005
neurogenesis buffers stress responses and depressive behaviour. Nature. (2011)
79. Ma J, Li Z, Zhang W, Zhang C, Zhang Y, Mei H, et al. Comparison of gut 476:458–61. doi: 10.1038/nature10287
microbiota in exclusively breast-fed and formula-fed babies: a study of 91 term infants.
105. Yassa MA, Mattfeld AT, Stark SM, Stark CE. Age-related memory deficits linked
Sci Rep. (2020) 10:15792. doi: 10.1038/s41598-020-72635-x
to circuit-specific disruptions in the hippocampus. Proc Natl Acad Sci USA. (2011)
80. Deoni SC, Dean DC, Piryatinsky I, O'Muircheartaigh J, Waskiewicz N, Lehman 108:8873–8. doi: 10.1073/pnas.1101567108
K, et al. Breastfeeding and early white matter development: a cross-sectional study.
106. Zainuddin MS, Thuret S. Nutrition, adult hippocampal neurogenesis and mental
NeuroImage. (2013) 82:77–86. doi: 10.1016/j.neuroimage.2013.05.090
health. Br Med Bull. (2012) 103:89–114. doi: 10.1093/bmb/lds021
81. Luby JL, Belden AC, Whalen D, Harms MP, Barch DM. Breastfeeding and
107. Salim S. Oxidative stress and psychological disorders. Curr Neuropharmacol.
childhood IQ: the mediating role of gray matter volume. J Am Acad Child Adolesc
(2014) 12:140–7. doi: 10.2174/1570159X11666131120230309
Psychiatry. (2016) 55:367–75. doi: 10.1016/j.jaac.2016.02.009
108. Kandlur A, Satyamoorthy K, Gangadharan G. Oxidative stress in cognitive and
82. Blesa M, Sullivan G, Anblagan D, Telford EJ, Quigley AJ, Sparrow SA, et al. Early
epigenetic aging: a retrospective glance. Front Mol Neurosci. (2020) 13:41. doi: 10.3389/
breast milk exposure modifies brain connectivity in preterm infants. NeuroImage. (2019)
fnmol.2020.00041
184:431–9. doi: 10.1016/j.neuroimage.2018.09.045
109. Miranda-Díaz AG, García-Sánchez A, Cardona-Muñoz EG. Foods with potential
83. Kar P, Reynolds JE, Grohs MN, Bell RC, Jarman M, Dewey D, et al. Association
Prooxidant and antioxidant effects involved in Parkinson's disease. Oxidative Med Cell
between breastfeeding during infancy and white matter microstructure in early
Longev. (2020) 2020:1–17. doi: 10.1155/2020/6281454
childhood. NeuroImage. (2021) 236:118084. doi: 10.1016/j.neuroimage.2021.118084
110. Yuan Q, Zeng ZL, Yang S, Li A, Zu X, Liu J. Mitochondrial stress in metabolic
84. Anderson JW, Johnstone BM, Remley DT. Breast-feeding and cognitive
inflammation: modest benefits and full losses. Oxidative Med Cell Longev. (2022)
development: a meta-analysis. Am J Clin Nutr. (1999) 70:525–35. doi: 10.1093/
2022:8803404–17. doi: 10.1155/2022/8803404
ajcn/70.4.525
111. Diaz-Vegas A, Sanchez-Aguilera P, Krycer JR, Morales PE, Monsalves-Alvarez
85. Belfort MB, Anderson PJ, Nowak VA, Lee KJ, Molesworth C, Thompson DK, et al.
M, Cifuentes M, et al. Is mitochondrial dysfunction a common root of noncommunicable
Breast Milk feeding, brain development, and neurocognitive outcomes: a 7-year
chronic diseases? Endocr Rev. (2020) 41:bnaa005. doi: 10.1210/endrev/bnaa005
longitudinal study in infants born at less than 30 Weeks' gestation. J Pediatr. (2016)
177:133–139.e1. doi: 10.1016/j.jpeds.2016.06.045 112. Rahal A, Kumar A, Singh V, Yadav B, Tiwari R, Chakraborty S, et al. Oxidative
stress, prooxidants, and antioxidants: the interplay. Biomed Res Int. (2014) 2014:761264.
86. Bauer CE, Lewis JW, Brefczynski-Lewis J, Frum C, Schade MM, Haut MW, et al.
doi: 10.1155/2014/761264
Breastfeeding duration is associated with regional, but not global, differences in white
matter tracts. Brain Sci. (2019) 10:19. doi: 10.3390/brainsci10010019 113. Tan BL, Norhaizan ME, Liew WP. Nutrients and oxidative stress: friend or foe?
Oxidative Med Cell Longev. (2018) 2018:9719584. doi: 10.1155/2018/9719584
87. Sarkar A, Yoo JY, Valeria Ozorio Dutra S, Morgan KH, Groer M. The association
between early-life gut microbiota and long-term health and diseases. J Clin Med. (2021) 114. Yuan TF, Gu S, Shan C, Marchado S, Arias-Carrion O. Oxidative stress and adult
10:459. doi: 10.3390/jcm10030459 neurogenesis. Stem Cell Rev. (2015) 11:706–9. doi: 10.1007/s12015-015-9603-y
88. Codagnone MG, Spichak S, O'Mahony SM, O'Leary OF, Clarke G, Stanton C, et al. 115. Santos R, Ruiz de Almodovar C, Bulteau AL, Gomes CM. Neurodegeneration,
Programming bugs: microbiota and the developmental origins of brain health and neurogenesis, and oxidative stress. Oxidative Med Cell Longev. (2013) 2013:730581. doi:
disease. Biol Psychiatry. (2019) 85:150–63. doi: 10.1016/j.biopsych.2018.06.014 10.1155/2013/730581
89. Blakemore SJ, Choudhury S. Development of the adolescent brain: implications 116. Xie K, Sheppard A. Dietary micronutrients promote neuronal differentiation by
for executive function and social cognition. J Child Psychol Psychiatry. (2006) modulating the mitochondrial-nuclear dialogue. BioEssays. (2018) 40:e1800051. doi:
47:296–312. doi: 10.1111/j.1469-7610.2006.01611.x 10.1002/bies.201800051
90. Sarris J, Logan AC, Akbaraly TN, Amminger GP, Balanzá-Martínez V, Freeman 117. Agostini M, Romeo F, Inoue S, Niklison-Chirou MV, Elia AJ, Dinsdale D, et al.
MP, et al. International Society for Nutritional Psychiatry Research. Nutritional Metabolic reprogramming during neuronal differentiation. Cell Death Differ. (2016)
medicine as mainstream in psychiatry. Lancet. Psychiatry. (2015) 2:271–4. doi: 10.1016/ 23:1502–14. doi: 10.1038/cdd.2016.36
S2215-0366(14)00051-0
118. Zheng X, Boyer L, Jin M, Mertens J, Kim Y, Ma L, et al. Metabolic reprogramming
91. O'Toole PW, Jeffery IB. Gut microbiota and aging. Science. (2015) 350:1214–5. doi: during neuronal differentiation from aerobic glycolysis to neuronal oxidative
10.1126/science.aac8469 phosphorylation. elife. (2016) 5:e13374. doi: 10.7554/eLife.13374
92. GBD 2019 Risk Factors Collaborators. Global burden of 87 risk factors in 204 119. Yao B, Christian KM, He C, Jin P, Ming GL, Song H. Epigenetic mechanisms in
countries and territories, 1990-2019: a systematic analysis for the global burden of neurogenesis. Nat Rev Neurosci. (2016) 17:537–49. doi: 10.1038/nrn.2016.70
disease study 2019. Lancet. (2020) 396:1223–49. doi: 10.1016/S0140-6736(20)30752-2
120. Mattick JS, Mehler MF. RNA editing, DNA recoding and the evolution of human
93. Bobo WV, Grossardt BR, Virani S, St Sauver JL, Boyd CM, Rocca WA. Association cognition. Trends Neurosci. (2008) 31:227–33. doi: 10.1016/j.tins.2008.02.003
of Depression and Anxiety with the accumulation of chronic conditions. JAMA Netw
121. Meaney MJ, Ferguson-Smith AC. Epigenetic regulation of the neural
Open. (2022) 5:e229817. doi: 10.1001/jamanetworkopen.2022.9817
transcriptome: the meaning of the marks. Nat Neurosci. (2010) 13:1313–8. doi: 10.1038/
94. Stern Y, Barulli D. Cognitive reserve. Handb Clin Neurol. (2019) 167:181–90. doi: nn1110-1313
10.1016/B978-0-12-804766-8.00011-X
122. Meagher RB. 'Memory and molecular turnover,' 30 years after inception.
95. O'Brien C, Holtzer R. Physical reserve: construct development and predictive Epigenetics Chromatin. (2014) 7:37. doi: 10.1186/1756-8935-7-37
utility. Aging Clin Exp Res. (2023) 35:1055–62. doi: 10.1007/s40520-023-02371-5
123. Rodriguez RL, Albeck JG, Taha AY, Ori-McKenney KM, Recanzone GH,
96. Smyth A, Dehghan M, O'Donnell M, Anderson C, Teo K, Gao P, et al. Healthy Stradleigh TW, et al. Impact of diet-derived signaling molecules on human cognition:
eating and reduced risk of cognitive decline: a cohort from 40 countries. Neurology. exploring the food-brain axis. NPJ Sci Food. (2017) 1:2. doi: 10.1038/s41538-017-0002-4
(2015) 84:2258–65. doi: 10.1212/WNL.0000000000001638
124. Sobrino Crespo C, Perianes Cachero A, Puebla Jiménez L, Barrios V, Arilla FE.
97. World Health Organization (2020). Healthy diet. World Health Organization. Peptides and food intake. Front Endocrinol (Lausanne). (2014) 5:58. doi: 10.3389/
Available at: https://www.who.int/news-room/fact-sheets/detail/healthy-diet fendo.2014.00058
98. Clare L, Wu YT, Teale JC, MacLeod C, Matthews F, Brayne C, et al. Potentially 125. Khavinson VK, Popovich IG, Linkova NS, Mironova ES, Ilina AR. Peptide
modifiable lifestyle factors, cognitive reserve, and cognitive function in later life: a cross- regulation of gene expression: a systematic review. Molecules. (2021) 26:7053. doi:
sectional study. PLoS Med. (2017) 14:e1002259. doi: 10.1371/journal.pmed.1002259 10.3390/molecules26227053
99. Askarova S, Umbayev B, Masoud AR, Kaiyrlykyzy A, Safarova Y, Tsoy A, et al. The 126. Johnson RW. Feeding the beast: can microglia in the senescent brain be regulated
links between the gut microbiome, aging, modern lifestyle and Alzheimer's disease. by diet? Brain Behav Immun. (2015) 43:1–8. doi: 10.1016/j.bbi.2014.09.022

Frontiers in Nutrition 10 frontiersin.org

Merlo et al. 10.3389/fnut.2024.1337889

127. Harry GJ. Microglia during development and aging. Pharmacol Ther. (2013) 140. Dinan TG, Cryan JF. Gut microbiota: a missing link in psychiatry. World
139:313–26. doi: 10.1016/j.pharmthera.2013.04.013 Psychiatry. (2020) 19:111–2. doi: 10.1002/wps.20726
128. Ayata P, Badimon A, Strasburger HJ, Duff MK, Montgomery SE, Loh YE, et al. 141. Donoso F, Cryan JF, Olavarría-Ramírez L, Nolan YM, Clarke G. Inflammation,
Epigenetic regulation of brain region-specific microglia clearance activity. Nat Neurosci. lifestyle factors, and the microbiome-gut-brain Axis: relevance to depression and
(2018) 21:1049–60. doi: 10.1038/s41593-018-0192-3 antidepressant action. Clin Pharmacol Ther. (2023) 113:246–59. doi: 10.1002/cpt.2581
129. Bilbo SD, Schwarz JM. Early-life programming of later-life brain and behavior: a 142. Lassale C, Batty GD, Baghdadli A, Jacka F, Sánchez-Villegas A, Kivimäki M, et al.
critical role for the immune system. Front Behav Neurosci. (2009) 3:14. doi: 10.3389/ Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-
neuro.08.014.2009 analysis of observational studies. Mol Psychiatry. (2019) 24:965–86. doi: 10.1038/
s41380-018-0237-8
130. Shao L, Martin MV, Watson SJ, Schatzberg A, Akil H, Myers RM, et al.
Mitochondrial involvement in psychiatric disorders. Ann Med. (2008) 40:281–95. doi: 143. Jacka FN, O'Neil A, Opie R, Itsiopoulos C, Cotton S, Mohebbi M, et al. A
10.1080/07853890801923753 randomised controlled trial of dietary improvement for adults with major depression
(the 'SMILES' trial). BMC Med. (2017) 15:23. doi: 10.1186/s12916-017-0791-y
131. Hroudová J, Fišar Z. Connectivity between mitochondrial functions and
psychiatric disorders. Psychiatry Clin Neurosci. (2011) 65:130–41. doi: 144. Saghafian F, Malmir H, Saneei P, Milajerdi A, Larijani B, Esmaillzadeh A. Fruit
10.1111/j.1440-1819.2010.02178.x and vegetable consumption and risk of depression: accumulative evidence from an
updated systematic review and meta-analysis of epidemiological studies. Br J Nutr.
132. Petschner P, Gal Z, Gonda X. Impaired mitochondrial bioenergetics in psychiatric
(2018) 119:1087–101. doi: 10.1017/S0007114518000697
disorders. Clinical. Bioenergetics. (2021) 2021:195–221. doi: 10.1016/
b978-0-12-819621-2.00008-5 145. Malhi GS, Bell E, Singh AB, Bassett D, Berk M, Boyce P, et al. The 2020 Royal
Australian and new Zealand College of Psychiatrists clinical practice guidelines for
133. Physical Health and Mental Health (2022). Mental Health Foundation. Available
mood disorders: major depression summary. Bipolar Disord. (2020) 22:788–804. doi:
at: https://www.mentalhealth.org.uk/explore-mental-health/a-z-topics/physical-health-
10.1111/bdi.13035
and-mental-health#:~:text=Physical%20health%20problems%20significantly%20
increase,most%20often%20depression%20or%20anxiety 146. Marx W, Manger SH, Blencowe M, Murray G, Ho FY, Lawn S, et al. Clinical
guidelines for the use of lifestyle-based mental health care in major depressive disorder:
134. Kuppili PP, Nebhinani N. Role of integrated and multidisciplinary approach in
world Federation of Societies for biological psychiatry (WFSBP) and Australasian
combating metabolic syndrome in patients with severe mental illness. Indian J Psychol
Society of Lifestyle Medicine (ASLM) taskforce. World J Biol Psychiatry. (2023)
Med. (2019) 41:466–71. doi: 10.4103/IJPSYM.IJPSYM_48_19
24:333–86. doi: 10.1080/15622975.2022.2112074
135. Kris-Etherton PM, Petersen KS, Hibbeln JR, Hurley D, Kolick V, Peoples S, et al.
Nutrition and behavioral health disorders: depression and anxiety. Nutr Rev. (2021) 147. Office of the Surgeon General (OSG). Our epidemic of loneliness and isolation: the
79:247–60. doi: 10.1093/nutrit/nuaa025 U.S. Surgeon General’s advisory on the healing effects of social connection and community.
Washington (DC): US Department of Health and Human Services (2023).
136. Moffitt TE, Caspi A, Taylor A, Kokaua J, Milne BJ, Polanczyk G, et al. How
common are common mental disorders? Evidence that lifetime prevalence rates are 148. Loneliness and Social Isolation in the United States. Available at: https://www.
doubled by prospective versus retrospective ascertainment. Psychol Med. (2010) kff.org/report-section/loneliness-and-social-isolation-in-the-united-states-the-
40:899–909. doi: 10.1017/S0033291709991036 united-kingdom-and-japan-an-international-survey-section-1/ (accessed November
01, 2023).
137. Herrman H, Patel V, Kieling C, Berk M, Buchweitz C, Cuijpers P, et al. Time for
united action on depression: a lancet-world psychiatric association commission. Lancet. 149. Thompson HJ, Brick MA. Perspective: closing the dietary fiber gap: an ancient
(2022) 399:957–1022. doi: 10.1016/S0140-6736(21)02141-3 solution for a 21st century problem. Adv Nutr. (2016) 7:623–6. doi: 10.3945/
an.115.009696
138. Gold SM, Köhler-Forsberg O, Moss-Morris R, Mehnert A, Miranda JJ, Bullinger
M, et al. Comorbid depression in medical diseases. Nat Rev Dis Primers. (2020) 6:69. 150. Martínez Leo EE, Segura Campos MR. Effect of ultra-processed diet on gut
doi: 10.1038/s41572-020-0200-2 microbiota and thus its role in neurodegenerative diseases. Nutrition. (2020) 71:110609.
doi: 10.1016/j.nut.2019.110609
139. Zhang Y, Fan Q, Hou Y, Zhang X, Yin Z, Cai X, et al. Bacteroides species
differentially modulate depression-like behavior via gut-brain metabolic signaling. Brain 151. Crowley J, Ball L, Hiddink GJ. Nutrition in medical education: a systematic
Behav Immun. (2022) 102:11–22. doi: 10.1016/j.bbi.2022.02.007 review. Lancet Planet Health. (2019) 3:e379–89. doi: 10.1016/S2542-5196(19)30171-8

Frontiers in Nutrition 11 frontiersin.org