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Citation: García-Montero, C.; Ortega,
M.A.; Alvarez-Mon, M.A.;
Fraile-Martinez, O.; Romero-Bazán,
A.; Lahera, G.; Montes-Rodríguez,
J.M.; Molina-Ruiz, R.M.; Mora, F.;
Rodriguez-Jimenez, R.; et al. The
Problem of Malnutrition Associated
with Major Depressive Disorder from
a Sex-Gender Perspective. Nutrients
2022,14, 1107. https://doi.org/
10.3390/nu14051107
Academic Editors: Paolo Brambilla
and Alessandra Mazzocchi
Received: 15 February 2022
Accepted: 3 March 2022
Published: 6 March 2022
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nutrients
Review
The Problem of Malnutrition Associated with Major Depressive
Disorder from a Sex-Gender Perspective
Cielo García-Montero 1, 2, *,† , Miguel A. Ortega 1 ,2 ,*, † , Miguel Angel Alvarez-Mon 1,2,3,
Oscar Fraile-Martinez 1,2 , Adoración Romero-Bazán1, Guillermo Lahera 1,2,4 ,
JoséManuel Montes-Rodríguez 1,5 , Rosa M. Molina-Ruiz 6, Fernando Mora 3,7 , Roberto Rodriguez-Jimenez 7,8,
Javier Quintero 3,7 and Melchor Álvarez-Mon 1,2,9
1Department of Medicine and Medical Specialities, University of Alcala, 28801 Alcaláde Henares, Spain;
maalvarezdemon@icloud.com (M.A.A.-M.); oscarfra.7@hotmail.com (O.F.-M.);
arb00031@red.ujaen.es (A.R.-B.); guillermo.lahera@gmail.com (G.L.); j_m_montes@hotmail.com (J.M.M.-R.);
mademons@gmail.com (M.Á.-M.)
2Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
3Department of Psychiatry and Mental Health, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain;
fernando.mora@salud.madrid.org (F.M.); fjquinterog@yahoo.es (J.Q.)
4Psychiatry Service, Center for Biomedical Research in the Mental Health Network,
University Hospital Príncipe de Asturias (CIBERSAM), 28806 Alcaláde Henares, Spain
5Psychiatry Service, Center for Biomedical Research in the Mental Health Network,
University Hospital Ramon y Cajal (CIBERSAM), 28034 Madrid, Spain
6Department of Psychiatry and Mental Health, San Carlos Clinical University Hospital, IdiSSC,
28034 Madrid, Spain; rosamolina18@hotmail.com
7Department of Legal Medicine and Psychiatry, Complutense University, 28040 Madrid, Spain;
rodriguez.jimenez.psiquiatra@gmail.com
8Institute for Health Research 12 de Octubre Hospital, (Imas 12)/CIBERSAM (Biomedical Research
Networking Centre in Mental Health), 28041 Madrid, Spain
9Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine,
University Hospital Príncipe de Asturias, (CIBEREHD), 28806 Alcaláde Henares, Spain
*Correspondence: cielo.gmontero@gmail.com (C.G.-M.); miguel.angel.ortega92@gmail.com (M.A.O.)
† These authors contributed equally to this work.
Abstract:
Major depressive disorder (MDD) is an incapacitating condition characterized by loss
of interest, anhedonia and low mood, which affects almost 4% of people worldwide. With rising
prevalence, it is considered a public health issue that affects economic productivity and heavily
increases health costs alone or as a comorbidity for other pandemic non-communicable diseases
(such as obesity, cardiovascular disease, diabetes, inflammatory bowel diseases, etc.). What is even
more noteworthy is the double number of women suffering from MDD compared to men. In fact,
this sex-related ratio has been contemplated since men and women have different sexual hormone
oscillations, where women meet significant changes depending on the age range and moment of
life (menstruation, premenstruation, pregnancy, postpartum, menopause
. . .
), which seem to be
associated with susceptibility to depressive symptoms. For instance, a decreased estrogen level
promotes decreased activation of serotonin transporters. Nevertheless, sexual hormones are not
the only triggers that alter neurotransmission of monoamines and other neuropeptides. Actually,
different dietary habits and/or nutritional requirements for specific moments of life severely affect
MDD pathophysiology in women. In this context, the present review aims to descriptively collect
information regarding the role of malnutrition in MDD onset and course, focusing on female patient
and especially macro- and micronutrient deficiencies (amino acids,
ω
3 polyunsaturated fatty acids
(
ω
3 PUFAs), folate, vitamin B12, vitamin D, minerals
. . .
), besides providing evidence for future
nutritional intervention programs with a sex-gender perspective that hopefully improves mental
health and quality of life in women.
Nutrients 2022,14, 1107. https://doi.org/10.3390/nu14051107 https://www.mdpi.com/journal/nutrients
Nutrients 2022,14, 1107 2 of 39
Keywords:
depression; stress; malnutrition; deficiencies; sex differences; menstrual cycle; premenstrual
syndrome; premenstrual dysphoric disorder; pregnancy; postpartum; menopause
1. Introduction
Major depressive disorder (MDD), commonly known as depression, is an incapaci-
tating global health problem characterized by altered mood, including loss of interest and
pleasure, as well as impaired cognitive and vegetative functions [
1
]. This disorder affects at
least 3.8% of the population and it is estimated that there are approximately 290 million
new cases per year [
2
], becoming one of the six drivers that increased the global burden of
disease in the period from 1990 to 2019 [
3
]. Likewise, according to the projections foreseen
for 2030 by the World Health Organization (WHO), MDD will lead the group of disabling
diseases [4].
In addition, depression leads to a prolonged disturbance in daily activities [
5
] that,
consequently, will be associated with both direct and indirect costs. Presenteeism and
absenteeism accounted for around 50% of the USD 210 billion of total spending in the US
in 2010. Although the indirect costs imply a greater economic impact, we must consider the
direct costs, which involved an outlay of USD 98.9 billion in the same year [
6
]. Likewise,
according to the report carried out by the WHO in 2007 the socioeconomic costs in Europe
follow the same trend, accumulating an amount of EUR 136.3 billion invested, with around
70% of this attributable to the lack of productivity [7].
A greater number of women with depression have been detected compared to men;
the ratio remains at 2:1 [
8
]. The main source of this difference has been found in the
biological factor; it is estimated that the heritability of this disorder ranges between 30
and 40%, assuming a greater probability of inheritance in women compared to men [
9
,
10
].
Moreover, the patient’s vulnerability to external factors during the course of depressive
episodes will be increased by the action of sexual hormones and the repercussion of the
oscillations will be significant and will change depending on the age range [
11
]. Thus, for
example, in adolescence, the initial moment of activation of these hormones and the start
of menstruation are a focus in the case of girls, who suffer higher levels of chronic stress
than boys [
12
]. Fluctuations in ovarian hormones could be one of the potential causes
of the disparity in prevalence between the sexes, since the group in question develops
forms of depression such as premenstrual syndrome (PMS), postpartum depression and
postmenopausal depression [
13
]. Certain cycle imbalances such as heavy bleeding have
been significantly associated with the diagnosis of MDD [
14
]. In addition, MDDs trigger
the appearance of suicidal thoughts in at least 60% of adolescents [
15
], making it the second
leading cause of death in this group [
16
]. These events have also been related to the first
menses of puberty in girls [17].
On the other hand, the impact of socioeconomic aspects, age, race and the presence
of other comorbidities cannot be ignored [
18
]. In this sense, it has also been shown that
the risk of suffering from MDD worsens when the framework of difference in political
participation or economic independence is less egalitarian, leading to a clear increase in
symptoms, as well as persistent depression [
19
,
20
]; if we find ourselves again in the range
between 14 and 25 years, the dissimilarity will be more accentuated between both sexes,
while it is not so evident in older age groups [21].
Going deeper into the investigation of MDD in women would help to decipher the
causes of the events, thus providing new management and treatment tools. It is true that
the patient’s nutritional status is closely related to depression and may be a key tool for its
prevention and treatment [
22
]. In this line, repeated eating patterns and specific physio-
logical situations have been observed in the case of women (menstrual cycle, childbirth,
postpartum, menopause), which lead to marked nutritional deficiencies, especially mi-
cronutrients such as vitamin D, omega-3 fatty acids (FA
ω
-3), methyl-folate and S-adenosyl
methionine (SAMe). These components have also been the object of study in preclinical and
Nutrients 2022,14, 1107 3 of 39
clinical trials, standing out for their benefit as potential adjuvant nutraceuticals in patients
with MDD [23,24].
The main objective of this paper is to critically and descriptively review the impact
of malnutrition on the pathophysiology of MDD in women, also evaluating possible
strategies based on nutritional intervention that may be helpful in limiting the progression
or promoting recovery from depression, as well as preventing the appearance of future
depressive episodes.
2. Major Depressive Disorder in Women
2.1. General Pathophysiology
2.1.1. Can MDD Be Located in the Brain?
One of the big questions that many researchers have historically asked is: Can MDD
be located in the brain? Unlike other neuropsychiatric diseases that affect specific regions
or mechanisms of the nervous system, in MDD, the alteration is not located in any specific
region. In contrast to other diseases where the main organ affected is the brain, in MDD the
alteration is not localized, thus affecting different parts of this organ.
Several investigations show structural and functional alterations; the findings are
mainly presented in the fluctuations in the amount of gray matter in the frontal and
parietal lobes, hippocampus, amygdala, corpus striatum, caudate nucleus, thalamus and
cingulum [
25
–
27
]. Wei Peng et al. determined in their study that gray matter volume
abnormalities in the fronto-limbic region of the brain are basic evidence of depression in the
first episodes of patients without prior medication. Gray matter mass in this situation has
been found to increase in the middle superior frontal gyrus, cuneus, left paracentral lobe
and bilateral thalamus; however, it decreases in the region of the left insula, middle frontal
gyrus, superior frontal gyrus and right dorsolateral [
28
]. The frontal lobe is considered
to be the area that undergoes the most changes in patients with MDD. The thickness of
the anterior cingulate cortex (ACC) is modified. It has been shown that in patients with
treatment-resistant depression, the thickness increases when depressive episodes subside
over time, with the opposite effect occurring in recurrent patients [29].
On the other hand, the thalamus is a structure formed by different nuclei connected
to the cerebral cortex, as well as the amygdala, hippocampus and striatum. It is closely
linked with the regulation of emotions, memory control and arousal [
30
]. Likewise, it
intervenes directly in the maintenance of circadian rhythms and the generation of sleep-
wake patterns [
31
]. In patients with depression, it has been shown that there is a decrease
in volume due to loss of gray matter [
32
] and changes in its shape. This last parameter
maintains a direct relationship with the classification of the severity of depression proposed
by Hamilton (HAM-D) [33].
In addition, it should be noted that the volume of the hippocampus is reduced by up
to 1.2% in people with recurrent depressive episodes or when the onset of the pathology
manifests itself at an early age, not showing this difference in the first episodes or in people
with late onset [
34
]. Atrophy occurs as a consequence of an increase in glucocorticoid levels
due to the alteration of the hypothalamic-pituitary-adrenal (HPA) axis [
35
]. Moreover, it
has been proven that functional and structural changes in this brain region lead to abnormal
emotional processing and defective cognition [36].
2.1.2. Cellular and Molecular Changes Associated with MDD
The alteration of the reorganization capacity of the nervous system induced by the
response to stimuli can be explained with the neurotrophic hypothesis of MDD, which
postulates that the reduced expression of growth factors triggers neuronal atrophy, lead-
ing to decreased neuroplasticity, as well as errors in the neurogenesis of brain regions
responsible for regulating mood and memory [
37
]. Neurotrophic factors intervene in the
regulation of the plasticity and formation of neuronal networks [
38
]. The brain-derived
neurotrophic factor (BDNF) belongs to this family and is involved in the modulation of
neurogenesis, synaptic plasticity, as well as basic neuronal functions [
39
]. It is possible
Nutrients 2022,14, 1107 4 of 39
that this factor triggers both depressive and antidepressant behaviors, obeying the BDNF
signaling regulation network, although it is true, even though it is a key element, that the
isolated interruption of its signaling is not enough to result in the spectrum of depressive
symptomatology [
40
]. There is a close relationship between stress and changes in the
expression and signaling of BDNF in different brain regions (amygdala, hippocampus,
prefrontal cortex, etc.); these alterations are correlated with the appearance of depressive
behavior [41].
In the same context, cortisol (steroidal hormone or glucocorticoid) plays a substantial
role in the development of the pathophysiology of depressive disorder. Under the effect of a
stressful stimulus, the HPA axis will be activated by the secretion of corticotropin-releasing
factor (CRF), arginine-vasopressin (AVP) and other neuropeptides. As a consequence, the
adrenocorticotropic hormone (ACTH) is produced, which, in turn, stimulates the adrenal
glands, synthesizing them as cortisol. In patients with MDD, hypercortisolemia leads
to overstimulation of the HPA axis, followed by a clear disruption of neurotransmitter
metabolism [42].
In this sense, it is of great importance to know the monoaminergic hypothesis, which
maintains that there is a decrease in monoamines in the synaptic space due to disturbances
in physiological mechanisms; that is, low sensitivity of the receptors, alteration of the secre-
tion to the synaptic space or storage failure [
43
]. Until now, the monoamine hypothesis has
been a pioneer as the basis for the target of the development of antidepressants. One of the
keys to the pathophysiology of this condition lies in the serotonin transporter membrane
protein (SERT), as well as neuronal serotonin receptors [
44
]. It has also been shown that
norepinephrine and its alpha-adrenergic receptors are highly relevant in the regulation
of cognitive development or response systems to adverse situations, such as fear or anxi-
ety [
45
]. Similarly, understanding the disruption of the dopaminergic system mechanisms
is the key to mediating characteristic symptoms of this disease, such as anhedonia [
46
]. On
the other hand, low concentrations of other types of neurotransmitters, such as glutamate,
GABA or acetylcholine, have been shown in patients with MDD compared to controls,
which opens up an interesting research opportunity for more effective therapies [
47
]. Oxy-
tocin (OXT) and AVP, whose release is promoted by anxiogenic, stressful and notably social
stimuli, both positive and negative, have also become attractive research targets [
48
,
49
].
The predominance of one of these neuropeptides has a direct impact on the other and vice
versa; this could be explained by the benefits obtained by inhibiting AVP so that the balance
shifts towards OXT secretion in order to improve depressive behavior [50].
2.1.3. Systemic Alterations Associated with MDD
As can be seen, major depressive disorder has a large network of interconnected
mechanisms that give rise to its pathophysiology, which is why other fields such as the im-
mune system have been investigated more thoroughly. A wide variety of proinflammatory
cytokines, such as IL-1
β
, IL-2, IL-6, IL-12 and tumor necrosis factor (TNF-
α
), in addition to
some antibodies (ribosomal antibody-P and anti-N-receptor methyl-D-aspartate) interfere
in the mediation of the inflammatory processes of depression [
51
]. The lesions produced in
the central nervous system, mainly due to stressors, will trigger the activation of microglia
and this will lead to the start of the immune cascade. During this process, there will be an
increase in the secretion of cytokines, which could pass the blood-brain barrier and, as a
consequence, increase blood levels, thus becoming highly relevant markers. In addition,
this dysregulation will contribute to an exacerbated activation of the HPA axis, giving rise
to the cycle of pathological mechanisms characteristic of depressive disorder [52].
In this sense, there is evidence that suggests the close relationship between the immune
system and the intestinal microbiota, an example of which is the production of immunocy-
tokines in response to the metabolism of intestinal bacteria [
53
]. The overstimulation of the
HPA axis will lead to an increase in the permeability of the intestinal barrier; subsequently,
a phenomenon known as endotoxemia occurs, in which the bacterial endotoxins pass into
the blood circulation, triggering the onset of peripheral inflammation; the signals will
Nutrients 2022,14, 1107 5 of 39
arrive at the CNS via the vagus nerve, again promoting the neuroinflammatory response of
glial cells [
54
]. This fact will lead to a greater systemic deterioration of the subjects with
depression [55].
Other factors also intervene in the pathophysiology of MDD; since time immemorial,
it has been suspected that sleep is essential to good health. This idea led, decades ago, to
the search for keys to understanding depression, and a plethora of studies argue for the
disruption of circadian rhythms in patients with MDD [
56
,
57
]. Additionally, the brain is
especially vulnerable when we talk about the action of reactive oxygen species (ROS), as
this is a structure with high content of oxidizable lipids and an oxygen requirement. It has
been observed that there is an increase in ROS as a consequence of the alteration of the
antioxidant power of cells in depressive subjects. Due to this, it has become another of the
factors in the investigation of this pathology [
58
,
59
]. A summary related to the three main
points herein exposed can be found in Figure 1.
Nutrients 2022, 14, 1107 5 of 40
munocytokines in response to the metabolism of intestinal bacteria [53]. The overstimula-
tion of the HPA axis will lead to an increase in the permeability of the intestinal barrier;
subsequently, a phenomenon known as endotoxemia occurs, in which the bacterial endo-
toxins pass into the blood circulation, triggering the onset of peripheral inflammation; the
signals will arrive at the CNS via the vagus nerve, again promoting the neuroinflamma-
tory response of glial cells [54]. This fact will lead to a greater systemic deterioration of
the subjects with depression [55].
Other factors also intervene in the pathophysiology of MDD; since time immemorial,
it has been suspected that sleep is essential to good health. This idea led, decades ago, to
the search for keys to understanding depression, and a plethora of studies argue for the
disruption of circadian rhythms in patients with MDD [56,57]. Additionally, the brain is
especially vulnerable when we talk about the action of reactive oxygen species (ROS), as
this is a structure with high content of oxidizable lipids and an oxygen requirement. It has
been observed that there is an increase in ROS as a consequence of the alteration of the
antioxidant power of cells in depressive subjects. Due to this, it has become another of the
factors in the investigation of this pathology [58,59]. A summary related to the three main
points herein exposed can be found in Figure 1.
Figure 1. General pathophysiology of MDD. Elevated stress affects the HPA axis involving cellular
and molecular changes, resulting in brain structural and functional changes. For instance, abnormal
neurotransmission, microglial activation, neuronal damage and dysregulation of neuroplastic and
neurotrophic factors can be reported in patients with MDD. These alterations are frequently accom-
panied by enhanced oxidative stress and circadian rhythms disruption. Exacerbated systemic in-
flammation and gut dysbiosis and enhanced intestinal barrier permeability are also major charac-
teristics of patients with MDD. It is of note that all these mechanisms boost each other, perpetuating
the damage and pathologic environment related to MDD.
2.2. Pathophysiology Specific to MDD in Women
2.2.1. Biological Mechanisms
It has been observed that there is divergence in molecular processes in both sexes. In
the case of women, there is an increase in genes linked to neuronal synapses, as well as a
Figure 1.
General pathophysiology of MDD. Elevated stress affects the HPA axis involving cellular
and molecular changes, resulting in brain structural and functional changes. For instance, abnor-
mal neurotransmission, microglial activation, neuronal damage and dysregulation of neuroplastic
and neurotrophic factors can be reported in patients with MDD. These alterations are frequently
accompanied by enhanced oxidative stress and circadian rhythms disruption. Exacerbated systemic
inflammation and gut dysbiosis and enhanced intestinal barrier permeability are also major charac-
teristics of patients with MDD. It is of note that all these mechanisms boost each other, perpetuating
the damage and pathologic environment related to MDD.
2.2. Pathophysiology Specific to MDD in Women
2.2.1. Biological Mechanisms
It has been observed that there is divergence in molecular processes in both sexes.
In the case of women, there is an increase in genes linked to neuronal synapses, as well
as a reduction in markers of immune function and microglia, in contrast to the findings
observed in men [
60
]. In accordance with the above, different investigations agree that the
pro- and anti-inflammatory response is attenuated in women with depression and there
Nutrients 2022,14, 1107 6 of 39
is greater reduction in those with more severe symptoms [
61
,
62
]. A possible explanation
for this finding is an increase in tolerance due to pre-exposure to endotoxins due to the
imbalance of the intestinal barrier [
61
]. Moreover, the recent study by Chen et al. has
observed significant differences in the microbiota according to the sex of the patient; among
other things, it is possible to relate the severity of the pathology to the state of the microbiota,
finding a negative relationship in women when there is a predominance of Streptococcus or
Clostridium [
63
]. The latter plays an important role in the regulation of non-ovarian estrogen
levels, affecting the risk of suffering from conditions of a different nature in postmenopausal
women and elderly men [64].
In this sense, and based on new findings, it is worth highlighting the role of the es-
trobolome, which is the set of genes belonging to intestinal microorganisms responsible for
modulating estrogen levels in the blood through various mechanisms [
65
]. The appearance
of contemporary depressive episodes with hormonal fluctuations is evident, which are
manifested above all in puberty, postpartum or menopausal transition periods [
66
–
68
]. In
the follicular phase and in perimenopause, where normal levels of estradiol (E2) are low,
a greater vulnerability when receiving stressful events or negative emotions has been ob-
served, all due to hormonal disturbance of the activity of the structures involved in affective
regulation; the opposite occurs in phases of the cycle with high levels [
69
]. Several pieces
of evidence confirm the relationship between hormones and the estrobolome; for example,
genera that produce short-chain fatty acids, such as Prevotella,Ruminoccocus and Roseburia,
decrease in postmenopausal women compared to premenopausal women [
70
]. Moreover,
animal models reflect the existence of a change in the intestinal microbial composition due
to the hormonal changes typical of menopause [
71
]. In the same way, the induction of
progesterone in ovariectomized mice led to an improvement in depressive behavior, all of
which was related to the increase in Lactobacillus and the decrease in IL-6 [72].
On the other hand, we will discuss the pathophysiology of specific conditions that
occur during these fluctuations in female gonadal steroid hormones. PMS and premenstrual
dysphoric disorder (PMDD) occur during the luteal phase of the menstrual cycle and are
related to progesterone, which, in turn, could interact with GABA and 5-HT by changing the
configuration of their receptors; as a consequence, there will be a pause of its activation [
73
].
However, there are more mechanisms involved, but the path of the disorder is not known
with certainty [
74
]. Another variant of MDD, postpartum depression (PPD), has hormonal,
genetic and immunological precursors implicated in its pathophysiology. A clear biomarker
is allopregnanolone, a progesterone metabolite with anxiolytic and antidepressant power,
whose low levels after childbirth have been associated with an increased risk of developing
PPD. One possible explanation is its interaction with GABA receptors [
75
]. Likewise, in
premenopausal depressive disorder, progesterone levels remain constant [
76
] but E2 stands
out when its levels are higher, assuming a direct risk of the intensification of depressive
symptoms at this stage [77].
Biological particularities related to women in different moments of life are briefly
shown in Figure 2.
Nutrients 2022,14, 1107 7 of 39
Nutrients 2022, 14, 1107 7 of 40
Figure 2. Hallmarks in women-specific MDD pathophysiology. Different moments in a woman’s
life entail different hormone fluctuations with consequences at the neurotransmitter level. These
changes also affect estrobolome functions and positively correlate with MDD severity. Different im-
mune response compared to men is also emphasized. MDD = major depressive disorder; PMS =
premenstrual syndrome; PMDD = premenstrual dysphoric disorder; PPD = postpartum depression;
E2 = estradiol.
2.2.2. Psychological and Sociocultural Factors
It must not be forgotten that there are plenty of non-biological factors that help to
explain the different rates of MDD in women in comparison to men. As mentioned above,
psychological stress is a major driver of depression, associated with multiple structural
and functional changes in the brain. Chronic stress and early life stress (ELS) are fre-
quently involved in the onset and development of depression independently from sex-
gender [78,79]. However, different studies have observed that there is a differential re-
sponse in the brain between men and women, and also the perceived origin stress can be
different in both populations. ELS comprises various forms of child abuse and neglect
affecting a large number of children worldwide, being closely related with the develop-
ment of several psychiatric disorders [80]. Prior mice models have suggested that women
appear to be more sensitive to the detrimental effects of ELS, showing an early emerging
female-specific depressive phenotype and a rapid response to antidepressants [81]. For
instance, it is known that despite the hippocampus not being affected due to ELS in fe-
males, the reward system may be altered, explaining the differential long-term conse-
quences of ELS observed in women, including the higher risk of MDD [82,83]. On the
other hand, women with higher levels of chronic stress are more prone to suffer from
depressive episodes, especially after an occurrence of acute stress [84]. Interpersonal rela-
tionships can be considered a major source of stress and depression risk in women, as
depressed women often inhabit a complicated interpersonal environment, including di-
vorce, marital problems or difficulties with their children [85,86]. Other psychosocial fac-
tors implicated in the onset and development of MDD in women include negative and
ruminative thinking, low self-esteem, depression stigma and the diagnosis of a chronic
disease, with an inverse relationship with spiritual well-being [87].
Figure 2.
Hallmarks in women-specific MDD pathophysiology. Different moments in a woman’s life
entail different hormone fluctuations with consequences at the neurotransmitter level. These changes
also affect estrobolome functions and positively correlate with MDD severity. Different immune re-
sponse compared to men is also emphasized. MDD = major depressive disorder;
PMS = premenstrual
syndrome; PMDD = premenstrual dysphoric disorder; PPD = postpartum depression; E2 = estradiol.
2.2.2. Psychological and Sociocultural Factors
It must not be forgotten that there are plenty of non-biological factors that help to
explain the different rates of MDD in women in comparison to men. As mentioned above,
psychological stress is a major driver of depression, associated with multiple structural and
functional changes in the brain. Chronic stress and early life stress (ELS) are frequently in-
volved in the onset and development of depression independently from sex-gender
[78,79]
.
However, different studies have observed that there is a differential response in the brain
between men and women, and also the perceived origin stress can be different in both pop-
ulations. ELS comprises various forms of child abuse and neglect affecting a large number
of children worldwide, being closely related with the development of several psychiatric
disorders [
80
]. Prior mice models have suggested that women appear to be more sensitive
to the detrimental effects of ELS, showing an early emerging female-specific depressive
phenotype and a rapid response to antidepressants [
81
]. For instance, it is known that
despite the hippocampus not being affected due to ELS in females, the reward system may
be altered, explaining the differential long-term consequences of ELS observed in women,
including the higher risk of MDD [
82
,
83
]. On the other hand, women with higher levels
of chronic stress are more prone to suffer from depressive episodes, especially after an
occurrence of acute stress [
84
]. Interpersonal relationships can be considered a major source
of stress and depression risk in women, as depressed women often inhabit a complicated
interpersonal environment, including divorce, marital problems or difficulties with their
children [
85
,
86
]. Other psychosocial factors implicated in the onset and development of
MDD in women include negative and ruminative thinking, low self-esteem, depression
stigma and the diagnosis of a chronic disease, with an inverse relationship with spiritual
well-being [87].
Nutrients 2022,14, 1107 8 of 39
Last but not least, there is no denying the fact that cultural dictation of female roles
is one of the key determinants of depression in women, along with the lack of emotional
and social support [
88
]. The influence of some traditions or religions and immigration
in the higher prevalence of depression in certain groups of women is of note [
89
–
91
]. A
low socioeconomic status, especially at old age, is directly correlated with a greater risk of
depression in women [
92
]. Educational level, occupational situation, sexual satisfaction
and even the neighborhood or living in rural versus urban areas can also influence the
development of depression in women [
93
–
96
]. Despite depression affecting virtually all
ethnic groups, there are some disparities in the prevalence and treatment-seeking behavior
across race [97].
Overall, there are numerous psychological, social and cultural factors associated with
the development of depression in women. Besides, these factors appear to be frequently
accompanied and exert a cumulative effect on depression (i.e., ELS causes functional and
structural changes in the brain that may be related with interpersonal difficulties, low
self-esteem, professional difficulties and other factors with detrimental effects on the life
of women). All these multiple factors involved in the onset and pathophysiology should
be considered collectively in the clinical management of women with MDD in order to
properly address the different causes and consequences of depression.
2.3. MDD Clinic
2.3.1. General MDD Manifestations and Approaches
The diagnostic criteria proposed by the “Diagnostic and Statistical Manual of Mental
Disorder (DSM-V)” state that there must be a deficit in the functional capacity of the
individual that lasts for more than two weeks, a period during which there is a continuous
manifestation of five or more symptoms, among which we must include the loss of reactivity
to pleasant stimuli, which is usually caused by the daily activities carried out, and the
presence of a sad or irritable mood, which we find in some cases of children and adolescents.
These main criteria are accompanied by secondary disturbances, both somatic, including
insomnia and hypersomnia, loss of energy, changes in appetite or weight, and non-somatic,
for example, poor concentration or the appearance of suicidal thoughts [
98
]. The clinical
guidelines for the diagnosis should focus on aspects related to the repetitiveness of the
episode (one-off or periodic), improvement of symptoms, attention to the appearance of
psychotic symptoms, as well as their severity
6
. To make a quantitative evaluation of this
last parameter, the Hamilton Depression Rating Scale (HAM-D) is used, which stipulates a
question for each clinical criterion that will be given a certain score, the sum of which will
be between the values of 0 and 56 [
99
]. According to Zimmerman et al. various reference
ranges have been established; a score of 0–7 is considered a non-depressive state; 8–16 is
diagnosed as mild or moderate depression; at 17–23, the patient suffers from severe MDD,
while values > 24 are categorized as very severe depression [100].
To address the development of the disease until its remission, non-pharmacological
treatments are generally used, such as psychotherapy, as well as pharmacological ones.
Individualized management is attempted, although it is classified according to the stage
in which the patient is. In states of mild depression, no facts have been found that affirm
that the use of drugs is beneficial, so active monitoring of the patient is recommended, as
well as moderate psychological intervention [
101
]. Several studies show that in the case
of moderate MDD, the use of psychotherapy gives better results than the isolated use of
drugs, although it is true that the combination of both methods is the most effective on this
occasion [
102
]. Likewise, in severe states of depression, the use of psychological techniques,
such as cognitive behavioral therapies, together with the prescription of antidepressants, is
strictly recommended [
101
]. In approximately 30% of individuals the first two antidepres-
sant trials do not work adequately, which is known as treatment-resistant depression. In
these cases, complementary therapies should be applied, such as the use of second-degree
antipsychotics (SGA) or electroconvulsive therapy with remission effectiveness of 75% of
Nutrients 2022,14, 1107 9 of 39
cases [
103
]. In the same way, recent lines of research have put forth a potential proposal for
hormonal therapies as a complementary treatment [104].
2.3.2. Women’s MDD Clinic
MDD has twice the incidence in the female population compared to the male [
2
]. This
fact is also reflected in the fact that the prescription of antidepressants is around 17.2% in
women, while 8.2% of male patients receive this treatment [
105
]. As previously mentioned,
ovarian hormone fluctuations could be one of the potential causes of the disparity in
prevalence, giving rise to unique clinical presentations such as PMS, postpartum depression
(PPD) and postmenopausal depression (PMD) [13].
Studies from the end of the last century have already revealed the differences that major
depression presents in relation to the sex of the patients [
106
,
107
]. There is clear evidence
of the symptomatologic disparity; in women a greater presence of some classic symptoms
of this disorder has been observed, such as loss of interest or alteration of the sleep cycle,
added stress and irritability, both associated with a bad mood. Increased appetite, linked
to weight gain, or the appearance of obsessive thoughts is very representative in this
group [
108
]. In addition, in women, the appearance of anxiety disorders is frequent in
MDD, while in men it has comorbidity with substance use. The severity of the symptoms
is greater in the female population; however, the appearance of more episodes in the other
group stands out [
109
]. In the same way, it was deduced that the prescription of drugs that
stimulate immune function would be convenient for female patients, while antidepressants
that reduce immune activation are indicated for males [
60
]. It cannot be neglected that the
factors that confirm the differences between the responses to treatment are not decisive
at all, although it is stated that the efficacy of serotonergic antidepressants is increased
in women compared to men, and another important observation is that women in the
postmenopausal period experience a decrease in response compared to those of a younger
age [110].
3. The Importance of Malnutrition in MDD from a Sex-Gender Perspective
Malnutrition in general encompasses various manifestations that reflect a poor diet,
both in terms of lack and excess, leading to an imbalance between energy intake and
expenditure [
111
]. In this sense, the relationship between depression and poor nutritional
intake has been investigated, confirming the existence of this; however, in all the studies,
they highlight the need to continue investigating this aspect further, due to the limitations
of the studies carried out [112–114].
Eating behavior in women seems to play an important role. A recent study suggested
that 13% of participants with MDD had lifelong eating disorders and 39% showed clinically
significant disordered eating behavior, versus 3% and 11%, respectively, of participants
without diagnosed depressive disorders. Therefore, the authors concluded that the rate of
altered eating behaviors is higher in women with depression [115]. Along these lines, it is
well known that emotional hunger is one of the basic characteristics of eating disorders [
116
].
The oscillations of ovarian hormones could have a close link with “emotional hunger” and
the desire for more palatable foods rich in sugars. It has been observed in girls that high
levels of leptin in the blood are related to high stress [
117
]. Several investigations in women
have investigated the existence of differential responses to appetizing food throughout
the cycle, concluding that in phases with a high concentration of estrogen, motivation
for reward is lower, so emotional hunger is reduced; on the contrary, in the luteal phase
where the predominant levels are those of progesterone, the desire for appetizing food
increases exponentially [
118
]. Women more susceptible to binge eating have compromised
interoceptive awareness of physiological states [
119
], resulting in dietary limitation that, as
a consequence, could negatively affect the dopaminergic system [118].
However, binge eating is not the norm in MDD in general. On the other hand,
we know that, especially in depressed older people, there is a great tendency to loss of
appetite, skipping meals and involuntary weight loss [
120
,
121
], due to hypoactivation of
Nutrients 2022,14, 1107 10 of 39
the middle insular cortex. It would be interesting to carry out studies in which, when
monitoring pregnant women, it can be detected if their frequent lack of appetite or other
irregularities [
122
] are related to prevalence of postpartum depression; or to determine
if, in women with postpartum depression, there is a tendency towards loss of appetite or
binge eating in pregnancy.
From this association between eating disorders and MDD, the terms “depression-
related increased appetite” and “depression-related loss of appetite” can be found in the
scientific literature [
123
]. In any case, different eating patterns will lead to excesses in certain
macronutrients and deficiencies in others, as well as deficiencies in certain micronutrients
that seem to play important roles in the patient’s homeostasis.
3.1. Macronutrients
Macronutrients encompass carbohydrates, proteins and fats, and they play a central
role in cognition and brain functioning [
124
]. In the case of women, macronutrients
consumption appears to vary across the menstrual cycle. For instance, an increased intake
of protein, particularly animal protein, can be reported during the luteal phase of the
menstrual cycle [
125
], with more carbohydrate intake per day after ovulation [
126
]. These
variations are due to sexual hormonal fluctuations and, in turn, adequate food intake is
crucial for ensuring the functioning and actions of these hormones in tShe body [
127
]. In
this part we will summarize the role of macronutrients and their deficiency in the onset
and progression of MDD, PMS, PPD and PMD.
In recent decades, carbohydrate consumption has been stigmatized and closely linked
to mood. The mechanisms that allow this interaction appears to be linked to the synthesis of
different neurotransmitters, although special emphasis is placed on the serotonergic system
due to the ability of insulin to increase tryptophan bioavailability in the brain [
128
]. There
seems to be a clear derangement of glucose metabolism in patients with MDD [
129
], and
high glycemic blood levels have been linked to suicidal behavior [
130
] and disruption in
brain networks [
131
]. Despite the widespread belief that sugar consumption is necessary for
the brain and improves mood, compelling evidence refutes this hypothesis, also suggesting
projected harm in greater fatigue, a symptom associated with MDD [
132
]. Conversely, diets
with poor carbohydrate intake could also be counterproductive, causing compromised
metabolism [
133
]. There have been some studies conducted in women correlating carbo-
hydrate consumption, mood and the risk of suffering PMS. Houghton et al. [
134
] found a
direct association between maltose intake and the development of PMS, although high di-
etary glycemic index was found to be correlated with decreased premenstrual symptoms in
a group of young Japanese women [
135
]. In the same line, high dietary glycemic index but
not glycemic load was found to be associated with fewer depressive symptoms in young
and middle-aged women [
136
]. It should be remarked here that the origin of the dietary
carbohydrates should be deeply studied, although it seems that high dietary glycemic index
may benefit women’s mood and brain function in reproductive ages. However, further
studies are required, as there are other works suggesting the opposite conclusions without
considering a sex-gender perspective [
137
,
138
]. On the other hand, the evidence has failed
to find any relationship between carbohydrate intake and PPD [
139
,
140
]. Besides, a study
carried out in a cohort of postmenopausal women revealed the negative influence of diets
rich in refined carbohydrates, which consequently increase the risk of depression [
141
].
Conversely, high consumption of fiber appears to be directly correlated with sex-hormone-
binding globulin (SHBG), a protein involved in sex hormone transportation. Interestingly,
in postmenopausal women, SHBG and sex hormone levels have been associated with
depressive symptoms, although more efforts are needed in this field [142].
Proteins also play a vital role in multiple biological processes. They are molecules
formed by amino acids linked together forming chains; the products derived from the
hydrolysis of these will be used by the bacteria of the digestive system, by the cells for the
synthesis of metabolites involved in relevant physiological processes and are destined to
play a role in the formation of other tissues such as the muscle [
143
]. Animal studies have
Nutrients 2022,14, 1107 11 of 39
helped us gain further insights into the negative effects of deficient protein intake. For
instance, greater susceptibility has been observed in female mice in developing depressive
symptoms at an early age when they have been deprived of protein intake in the perinatal
stage [
144
]. Likewise, there was loss of neurons and alteration of the precursor genes of
hippocampal neuroplasticity in young adult female mice with protein malnutrition [
145
].
In addition, not only the amount of protein but also its quality is essential for a healthy
diet [
143
]. Despite some studies reporting a negative association between excessive protein
intake and depressed mood in women [
146
], no relationship has been found between
protein consumption and PMS [
147
]. More studies are needed to evaluate the effects of
protein intake and depression in women.
Another of the macronutrients that are linked to depression is lipids. It seems that
women are in general more prone to having intakes that exceed recommendations for total
and saturated fat [
148
]. First of all, it should be highlighted that trans fatty acids, as poor-
quality lipids in the induction of dysbiosis, promote the proliferation of harmful bacteria
such as Proteobacteria and reduce those that provide benefits to metabolic processes [
149
].
Thus, in premenopausal women, a positive link between high trans fatty acids intake
and depressive symptoms has been reported [
150
]. Likewise, their consumption seems
to increase proinflammatory responses [
151
] and enhance the permeability of neuronal
membranes, implying the compromise of the dopaminergic system and the appearance of
anxious symptoms [152]. On the other hand, there is evidence of the benefits provided by
some, such as omega 3 polyunsaturated fatty acids (
ω
-3 PUFAs), specifically eicosapen-
tanoic acid (EPA) and docosahexaenoic acid (DHA). Mainly, two physiological mechanisms
associate them with depression; EPA and DHA, being part of the cell membranes of neu-
rons, are crucial for the correct neurotransmission and cell signaling and, in turn, have
the power to inhibit the proinflammatory cytokines characteristic of patients with MDD
and inflammatory eicosanoids that are elevated in these cases [
153
]. Women with MDD
usually present low intake of
ω
-3 PUFAs, which is inversely correlated with depressive
symptoms and is directly associated with brain functional connectivity [
154
]. Besides,
the benefits from increasing
ω
-3 PUFAs have also been reported in PMS, PPD and PMD,
although further studies are required to confirm these results [
155
–
157
]. Linked to the low
intake of
ω
-3 PUFAs, the consumption of omega 6 fatty acids (
ω
-6 FAs) is increased in
Westernized diets. Over the decades, the ratio has changed from a balance of both fatty
acids to
ω
-6/
ω
-3 ratios between 10:1 and 20:1. These long-chain polyunsaturated lipids
are derived from linoleic acid and share the enzymes (elongases and desaturases) that are
involved in their biosynthesis. Consequently, abundant consumption of
ω
-6 PUFAs inter-
feres with the desaturation of
ω
-3 PUFAs, thus leading to loss of homeostasis, promoting
the genesis of cardiovascular, inflammatory or cancer disorders, among others [
158
]. High
ω
-6 PUFAs intake appears to be linked with a higher risk of depressive symptoms among
pregnant women, with total fatty acids intake and omega-6/omega-3 ratio above recom-
mendation [
159
] also being predictive as a potential risk factor of later PPD [
160
]. In this
sense, the fatty acids in question stand out for their role in the regulation of inflammatory
pathways. The association of the
ω
-6/
ω
-3 imbalance has been found with the increase in
IL-6, exacerbating inflammatory reactivity; therefore, it will mean greater vulnerability to
the appearance of depressive symptoms [
161
]. The reversal of the balance towards the fatty
acids balance could be beneficial for the improvement of subjects with MDD.
3.2. Micronutrient Deficiencies Related to Reproductive Age, Postpartum and Later Life
Firstly, vitamins are a group of essential micronutrients that appears to be affected in
women with MDD. Vitamin D (Vit D) is a fat-soluble hormone, known for its role in calcium
homeostasis and bone growth. It also plays a decisive role in neurological development.
The synthesis and elimination of this micronutrient, as well as vitamin D receptors (VDR),
are found in the brain [
162
]. Consequences of vitamin deficiency that have been related to
the pathogenesis of MDD are alterations in the hippocampus in animal models [
163
] and
imbalance in neuronal excitation and inhibition pathways [
164
]. Evidence has been found of
Nutrients 2022,14, 1107 12 of 39
the improvement that this nutrient produces in depressive symptoms; however, it is not so
conclusive that adequate concentrations can prevent the development of depression [
165
].
Among the processes in which vitamin B12 is involved, DNA synthesis, blood cell
synthesis and neurological functions stand out for their relevant action [
166
]. Interdepen-
dence with folate increases the processes in which B12 interferes [
167
]. Research, both in
childhood and adolescence as well as in adulthood [
168
], shows that these two micronu-
trients, as well as homocysteine, are involved in one-carbon metabolism and methylation
processes of neurotransmitters, proteins and phospholipids of the cell membrane. Low
concentrations of B12 and folate are linked to the alteration of the above [
169
]. Moreover,
in this situation, the production of a neurotoxic metabolite of homocysteine is stimulated;
as a consequence, there is overstimulation of NMDA receptors that increases the flow of
intracellular calcium, increasing oxidative stress and apoptotic responses [
170
]. All this
leads to the contribution of the pathogenesis of MDD [168].
On the other hand, women with MDD seldom meet mineral requirements. Several
studies point to a usual low serum zinc level in patients with MDD [
171
]. The influence
of the micronutrient on the glutamatergic system has been demonstrated, producing the
inhibition of the N-methyl D-aspartate (NMDA) receptor via the zinc receptor GPR39,
a process necessary to preserve glutamate and GABA homeostasis [
172
]. Likewise, it is
stipulated that part of its benefit lies in its ability to activate neuronal plasticity processes
and its interaction with monoamines [
173
]. Selenium (Se), among other things, is part
of the selenoproteins highly involved in the signaling of redox processes [
174
]. In this
line, other organic compounds containing selenium have been investigated, such as, for
example, 3-((4-chlorophenyl) selanyl)-1-methyl-1H-indole (CMI), which has shown results
regarding its inhibitory power on the inflammation associated with oxidative stress in
in vitro
studies [
175
] and in mice models [
176
]. The cross-sectional study by Li et al., in
a population of American adults with MDD shows, once again, the indirect association
between the concentrations of this element and other essential elements and depressive
behavior [
177
]. The meta-analysis led by the same researcher suggests that there could be
an inverse relationship between iron intake (Fe
2+
) and the risk of MDD [
178
]. Fe
2+
levels
are known to be closely associated with brain function [
179
]; for example, they are cofac-
tors of tyrosine and tryptophan hydrolase, involved in the genesis of monoamines [
180
].
The functions of the striatum and the hippocampus are compromised by Fe
2+
deficiency,
affecting even the embryonic stage of the individual [
181
]. Magnesium (Mg
2+
) is involved
in many physiological processes in the human body; of these, its calcium antagonist power
has been related to mood by blocking NMDA receptors; in the same way, it is involved in
the monoaminergic and glutamatergic systems and increases BDNF expression and reduces
systemic inflammation, among other things [182].
Importantly, plenty of studies have been found to be related to specific micronutrient
deficiencies at reproductive age, postpartum and later life; all of them are to be regarded as
potential risk factors for different manifestations of depression. For this reason, it is of note
to consider the different moments of life in women to manage specific requirements they
may need with the aim to improve their prognosis in the case of diagnosed MDD, or to
prevent the onset.
3.3. Specific Micronutrient Deficiencies Related to Menstruation, PMS and PMDD
Approximately 20–25% of women have moderate to severe PMS; and it is estimated
that 5% of women have been diagnosed with its most severe form, PMDD [
183
]. It should
be noted that prevalence increases in adolescence [
184
]. Lower levels of calcium and Mg
2+
,
but not vitamin D, have been observed in women with PMS compared to controls [
185
].
Based on these facts, there seems to be an association between cyclical changes in women
and calcium levels, thus affecting patients with PMS. Generally, serum calcium concentra-
tion is lower in this group, being inversely correlated with the incidence and symptoms
of PMS [
186
]. However, despite the fact that there is the possibility of a relationship be-
Nutrients 2022,14, 1107 13 of 39
tween vitamin D concentrations in women and premenstrual disorders, the benefits of its
prescription are still not clear [187].
On the other hand, zinc seems to play a prominent role not only in mental but also
in physical health, as has been shown in several placebo-controlled trials [
188
,
189
]. The
review carried out by McCabe et al. shows the possible effectiveness of essential fatty acids
in reducing premenstrual anxiety, having detected positive effects with the combination
of vitamin B6 and Mg
2+
[
190
]. To date, only one study has determined the relationship
between iron and premenstrual syndrome; it is intuited that the mechanism that links
them could be related to hormonal fluctuations, as happens in PPD. Having said that,
the authors were able to affirm that high intake of non-heme iron is positively related to
the reduction of premenstrual symptoms. In addition, the opposite occurred with high
amounts of potassium, which produced an increased risk of PMS, possibly due to its
aldosterone agonist power, which consequently increases fluid retention [
191
]. We cannot
ignore the changes in appetite during the different phases of the menstrual cycle; estrogens
and progestogens participate in this [
192
]. Due to the fact that patients with PMDD are
more sensitive to hormonal variations, it has been concluded that there is an increased
desire for sweet foods in the late luteal phase; this does not happen with foods with high
salt content. It is proposed to focus on this fact to achieve new strategies that help in the
clinical intervention of women with PMDD [193].
3.4. Specific Micronutrient Deficiencies Related to Perinatal and Postpartum Depression
There is a clear link between disruptions in both neurotransmitter and hormonal levels
and fluctuations in micronutrients in women with PPD; therefore, it is important to know
their influence and the antidepressant power of each one, with the aim to find alternative
therapies with optimal effects. It is desired to obtain null adverse effects for lactation or
ability to create addiction [
194
], which, a priori, will have a positive reception by patients
in this group due to the harmless effect on their babies [195].
Several cohort studies suggest low levels of the circulating form of vitamin D, that is,
25-hydroxyvitamin D (25-[OH]-D), in patients with PPD [
196
,
197
]. The interdependence of
vitamin D with calcium is widely known, and it is intuited that it plays an important role in
the matter in question, since calcium stimulates signaling for the activation of gonadotropin,
which in turn will lead to an increase in luteinizing and follicle-stimulating hormone
which, as a consequence, increases the production of estradiol (E2). After childbirth, the
demand for calcium increases and, with it, the demand for vitamin D. However, a study in
which supplementation with vitamin D and calcium was combined in women with PPD
versus placebo concluded that it cannot be stated that vitamin D decreases the severity
of symptoms through increased E2 [
198
]. It should be noted that vitamin D could play
an important role in improving depression in this group, but the lack of studies casts
uncertainty on whether its effect is due to the relationship in the HPA axis, serotonin,
hormonal and inflammatory levels or other mechanisms involved in the pathophysiology
of PPD [199–201]. The same facts accompany perinatal depression [200,201].
Pregnancy is accompanied by increased blood cell volume and fetal and placental
development, suggesting a sharp increase in Fe
2+
demand [
202
]. A cross-sectional study
with 142 pregnant women of more than 20 weeks, all of them with a history of mental
disorders, such as anxiety or depressive episodes, concluded that there is a relationship
between iron deficiency and perinatal depression [
203
]. The same thing happened in a
study related to PPD, again evidencing this inverse relationship [
204
]. In contrast, the
research carried out by Armony-Sivan et al. found no relationship between these two
variables [
205
]. There is divergence in the results; however, there seems to be a significant
relationship between low concentrations of hemoglobin or iron and the risk of suffering
from depression after childbirth [
206
,
207
]. As in previous cases, it has been suggested
that the decrease in
ω
-3 PUFAs levels is a factor that encourages the development of PPD.
Women with an index greater than 5% of
ω
-3 during pregnancy have a lower risk of
suffering from depression during the following year after birth [
208
]. However, a study
Nutrients 2022,14, 1107 14 of 39
of a cohort of Japanese women found no benefit of EPA and DHA supplementation in
reducing risk [
209
]. Generally, prescription is not recommended as the main therapy, but it
is considered a good complement [
210
]. NMDA receptor antagonist micronutrients such as
Zn and Mg
2+
have also been studied in this area, although it is true that the results have
not been significant in improving symptoms in patients treated versus placebo [
211
], or a
very slight positive effect has been seen [
212
]. However, in animal models, it seems that the
combination of these microelements reduces the percentage of depressive symptoms after
birth [
213
], which turns out to be encouraging data in order to continue focusing on the
research on these micronutrients.
3.5. Specific Micronutrient Deficiencies Related to Peri- and Postmenopausal Depression
Perimenopause is considered a stage of high vulnerability for the development of
depressive symptoms or behaviors, even in women without precedent [
214
]. The same
thing happens in the post-menopausal phase [215].
Serum levels of some micronutrients such as vitamin D, iron, calcium and Mg
2+
are
lower in women with postmenopausal depression. Vitamin D deficiency is correlated with
an increased incidence of changes in bone mass, commonly related to menopause [
216
]. In
perimenopause, a negative association between vitamin D levels and depressive symptoms
has also been found [
217
]. The deficiency is mainly due to low intake in the diet, little
exposure to the sun due to the limitation of outdoor activities and reduced capacity for
calcitriol synthesis [
218
]. Another trace element whose values are above the norm in
postmenopausal women is copper, which, combined with the low concentration of Mg
2+
,
seems to increase vulnerability to depression [
219
]. In contrast, the levels of vitamin B12 and
folate are not altered in these depressive patients.
ω
-3 PUFAs have also been investigated
in this field; it was determined that when the intake of these fats is higher, the prevalence is
reduced, although the causes are unknown [220].
All these common nutritional deficiencies observed in women with MDD at different
ages are summarized in Figure 3.
Nutrients 2022, 14, 1107 15 of 40
Figure 3. Nutritional deficiencies observed at different moments in a woman’s life that are associ-
ated with depressive symptoms. As summarized, there is in general a poor dietary context in
women with depression, characterized by low fiber intake, high refined carbohydrates and sugar,
unhealthy fats and low-quality protein intake, with detrimental effects on the brain. The improper
dietary context is also related to several micronutritional deficiencies in women, with some partic-
ularities depending on the moment of their lives. MS: premenstrual syndrome; PMDD: premen-
strual dysphoric disorder, PPD: postpartum depression; E2: estradiol.
4. Nutritional Intervention in Women with MDD
Addressing the nutritional status of patients with depression can be a profitable tool
to aid in the possible pharmacological and psychological treatment of MDD, as well as
prevention. Next, some of the most relevant findings will be detailed in relation to nutri-
ents and bioactive components that have been gathered as evidence in clinical trials, in an
attempt to translate the results by specifically focusing on women with depression. In this
line, the concept of nutraceuticals stands out, which encompasses those food components
that are essential and/or beneficial for the pathophysiology of the patient [221].
4.1. Fatty Acids
The human body does not synthesize fatty acids by itself, so it is necessary to incor-
porate them into the diet; the adequate amount of omega 3 should be 250 mg daily. The
foods that most contribute this molecule are of both plant and animal origin; among them
are chia seeds, soybeans, flax, nuts, vegetable oils, oily fish and shellfish [222]. There is
strong evidence for the benefit of ω-3 PUFAs in depression [223,224]. The increase in EPA
and DHA in cell walls correlates with the improvement of depressive symptoms and
greater treatment effect [225]. Similarly, their antidepressant effect could be their anti-in-
flammatory and serotonin-modulating power, among others. Proinflammatory cytokines
and BDNF mediate serotonin neurotransmission; cyclic AMP-responsive element-binding
protein (CREB) has been found to be key to BDNF activation [226] which, as a conse-
quence, translates into increased serotonin synthesis and reduced TNF-α, IL-6 and other
proinflammatory cytokines. DHA and EPA modulate the levels of the neurotransmitter
Figure 3.
Nutritional deficiencies observed at different moments in a woman’s life that are associated
Nutrients 2022,14, 1107 15 of 39
with depressive symptoms. As summarized, there is in general a poor dietary context in women with
depression, characterized by low fiber intake, high refined carbohydrates and sugar, unhealthy fats
and low-quality protein intake, with detrimental effects on the brain. The improper dietary context is
also related to several micronutritional deficiencies in women, with some particularities depending
on the moment of their lives. MS: premenstrual syndrome; PMDD: premenstrual dysphoric disorder,
PPD: postpartum depression; E2: estradiol.
4. Nutritional Intervention in Women with MDD
Addressing the nutritional status of patients with depression can be a profitable tool
to aid in the possible pharmacological and psychological treatment of MDD, as well as
prevention. Next, some of the most relevant findings will be detailed in relation to nutrients
and bioactive components that have been gathered as evidence in clinical trials, in an
attempt to translate the results by specifically focusing on women with depression. In this
line, the concept of nutraceuticals stands out, which encompasses those food components
that are essential and/or beneficial for the pathophysiology of the patient [221].
4.1. Fatty Acids
The human body does not synthesize fatty acids by itself, so it is necessary to incorpo-
rate them into the diet; the adequate amount of omega 3 should be 250 mg daily. The foods
that most contribute this molecule are of both plant and animal origin; among them are
chia seeds, soybeans, flax, nuts, vegetable oils, oily fish and shellfish [
222
]. There is strong
evidence for the benefit of
ω
-3 PUFAs in depression [
223
,
224
]. The increase in EPA and
DHA in cell walls correlates with the improvement of depressive symptoms and greater
treatment effect [
225
]. Similarly, their antidepressant effect could be their anti-inflammatory
and serotonin-modulating power, among others. Proinflammatory cytokines and BDNF me-
diate serotonin neurotransmission; cyclic AMP-responsive element-binding protein (CREB)
has been found to be key to BDNF activation [
226
] which, as a consequence, translates
into increased serotonin synthesis and reduced TNF-
α
, IL-6 and other proinflammatory
cytokines. DHA and EPA modulate the levels of the neurotransmitter by this pathway [
227
].
Likewise, a study with ovariectomized rats investigated the synergy of estradiol and
ω
-3
PUFA, determining its antidepressant effects by the same route described previously. In
addition, estradiol produced the regulation of glutamate, myo-inositol and cerebral glu-
cose, which is related to less neuroinflammation and reduced neuronal death promoted
by Glu [
227
,
228
]. The supplementation of
ω
-3 FA has been suggested in pregnant and
lactating women; animal studies have shown a transfer of 25% of brain DHA to the fetus,
which translates into a progressive depletion of the resource if the intake is not adequate;
as a consequence, there would be a disruption of the release, reuptake and transmission of
serotonin, as it is a main component of the terminal synaptic membranes. EPA correction,
mainly in postmenopausal women, is recommended, among other things, for providing an
improvement in psychotic symptoms [222].
4.2. Vitamins
4.2.1. Vitamin D
The way in which we can obtain more of this fat-soluble molecule is by exposing the
skin to ultraviolet radiation from the sun. To a lesser extent, it is found in foods such as
milk, fatty fish or some vegetables [23].
Due to the production of active forms of vitamin D and the presence of VDR in intesti-
nal cells, the close interaction of this microelement and the intestine could be intuited. On
the one hand, several animal studies show the joint action of the intestinal microbiota and
25-[OH]-D in the modulation of inflammatory pathways, since it has been suggested that it
is due to interaction with certain microbial metabolites, such as, for example, butyrate [
229
].
Some facts that prove this are the ability of both to repress the proliferation of inflammatory
cytokines and regulate the signaling of nuclear factor kB (NFkB), the latter involved in the
gene expression of inflammatory and immune responses [
230
]. Likewise, the importance
Nutrients 2022,14, 1107 16 of 39
of vitamin D in maintaining the integrity of the intestinal barrier has been observed. The
intestinal mucous layer restricts the passage of bacteria through the epithelium; vitamin D
can maintain adequate levels of antimicrobial peptides, for example, favoring the prolif-
eration of Treg which, consequently, will inhibit the expression of Th1 immune cells and
Th17, activating response due to bacterial penetration of endothelial cells [
231
]. On the
other hand, germ-free mice presented hypovitaminosis and hypocalcemia, which were
reversed with the inoculation of the intestinal microbiota, which suggests the direct effect
of the microbiota on the metabolism of vitamin D [232].
In summary, vitamin D deficiency in patients with MDD could lead to increased
permeability of the intestinal barrier, favoring endotoxemia and the consequent inflam-
mation; likewise, the dysbiosis of microorganisms contributes to a decrease in vitamin D
concentration, producing the attenuation of processes that contribute negatively to the
pathophysiology of depression. In the case of women, the stages surrounding menopause
and post-menopause are detrimental to the balance of bacterial species in the intestinal
tract [
233
]. Supplementation with vitamin D3 would lead to a balance of microorganisms
and a reduction in inflammation resulting from sudden estrogenic changes. The influence
of this nutraceutical on quality of life, sleep hygiene and mood seem to be related to differ-
ent pathways. Calcitriol mediates the formation of serotonin by activating the synthesis
of tryptophan hydrolase 2 in different brain regions. In addition, its deficiency can affect
the serotonergic system in another way; possibly melatonin and serotonin share common
mechanisms; sun exposure and being able to influence mood through sleep quality may
be important in MDD [
234
]. In relation to the above, the decrease in sleep quality, loss
of energy and changes in eating habits in pregnant women or in postpartum periods are
well known. The cohort study that was carried out in 890 women in the middle of their
pregnancy used measurements of 25-[OH]-D in plasma, determining levels < 50 nmol/L to
be insufficient; in addition, sleep patterns were monitored with the sleep quality index of
Pittsburgh (PSQI), as well as the moment of the consumption of the highest percentage of
calories (day or night). The results determined that insufficiency of 25-[OH]-D increases
the risk of eating at night and the detriment of the quality of rest [
235
]. However, there is
controversy about the relationship between vitamin D levels and the risk of PPD [236].
This nutraceutical not only seems to have an impact on the aforementioned; in re-
search carried out in a population with a sample size of 897 adolescent girls, both without
problems and with some condition associated with the menstrual cycle, they were given
50,000 IU/week of cholecalciferol during the nine weeks that the intervention lasted. Sup-
plementation led to a drop in the prevalence of PMS and dysmenorrhea, from 14.9% to
4.8%, and 35.9% decreasing to 32.4%, respectively, as well as associated psychological
and physical symptoms [
237
]. A clinical trial also observed the positive effect of vita-
min D supplementation, this time combined with probiotics, on women with polycystic
ovary syndrome [
238
]; this endocrine disorder appears to be linked to depression and
anxiety [239].
4.2.2. Vitamin B
Vitamin B deficiency seems to be a risk factor for the development of brain disorders
such as cognitive disorders or dementia, due to its essential role in the folate and methionine
cycles involved in nucleic acid methylation and homocysteine regulation. In addition, they
are important cofactors in the biosynthesis of phospholipids and neurotransmitters [
240
].
Vitamin B9, also known as folic acid or folate (anionic form) is involved in the one-carbon
cycle through the methionine cycle. Its active form, 5-methyltetrahydrofolate (5-MTHF),
is crucial for the conversion of homocysteine to methionine through a reaction catalyzed
by vitamin B12 and methionine synthase [
241
]. Likewise, methionine is the precursor
for the production of SAMe, an important methyl donor for histones and DNA. Low
levels of vitamin B stimulate the production of homocysteine [
242
]. These facts are closely
linked with the menstrual cycle, assuming constant regeneration of endothelial tissue and
follicular development; in this sense, a clinical study observed, by means of senescence
Nutrients 2022,14, 1107 17 of 39
markers p16, p21 and p53, the importance of folate as an antagonist of homocysteine
in cell proliferation [
243
]. In accordance with the above, Michels et al. suggest that
high homocysteine concentrations are related to altered hormonal changes and sporadic
anovulation [
244
], abnormalities associated with polycystic ovary syndrome (PCOS) [
245
],
assuming a risk factor for depressive symptoms and other psychiatric disorders [
246
].
Supplementation of B vitamins is suggested as a treatment to improve ovulation and
fertility [
244
]. The prescription of folic acid during pregnancy is well known, among
other things, because of its importance in the development of the fetus and the formation
of the neural tube. Recent research correlates this with a lower risk of suffering from
psychotic symptoms during pregnancy; in fact, in the animal model that was given doses
of 1 and 5 mg/kg of folic acid, this nutrient was postulated as a potential contributor of
cognitive alterations in the prenatal stage postpartum [
247
]; clinical trials agree with this
evidence; thus its supplementation is recommended to reduce the risk of PPD [
248
]. This
improvement appears to be linked to increased expression of pathways related to neuronal
genesis, BDNF and synaptic transmission in the hippocampus [247].
4.2.3. Minerals
Minerals play a key role in our development; therefore, they are considered essen-
tial molecules. They are divided into two: macromineral groups whose intake should
be >100 mg/day
and trace elements whose recommended dose ranges between 1 and
100 mg/day [
249
]. As previously mentioned, mineral levels are disturbed in patients
with MDD; generally, there is a deficit of them, except for copper, which is in excess [
250
].
Magnesium is a macromineral highly implicated in the pathophysiology of neurological
disorders [
251
]. In a clinical trial, differences were shown in the monitoring of participants
for 12 weeks; for half of that time, they were supplemented with 248 mg/day of magnesium
and the remaining time was for control. The findings were conclusive as to the effectiveness
for the improvement of mild-moderate MDD without differences in age or sex; in addition,
its low toxicity and rapid power of action were demonstrated [
252
]. In the research carried
out on people with PCOS, 100 mg of magnesium, 4 mg zinc, 400 mg calcium plus 200 IU
vitamin D were offered for 12 weeks compared to the placebo group; this had beneficial
effects on hormonal profiles, biomarkers of inflammation and oxidative stress in women
with PCOS [
253
]. The interest of this fact is the advantage it entails for the quality of life
of the patient of childbearing age, thus being able to reduce the risk of the appearance of
mental discomfort or depressive symptoms.
For its part, iron is an important trace element that seems to be related to MDD.
Although there is no solid evidence of the benefit of its supplementation in patients with
MDD, the indications in animal tests justify future investigations. A randomized trial
developed an experiment in which half of their patients were treated during the last 6 weeks
of pregnancy with 50 mg of ferrous sulfate and the other half was the placebo group; the
result was the improvement of PPD [
254
]. Additionally, the systematic review carried out
by Lomagno et al. maintains that research in women would be of special importance due
to the changes in levels such as those that can occur during menstruation, pregnancy or
menopause. In this same study, the potential of zinc as a nutraceutical was also evaluated; in
this case, the studies seem to point to the positive influence it has on mood regulation [
255
].
In the double-blind, placebo-controlled trial in young women, a multivitamin capsule
and zinc 7 mg/day were combined for 10 weeks. The intake led to a reduction in scores
related to anger, depression and discouragement along with an increase in serum zinc; these
changes were not seen in the placebo group [
256
]. Accordingly, the general population
with MDD could also obtain advantages, since the research review of patients treated
with antidepressants plus supplementation versus placebo concluded that there was better
response and recovery for those treated with this trace element [
257
]. Selenium is also a
vital molecule for our body; the proper dose of it, along with other nutrients, can have a
moderate impact on rectifying the development of TDM [
258
]. Furthermore, the possible
protective effect on DPP has been suggested [259].
Nutrients 2022,14, 1107 18 of 39
The inconsistency and scarcity of studies carried out on treatment with minerals justify
the increase in research of this nature.
4.2.4. S-Adenosyl Methionine
SAMe is the major known methyl donor in living organisms. It is a metabolite pro-
duced in the methionine cycle thanks to the enzyme methionine-adenosyl transferase
(MAT2A), responsible for the transfer of adenosine to the sulfur of methionine, obtaining
SAMe. This undergoes a series of transformations that leads to homocysteine; its remethyla-
tion mediated by 5-methyltetrahydrofolate will end up forming a new methionine molecule;
this last step is connected to the folate cycle, vitamin B12 being necessary to complete the
reaction in mammals [
260
]. The quality of donor of methyl groups makes SAMe a powerful
mediator of epig6enetic mechanisms of both physiological functions in general and those
related to the central nervous system due to its intervention in processes of transmethyla-
tion of DNA, histones, protein phosphatase 2A and catecholamine fractions. The alteration
of one of the two cycles will contribute to the pathophysiology of psychiatric conditions,
such as Alzheimer’s or MDD [
261
]. The synthesis of the cofactor tetrahydrobiopterin BH4
involved in the regulation of the production of monoaminergic neurotransmitters, together
with the modulation of enzymes, transporters and monoaminergic receptors, is mediated
by SAMe. It has been shown that patients with depressive disorders appear to have low
levels of SAMe and MAT2A, which consequently compromises the previously described
pathways [
262
], exacerbating the progress of the pathology. In addition, it is involved in
inflammatory regulation and intestinal dysbiosis. A basic pillar of the anti-inflammatory
action of SAMe against endotoxins is the downregulation of the expression of TNF
α
in
immune cells (monocytes or macrophages) derived from the transcriptional induction
promoted by lipopolysaccharide [263].
Mischoulon et al. demonstrated in their trial the improvement of cognitive impairment
and depressive symptomatology using 800–1600 mg/day of SAMe for 6 weeks as an
adjunct to antidepressant drugs [
264
]. It could even be recommended in patients with
resistance to treatment. In addition, a plethora of clinical trials have studied its efficacy
as monotherapy, showing positive effects against placebo and, in comparison, with other
antidepressants [
265
]. However, sometimes it has not turned out to be as beneficial as
expected [
266
]. There is gender-dependent divergence regarding the effectiveness of the
nutraceutical, since the efficacy of the treatment led to a significant improvement in the
severity of depressive symptoms measured with HAM-D in the sample of male subjects,
while no differences were observed in women [
267
]. It would be convenient to investigate
the mechanisms involved behind this difference in order to optimize the treatment of
patients. The lack of studies in the female population with depression hinders the possible
advantages that SAMe supplementation can provide in the specific alterations of this group.
In summary, the prescription of SAMe as a supplement in patients with MDD seems to
be beneficial, mainly when it acts together with antidepressants; however, the particularities
of each patient should be studied before doing so. The need to delve into the mechanisms
of which SAMe is a part can be glimpsed for future research.
4.2.5. Creatine and Amino Acids
Creatine (N-aminoiminomethyl-N-methyl glycine) is an endogenous nitrogenous
molecule composed of amino acids. Its synthesis occurs in the liver, pancreas and kidney,
but this supplies only half of the necessary amount, so its intake in the diet is essential,
through foods such as red meat and fish, or by supplementation. It is known for its
ergogenic benefits in athletes; however, recent research shows its interest in other areas [
268
].
Arginine, methionine and glycine are the amino acids necessary for its synthesis. The
amidino group of arginine is transferred to the glycine molecule whose products will be
ornithine and guanidinoacetate; then, SAMe donates a methyl group to guanidinoacetate
to form creatine [
269
]. Creatine is mainly found in tissues with high energy demand due
to its transformation into derivatives with great potential as rapid energy intermediates,
Nutrients 2022,14, 1107 19 of 39
such as phosphocreatine [
268
]. Compromise in the ability to metabolize creatine and
alteration of serum levels in patients with MDD have been demonstrated [
270
], as well as
the relationship of these with low intake from the diet [
271
]. Both preclinical and clinical
studies demonstrate the antidepressant power of creatine due to its involvement in different
pathways [270].
An animal model suggests sex-dependent differences in the effect of creatine supple-
mentation, assuming an improvement in depressive behavior in females [
272
]. Consistent
with this finding, the clinical study conducted on a group of women of different ages
suggested that this protein improves the effects of antidepressant drugs, increases the
connection of neural networks, which are attenuated in people with these conditions, and
increases levels of N-acetyl aspartate in the prefrontal cortex, indicative of the improvement
in neuronal integrity [
273
]. Likewise, dopaminergic and serotonergic neurotransmitters
are increased with the presence of creatine detected in the cerebrospinal fluid [
274
]. Fur-
thermore, modulation of sex hormones could affect creatine homeostasis. The difference
in serum creatine kinase levels according to cycle phase and age has been observed; these
increase in the luteal phase of the menstrual cycle synchronous with fluctuations in estro-
gen concentrations; however, they decrease during pregnancy and menopause. Creatine
supplementation leads to improvements of various kinds, such as increased muscle tone
and bone strength in menopause, lower risk of brain damage during pregnancy, as well as
preservation of sleep patterns and cognition [274].
Depressed patients have reduced amino acid levels [
275
]; it is therefore logical to think
that they are a viable nutraceutical for MDD. As mentioned in previous sections, tryptophan
promotes the release of serotonin, and this is where its effectiveness in the treatment of MDD
lies. A randomized crossover study supported these claims as to the benefits of tryptophan
supplementation reversing pre-treatment anxious and depressive symptoms [
276
]. In
addition, the balanced diet together with the consumption of tryptophan suggested the
improvement of the general mood in patients without affective pathologies [
277
]. There also
seems to be divergence in the effectiveness of the tryptophan supplement according to sex,
since it was observed that the S/S
0
genotype in women is indicative of greater protection
from neurodegeneration, decreased cortisol and consequent mood repair. This effect
was not seen in men [
278
]; however, more studies must be conducted before convincing
recommendations can be given in this regard.
Along these lines, other amino acids such as tyrosine could also have antidepressant
therapeutic properties, although the current literature is not conclusive [279].
4.2.6. Bioactive Compounds
Various authors have debated the most approximate definition of a bioactive com-
pound. Assessing the different points of view, Guaadaoui et al. [
280
] described it as “a
compound that has the capacity and ability to interact with one or more components of
living tissue, presenting a wide range of probable effects” We can extract them from plant,
animal, microorganism or synthetic sources.
Phytoestrogens
They are polyphenols with functions similar to estrogens due to the similarity of
their structures. Soy is the main source of this nutrient, although we can also find it in
other legumes and vegetables. There are several benefits that phytoestrogens seem to
have. Benefits have been observed in cancer, vascular diseases, osteoporosis and even in
menopause. In the same way, it seems to have neuroprotective potential, related to its
antioxidant power and its link with estrogen receptors [281].
Flavonoids, a type of phytoestrogens, positively intervene in neuroinflammatory pro-
cesses, neurogenesis or GABAergic and monoaminergic transmission [
282
]. In humans, the
consumption of orange juice rich in flavonoids (5.4 mg of flavonoids daily) for 8 weeks led
to the modification of the intestinal microbiota, increasing species of the Lachnospiraceae
family, correlated with the activation of BDNF signaling. Likewise, the evaluation of the
Nutrients 2022,14, 1107 20 of 39
Depression Scale of the Center for Epidemiological Studies noted an improvement in de-
pressive symptoms [
283
]. Another clinical study, this time with women in the postnatal
period, supports the facts stated above. Daily intervention with flavonoids over the course
of two weeks showed significant differences between groups in the parameters of anxiety
and perceived quality of life [
284
]. On the other hand, phytoestrogens have gained popular-
ity among menopausal women, especially those who have certain doubts about hormone
replacement therapy, due to the different advantages that their consumption entails. A
meta-analysis determined that low doses of phytoestrogens (25 mg/d–100 mg/d) could
relieve depressive symptoms [
285
]. However, the limitations of the studies make its use as
monotherapy unfeasible; therefore, further research is necessary.
Caffeine
Caffeine is one of the most important bioactive components since it has neuroprotective
effects. Although there are other compounds such as chlorogenic acid or caffeic acid,
caffeine is the most widely used coffee nutraceutical [
286
]. Caffeine consumption has been
linked to a lower risk of depression [
287
], in addition to the fact that some studies show
that its consumption improves the effectiveness of antidepressant therapy [
288
], producing
improvements in the treatment of motivational dysfunction and increasing dopamine levels
as a result of the non-selective antagonist for adenosine A1/A2 receptors [289].
Similarly, in another study, positive results were obtained in those women with higher-
than-average caffeine consumption (>261 mg), showing lower probability of developing
dementia or other cognitive impairment disorders, unlike those who had lower than aver-
age consumption (<64 mg), indicating an inverse association between caffeine consumption
and age-related cognitive decline [
290
]. These facts were supported in the longitudinal
study by Lucas et al. [
291
]; in the study that was carried out with women divided by
age, it caused an increase in blood pressure and a decrease in subjective feelings of mood,
especially in those who were older. In addition, it was found that caffeine side effects
were more likely in less physically active young women compared to physically active
women [
292
]. Accordingly, its consumption is contraindicated in people suffering from
PMS because it reduces the irritability and insomnia typical of this phase [
293
]. Finally,
it should be noted that the dose of caffeine ingested affects some health factors of people
with depression; high doses can generate mixed affective states, changes in the circadian
rhythm, increased anxiety and/or dysregulation [294].
Anthocyanins
Anthocyanins are pigments from the group of flavonoids that we can find in red fruits,
with blueberries being the largest natural source of this resource. In recent decades, their
contribution to guarding against the risk of suffering from cardiovascular, neurological or
diabetes diseases, among others, has been known [
295
]. The microorganisms of the intestine
are involved in the complex degradation of this molecule at different levels. Likewise, its
consumption will directly influence the colonizing species, since, according to the ample
evidence provided in both
in vitro
, animal and human studies, an increase in beneficial
flora such as Lactobacillus spp. and Bifidobacterium spp. inhibits the uncontrolled growth of
harmful microorganisms. The ability to mold the microbial community and the precursor of
short-chain fatty acids contributes to the possibility that anthocyanins also act as prebiotic
agents [
296
]. In a study, the inflammatory improvement of the offspring of rats fed with
different types of diets, one of them rich in anthocyanins, was verified. The results reflected
the intervention of these flavonoids by decreasing the activation of the NF
κ
B pathway,
and expression of mRNA of TNF-
α
, IL-6 and proteins of the zona occludens (ZO-1), thus
improving the general health of the digestive system [297].
On the other hand, their antioxidant power is widely known;
in vitro
studies and
animal models highlight delphidin, cyanidin-3-glucoside and malvidin for their ability to
bind oxygen radicals, be scavengers of superoxide anions and protect against oxidative
stress [298].