Anti-Depressive Effects of Tea Consumption

Anti-Depressive Effects of Tea Consumption: History

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Subjects: Nutrition & Dietetics

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Current theories on the neurobiology of depression may be utilized to understand tea (Camellia sinensis)-mediated mechanisms of antidepressant activity. Major nodes within a unified network framework of depression, or major depressive disorder (MDD), included hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, inflammation, weakened monoaminergic systems, reduced neurogenesis/neuroplasticity, and poor microbiome diversity affecting the gut–brain axis. We detail how each node has subsystems within them, including signaling pathways, specific target proteins, or transporters that interface with compounds in tea to mediate their antidepressant effects. A major pathway was found to be the ERK/CREB/BDNF signaling pathway, up-regulated by a number of compounds in tea including teasaponin, L-theanine, EGCG and combinations of tea catechins and their metabolites. Black tea theaflavins and EGCG are potent anti-inflammatory agents via down-regulation of NF-κB signaling. Multiple compounds in tea are effective modulators of dopaminergic activity and the gut–brain axis. Together, tea-mediated effects on depression pathology are encompassed by our original “reduce and restore” hypothesis; tea phytonutrients act upon multiple MDD nodes to ameliorate depression pathology, including reduction of HPA axis hyperactivity; reduction of inflammation; restoration of monoaminergic systems, including restoration of neurologically active gut microbiota, and restoration of neurogenesis/neuroplasticity.

Camellia sinensis
depression
inflammation
HPA axis
gut–brain axis
neurogenesis
neurotransmission
SCFA
EGCG
theaflavin
L-theanine

1. Introduction

Depression is the most common mental health condition in the general population [1,2], characterized by despondency, loss of motivation or pleasure, feelings of guilt or low self-esteem, poor appetite, insomnia, fatigue, and difficulty concentrating [3]. In extreme cases, depression can lead to suicide [4,5], and increase the risk of morbidity and all-risk mortality [6]. Depression can become an all-consuming disorder that affects occupational potential [7] and quality of life [8,9]. The World Health Organization (WHO) predicts that, by 2020, depression will rank second in global disease burdens and one of the priority conditions covered by the WHO’s Mental Health Gap Action Programme [10].

Progress in the treatment of major depressive disorder (MDD) has been modest at best, in part because of the withdrawal of much of the pharmaceutical industry from the development of new psychotropic drugs [11]. Average estimates calculate that, among patients entering treatment for major depressive disorder (MDD), only about one third enter remission four months later [12]. With rates of MDD rising and treatments and efficacy of MDD treatments remaining stagnant, it is time to start looking elsewhere for ways to treat MDD. Some data have been encouraging for the ability of lifestyle changes to reduce risk of MDD such as less smoking [13], less alcohol consumption [14], fewer high-fat foods [15], and more exercise [16]. It has also been found that regular tea consumption has a strong linear relationship with reduced MDD [17]. This has led researchers to look more deeply into the mechanisms underlying the use of tea as an antidepressant agent.

Tea is the second most consumed beverage after water, mostly because it is an affordable luxury consumed by all socioeconomic classes around the world. As such, even minor benefits to mental or physical health could carry considerable implications for public health. Tea has been well established to confer a number of benefits, including anti-diabetic, anti-aging, pro-cardiovascular, and pro-metabolic effects [18,19,20]. The mechanisms of tea phytochemicals in reducing the risk of depression are complex and multidimensional, since neurologists and psychiatrists are coming to realize that depression itself is a multifaceted neurobiological pathology.

2. Concept of Tea within an Integrative Theory of Depression

Neuroimaging data have provided scientists with insights that have elucidated our understanding of the human brain. These insights have led to the development of an integrated theory of depression, in which multiple dysfunctional systems are viewed as a single interconnected pathology [21,22,23]. In the instance of an outdated theoretical model, for example the monoamine hypothesis, low monoamine levels (typically serotonin) is the cause of depression, and the way to treat the illness is by increasing circulating levels of serotonin. This treatment methodology has proven to be far too reductionist, and that is reflected in low efficacy rates of selective serotonin reuptake inhibitors (SSRIs) in long-term MDD treatment. The monoamine hypothesis fails to address what is responsible for the upstream causes of initial dysfunction within the serotonergic system, and thus simply supplying more serotonin has been shown to be an effective short-term alleviation of depressive symptoms, but not a long-term solution to the pathology.

A unified theory of depression, sometimes referred to as an integrated theory of depression, is one that underscores the interconnectivity among neurobiological systems involved in depression pathology, including inflammation, hypothalamic–pituitary–adrenal (HPA) axis activity, neurogenesis/neuroplasticity, and monoaminergic systems, including the gut–brain axis [23]. This article uses an integrative theory of depression pathology to explain the multitude of ways in which compounds in tea may be exerting anti-depressive effects in humans. Conceptually speaking, individual compounds in tea are not exerting potent pharmacological effects on individual neurobiological systems, as SSRIs do on the serotonergic system, but rather multiple constituents in tea, including L-theanine, L-arginine, polyphenols and their metabolites are collectively and simultaneously exerting modest effects within multiple neurobiological systems, leading to an overall significant net risk reduction in depression.

Thus, the primary focus of this entry is to review research detailing the mechanistic actions of tea compounds within neurobiological systems pertaining to depression, compare and contrast those findings, and map their functional significance within the larger network of integrated depression pathology.

3. Antidepressant Effects of Tea Consumption in the Literature

In accordance with rigorous standards of research quality, 11 studies with 13 reports were selected for meta-analysis that evaluated the association between tea consumption and depression risk [17]. Meta-data were comprised of five cohort reports and eight cross-sectional reports, all of which yielded at least moderate quality assessment scores, averaged at good within Newcastle–Ottawa and Agency for Healthcare Research and Quality assessment scales. Studies included 22,817 participants with 4743 cases of depression, and a dose–response analysis of 10,600 participants with 2107 cases. This meta-analysis found that higher consumption of tea was associated with lower risk of depression. Dose–response analysis identified a negative correlation between tea consumption and depression risk, with every three cups/day increment in tea consumption associated with a 37% decrease in the risk [17]. A subgroup analysis was conducted to assess whether lifestyle factors such as physical exercise, smoking, alcohol consumption, etc. were confounding the results; however, similar results were obtained in these subgroup analyses. The aggregated risk ratio (RR) for studies measuring green tea (n = 3) was comparable to studies measuring “diverse tea types” (n = 5), which included oolong, black, white, and pu-erh teas, with RR (95% confidence interval (CI)) of 0.67 (0.56–0.79) and 0.69 (0.62–0.77) for green and diverse tea types, respectively.

In the meta-analysis of association in the 13 reports, all but one subgroup found similar results regarding associative risk. The inconsistent finding came from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study taken between 1984 and 1989 and followed until the end of 2006, which investigated the association between intake of coffee, tea and caffeine and severe depression in middle-aged Finnish men [24]. No association was observed between severe depression and intake of tea in this study. However, this prospective study should be interpreted with caution, since it focused only on severe depression based on discharge diagnosis, which may have overlooked cases of mild and moderate depression in which patients were not hospitalized. Therefore, it is possible that this study was biased towards a null hypothesis. The meta-analysis by Dong et al. offered a brief mention of feasible mechanistic explanations for the results. However, it did not take into consideration comprehensive integrated views of depression pathology, perhaps because these theories on depression have only emerged in very recent years [21,22,23].

We conducted another search for high quality data measuring tea consumption and depression risk to supplement the meta-analytical data from Dong et al. [17] with more recent research. The MEDIS study published in May 2018 enrolled 2718 older individuals from 22 Mediterranean islands in cross-sectional sampling in the period of 2005–2011. A broad ranging set of dietary habits and socio-demographic characteristics were analyzed through cross-sectional examination for associations with depression [25]. Diet-related factors included consumption quantities and frequencies of fish, meat, vegetables, legumes, coffee, tea, and various alcoholic beverages. Factors such as age, education, financial status, physical activity, various blood lipid parameters and BMI were measured. Logistic regression model evaluating the various factors associated with depression found that daily tea consumption showed the lowest RR of any metric measured in the study (RR: 0.51; 95% CI; 0.40–0.65, p value < 0.001). The MEDIS study provided no detailed mechanistic explanation for the observed risk reduction resulting from daily tea consumption [25].

Using data from the Korean National Health and Nutrition Examination Survey, a total of 9576 (3852 men and 5725 women) aged 19 years or older were cross examined for associations between green tea consumption and self-reported depression [26]. Consumers of more than three cups/week had 21% lower prevalence of depression (RR = 0.79, 95% CI = 0.63–0.99, p value = 0.0101) after adjusting for confounding factors. A weakness of this study was that the highest consumption bracket reported was three cups/week, when in fact several studies found significant differences in risk reduction between consuming three cups/week, considered moderate consumption, and one or more cups/day, considered high consumption. If this study had stratified between moderate and high consumption groups, it is possible there would have been lower RR for high consumption groups, as was the case in meta-data by Dong et al. [17].

Seventy-four healthy subjects participated in a double-blind, randomized placebo-controlled study with oral administration of green tea or placebo for five weeks, after which measurements were taken that included reaction time of reward responsiveness, and scores on the Montgomery–Asberg depression rating scale (MADRS) and 17-item Hamilton Rating Scale for Depression (HRSD-17) to estimate the depressive symptoms in these two groups. The results show chronic treatment of green tea increased reward learning compared with placebo by decreasing the reaction time in monetary incentive delay task. Moreover, participants treated with green tea showed reduced scores measured in MADRS and HRSD-17 compared with participants treated with placebo [27].

Taken together, these data suggest that regular daily tea consumption contribute to risk reduction in healthy individuals, and evidence was particularly strong among aging populations.

4. Mechanistic Considerations

Four primary nodes are named as mechanistic systems, which interrelate within a network of depression pathology: the HPA axis; immune inflammatory response; monoaminergic systems, which includes the gut–brain axis; and neurogenesis/neuroplasticity (Figure 1). These four nodes each have important subsystems within them, including signaling pathways, specific target proteins, or transporters that interface with compounds in tea, mediating their antidepressant effects. The healthy functioning of each node has the potential to be compromised by genetic or biological factors, representing poor “hardware” of these nodes, or by environmental stressors, learned behaviors, psychosocial stress, etc., representing poor “software” of this system [28]. Regardless of the upstream cause, when compromised, these nodes are able to reduce the functional capacity of other nodes through the formation of harmful positive feedback loops, creating an interrelated network of neuro-pathologies that can predispose MDD. Thus, the alleviation of depressive pathology within any single node has the capacity to reverberate through to other nodes, and similarly, targeting multiple nodes simultaneously may translate to significant risk reductions, which we hypothesize is the mode of action underlying the observed antidepressant effects of tea consumption. We call this the “reduce and restore” hypothesis, and the network nodal targets include reduction of HPA axis hyperactivity; reduction of inflammation; restoration of monoaminergic systems, including restoration of neurologically active gut microbiota; and restoration of neurogenesis/neuroplasticity.

Figure 1. The effects of regular tea intake within a unified theory of depression pathology. External stressors induce an HPA-mediated stress response and inflammation. If acute stress and inflammation become a chronic, persisting physiological state, there can be detrimental effects on neuronal health and monoaminergic systems. Compromised cognitive emotional processing resulting from cumulative neuro-pathologies inhibits the ability to cope with future external stressors, re-feeding the state of chronic stress/inflammation. Green lines represent attenuating effect, while red lines represent exacerbating effect. HPA, hypothalamic–adrenal-pituitary.

4.1. Reduction of HPA Axis Hyperactivity

The hypothalamic–pituitary–adrenal (HPA) axis is a feedback loop in which stress activates a hormonal pathway that induces a “fight-or-flight” response to a perceived threat. Due to its stress-induced nature, the HPA axis is referred to as the “stress circuit”. Mechanistically speaking, when mammals experience stress, the hypothalamus releases corticotropin-releasing hormone (CRH). CRH then acts on the pituitary gland to trigger the release of adrenocorticotropin (ACTH) into the bloodstream. In response to CRH, ACTH acts on the adrenal cortex by binding to the adrenal melanocortin 2 receptor (MC2R), which signals through cyclic AMP to stimulate the production and secretion of glucocorticoids (CORT). In humans, the primary CORT is cortisol, or known more colloquially as the “stress hormone”. Two of cortisol’s primary functions are promotion of gluconeogenesis in order to increase blood glucose levels, and the suppression of immune function. The HPA axis has considerable impact on an individual’s mood at any given time, as this system communicates readily with other neurocircuitry in the brain, such as the limbic system, which serves to regulate mood and motivation.

Within a typical HPA axis response, the acute stressor will pass, and stress hormone cortisol will exert a negative feedback effect on the stress circuit by down-regulating CRH synthesis in the hypothalamus. However, unresponsiveness to cortisol’s negative feedback signaling, or periods of constant perceived stress will cause the stress circuit to operate continuously, a physiological state referred to as HPA axis hyperactivity. Under such conditions, the limbic system is over-stimulated, leading to a condition of “learned helplessness”, in which the overwhelmed subject loses motivation and detaches from external engagement, at which point in humans, depressive symptoms are reported and MDD is often diagnosed. Furthermore, with HPA hyperactivity, the hippocampus becomes desensitized to constant elevated levels of CRH, causing the body to release more cortisol in an attempt to down-regulate CRH production. The elevated cortisol causes more stress and inflammation, in turn triggering the release of more cortisol, and the stress circuit becomes a positive feedback loop of neuropathology (Figure 2). Over time, chronic elevated stress hormone levels deteriorate important neural networks in the brain, including monoaminergic and limbic systems, and reduce hippocampal volume and neuroplasticity. As discussed below, these downstream effects can further exacerbate MDD neuropathology and symptomology. For these reasons, some have described MDD to be nearly synonymous with dysfunctional HPA axis activity [29,30]. This section reviews in vitro and in vivo studies measuring how the bioactive constituents in tea have been observed to affect HPA axis activity under stressful conditions, including the mechanistic explanations proposed for the observed effects (summarized in Table 1).

Figure 2. The positive feedback loop of chronic stress and inflammation. Dysregulated HPA axis and chronic inflammation represent two mechanistic nodes within an interrelated system of depression pathology. Bullet points represent signaling pathways and pathological targets for tea phytochemicals. Green lines represent attenuating effect, while red lines represent exacerbating effect. HPA, hypothalamic–pituitary–adrenal; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropin hormone; MCP-1, monocyte chemoattractant protein-1.

Table 1. Tea compounds and their effects on physiological stress-response.

Tea Compound	Effect on Physiological Stress Response
L-theanine	Reduction in stress as measured by attenuated adrenal hypertrophy [31] Reduced sAA and subjective stress levels [32] Reduction in elevated plasma ACTH and CORT [32,33]
L-arginine	Reduction in stress as measured by attenuated adrenal hypertrophy [31]
Green tea polyphenol mixture	Reduced CORT and ACTH, reduced immobility in FST and TST [34] Restored HPA activity via ERK upregulation [35]
EGCG (anti-stress effects)	Restored HPA activity via ERK upregulation [35] Lowered corticosterone/CRH/ACTH [36] stress-reduction via reduction of neuron over-excitation [37,38,39] improved GABA transmission via activation of the SIRT1/PGC-1α pathway [40] Antagonized stress-reduction effects of L-theanine/L-arginine [31]
Epigallocatechin	Restored anti-stress effects of L-theanine/L-arginine [31] through competitive inhibition of EGCG [31]
Low-Caffeine Green Tea	Lowered sAA levels, improved sleep quality more effectively than standard caffeinated green tea [41] Reduction in adrenal hypertrophic stress response, more significant than standard green tea [31]
Green Tea, Shade-Grown White Tea	Lowered CgA levels following stress load task for both tea types, more effect for Shade-Grown White Tea [42]
Green Tea Aroma	Lowered CgA levels following stress load task [43]
Black Tea Aroma	Lowered CgA levels following stress load task [44]

sAA, salivary α-amylase; ACTH, adrenocorticotropin hormone; CORT, glucocorticoids; FST, forced swimming test; TST, tail suspension test; HPA, hypothalamic–pituitary–adrenal; ERK, extracellular signal-regulated kinase; CRH, corticotropin-releasing factor; GABA, gamma-aminobutyric acid; SIRT1, sirtuin 1; PGC-1α, peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α; EGCG, epigallocatechin gallate.

4.2. Reducing Inflammation

Inflammation is triggered by the release of inflammatory cytokines such as interleukin (IL)-1β IL-2, IL-6, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP), which all have been found to be up-regulated in patients with depression [84,85]. The relationship between inflammation and depression can be traced in part back to an adaptive trait called “sickness behavior”, in which humans who are attempting to fight infection reduce participation in activities such as exploration or seeking mates, which compete with an active immune system for energy stores [86]. For an acute infection during evolutionary times, behaviors of anhedonia, fatigue, and internal focus allowed one to allocate bodily resources to the immune system, which can consume 30% of basal metabolic rate during an immune response. However, in cases of chronic inflammation, which can come as a result of poor sleep, poor diet, smoking, lack of exercise, psychological stress, or a number of other lifestyle factors, sickness behavior can persist indefinitely, no longer serving its evolutionary purpose [87].

Additionally, inflammation coincides with a significant decrease in serotonin levels. The mechanistic explanation is that serotonin synthesis and bacterial growth both depend on tryptophan as a precursor. The immune system attempts to arrest bacterial growth by up-regulating a metabolic pathway that metabolizes tryptophan into kynurenine (KYN) via the enzyme indoleamine 2,3-dioxygenase (IDO). Inflammatory cytokines induce IDO activity, causing a significant drop in tryptophan levels and a corresponding decline in serotonin synthesis. The KYN pathway might not necessarily be a part of sickness behavior, however low serotonin levels resulting from inflammation almost certainly exacerbate depression symptomology.

Finally, inflammatory cytokines can boost cortisol levels and activate the HPA axis, which is in turn inflammatory. As discussed in the previous section, inflammation can form a positive feedback loop with the HPA axis, creating a state of chronic stress and inflammation, leading to the deterioration of important neural networks in the brain, such as the monoaminergic and limbic systems, and hippocampal neuroplasticity. For these reasons, reducing inflammation has become a critical target in the treatment of depression [11,88,89,90]. Here, we review in vitro and in vivo studies that have measured the effect on inflammation of ingesting tea or individual bioactive compounds in tea, including the mechanistic explanations proposed for the observed effects (summarized in Table 2).

Table 2. Various tea compounds and their anti-inflammatory effects.

Tea Compound	Effect on Inflammatory Response
Theaflavins (TF)	Reduced LPS-induced neural inflammation, suppressed cytokine production, reduced immobility in TST. TF showed better anti-inflammatory capacity than common polyphenols, but comparable to EGCG [91].
Theaflavin-3,3′-digallate (TF3)	Inhibited LPS-induced expression TNF-α, IL-1β, and IL-6 [92,93]
Green Tea Extract	Reduced hepatic inflammation by attenuating NFκB activation via down-regulation on TNFR1 and TLR4 in HFD model [94]
Epigallocatechin gallate (EGCG)	Reduced neuroinflammation via inhibition of MAPK and NFκB pathways in HFFD model [95]. Reduced SPS-induced increase in IL-1β and TNF-α in mouse hippocampi, decreased expression level of IL-1β mRNA with RT-PCR analysis [36]. Downstream inhibitor of inflammatory signaling through occupation of TAK1 site, inhibition of p38 and NFκB [96]. Reduced CSM-induced IL-8 production via inhibition of p38, MAPK and NFκB in AC16 cardiomyocytes [97]. Inhibited phosphorylation of p65, showed in vitro NFκB regulation [98]. Inhibited activity of NO, COX-2, TNF-α, IL-6 and IL-1β in LPS-induced murine macrophage cell line [99] In cultured human epidermal keratinocytes exposed to airborne PM10, suppressed TNF-α, IL-1β, IL-6, IL-8 and MMP-1 [100]. Topical application in 8-week RCT improved acne via suppression of NFκB/AP-1 pathway [101]
EGC and EC	Effective downstream inhibitors of inflammatory signaling through occupation of TAK1 site [96]
Gallic acid	Reduced airway inflammation by decreasing IL-4, IL-5, IL-13, IL-17 in nasal lavage fluid of mice with allergic rhinitis [102]
Gallocatechin gallate	Inhibited LPS-induced expression of MCP-1 and IL-6 as effectively as EGCG in 3T3-L1 cells [98].
Oolong tea ethanol extract	Inhibited activity of NO, COX-2, TNF-α, IL-6 and IL-1β in LPS-induced murine macrophage cell line [99]
L-theanine	Topically delivered, reduced skin inflammation via inhibition of IL-1β, TNF-α and COX-2 [103]. Alleviated airway inflammation via suppression of NFκB pathway, reduced production of MCP-1, IL-4, IL-5, IL-13, TNF-α and interferon-gamma, attenuated trafficking of inflammatory cells into bronchoalveolar lavage fluid [104].
Teasaponin	Attenuated TLR-4, NF-κB, IL-1β, IL-6 and TNF-α in HFD mouse model [105].

NO, nitric oxide; COX-2, cyclooxygenase-2; TNF-α, tumor necrosis factor alpha; IL, interleukin; LPS, lipopolysaccharide; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; RT-PCR, reverse transcription polymerase chain reaction; MCP-1, monocyte chemoattractant protein-1; HFD, high-fat diet; EGCG, epigallocatechin gallate; MAPK, mitogen-activated protein kinase; TNFR1, TNF receptor 1; TLR4, Toll-like receptor 4; HFFD, high-fat/high-fructose diet; EGC, epigallocatechin; EC, epicatechin.

4.3. Restoration of Monoaminergic Systems

The monoamine hypothesis posits that depression results from dysregulated neurotransmission of one of more monoamines, including serotonin (5-HT), norepinephrine (NE) and dopamine (DA). This theory has been criticized as reductionist [106], and insufficient in considering the upstream factors that induce abnormal monoamine neurotransmission, such as chronic stress and inflammation. Despite the validity of these criticisms, the most common and effective current pharmacological approaches to treating MDD are monoamine reuptake inhibitors, such as selective serotonin reuptake inhibitors (SSRIs) or norepinephrine-dopamine reuptake inhibitors (NDRIs) [11], which function to increase circulating monoamine levels through the inhibition of their reuptake. These medications have been reported to be effective in preventing relapse of MDD in some cases, although data suggest that they are less effective as an isolated treatment than when used alongside other approaches, such as cognitive behavioral therapy [107]. While shortcomings of the monoamine theory are evident, it does not invalidate the notion that targeting monoaminergic systems is one sensible tactic in combating MDD.

As discussed in the previous section, inflammation significantly reduces circulating 5-HT levels, and individuals with MDD are likely to be found with dampened serotonergic systems. It was found that denervation of serotonergic projections reduced the generation of granule cells in the dentate gyrus of the hippocampi of rats, and these effects were reversed by stimulating 5-HT1A receptors or by boosting activity in 5-HT fibers, suggesting the close interconnection between serotonergic systems and hippocampal neuronal health [108] (Figure 3). Additionally, the mesolimbic pathway, consisting of dopaminergic neurons originating in the ventral tegmental area and projecting to the nucleus accumbens, amygdala and hippocampus, mediates motivation and the reward pathway. Numerous data have implicated altered dopaminergic neurotransmission within the mesolimbic pathway in the neuropathology of depression [109]. Norepinephrine (NE) is released together with cortisol from the adrenal gland following stimulation by ACTH. As with cortisol, NE can become chronically elevated under circumstances of constant perceived stress, driving the release of cytokines, which can exert reciprocal effects on the HPA axis [23].

Figure 3. The positive feedback loop of weakened monoaminergic systems and reduced neurogenesis. Weakened monoaminergic systems and reduced neurogenesis represent two mechanistic nodes within an interrelated system of depression pathology. Bullet points identify symptoms of weakened functional status, and key targets for tea phytochemicals. Green lines represent attenuating effect, while red lines represent exacerbating effect. BDNF, brain-derived neurotrophic factor.

Finally, there exists interconnectivity among 5-HT, DA and NE, wherein any action on one system has the potential to reverberate through to the other systems [110]. For example, DA can inhibit the release of NE from the locus ceruleus. NE can have excitatory and inhibitory effects on DA release in the ventral tegmental area through stimulation of α-1 and α-2 receptors, respectively [23]. Likewise, both NE and DA can act on α-1 and D-2 receptors, respectively, to increase 5-HT release from the dorsal raphe nucleus. As more recent data show, these monoaminergic systems show the potential to be modulated by microbiota species in the intestines, characterizing a relationship known as the gut–brain axis. Taken together, these data indicate that restoration of monoaminergic systems represents an important and interconnected node within the larger network of MDD pathology. Reviewed here are studies that measured how compounds in tea interact directly with monoaminergic systems, and indirectly through their modulations of GM, including mechanistic explanations for the observed effects (summarized in Table 3).

Table 3. Various tea compounds and their effects on monoaminergic systems.

Tea Compound	Effect on Monoaminergic Systems
L-Theanine	Increased levels of 5-HT, NE and DA in the PFC, NAC, and HIP. Increased levels of 5-HT and DA in the ST. Increased DA levels in the HIP [111]. Promoted DA transmission in HIP via DA D1/5 receptor-PKA pathway activation in AD mouse model [112]
Green tea	Administration for 5 weeks, tone of 5-HT was normalized, reduced stress response [113].
Epicatechin	Functioned as anxiolytic in OF and EPM via decreased expression of MAO-A in cortex, and increased pro-BDNF and BDNF via Akt pathway [114].
Tea Polyphenol Mixture	Reversed CUMS-induced reduction in 5-HT and NE in the HIP, PFC [115]. Partial restoration of normal DA and 5-HT following stress-induced neural injury [35]. Null effect on human GM in 12-week RCT [116]. BTP supplementation more than doubled butyric acid levels. Significant increases were observed for GTP, but to a lesser extent than BTP. Increases in SCFA upregulated AMPK activation by 70% and 289% for GTP and BTP, respectively [117].
EGCG	Partial restoration of normal DA and 5-HT following stress-induced neural injury [35]. Promoted growth of Bifidobacterium spp. and Lactobacillus/Enterococcus groups, induced higher concentrations of SCFA when incubated with human GM [118]. Enhanced adhesion of certain Lactobacillus strains to human epithelial intestinal lines [119].
Theaflavins	Increased DA turnover in FC, as measured by increased DOPAC and DOPAC/DA ratio [120]. Reduced oxidative stress, preserved DA levels in ST via and protection of dopaminergic neurons against degeneration by MPTP, improving motor behavior and expression of DAT and VMAT2 in ST and substantia nigra [121].
Catechin	Significantly increased Bifidobacterium spp. following in vitro incubation with human fecal samples [122].
EGCG3”Me	Significantly increased Bifidobacterium spp. and SCFA-generating GM species in vivo in mouse model [123]. Promoted growth of Bifidobacterium spp. and Lactobacillus/Enterococcus groups, induced higher concentrations of SCFA when incubated with human GM [118].
Gallocatechin gallate	Promoted growth of Bifidobacterium spp. and Lactobacillus/Enterococcus groups, induced higher concentrations of SCFA when incubated with human GM [118].
Epigallocatechin	Enhanced adhesion of certain Lactobacillus strains to human epithelial intestinal lines [119].

BTP, black tea polyphenol mixture; GTP, green tea polyphenol mixture; EGCG, epigallocatechin gallate; EGCG3”Me, O-Methylated EGCG; 5-HT, serotonin; NE, norepinephrine; DA, dopamine; PFC, prefrontal cortex; FC, frontal cortex; NAC, nucleus accumbens; HIP, hippocampus; PKA; AD, Alzheimer’s disease; OF, open field; EPM, elevated plus maze; MAO, monoamine oxidase; Akt, protein kinase B; CUMS, chronic unpredictable mild stress; SCFA, short-chain fatty acids; AMPK, 5′adenosylmonophosphate-activated protein kinase; GM, gut microbiota; DOPAC, 3,4-dihydroxyphenylacetic acid; DAT, dopamine transporter; VMAT2, vesicular monoamine transporter 2; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

4.4. Restoring Neurogenesis and Neuroplasticity

As mentioned above, chronic stress and inflammation lead to hypercortisolemia, or chronic elevated cortisol levels with neurotoxic effects, leading to reduced neurogenesis, as seen in neuroimaging studies showing reduced volume in the prefrontal cortex (PFC), especially in the subgenual PFC, basal ganglia and hippocampus of patients with MDD [168,169]. Additionally, natural age-related stress in the brain [170,171,172], or environmentally imposed stressors such as air pollution [173] can cause oxidative damage to neurons [174] and reduce their functionality, a process that has been linked to depression in meta-analyses [175]. The regions of the brain including the amygdala, hippocampus, basal ganglia, and nucleus accumbens are responsible for mediating raw, unprocessed emotion, while areas of the PFC mediate cognitive processing of emotions [176]. With reduced volume and interconnectivity among these critical emotion-processing centers, individuals become less capable of executive function and mood regulation, a proposed pathophysiology of depression [177]. Meta-analyses of human neuroimaging studies showed that patients with MDD had increased activation of the interior cingulate and amygdala and decreased activation of striatum and dorsolateral PFC, which presented as hyperactivation for negative stimuli and hypoactivation for positive stimuli [178]. The impeded ability to process emotion properly causes an individual to feel more overwhelmed, respond more reactively to external stimuli, all of which further fuel the cycle of chronic stress/inflammation. For these reasons, fighting the stress-induced reduction in neurogenesis has been said to be critical to the efficacy of antidepressant treatment [179].

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that promotes the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses [180]. It was found that serum levels of BDNF are reduced in patients diagnosed with MDD [181] and that depressive behavior could be induced in rats following a knock-out experiment of BDNF in the dorsal dentate gyrus [182]. BDNF has been shown to protect against stress-induced neuronal damage [183] and affect hippocampal neurogenesis [184], which has led some to suggest that BDNF may be an important agent for therapeutic recovery from MDD [185,186,187]. Conceptually, the role of BDNF and neurogenesis in treating MDD is to help the brain return to a state of juvenile-like plasticity by encouraging the growth of new neurons and synapses that can be utilized to establish new pathways for emotional processing which mitigate stress and encourage healthy cognitive behavior. Here, we review studies that have measured how compounds in tea have been observed to interact with neurons to affect BDNF or neuroplasticity, including the proposed mechanisms for those effects (summarized in Table 4).

Table 4. Various tea compounds and their effects on BDNF, neurogenesis and neuroplasticity.

Tea Compound	Effect on Neurogenesis/Neuroplasticity
Teasaponin	Six-week supplementation in HFD model attenuated BDNF deficits in the HIP, prevented recognition memory impairment [105].
L-theanine	Increased exploratory activity in OFT, enhanced object recognition memory, significantly increased BDNF levels and BrdU-, Ki67, and DCX-labeled cells in the granule cell layer [188].
EGCG	DCX-positive neurons showed more elaborate dendritic trees, accompanied by significantly increased HIP neurogenesis [189]. Attenuated HFFD-induced neuronal damage, reduced cognitive disorder via upregulation of CREB/BDNF pathway [95]. Submicromolar concentrations potentiated the neuritogenic ability of BDNF in PC12 cells [190]. Attenuated corticosterone-induced cytotoxicity, up-regulated Shh pathway [191]. Induced SH-SY5Y cell growth in vitro [192]. RT-PCR showed enhanced BDNF and TrkB mRNA levels, activated Akt and CREB/BDNF pathways, inhibited sevoflurane-induced neurodegeneration, improved learning and memory retention [193]. Targeted BDNF and proBDNF signaling pathways, normalized tat-mediated increases in proapoptotic proBDNF, normalized tat-mediated decreases in mature BDNF protein in hippocampal neurons [194]. Following spinal cord injury in rats, increased expression of BDNF, GDNF, improved locomotor recovery [195].
Epigallocatechin	Enhanced the neurogenic properties of EGCG [190]. Primary EGC metabolite, EGC-M5, and several conjugated forms improved neurite length and neurite number in SH-SY5Y cells [196].
Epicatechin	Enhanced the neurogenic properties of EGCG [190]. Targeted BDNF and proBDNF signaling pathways, normalized tat-mediated increases in proapoptotic proBDNF, normalized tat-mediated decreases in mature BDNF protein in hippocampal neurons [194].
Non-EGCG GTP	Plastic changes in dendritic arborizations of dentate granule cells, improved spatial learning in Morris water maze [197].
Gallic acid	Ameliorated TMT-induced anxiety and depression, improved cell densities in the CA1, CA2, CA3 and DG hippocampal subdivisions [198].

HFD, high-fat diet; BDNF, brain-derived neurotrophic factor; HIP, hippocampus; OFT, open-field test; BrdU, 5-Bromo-2′-deoxyuridine; DCX, doublecortin; HFFD, high-fat/high-fructose; Shh, Sonic hedgehog; CREB, cyclic AMP response element binding protein; RT-PCR, reverse transcription polymerase chain reaction; TrkB, tropomyosin receptor kinase B; Akt, protein kinase B; GDNF, glial cell line-derived neurotrophic factor; EGCG, epigallocatechin gallate; GTP, green tea polyphenol mixture.

4.5. Mood Enhancement

It may be that, for some people, the very activities of preparing and consuming tea bring about mood-enhancing effects that are separate from and additional to the physiological effects within the four nodal systems discussed above. For those who derive pleasure from the taste, aroma, aesthetics, or the moment of time taken away from a busy routine to stop and consume tea, there may be improvements to affective state that confer anti-depressive effects by their own right. It has been shown that positive affective states build enduring personal and cognitive resources [204] and higher levels of creativity compared to neutral mood states in meta-data from mood-creativity research [205]. Furthermore, mood may impact not only cognitive control processes, but also attention, perception, and memory [206,207,208]. Likewise, neuroimaging data suggest that a reciprocal relationship may exist, in which mood affects cognition, but cognition also affects mood [209], and that components of this neural network are predictive of response efficacy to MDD treatment [210].

4.6. Determining Bioavailability, Pharmacokinetics and Pharmacodynamics

In 2010, Del Rio et al. [241] discovered that the overall bioavailability of green tea flavan-3-ols was an order of magnitude higher than previous estimations ranging from 2% to 8.1% [242,243]. Del Rio found bioavailability averaged 39% in humans after considering polyphenol metabolites generated from interactions with colonic microbiota [241]. Examining the interactions between polyphenols and the GM is critical to understanding the bioavailability of these compounds in the body, since 90–95% of dietary polyphenols have been shown to accumulate and break down in the large intestine [244]. Since discovering the importance of GM to polyphenol bioavailability, more research has emerged which seeks to measure the mechanisms by which GM cleave flavonoid conjugates and glycosides, thereby modulating their health effects [245,246,247]. Shang et al. [248] showed in rats that a single oral administration of EC (350 mg/kg) underwent in vivo metabolic reactions, including methylation, dehydration, hydrogenation, glucosylation, sulfonation, glucuronidation and ring-cleavage, resulting in 67 metabolites found in urine [248].

This entry is adapted from the peer-reviewed paper 10.3390/nu11061361

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