5-HT, commonly known as serotonin, plays diverse roles in the central and peripheral nervous systems. It was first isolated and identified by Maurice Rapport and Irvine Page in 1948 (45). In the central nervous system, 5-HT interacts extensively with the 5-hydroxytryptaminergic nervous system, which spans the forebrain, brainstem, and cerebellum. Neural projections from the anastomosing lateral nucleus regulate fundamental physiological functions, including temperature regulation, appetite control, sleep-wake cycles, vomiting, and sexual behavior. Meanwhile, projections to the caudate nucleus are linked to pain perception and motor tone regulation (46). Additionally, 5-HT is essential for emotional stability (47), and disruptions in 5-HT function can lead to depression, impulsive behaviors, and, in some cases, a heightened risk of suicide (48).

Pathophysiological studies have further explored serotonin’s role in emotional regulation, with reduced transmission efficiency identified as a key hypothesis for depression mechanisms (49). Research supports this, showing that estrogen (E2) regulates gene expression by binding to the endoplasmic reticulum, a process validated in cell line models (50). This regulation is particularly evident in brain regions such as the nucleus accumbens, where 5-HT neurons are abundant (51). Furthermore, studies reveal that E2 enhances postsynaptic 5-HT transmission by downregulating 5-HT1A autoreceptors and upregulating 5-HT2A receptors (52). These findings form the foundation for understanding how E2 modulates 5-HT neurotransmission.

In mammals, 5-HT is widely distributed, with approximately 90% synthesized and concentrated in intestinal tissues (53, 54). Animal models have been instrumental in examining the relationship between serotonin, depression, and emotional regulation. For example, estrogen deficiency induced by ovariectomy in monkeys led to decreased 5-HT efficacy and reduced expression of 5-HT-related genes compared to controls (55). Moreover, research shows that E2 selectively increases serotonin receptor density in brain regions containing estrogen receptors, including the hypothalamus, preoptic area, and amygdala (56). These findings suggest that E2-mediated regulation of 5-HT transmission may play a crucial role in protecting against depression.

Clinical studies further highlight the association between 5-HT concentration and psychiatric disorders such as depression, mania, and anxiety. Kandel et al. demonstrated that reduced 5-HT concentration in the central nervous system significantly correlates with the onset of these conditions (57). Specifically, patients with depression and suicidal tendencies exhibit lower 5-HT1A mRNA expression in the hippocampus compared to non-depressed individuals (58). These observations underscore serotonin’s vital role in emotional and behavioral regulation and provide a basis for its therapeutic application in depression treatment.

Early antidepressant therapies, including Monoamine Oxidase Inhibitors (MAOIs) and Tricyclic Antidepressants (TCAs), improved neurotransmitter availability in synaptic gaps by targeting 5-HT, dopamine (via DAT), and norepinephrine (via NET). Subsequent research has refined these approaches, with serotonin-specific drugs demonstrating greater efficacy. However, scholar Sameer Jauhar (59) has argued that while these drugs modulate serotonin effectively, they often fail to address underlying etiological factors of depression.

Research across various experimental platforms emphasizes that serotonin’s role extends beyond emotional regulation, as it is influenced by numerous factors. Estrogen’s modulation of gene expression and its regulation of 5-HT receptors, for example, likely contribute to its protective effects against depression. Collectively, these studies indicate that serotonin system dysfunction is linked to multiple psychiatric disorders and provide an experimental basis for developing future therapeutic strategies.

GABA (γ-aminobutyric acid) is the primary inhibitory neurotransmitter widely distributed throughout the mammalian central nervous system (CNS) (60). Approximately 30% of central nervous fibers utilize GABA as a neurotransmitter. Although GABAergic neurons constitute only a small proportion of the total neuronal population, their inhibitory functions and balance with excitatory transmission are critical for maintaining normal brain activity. GABA receptors are highly distributed throughout the nervous system, particularly on postsynaptic membranes, as well as in the cerebellum and hippocampus. GABA primarily exerts its physiological functions through three receptor types: the ion channel receptors GABAA and GABAC, and the metabotropic receptor GABAB (61).

In recent years, research has highlighted the critical role of GABAergic system dysfunction in the neurobiological mechanisms of depression (62–64). Fundamental studies have demonstrated that as a metabotropic receptor, the GABAB receptor plays a pivotal role in regulating postsynaptic signal transduction, and its dysfunction is regarded as an important target in the pathological processes of depression (61, 65). Additionally, Kelly et al.’s cell line studies suggest that estrogen (E2) may exert antagonistic effects on GABAA receptors, indicating that E2 might regulate emotional states and brain functions associated with depression through GABA signaling (66).

Animal model studies have provided significant experimental evidence of E2’s regulatory effects on the GABA system (67). E2 inhibits presynaptic GABA release via a rapid nongenomic mechanism, a phenomenon prominently observed in female mice but not in male mice. This sex-specific difference may be closely associated with variations in the production of inositol 1,4,5-triphosphate (IP3) and the activation state of its corresponding receptor (IP3R) (68). The regulatory effects of E2 significantly influence GABAergic neurotransmission in key brain regions, such as the prefrontal cortex and hippocampus, offering potential explanations for the molecular mechanisms underlying the sex differences in depression.

Clinical studies further indicate that during the critical periods of steroid hormone-mediated brain sexual differentiation, the GABA system is highly sensitive to E2 (69). For instance, during puberty and perimenopause, fluctuations in E2 levels significantly impact the expression and function of GABA receptors, particularly in brain regions associated with emotional regulation. These findings suggest that E2 may play a vital role in the pathological processes of depression by modulating GABAergic transmission and synaptic plasticity.

Norepinephrine (NE), a critical neurotransmitter and hormone, plays a vital role in the central nervous system through various molecular mechanisms. Experimental studies demonstrate that NE functions primarily via the α- and β-adrenergic receptor families, which regulate essential neural activities, including alertness, arousal, attention, and motivation-driven behaviors (70). Research also indicates that estrogen modulates NE activity by influencing the distribution and expression of these receptors (71). Additionally, 17β-estradiol (E2) indirectly increases NE levels by inhibiting monoamine oxidase expression, thereby reducing NE’s metabolic degradation (72). E2 further enhances tyrosine hydroxylase activity, a key enzyme in the catecholamine synthesis pathway, promoting NE synthesis (73). These findings provide critical insights into NE’s regulatory mechanisms at both the molecular and receptor levels.

Animal studies offer additional evidence of how estrogen regulates NE neurotransmission and its impact on emotional and cognitive functions. In ovariectomized mouse models, estrogen receptors are expressed in norepinephrine neurons, which project to multiple brain regions, including the hypothalamus, a critical area for emotional regulation (72, 74). E2 treatment significantly increases the metabolic turnover rate of NE in the hypothalamus and cerebral cortex (75). These results suggest that estrogen influences NE levels through multiple mechanisms, profoundly affecting emotional regulation and cognitive processes.

Clinical studies further support the interplay between NE and estrogen in emotional regulation. Research shows that fluctuations in estrogen levels are closely associated with the onset and progression of depressive symptoms (72, 74). During perimenopausal and postpartum periods, declining estrogen levels may reduce NE utilization efficiency, contributing to emotional instability. Clinical evidence also reveals that E2 enhances NE synthesis and utilization while reducing its metabolic degradation, alleviating depressive symptoms in patients. Additionally, estrogen modulates adrenergic receptor function, significantly influencing reward mechanisms and cognitive functions, including attention (71). These findings provide a foundation for developing targeted interventions to regulate NE in depressive disorders.

Dopamine (DA), a key neurotransmitter in the central nervous system (CNS), belongs to the catecholamine family and is closely linked to the pathophysiology of depression (76). Synthesized and released by dopaminergic neurons, DA acts through five major receptor subtypes: D1, D2, D3, D4, and D5. Among these, D1, D2, and D3 receptors are regulated by E2 (17β-estradiol). These receptors are unevenly distributed across brain regions and play critical roles in motor control, emotional processing, cognitive function, motivation, reward mechanisms, and endocrine regulation.

Basic research has demonstrated that E2 regulates the DA system by upregulating the mRNA expression of the long isoform of the D2 receptor, thereby enhancing DA neurotransmission. This effect is primarily observed in the midbrain, where DA neurons are highly concentrated, indicating that E2 directly modulates DA synthesis and utilization at the molecular level (77).

Animal studies further emphasize E2’s extensive regulatory effects on the DA system and its role in physiological processes. In ovariectomized animal models, the density of D1 and D2 receptors in the striatum is significantly reduced, while D3 receptor density remains unchanged (77–79). E2 treatment restores D1 and D2 receptor density, indicating its ability to modulate postsynaptic receptor function and normalize DA system activity (78). Furthermore, E2’s effects are not confined to specific regions. One study shows that E2 affects not only the hypothalamus but also extra-hypothalamic brain areas involved in motor function and behavior regulation, highlighting its broad regulatory role in the DA system (78).

Clinical studies show that DA activity declines with age, potentially contributing to the onset of depression (80). Additionally, multiple studies report that DA D1 and D2 receptor activity in the striatum fluctuates cyclically during the menstrual cycle (81–83). These fluctuations closely correspond to changes in estrogen levels, further supporting E2’s regulatory influence on DA receptors. Furthermore, E2 enhances DA utilization and significantly affects emotional regulation. These findings provide critical evidence for the potential application of E2 in treating mood disorders such as depression.

Kisspeptin (Kiss1) neurons play a central role in the sex steroid feedback mechanism within the human hypothalamus. Current research on Kisspeptin neurons predominantly focuses on animal models and clinical studies, with limited investigation at the basic molecular level. Studies of Kisspeptin receptor signaling pathways suggest that estrogen regulates the activity of Kisspeptin neurons through molecular mechanisms, shedding light on their integration within neural networks.

Animal studies have demonstrated that Kisspeptin and its receptors are essential for regulating sex hormones and related behaviors. Kiss1 neurons are primarily located in the lateral septum, the bed nucleus of the stria terminalis (BNST), and the medial amygdala (84). These neurons stimulate the release of gonadotropins by responding to sex steroid signals, increasing the pulsatile activity of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH), a mechanism observed in both sexes (85, 86). Furthermore, Kisspeptin signaling is associated with behaviors such as anxiety and depression (87). Estradiol (E2) significantly increases Kiss1 expression in the preoptic area (POA) of both male and female monkeys (88, 89). In ovariectomized young monkeys, researchers observed hypertrophy in basal ganglia neurons of the hypothalamus, a phenomenon also identified in postmenopausal women (90). Conversely, E2 deficiency markedly suppresses Kiss1 expression, underscoring the detrimental effects of reduced estrogen levels on Kisspeptin neurons (91).

Clinical studies further emphasize the critical role of Kisspeptin neurons in the sex steroid feedback mechanism. A specific population of Kiss1 neurons in the lateral hypothalamus decreases after menopause, suggesting that estrogen positively regulates neuronal activity and homeostasis in this brain region (92). Additionally, basal nucleus neurons in the hypothalamus of postmenopausal women exhibit enlargement alongside a significant increase in Kisspeptin gene expression (85, 93). These findings highlight the regulatory influence of estrogen on Kiss1 neurons, their role in modulating GnRH secretion, maintaining reproductive function, and promoting emotional stability.

In conclusion, Kiss1 neurons are key regulators of GnRH secretion and demonstrate significant sensitivity to fluctuations in estrogen levels, as shown in animal and clinical studies. These findings underscore their central role in the sex steroid feedback mechanism. However, further studies using cellular models and primary culture systems are necessary to elucidate the molecular regulatory mechanisms of Kisspeptin neurons, advancing our understanding of their roles in neural and hormonal regulation.

BDNF is a protein widely expressed in the brain and classified within the neurotrophin family. It is secreted by various cell types in the central nervous system (CNS), including neurons, astrocytes, and microglia (94). BDNF plays a critical role in physiological processes such as cognition, memory, and emotional regulation (94). Additionally, it is essential for neuronal growth, differentiation, survival, and synaptic plasticity.

Research using cell lines and primary cultures has elucidated the molecular mechanisms of BDNF production. For instance, in vitro studies reveal that activation of the MAPK signaling pathway enhances BDNF gene transcription via CREB phosphorylation, further supporting the regulatory influence of estrogen on BDNF expression (95). These findings provide direct evidence of the molecular and signaling pathways involved in BDNF regulation.

Animal model studies have shown that changes in BDNF levels are linked to specific physiological and pathological states. For example, research on ovariectomized mice demonstrates a significant reduction in BDNF transcription and translation in the brain, suggesting that BDNF is regulated by sex hormones (96). Moreover, the BDNF gene contains a homologous sequence of estrogen response elements (ERE), which mediates estrogen’s effects on BDNF gene expression (97).

Clinical studies further confirm the connection between BDNF levels and depression. Evidence shows that reduced BDNF levels significantly increase the risk of depression during pregnancy and the postpartum period (98–100). In non-pregnant women, serum BDNF levels correlate positively with estradiol (E2) levels, with both peaking during ovulation (101). Additionally, postmenopausal women experience decreased BDNF levels, which can be restored through hormone replacement therapy (102).

In conclusion, research across multiple models—including animal studies, clinical investigations, cell line experiments, and primary cultures—consistently underscores the vital role of BDNF in cognitive regulation, depression, and hormone-mediated modulation. These findings, based on multi-level experimental approaches, offer valuable insights into the complex functions and regulatory mechanisms of BDNF in the nervous system.

Acute neuroinflammation initially functions as a temporary physiological mechanism to defend and repair neural tissue damage. However, in chronic neurodegenerative diseases and aging, neuroinflammation transitions into a persistent pathological state. This prolonged inflammatory response not only fails to protect neural tissue but also exacerbates neuronal damage and disrupts the overall neural structure (103–105).

Animal studies provide robust evidence linking neuroinflammation to neurodegenerative diseases and depressive-like behaviors. For example, experiments in animal models have demonstrated that central nervous system (CNS) inflammation can induce depressive-like behaviors (106). Additionally, chronic neuroinflammation has been shown to impair neuronal survival and function, highlighting its central role in these pathological conditions.

Basic research has clarified the mechanisms through which estradiol (E2) modulates neuroinflammation and apoptosis. Studies using primary cultures of astrocytes and microglia reveal that E2 suppresses local inflammation, promotes gliogenesis, and regulates the release of neurotrophic factors to improve the neural environment (107, 108). Moreover, cell-based studies indicate that E2 enhances the expression of molecules critical for neuronal survival via estrogen receptor subtypes, including ERα, ERβ, and G-protein-coupled receptors (GPCRs), while concurrently downregulating pro-apoptotic and pro-inflammatory molecules (109–111).

Clinical research further supports the neuroprotective and antidepressant properties of E2. Evidence suggests that E2 preserves neurological health by mitigating inflammation and inhibiting apoptosis (112). Furthermore, clinical studies demonstrate that E2 synergizes with insulin-like growth factor 1 (IGF-1) to activate neuroprotective and anti-inflammatory signaling pathways, thereby amplifying its neuroprotective and antidepressant effects (113–115).

In conclusion, E2 may significantly contribute to depression in premenopausal women through various known pathways and potentially unknown mechanisms. Thus, appropriate monitoring and regulation of E2 levels are crucial when addressing and managing the mental health of non-menopausal women.

Forty years ago, Coombe et al. (120) documented the initial degradation pathway of E1 by the soil bacterium Nocardia sp. E110. Their study identified a dioxygenase that crucially catalyzes the cleavage of the ‘a’ region within the ring structure of the E1 molecule. This pathway has been integrated into the aerobic E2 degradation pathway, which has been uncovered in recent years. The initial stages of E2 degradation entail four distinct processes: (I) dehydrogenation of the D-ring at C-17; (II) hydroxylation of the A-ring at C-4; (III) dehydration of the D-ring at C-17; and (IV) hydroxylation of the saturated ring.

Denitratisoma sp. strain DHT3, also referred to as the denitrosomal strain DHT3 (133), is a denitrifying bacterium known for its capability to degrade E2. Under anaerobic conditions, it enzymatically converts E2 to the primary product DHT through cobalamin-dependent methyltransferase-mediated methylation. Subsequently, it further metabolizes the androgenic intermediate via the established 2,3-seco pathway, yielding 17β-hydroxy-1-oxo-2,3-seco-androstan-3-oic acid (2,3-SAOA) and 3aα-H-4α(3′-propanoate)-7aβ-methylhexahydro-1,5-indanedione (HIP). Additionally, the text mentions the 4,5-seco pathway of estradiol degradation under anaerobic conditions, where the end products are funneled to HIP.

Denitratisoma oestradiolicum AcBE2-1^T ( 134) is a Gram-negative denitrifying bacterium. It was isolated from activated sludge of municipal wastewater treatment plants and utilizes 17β-estradiol as its sole carbon and energy source. This bacterium exhibits the ability to thoroughly and completely biotransform E2 through the action of cytochrome oxidase. Consequently, E2 compounds undergo complete degradation and are ultimately converted into CO₂ and H₂O during this anaerobic oxidation process. White rot fungi, a group of fungi capable of effectively degrading lignin and various environmental pollutants, were first reported by Suzuki et al. (135) to degrade E2 efficiently through ligninolytic enzymes and laccase, consequently removing its estrogenic activity. However, the researchers observed that no metabolites were detectable in the reaction mixture after one hour of treatment. This phenomenon suggests that the loss of estrogenic activity of E2 and EE2 may result from the destructive cleavage of their aromatic ring structures. Therefore, future studies could focus on testing the hypothesis that the loss of estrogenic activity of the compounds is directly related to the breakage of the aromatic ring in their molecular structure. The literature (136) reports that Trametes versicolor can catalyze estrogen degradation using its produced laccase. However, the initial or direct metabolites involved in the degradation process are not explicitly described in this source. The final product of the complete degradation of E2 by Steroidobacter denitrificans FS^T ( 137) is N₂O. Novosphingobium sp. ARI-1 ( 116, 138) has the ability to degrade E2 into compounds with significantly lower molecular mass or simple organic acids. Pseudomonas aeruginosa TJ1 ( 139), Rhodococcus zopfii Y50158, along with Rhodococcus equi Y50155, Y50156, and Y50157 ( 140), Stenotrophomonas tumulicola ASc2, Serratia marcescens ASc5 ( 141), and Rhodococcus equi DSSKP-R-001 ( 142), are capable of degrading E2. However, the specific pathways for E2 degradation in these microorganisms remain unclear, necessitating further in-depth studies and revelations.

Isoflavones are bioflavonoids abundant in soy and its derivatives, commonly consumed in daily diets (143). Keung (144) discovered that isoflavones can inhibit the γ-isozymes of ethanol dehydrogenase (ADH) in vitro in mammals. It is noteworthy that these γ-isozymes are responsible for catalyzing the oxidation process of 3β-hydroxysteroids. Subsequent studies have revealed that isoflavones not only exhibit inhibitory effects on γ-isozymes but also on β-hydroxysteroid dehydrogenase (β-HSD), thus slowing down the metabolic catabolism rate of steroid hormones (e.g., E2) by inhibiting 3β-HSD activity. Epidemiological evidence has indicated that high dietary intake of isoflavones correlates with a reduced prevalence of depressive symptoms (145). Therefore, dietary consumption of isoflavones may potentially alleviate depression by inhibiting the activity of estradiol-degrading enzymes in gut bacteria. Some researchers (146) discovered that Fe²⁺, Fe³⁺, Zn²⁺, and Cu²⁺ all significantly inhibit the activity of the estradiol-degrading enzyme 17β-HSD. Among these, Zn²⁺ exhibited the most potent inhibitory effect, reducing enzyme activity by 62%. Additionally, other studies (147) suggested that zinc deficiency might be a potential risk factor for depressive symptoms. Given this, a pertinent scientific question is whether specific molecular tools such as Zn2+ and isoflavones can be used as modulators of E2-degrading enzymes. Exploring their potential in depression interventions involves precise modulation of enzyme activity.

Among environmental factors, temperature directly influences the activity and stability of enzymes. Zeng et al. (139), in their investigation of the isolation of the Pseudomonas aeruginosa TJ1 strain, proposed that the degradation of E2 occurred more rapidly within the temperature range of 20 to 30 degrees Celsius. This finding was corroborated by other researchers in their respective studies (148, 149), emphasizing the importance of optimal temperature as a key determinant for the efficient degradation of E2 by bacteria. It was reported (146) that the Microbacterium sp. strain MZT7, isolated from activated sludge in dairy farms, exhibited the highest activity of the estradiol-degrading enzyme 17β-HSD at 40°C. However, as the temperature surpassed 50°C, the enzyme activity displayed a notable decline, and it was entirely lost at 70°C. Another investigation (150) demonstrated that the degradation efficiency of the 17β-HSD enzyme from Microbacterium sp. MZT7 exceeded 50% within the temperature range of 20-40°C, reaching a peak degradation rate of 86.47%. In various segments of the intestine, local temperatures can fluctuate due to physiological functions and blood flow distribution. It has been observed (151) hat the stomach temperature is typically 0.2-0.6°C higher than that of the esophagus, which, in turn, is 0.3-1.0°C higher than the temperature in the axilla. Similarly, a canine study (152) yielded comparable findings: the luminal temperature in the duodenal region of dogs was approximately 6°C higher than the aortic temperature. Conversely, temperatures in the ileum, stomach, and large intestine regions, while relatively lower, remained around 0.5°C above the aortic temperature. This investigation underscores the presence of distinct temperature gradients within the mammalian digestive tract. Variances in gut temperature across different regions may impact the activities of estradiol-metabolizing enzymes within their resident microbial communities, suggesting a potential therapeutic avenue for addressing certain mental health disorders, such as depression in premenopausal women. However, the hypothetical connection and the precise pathways and mechanisms for clinical application require validation and further elucidation through rigorous scientific inquiry.

A study conducted by Deborah L. Carr (153)compared the biodegradation efficiency of 17β-estradiol in soil under aerobic and anaerobic conditions. It revealed that the half-life of 17β-estradiol was 2.1 days under aerobic conditions, whereas it decreased to 1.6 days under anaerobic conditions. This finding indicates that estradiol-degrading bacteria exhibit a higher degradation rate in anaerobic environments compared to aerobic ones in the soil samples examined. However, in a study conducted by Ying (154) on the biodegradation of E2 in marine sediments under both aerobic and anaerobic conditions, the findings contradicted those mentioned above. The experimental data revealed that the half-life of E2 degradation was 4.4 days under aerobic conditions, whereas it significantly extended to 70 days in anaerobic environments. This phenomenon was consistently corroborated in subsequent related studies by Ying (155). The reason for this difference may lie in the presence of enzymes that catalyze the oxidation reaction of E2 in aerobic bacteria, utilizing oxygen as the final electron acceptor. These enzymes are more active in aerobic environments. Conversely, anaerobic bacteria employ a different degradation mechanism, such as degradation through the reductive pathway or with the assistance of alternative electron acceptors like sulfate. Consequently, anaerobic bacteria demonstrate greater efficiency in degrading E2 under anoxic conditions. Notably, there are significant variations in the oxygen content of the intestinal lumen across different intestinal segments. One study (156) revealed that the partial pressure of oxygen in the distal small intestine (terminal ileum) of mice was extremely low, nearly zero (10 mm Hg), significantly lower than in the proximal digestive tract (60 mm Hg). This finding was corroborated by another study (157), which found that the partial pressure of oxygen in the mouse cecum was less than 1 mm Hg. The anaerobic environment in the distal intestinal lumen primarily arises from metabolic activities, including those of gastrointestinal (GI) microorganisms, oxidative reactions involving epithelial cells, and non-microbial sources such as lipid oxidation. Oxygen is continually depleted through these pathways, leading to a pronounced anaerobic environment in the region (156). Simultaneously, oxygen concentration serves as a pivotal factor influencing the structure of the gut microbial community (156, 157). Consequently, alterations in intestinal oxygen levels can affect both the composition of the gut microbial community and the activity of estradiol-degrading bacterial enzymes. Modulating oxygen levels in the gut could thus offer a prospective treatment avenue for certain mental health conditions, including depression in premenopausal women.

On one hand, enterobacteria residing in various segments of the intestinal tract may exhibit diverse E2 degradation activities due to variations in pH values. On the other hand, the intestinal microbiota can indirectly influence the functional activities of estradiol-degrading enzymes by actively regulating the acidity (pH) of their microenvironments (158). Estradiol-degrading enzymes from various microorganisms demonstrate varying activity levels across different pH environments. Hao et al. (146) observed that the estradiol-degrading enzyme 17β-HSD exhibited superior performance in alkaline conditions compared to acidic ones, with optimal catalytic activity occurring at pH 9. Additionally, the 17β-HSD enzyme derived from Microbacterium resistens MZT7 ( 150) demonstrated the highest degradation efficiency of 86.55% at pH 7. However, at pH 5 and 11, the degradation efficiency of E2 dropped significantly to 51.26% and 38.18%, respectively. In the human gastrointestinal tract, various regions exhibit distinct pH values. The differences in pH across intestinal segments arise from a multitude of physiological and microbiological factors. These include the regulation of digestive fluid secretion and acid-base balance, the metabolic activities of intestinal microbiota, and the anatomical location with its associated physiological properties. In a study involving wasps (159), researchers found that Lactobacillus Firm-5, a member of the Lactobacillus genus, metabolizes lactic acid, leading to a reduction in the intestinal pH of wasps. Previous studies (160) have indicated that the human gastric pH is highly acidic, ranging from 1.0 to 2.5, while the pH of the proximal small intestine, terminal ileum, and cecum averages 6.6, 7.5, and 6.4, respectively. Moreover, there is a gradual increase in pH from the right colon to the left colon, averaging 7.0. Research (161) has demonstrated that pH not only influences microbial community structure but also modulates pH sensitivity through microbial and metabolic interactions among fermenting species. Hence, precise modulation of gut pH through dietary adjustments, probiotic supplementation, pharmacotherapy, and lifestyle optimization presents a promising therapeutic approach for managing mental health issues, including depression in premenopausal women. These interventions target micro-level modifications in the gut environment, potentially affecting mental health and mood regulation in the host. Future research should delve deeper into how these methods influence interactions between the gut microbiota and the host nervous system, and their viability in treating mental disorders.

In terms of substrate concentration, while isolation studies of Achromobacter xylosoxidans and Ralstonia sp. picketii ( 162) suggested that changes in E2 concentration did not significantly affect the rate of degradation, Ternes et al. (163, 164) found in 1999 that under lower concentration conditions, microorganisms in activated sludge degraded E2 more efficiently. Additionally, Jiang et al. (129) observed in their study that the Bacillus sp. E2Y4 strain exhibited a positive correlation between the rate of E2 degradation and progressively higher initial steroid concentrations. The variation in the degradation rate of E2 by microorganisms in response to substrate concentration may be attributed to differences in enzyme properties, metabolic mechanisms, and ecological niche competition among different strains. In conclusion, varying substrate concentrations may regulate the enzyme activity of estradiol-degrading bacteria, thereby influencing their degradation rate performance.

In summary, the degradation rate of estradiol (E2) by microorganisms in nature depends significantly on the enzymatic activities within their bodies, which are influenced by various factors such as enzyme inhibitors, temperature, oxygen availability, pH, and substrate concentrations. By thoroughly investigating and modeling the biodegradation mechanisms and enzyme activities existing in nature, we may uncover innovative strategies to precisely regulate the enzymes involved in E2 metabolism within the gut microbial community. This approach aims to intervene in gut microecological processes that could potentially lower E2 levels associated with depression development, offering new perspectives on addressing this complex physiopathological condition.