What is the Impact of Dopamine D2 Receptor in the Brain-Gut Axis? A Narrative Review of the Mechanism Based on Gut Microbiota in Modulating Emotion and Behavior

Abstract

With the development of the brain-gut axis (GBA), the bidirectional communication between gut microbiota and the brain has become critical in emotion regulation research, and dopamine D2 receptors and gut microbiota play key roles in this process, especially in neurological and psychiatric disorders. This narrative review explores the impact of dopamine D2 receptors in the GBA, focusing on how gut microbiota modulates emotion and behavior via D2 receptors, analyzes their imbalance correlation, and looks forward to D2 receptor-based therapies.Comprehensive searches were conducted in PubMed, Web of Science, and Google Scholar (2000-2025) using keywords like “dopamine D2 receptor”, “brain-gut axis”, and “emotional disorders”, including animal and clinical studies. Research shows gut microbiota affects dopamine system activity and D2 receptor function mainly via metabolites, especially short-chain fatty acids (SCFAs, such as butyric acid and propionic acid). SCFAs cross the blood-brain barrier, bind to G protein-coupled receptors (GPCRs) to regulate dopamine synthesis/release, enhance brain immune function by improving astrocyte activity and blood-brain barrier integrity, and thus promote D2 receptor signal transduction. Gut microbiota also indirectly influences D2 receptor expression/activity by regulating dopamine precursor (such as tyrosine) metabolism. Gut microbiota imbalance is closely associated with D2 receptor dysfunction. In depression, anxiety, schizophrenia, and Parkinson’s disease, D2 receptor function is reduced or abnormally activated; gut dysbiosis (such as altered Firmicutes/Bacteroidetes ratio, increased Proteobacteria/Escherichia coli) disrupts gut metabolites (such as reduced SCFAs), aggravates systemic inflammation, and impairs the dopamine system. Overall, gut microbiota modulates D2 receptor activity through multiple mechanisms, exerting an important role in regulating emotion and behavior.

Graphical abstract

Keywords

dopamine / D2 receptor / GBA / gut microbiota / emotion / behavior / mechanism

Main Points

1. This review clarifies the core role of dopamine D2 receptors in the brain-gut axis (GBA), emphasizing their significance in mediating bidirectional communication between the gut microbiota and the brain for emotion and behavior regulation.

2. Key mechanisms by which gut microbiota modulates D2 receptor function are identified: short-chain fatty acids (SCFAs, such as butyric acid, propionic acid) cross the blood-brain barrier, bind to G protein-coupled receptors (GPCRs) to regulate dopamine synthesis/release, and enhance D2 receptor signal transduction by improving brain immune function (such as astrocyte activity, blood-brain barrier integrity); gut microbiota also indirectly affects D2 receptor expression/activity via regulating dopamine precursor (such as tyrosine) metabolism.

3. A close correlation between gut microbiota imbalance and D2 receptor dysfunction is confirmed: in neuropsychiatric disorders (such as depression, anxiety and schizophrenia) and neurodegenerative diseases (Parkinson’s disease), gut dysbiosis (such as altered Firmicutes/Bacteroidetes ratio, increased Proteobacteria/Escherichia coli) disrupts metabolites (such as reduced SCFAs), exacerbates systemic inflammation, and impairs D2 receptor function, contributing to symptom progression.

4. This review proposes potential therapeutic directions: targeting D2 receptors combined with gut microbiota modulation (such as probiotics, dietary adjustments) may provide new strategies for managing mood disorders and other GBA-related neurological/psychiatric conditions.

1. Introduction

In the gut–brain axis (GBA), the bidirectional communication mechanism between the gut and the brain has commonly drawn extensive attention [1]. The GBA signifies the complex regulatory network formed via multiple pathways, such as neural, endocrine, and immune, which not only influences digestive function, but also is crucial for emotion, behavior, and cognitive mechanisms [2, 3]. Currently, evidence has been reported that the impact of gut microbiota on modulating brain function and emotional state should not be overlooked, in particular, in the pathogenesis of neuropsychiatric disorders, including mood disorders, anxiety, and depression, the correlation between changes in gut microbiota and neural activity has been commonly documented [2, 4].

Among the most notable of these, the role of the dopamine system in emotion regulation has been broadly determined. As a major neurotransmitter in the brain, dopamine takes part in the regulation of emotion, motivation, learning, and behavior via its different types of receptors (especially D2 receptor) [5, 6, 7]. For instance, dopamine is crucial for modulating emotion, reward, and satiety, and gut microbiota is tightly linked to the bioavailability of dopamine via the microbiota-brain-gut axis, which indicates that gut microbiota, not only influences the synthesis and metabolism of dopamine in the context of modulating the nervous system, immune system, and intestinal metabolites, but also influences the brain’s emotion and behavior [8]. Furthermore, it is apparent that the gut microbiota interacts mutually with the brain via the vagus nerve and influences the dopamine concentration in the brain, in detail, the impact of metabolites, such as short-chain fatty acids (SCFAs), has a vital implication for the brain’s emotion regulation [8]. Thus, these microorganisms with metabolites play a vital role in the regulation of the dopamine system, and thus impact behavior and emotion [8]. However, it continues to be obscure what the exact interaction mechanisms are among gut microbiota, D2 receptor, and emotion regulation.

Consequently, this review is designed to delve into the impact of the dopamine D2 receptor in the GBA, deeply investigate how gut microbiota modulates emotion and behavior via this receptor, and assess its potential implications for neuropsychiatric disorders, such as mood disorders. Based on current research achievements, we also aspire to offer new perspectives and directions for future scholarly work in Dopamine D2 Receptor-related realms.

2. Methodology

2.1 Search Strategy

A comprehensive search was performed across multiple academic databases, including PubMed (https://pubmed.ncbi.nlm.nih.gov), Web of Science (https://www.webofscience.com), and Google Scholar (https://scholar.google.com). The search covered the period from January 2020 to March 2025, to capture the most recent and relevant studies. Keywords used in the search included “Dopamine D2 receptor”, “Brain-gut axis”, “Gut microbiota”, “Emotion regulation”, and “Mood disorders”, among others. Boolean operators (AND, OR) were used to combine these keywords and ensure the broadest possible coverage of the literature.

2.2 Inclusion and Exclusion Criteria

The inclusion criteria for selecting studies involved peer-reviewed publications that were published from 2000 onward; in detail, those that investigated the correlation between the dopamine D2 receptor and gut microbiota. Studies addressing the regulatory effects of gut microbiota on emotion and behavior, in particular, in mood disorders, such as depression, anxiety, and schizophrenia, were included. Animal and human studies were both considered. Conversely, studies not directly linked to the GBA or dopamine receptor function, and non-English language papers, were excluded. Editorials, opinions, and non-original research articles were also excluded from the review.

2.3 Study Selection Process

The study selection process followed a rigorous multi-step procedure to ensure relevance and quality. Initially, a broad search was conducted using the predefined keywords. The titles and abstracts of the retrieved papers were screened for relevance. Those that met the inclusion criteria were then subjected to a full-text review. After carefully evaluating the full-text articles, relevant data, including study design, methods, and key findings, were extracted for further analysis. This process ensured that only the most pertinent studies were included in the review.

2.4 Study Selection Process

To visually represent the study selection process, the following process was utilized: Initial Search: A broad search across selected databases. Screening of Titles and Abstracts: The first filter based on relevance to the topic. Full-Text Review: Evaluation of studies based on the inclusion/exclusion criteria. Data Extraction: Extraction of relevant data from eligible studies. Synthesis: Categorization and integration of data into the review’s narrative. This process ensured a comprehensive selection of studies, focusing on key areas like dopamine D2 receptor function, the impact of gut microbiota, and their implications for mood disorders.

2.5 Analysis and Reporting

The selected studies were analyzed to identify key mechanisms in the context of which gut microbiota influences dopamine receptor function, in particular, the D2 receptor. Special attention was given to how alterations in gut microbiota contribute to mood disorders, such as depression, anxiety, and schizophrenia, in the context of interrupting dopamine signaling. The findings from animal models and clinical studies were integrated, highlighting experimental evidence and clinical implications. This narrative review synthesizes findings to offer insights into the bidirectional communication between the gut microbiota and the dopamine system, offering new perspectives on potential therapeutic strategies for mood disorders.

3. Results

3.1 Basic Concepts and Roles of the GBA

The GBA holds significance within the domain of biological research, with its intricate network including different physiological and pathological mechanisms [9]. To obtain a in-depth understanding of this system, the crux lies in determining its definition and bidirectional regulatory mechanism. It is worth noting that the gut microbiota plays a vital role in the GBA, and its implications on brain function serve as one of the focal points in this research area. In the following sections, we will delve into these perspectives in detail.

3.1.1 Definition and Bidirectional Regulatory Mechanism of the GBA

The GBA signifies the bidirectional interconnected system. This gives rise to a regulatory system via the complex interaction of the nervous, endocrine, and immune systems, including an extensive scope of physiological and pathological mechanisms. Currently, research on the GBA has commonly drawn comprehensive attention in the academic community, specifically regarding the interaction between the nervous system, immune system, and gut microbiota [2]. The central mechanism of the GBA counts on the interaction. The gut not only functions as a digestive organ, but is also regarded as a vital regulatory factor impacting brain function, emotion, and behavior [10].

From the aspect of neurobiology, the GBA establishes a direct connection via the vagus nerve, forming a neural signal transmission path. The vagus nerve is a key part of the GBA. It not only carries information from the gut to the brain, but also allows the brain to reversely modulate the function of the gut via this nerve [11]. Besides, the signal transmission in the GBA also entails the integrated action of endocrine pathways (such as gastrointestinal hormones), immune pathways (such as cytokines), and metabolites (SCFAs), which jointly take part in the regulation of these interactions [3, 12].

During these interactions, the metabolites of gut microbiota step into the brain via the bloodstream and modulate the function of the nervous system. For instance, SCFAs, like butyric acid and propionic acid, synthesized by gut microbiota, can cross the blood-brain barrier and impact the neural activity of the brain, thus playing a vital role in the regulation of emotion, cognition, and behavior [3, 13]. Furthermore, about 70% of the immune cells in the body are centered in the gut. Thus, these immune cells perform immune defense function locally in the gut, and communicate with the immune system of the brain via inflammatory mediators (such as cytokines), hence impacting brain function and health [3, 13].

The bidirectional regulatory property is one of the central features of the GBA. Articles have reported that the bidirectional communication of the brain-gut-immune axis is crucial for sustaining the balance of the body. It is worth noting that gut microbiota can impact brain function via immune and neuroendocrine pathways [3, 14]. For instance, El Aidy et al. [15] reported that gut microbiota can communicate with the brain via the vagus nerve, impact neurotransmitters and immune signals, thus modulating the physiological state of the brain. Furthermore, the imbalance of gut microbiota (such as gut dysbiosis) is tightly linked to different neuroinflammatory diseases [12]. This bidirectional regulatory mechanism is displayed in the impact of changes in gut microbiota on brain function, regulation of emotion, behavior, and cognitive function [13]. Hence, the composition of gut microbiota and its metabolites may play a vital role in the occurrence and development of different neuropsychiatric disorders, thereby influencing emotional, behavioral, and cognitive processes [3].

Generally, the bidirectional regulatory mechanism of the GBA reflects the complex correlation reflects the complex correlation, and offers a new perspective for research on emotion, behavior, and cognitive function. In light of the role of the GBA, research in this field is expected to offer new ideas and methods for the prevention and treatment of neuropsychiatric disorders.

3.1.2 The Impact of Gut Microbiota on Brain Function

It is interesting that gut microbiota is crucial for modulating immune responses and maintaining the function of the blood-brain barrier via its metabolites, in detail, SCFAs. For instance, a study by Silva et al. [13] reported that these metabolites step into the brain via the bloodstream and can directly or indirectly impact the inflammatory response and neuroimmune environment of the brain. Specifically, gut microbiota can modulate the immune state of the brain via its microbial metabolic activities, thus playing a vital role in sustaining the integrity of the blood-brain barrier [13]. Hence, gut microbiota not only influences immune responses, but also is crucial for the immune regulation of the brain via microbial metabolites. Furthermore, it is worth noting that gut microbiota can further impact brain function in the context of impacting the synthesis and metabolism of neurotransmitters. For instance, gut microbiota can change the level of serotonin in the brain in the context of modulating the metabolic pathway of tryptophan, thus having vital implications for emotion, anxiety, and cognitive function [16]. This process determines that gut microbiota continues to participate in immune regulation, and at the same time, directly influences the emotional and cognitive mechanisms of the brain at the neurobiological level, in particular, the regulation of dopamine synthesis and receptor activity by gut microbiota further heightens its role in emotion and behavior regulation [8].

The impact of gut microbiota is not limited to directly modulating the level of neurotransmitters, and also modulates the systemic immune response via its interaction with the gut immune system. This process is especially vital in light of psychiatric disorders. Furthermore, the activities of immune cells and cytokines impact gut function, are transported to the brain via the bloodstream, modulate neuroimmune responses, and thus impact the physiological state of the brain [17, 18]. In particular, regarding gut microbiota imbalance, the occurrence of systemic inflammatory responses not only influences gut function, but also acts on the brain via immune-mediated pathways, thus modifying the emotion and behavior [12].

Through these mechanisms, gut microbiota can impact the function of the brain via multiple pathways, and play a key role in modulating emotion and cognitive function. In particular, in light of mood disorders, such as depression and anxiety, changes in gut microbiota may be crucial for brain dysfunction. Thus, the interaction between gut microbiota and the brain not only offers a new biological perspective, but also provides a theoretical basis for the development of new treatment strategies for psychiatric disorders.

3.2 The Impact of Dopamine D2 Receptor in Emotion Regulation

As a vital part of the neurotransmitter system, the dopamine D2 receptor plays a key role in emotion regulation. In the following sections, we will further delve into its status within the neurotransmitter system and the intimate associations it has with mood disorders. Fig. 1 exhibits the central impact of Dopamine D2 Receptor in emotion regulation.

3.2.1 The Status of D2 Receptor in the Neurotransmitter System

The dopamine system is central to emotion and behavior regulation, in detail, the D2 receptor, which is crucial for dopaminergic signal transduction [7]. The D2 receptor is part of the dopamine receptor family, and is broadly distributed in the central nervous system (CNS), in particular in brain regions linked to emotion, reward, cognition, and movement, including the nucleus accumbens, striatum, and prefrontal cortex [19]. The D2 receptor, via its self-inhibitory effect, serves as a central component of the negative feedback mechanism, modulating the release and reuptake of neurotransmitters and sustaining the normal function of the dopamine neural pathway [20]. Hence, the normal function of the D2 receptor is vital for emotional stability. In this regard, an article has displayed that the D2 receptor inhibits the excessive release of dopamine via negative feedback regulation to avoid overstimulation of the nervous system [21]. When the dopamine system is dysregulated, particularly when the activity of the D2 receptor is compromised, mood disorders frequently arise [22]. The overstimulation of the D2 receptor may result in “dopamine supersensitivity”, which is especially ubiquitous in some schizophrenia patients who have received chronic antipsychotic therapy [21].

3.2.2 The Correlation Between D2 Receptor and Mood Disorders

In light of mood disorders, the dysfunction of the D2 receptor is tightly linked to different psychiatric disorders. Studies have reported that patients with depression generally display a reduction in the expression of D2 receptors, and it is evident that this change may weaken the reactivity of the brain’s reward system, thus eliciting symptoms, including low mood and lack of motivation [7, 23]. Moreover, the alterations in the activity of D2 receptors in patients with anxiety also suggest that the dopamine system is crucial for the stress response to environmental threats [24, 25]. The change in this regulatory capacity may give rise to the emergence of anxiety symptoms [7, 26]. Furthermore, the dysfunction of D2 receptors in patients with schizophrenia is particularly vital. For instance, articles have determined that the hyperactivation of the dopamine system is directly linked to the emergence of psychotic symptoms, such as hallucinations and delusions. Hence, the D2 receptor turns into the main target of antipsychotic drugs [27, 28].

3.3 The Interaction Between Gut Microbiota and D2 Receptor

After determining the key impact of the dopamine D2 receptor in emotion regulation, we will next delve into the critical aspect of the crosstalk between the gut microbiota and the D2 receptor [8, 29]. Among these most notable of these, the regulatory mechanisms through which the gut microbiota modulates the function of the D2 receptor and the exact mechanisms by which the D2 receptor is involved in the GBA are central to gaining a key understanding of their correlation between them. We will analyze these in detail below [8, 30].

The crosstalk between gut microbiota and the dopamine D2 receptor emerges as a key research direction. Specifically, through a range of metabolic pathways, gut microbiota can directly or indirectly modulate the function of the D2 receptor [8, 13]. Studies have revealed that gut microbiota, via its metabolites, in particular SCFAs, has vital implications for the activity of the dopamine system in the brain, in detail, the D2 receptor [8, 13]. Fig. 2 exhibits the interaction between Gut Microbiota and D2 Receptor.

3.3.1 How Gut Microbiota Modulates the Function of D2 Receptor

Current evidence has reported that gut microbiota influences the function of the D2 receptor via its metabolites, in particular SCFAs, such as butyric acid and propionic acid [8, 31]. For instance, these SCFAs can not only traverse the blood-brain barrier (BBB), but also bind to GPCRs in the brain to promote signal transmission, hence influencing different physiological mechanisms [13]. Specifically, SCFAs, such as butyric acid and propionic acid, have been reported to enhance the integrity of the blood-brain barrier in the context of modulating the function of astrocytes, which are crucial in forming and maintaining the barrier. Additionally, these metabolites modulate brain inflammatory responses in the context of impacting microglial cells, which play a key role in immune surveillance and neuroinflammation [32]. This interaction not only modulates the function of neurons and astrocytes, but also vitally influences emotion and behavior.

In addition, the potentiating effect of SCFAs on D2 receptor signal transduction further determines the regulatory impact of gut microbiota on emotion and behavior processes [8, 33]. In the context of acting on neurotransmitter synthesis, in particular dopamine, gut microbiota can significantly impact the function of the D2 receptor [32]. Gut microbiota indirectly influences the expression and activity of the D2 receptor in the context of modulating the metabolism of dopamine precursor molecules (such as tyrosine), providing a mechanistic basis for the impact of gut microbiota on emotion regulation [8].

In addition to dopamine transporter (DAT), other mechanisms also participate in the crosstalk between gut microbiota and the dopamine system [8]. For instance, research has reported that metabolites synthesized by specific gut bacteria, including indoles and phenolic compounds, can impact the expression and activity of dopamine D2 receptors. Notably, Scott et al. (2024) [34] uncovered that tryptophan metabolites produced by enteric bacteria counteract the invasion of intestinal pathogens by activating dopamine D2 receptors in the intestinal epithelium. Furthermore, Tennoune et al. (2022) [35] pointed out that indole compounds produced by the gut microbiota, such as indole and indole sulfonic acid, can cross into the brain via as-yet-unidentified mechanisms and affect neural activity and emotional behavior at varying doses, indicating that these metabolites play a crucial role in modulating neurotransmitter activity. These metabolites bind to GPCRs on the brain neurons, indirectly modulating dopamine receptor activity and influencing the neuroplasticity essential for emotion and behavior regulation [36].

Furthermore, gut microbiota can also modulate the biosynthesis pathways of dopamine precursors. For instance, gut bacteria may impact the metabolism of tyrosine, the amino acid precursor to dopamine, in the context of modulating gut-derived enzymes and metabolic pathways; intriguingly, this regulation of dopamine synthesis further influences the activity of the D2 receptor, enhancing or inhibiting its function based on based on dopamine levels in the synaptic cleft [8, 36]. Accumulating evidence indicates that the gut-brain axis plays a vital role in maintaining appropriate dopamine levels via sophisticated crosstalk between the gut microbiota and the brain. Microbial populations in the gut can directly impact the synthesis of neurotransmitters, including dopamine, hence impacting neurochemical signaling in the brain. Additionally, interruptions in gut microbiota composition may be linked to neurodegenerative diseases, such as Parkinson’s disease, by impairing dopaminergic function [8, 36].

Thus, the crosstalk between gut microbiota and the D2 receptor is multidimensional, including not only SCFAs but also other metabolites, as well as regulatory mechanisms such as DAT modulation and changes in dopamine precursor biosynthesis. These mechanisms, via their implications for dopamine signaling, play a vital role in regulating mood, behavior, and cognitive function.

3.3.2 The Mechanism of D2 Receptor in the GBA

As a critical hub in dopamine signal transduction, the D2 receptor plays a key role in the nervous system, and co-modulates neurotransmitter homeostasis in the brain with the metabolites of gut microbiota (such as SCFAs) [8, 37, 38]. The regulatory effect of gut microbiota metabolites on the D2 receptor can indirectly impact the regulation of emotion and behavior, and this mechanism is shaped by the impact of microbial metabolites on the immune and endocrine pathways [8].

Additionally, research has reported that the gut microbiota directly modulates key neurotransmitters including dopamine, serotonin, and glutamate via bidirectional crosstalk with the brain, which are crucial for emotion regulation. The gut microbiota influences emotional responses and behavior by influencing the levels of these neurotransmitters. For instance, some gut bacteria can synthesize neurotransmitters, such as dopamine, which not only act locally in the gut, but also impact brain function, hence modulating emotions and cognitive states [8]. Furthermore, metabolites generated by the gut microbiota also have a regulatory effect on the physiological functions and behaviors of the CNS and the enteric nervous system (ENS), suggesting that the gut microbiota influences mood and behavior by modulating neurotransmitters [39]. Precisely, studies have reported that the gut microbiota modulates emotions and behavior by influencing neural circuits and neurotransmitter expression. For instance, a study reports that the gut microbiota can impact the brain dopamine pathway linked to eating behavior, in particular, by modifying the expression of dopamine D1 and D2 receptors, hence impacting impulsive behavior and reward responses [40]. Notably, the composition of the microbiota and the levels of SCFAs are closely associated with human short-term memory and working memory, indicating that the gut microbiota is crucial for modulating emotions and behavior by affecting the dopamine system’s response to external stimuli [40]. These studies indicate that the gut microbiota not only influences the function of dopamine receptors, but also is tightly linked to the brain’s response to external stimuli by modulating neural circuits, ultimately playing an important role in modulating emotions and behavior [41, 42]. It is interesting that the microbiota interacts with the brain via multiple pathways, such as the vagus nerve, immune system, and hypothalamic-pituitary-adrenal axis, thus regulating emotional and behavioral processes [43]. In this process, the dysfunction of the D2 receptor, specifically, the abnormality in signal transduction, may emerge as a key factor in the occurrence of mood disorders triggered by gut microbiota imbalance, thus holding critical implications for the behavior and emotional state of individuals [44].

3.4 The Impact of D2 Receptor and Gut Microbiota Imbalance in Mood Disorders

Considering the intimate association between the gut microbiota and the D2 receptor, we further explore their roles in mood disorders [45, 46, 47]. Specifically, the correlation between gut microbiota dysbiosis and D2 receptor dysfunction, and the exact interactions between these two factors in mood disorders, are critical for understanding the pathogenesis of mood disorders [45, 48]. In the subsequent sections, we will perform an in-depth analysis of these perspectives. Figs. 3,4 exhibit the impact of D2 Receptor and Gut Microbiota Imbalance in Mood Disorders [8, 47, 49].

3.4.1 The Correlation Between Gut Microbiota Imbalance and D2 Receptor Dysfunction

The diversity and homeostasis of gut microbiota play a vital role in emotion regulation; specifically, holding significant implications for the brain’s emotion regulation function [46, 50]. Notably, recent research has reported that gut microbiota imbalance (such as reduced microbiota diversity and specific microbiota imbalance) is tightly linked to different neuropsychiatric disorders (such as depression, anxiety, and schizophrenia) [51]. This determines that gut microbiota dysbiosis not only influences the physiological function of the gut, but also holds significant implications for brain function via the GBA [49, 52]. The dysregulation of the dopamine system triggered by gut microbiota imbalance is strongly linked to the development of mood disorders [53].

3.4.1.1 The Association Between Reduced Microbiota Diversity and D2 Receptor Function

Decline in gut microbiota diversity is commonly accompanied by the overgrowth of harmful microbiota, and the reduced abundance of probiotics may result in the imbalance of neuro-immune regulation [54, 55, 56]. Probiotics play a vital role in sustaining the healthy homeostasis of gut microbiota and improving the immune function of the host. In particular, in the context of enhancing the abundance of beneficial bacteria, they can relieve the symptoms of chronic inflammation and metabolic disorders [57, 58]. For instance, evidences has determined that gut microbiota imbalance can impact the dopamine pathway in the brain, and thus modify the function of the D2 receptor, for example, the metabolites of gut microbiota, including SCFAs (such as butyrate and propionate), may impact the brain via modulating the activity of the D2 receptor, ultimately playing a vital role in emotion and behavior [58, 59]. Specifically, SCFAs modulate the dopamine system in the brain via the vagus nerve and immune response, and may further impact neurobehavior in the context of modifying the signal transduction pathway of the D2 receptor [57, 59].

Overall, this mechanism describes how gut microbiota modulates neurotransmitters and the functions of their related receptors in the brain via a complex biological signal network, thus impacting emotional stability and behavioral patterns.

3.4.1.2 The Impact of Exact Microbiota Imbalance on D2 Receptor Function

Dopamine is central to modulating mood, cognition, and behavior, with the D2 receptor being one of the key modulators of dopamine signaling in the brain [60]. Interruptions in dopamine signaling, in particular, via alterations in D2 receptor function, are broadly implicated in different neuropsychiatric disorders, including depression, anxiety, and schizophrenia [60]. The intestinal microbiota, with its diverse ecological network of prokaryotes, fungi, and other microorganisms, is increasingly recognized as a key regulator of dopaminergic receptor signaling, including the D2 receptor [61].

Recent studies have highlighted how gut dysbiosis—an imbalance in the gut microbial community—can impact dopamine signaling pathways, hence impacting brain function [8, 62]. In more detail, certain bacterial taxa have been found to be linked to alterations in D2 receptor function, which is involved in the pathophysiology of psychiatric disorders [63].

Gut Microbiota and D2 Receptor Function in Depression

According to literature, SCFAs play an important role in sustaining brain health. Exactly, SCFAs such as butyrate can directly impact the expression of brain-derived neurotrophic factor (BDNF) via the blood-brain barrier, which is vital for neuroplasticity and normal function of the dopamine system [64, 65]. In depression, a gut microbiota dysbiosis has been reported to impact the dopaminergic system, in particular, D2 receptors, which are vital for modulating emotions and emotional behavior. A feature of this dysregulation is changes in the abundance of enteric bacteria (such as Firmicutes and Bacteroidetes), which play an important role in modulating the expression and function of dopamine receptors in the brain. Research has reported that gut microbiota imbalance influences the development of depressive symptoms via abnormal synaptic pruning of glial cells and signal transduction mediated by complement C3 [66]. Furthermore, the imbalance of gut microbiota is tightly linked to the occurrence of depression, in detail, the correlation between changes in gut bacterial communities (such as Firmicutes and Bacteroidetes) and emotion regulation has been determined [67]. Specifically, studies have reported that Firmicutes are often overrepresented in patients with depression, while Bacteroidetes is underrepresented, triggering a gut microbiota dysbiosis and interrupting normal dopamine signaling. The literature reports that the increased abundance of Firmicutes is tightly linked to the occurrence of different neurological diseases, which is particularly vital in patients with depression [68]. Imbalanced gut microbiota not only influences neurotransmitter synthesis, but also triggers neuroinflammation [69]. Specifically, in animal models lacking gut microbiota entirely, the occurrence of anxiety-like behavior is tightly linked to the absence of gut microbiota [70]. This further confirms the close correlation between gut microbiota and neurological diseases. Hence, the imbalance of gut microbiota is regarded as an important factor in the pathogenesis of depression.

The effects of Firmicutes and Bacteroidetes on the dopamine system are mainly mediated by the secretion of SCFAs synthesized by specific gut bacteria, such as butyric acid and propionic acid. Research has reported that SCFAs are the main metabolites produced by gut bacteria via fermentation of dietary fiber and resistant starch; they can cross the blood-brain barrier, bind to GPCRs in the brain, and thus impact the activity of microglia and astrocytes. These cell types play a crucial role in regulating neuroinflammation and supporting dopamine receptor function [71]. Research has reported that reduced SCFAs are tightly linked to brain function degeneration, particularly in patients with depression. This change can decrease BDNF levels, impair synaptic plasticity, and exacerbate emotional regulation deficits [64]. Furthermore, gut microbiota imbalance leads to decreased SCFAs secretion, which contributes to the pathogenesis of depression—further demonstrating the crucial role of SCFAs in emotional regulation and neuroplasticity [65]. Notably, SCFAs such as butyrate can directly impact BDNF expression via the blood-brain barrier, which is vital for neuroplasticity and normal dopamine system function [64, 65].

Furthermore, recent reviews indicate that a high abundance of species of Lactobacilli and Bifidobacteria in the healthy gut microbiota can alleviate depressive symptoms by improving the function of dopamine receptors and lowering neuroinflammation. These species enhance the synthesis of SCFAs, which play an important role in sustaining neuronal plasticity and emotion regulation, in particular, in protecting dopamine receptor function, in the context of modulating immune responses and improving histone acetylation pathways. Research has reported that SCFAs can modulate dopamine and serotonin levels in the gut via the G protein coupled receptor (GPCR) pathway, which has vital implications emotions and behavior. Furthermore, SCFAs enhance intestinal barrier function, promotes the expression and formation of tight junction proteins, and further supports its important role in immune response and neurological health [13].

Gut Microbiota and D2 Receptor Function in Anxiety

Anxiety disorders, like depression, are linked to dysregulated dopamine signaling, in particular, at the D2 receptor [72]. The gut-brain axis plays a vital role in this regulation [73]. The overgrowth of pathogenic bacteria, such as Proteobacteria, Enterobacteriaceae, and Escherichia coli has been reported to increase gut permeability and promote the release of pro-inflammatory cytokines [74]. These cytokines can cross the blood-brain barrier, triggering dysregulated dopamine metabolism and D2 receptor dysfunction in regions of the brain linked to emotion and behavioral regulation, such as the prefrontal cortex and amygdala [75].

Additionally, the Firmicutes-to-Bacteroidetes ratio has been implicated in anxiety disorders, with a higher proportion of Firmicutes often seen in individuals with elevated anxiety [52]. This microbial imbalance can directly impact dopamine receptors by increasing neuroinflammation and downregulating dopamine receptor expression, triggering anxiety symptoms [42].

Gut Microbiota and D2 Receptor Function in Schizophrenia

Schizophrenia, a severe neuropsychiatric disorder, has also been reported to be impacted by gut microbiota [76]. The impact of the D2 receptor in schizophrenia is well-established, as dopamine dysregulation is regarded as a central feature of the disorder [77]. Recent studies have reported that gut dysbiosis can contribute to dopamine imbalance, in detail, via the crosstalk between microbial metabolites and dopamine receptors [78, 79]. Specific bacterial species, such as Prevotella and Ruminococcus, have been found to be vitally reduced in individuals with schizophrenia, and this dysbiosis has been linked to exacerbated symptoms of the disorder, including hallucinations and delusions [80, 81].

Research also reports that Clostridium species in the gut may impact the dopamine system by modulating the secretion of gamma-aminobutyric acid (GABA), which interacts with dopamine receptors, including D2 [82]. Furthermore, Bacteroides have been reported to promote dopamine receptor expression in the striatum, a key region involved in reward processing, highlighting the importance of a balanced gut microbiome in maintaining D2 receptor function and dopamine signaling in schizophrenia [83].

3.4.1.3 Gut Microbiota Imbalance Alters the Dopamine Signaling Pathway via the D2 Receptor

Gut microbiota imbalance is frequently accompanied by the aberrant release of microbial metabolites (such as endotoxin, SCFAs, neurotransmitters), and these metabolites can impact brain function via immune and endocrine pathways [84]. Additionally, these metabolites have been determined to directly or indirectly modulate the function of the dopamine system, in particular, the function of the D2 receptor [8, 85]. Gut microbiota imbalance may further interrupt the normal function of the D2 receptor in the context of modifying the synthesis and release of dopamine, causing emotional instability and dysregulated behavioral responses [8].

In addition, the gut microbiota indirectly influences the expression and function of the D2 receptor in the context of modulating the balance of neurotransmitters, such as serotonin, norepinephrine, and GABA in the brain [16]. This bidirectional regulation between the gut microbiota and the brain uncovers the vital impact of the gut microbiota on emotion and behavior regulation and offers a novel avenue for further investigation into the mechanism of neuropsychiatric dysfunction.

3.4.2 The Interaction Between the D2 Receptor and Gut Microbiota in Mood Disorders

The occurrence of mood disorders, specifically psychiatric disorders such as depression and anxiety, is intimately linked to the interaction between the D2 receptor and gut microbiota imbalance [49, 86]. The imbalance of gut microbiota can impact the neurotransmitter signaling mechanisms in the brain via the D2 receptor, hence triggering mood disorders [16]. In particular, the interaction between the D2 receptor and gut microbiota may contribute to the development of mood disorders via the following mechanisms [87].

3.4.2.1 The D2 Receptor and Gut Microbiota Imbalance in Depression

In the context of depression, evidence indicates a close association between gut microbiota imbalance and the occurrence and progression of depression [52, 88]. Patients with depression typically exhibit alterations in gut microbiota, and this imbalance can impact brain function via multiple pathways, specifically neurotransmitter signaling linked to the dopamine system [89].

Gut microbiota imbalance is prevalent among patients with depression. Alterations in gut microbiota composition are regarded as a risk factor for different psychiatric disorders. Particularly in depression, gut microbiota imbalance is tightly linked to changes in emotion, anxiety, stress response, and brain function [90]. Some research has revealed that the gut microbiota engages in bidirectional signaling with the brain via the “GBA”, and influences the function of the CNS [8]. Notably, gut microbiota imbalance may increase intestinal permeability and promote the release of inflammatory factors (such as lipopolysaccharide), hence triggering a systemic inflammatory response and ultimately impacting the neuroinflammatory process in the brain [90, 91]. These inflammatory responses can impact the synthesis and metabolism of neurotransmitters in the brain, consequently impacting emotion regulation and behavior.

The dopamine system in the brain of patients with depression generally exhibits functional abnormalities, specifically in the expression and activity of the D2 receptor [92]. The D2 receptor is regarded as a vital target in depression [93]. Studies has found that patients with depression commonly demonstrate low activity of the D2 receptor [8]. This is tightly correlated with the symptoms of depression (such as low mood, lack of interest), as the D2 receptor is crucial for regulating the reward system, motivation, and emotion [7, 94]. Additionally, gut microbiota imbalance may modulate the dopamine system via diverse pathways. For instance, gut microbiota can impact the synthesis of dopamine in the brain via metabolites (such as SCFAs), and intestinal inflammation may further disturb the synthesis of dopamine and the function of the D2 receptor in the context of modifying the inflammatory environment in the brain [8, 90].

The gut microbiota is crucial for modulating BDNF, which is crucial for neural plasticity, synaptic transmission, and overall brain health [95]. The gut microbiota produces metabolites like SCFAs, specifically butyrate, which act as histone deacetylase inhibitors [96]. This action increases the expression of BDNF, supporting brain functions involved in emotion regulation [97]. Reduced BDNF levels have been tightly linked to the development of depression and other mood disorders [98].

When the gut microbiota becomes imbalanced (known as dysbiosis), there is a reduction in SCFAs secretion, leading to increased neuroinflammation [99, 100]. Inflammatory cytokines produced in the gut can cross the blood-brain barrier and impact dopamine signaling, in particular, in the context of inhibiting dopamine receptors like the D2 receptor [101]. The D2 receptor is crucial for emotion regulation, and its dysfunction exacerbates symptoms of depression and anxiety [102]. Thus, gut dysbiosis indirectly impairs dopamine system function in the context of increasing inflammation and lowering BDNF expression [97].

Therefore, the gut microbiota serves as a key mediator in this process, linking BDNF, dopamine signaling, and neuroinflammation [97]. Restoring intestinal barrier integrity and addressing gut inflammation could potentially help to modulate BDNF levels and dopamine function, offering novel therapeutic avenues for managing mood disorders and other neuropsychiatric conditions [103].

In summary, gut microbiota imbalance is tightly tied to the development of depression. The abnormal dopamine system in the brain of patients with depression, specifically the dysfunction of the D2 receptor, may be intimately linked to alterations in the gut microbiota. Further research should delve into how gut microbiota modulates the dopamine system via multiple mechanisms, and explore novel treatment strategies, such as utilizing probiotics and other interventions to modulate the gut microbiota, thereby providing new ideas and approaches for the treatment of depression.

3.4.2.2 The D2 Receptor and Gut Microbiota Imbalance in Anxiety

Anxiety has also been determined to be tightly linked to gut microbiota imbalance and D2 receptor dysfunction [38, 49, 62]. It is worth noting that the manifestation of anxiety is generally accompanied by changes in the gut microbial community, and the function of the D2 receptor may be suppressed in such circumstances [104]. The proliferation of certain pathogenic bacteria is common in the gut microbiota of patients with anxiety; specifically, changes in the abundance of bacteria linked to the stress response, such as Firmicutes and Bacteroidetes, and their altered abundance is tightly linked to the aggravation of anxiety [67]. These bacterial changes are tightly correlated with the clinical manifestations of anxiety, in particular, in terms of the transmission of impact via the microbiota-gut-brain axis (microbiota-GBA), revealing the potential impact of gut microbiota on the occurrence of anxiety [104].

3.4.2.3 The Impact of the D2 Receptor in the Regulation of Anxiety in the Context of Gut Microbiota

Studies have reported that the D2 receptor plays a vital role in the brain and is tightly linked to anxiety regulation. The activation of the D2 receptor can impact emotion and behavior by modulating the brain’s neurotransmitter systems, specifically the dopamine system. Specifically, the release of dopamine and the activation of the D2 receptor are crucial for relieving anxiety symptoms [104, 105]. Modulating gut microbiota composition can influence the GBA, thereby modifying the activity of D2 receptors in the brain [106]. An article reported that the diversity and health status of the gut microbiota directly impact the function of the nervous system, in particular, in emotion regulation [106]. Beneficial gut microbiota influences the inflammation level and neurotransmitter balance in the brain via mechanisms such as the synthesis of SCFAs and the regulation of the immune response, which is directly linked to the alleviation of anxiety [105, 107]. The supplementation of probiotics has been proven to help improve the balance of the gut microbiota, hence modulating D2 receptor function and alleviating anxiety symptoms. Specific studies have reported that certain probiotics, such as Lactiplantibacillus plantarum, can vitally improve anxiety-like behaviors in mice in the context of modulating tryptophan metabolism and the gut microbiota structure [105]. A diet rich in fiber and variety (such as one abundant in different vegetables, fruits, and whole grains) also helps enhance the diversity of the gut microbiota, hence improving the symptoms of anxiety [104].

3.4.2.4 The Interaction Between the D2 Receptor and Gut Microbiota in Schizophrenia

Lately, more and more articles have suggested that the correlation between gut microbiota and schizophrenia may serve as a vital pathological basis of the disease [108, 109]. Studies have reported that the gut microbiota of patients with schizophrenia exhibits significant imbalance, which is tightly linked to neuroinflammation, immune response, and neurotransmitter metabolism [104, 110]. In particular, the abnormal function of the D2 receptor is tightly linked to the positive symptoms of schizophrenia, and the overactivation of the D2 receptor is regarded as a key pathological feature of the disease [110].

Dopamine is one of the main neurotransmitters in schizophrenia, and it acts in the brain via dopamine receptors, in detail, the D2 receptor. The overactivation of the D2 receptor is regarded as one of the main causes of schizophrenia symptoms, in detail, positive symptoms (such as hallucinations and delusions) [110]. For instance, in patients with schizophrenia, the D2 receptor generally shows functional overactivation, which is linked to the disorder of dopaminergic signal transduction in certain brain regions (such as the striatum) [111]. Studies have also reported that the excessive release of dopamine (a key neurotransmitter) is tightly linked to the abnormal overactivation of the D2 receptor [112]. Pharmacological experiments have found that using drugs that can inhibit the D2 receptor can significantly change the symptoms of schizophrenia [110]. These findings support the dopamine hypothesis, that is, dopamine is central to the occurrence and symptom formation of schizophrenia.

Lately, mounting studies have centered on the potential that changes in gut microbiota may indirectly impact the pathogenesis of schizophrenia via the GBA [113, 114]. Gut microbiota imbalance is believed to impact brain function via multiple pathways, including changes in inflammatory factors and alterations in neurotransmitter metabolism [110, 111]. Exactly, gut microbiota imbalance may impact the function of the D2 receptor in the context of increasing inflammatory factors in the brain and modifying dopamine metabolism [78, 115]. For instance, changes in gut microbiota can promote the activation of the body’s immune system, causing the entry of inflammatory factors (such as IL-6 and TNF-\alpha) into the brain [111]. These inflammatory factors can change neurotransmitter metabolism and trigger the functional abnormality of neurotransmitter receptors (such as the D2 receptor) [111]. Gut microbiota can impact the synthesis and metabolism of dopamine. For instance, some specific gut microbiota may promote the metabolism of tryptophan in the gut into 5-HT or other neurotransmitter precursors, hence indirectly impacting the level of dopamine in the brain [110]. These changes may promote the overactivation of the D2 receptor and result in the worsening of schizophrenia symptoms.

3.4.3 The Interaction Between the D2 Receptor and Leaky Gut Syndrome

Leaky Gut Syndrome (LGS) refers to a condition where the intestinal barrier becomes compromised, allowing harmful substances, including toxins and pathogens, to leak into the bloodstream [116]. This condition is linked to chronic low-grade inflammation and has been implicated in a range of neuropsychiatric disorders, including anxiety, depression, and schizophrenia [117, 118]. The interaction between the gut microbiota, the D2 receptor, and LGS is of critical interest in understanding the pathogenesis of these disorders [62].

The D2 receptor, a key player in the dopamine system, modulates multiple brain functions, including mood, cognition, and behavior [119]. It is also involved in the regulation of gastrointestinal function, highlighting its role in the gut-brain axis [120]. Recent studies have reported that the D2 receptor’s dysfunction may contribute to emotional disturbances and cognitive impairments seen in conditions such as depression and anxiety [45, 121]. Additionally, D2 receptor activity in the gut influences the microbiota composition, which can, in turn, impact brain function and behavior [120].

The integrity of the intestinal barrier is crucial for maintaining homeostasis in the gut-brain axis [122]. In LGS, this barrier is weakened, eliciting an overactive immune response and chronic inflammation [123]. This inflammation can alter the composition of the gut microbiota, increasing the growth of pathogenic bacteria and reducing the abundance of beneficial bacteria [124]. The resulting dysbiosis may interrupt the dopaminergic system in the context of impacting the metabolism and signaling of dopamine, which plays a crucial role in mood regulation and behavior [52]. Research has reported that inflammatory cytokines produced as a result of LGS can impact the function of the D2 receptor, potentially altering its activity [125]. This impairment can result in dysregulated dopamine signaling, causing the development of mood disorders and exacerbating symptoms of other neuropsychiatric conditions [126]. Besides, the inflammatory response in the gut may result in the release of substances that compromise the blood-brain barrier, further increasing susceptibility to neurological dysfunction [127].

Studies have also demonstrated that gut microbiota imbalances resulting from LGS can impact the expression of the D2 receptor in both the gut and the brain [128, 129]. A gut microbiota dysbiosis, in particular, an enrichment in pro-inflammatory microbes, can result in the upregulation of inflammatory pathways that perturb the dopaminergic system [130]. This dysregulation causes alterations in dopamine secretion and receptor expression, triggering an increased risk of developing psychiatric disorders such as depression and anxiety [131]. Additionally, alterations in dopamine metabolism due to LGS-induced inflammation may impact the brain’s reward pathways, further triggering the emotional and behavioral dysregulation observed in these conditions [132]. The D2 receptor, therefore, acts as a vital mediator in this pathway, and its dysfunction in light of LGS may significantly impact the onset and progression of neuropsychiatric disorders [133].

Given the interaction between LGS, gut microbiota, and the D2 receptor, therapeutic strategies aimed at restoring intestinal barrier integrity and reducing gut inflammation may offer novel approaches for controlling mood disorders and other psychiatric conditions [134]. Probiotics, prebiotics, and anti-inflammatory treatments targeting the gut microbiota may offer potential benefits in restoring D2 receptor function and alleviating symptoms linked to LGS and neuropsychiatric disorders [135].

3.5 Limitations

This review delves into key aspects of the correlation between dopamine D2 receptors and gut microbiota, particularly in the context of emotion regulation and neuropsychiatric disorders. However, it must be acknowledged that there are several limitations. Although there is evidence to suggest that gut microbiota influences dopamine metabolism and D2 receptor expression, the exact molecular mechanisms are still not fully elucidated. The specific pathways through which gut microbiota modulates dopamine signaling require further exploration to gain a more comprehensive understanding of these interactions. Furthermore, most studies have focused on general microbiota changes in neurological and psychiatric disorders. Additionally, there is currently limited research on the regional changes in microbial composition and their exact effects on brain regions involved in emotion and behavior regulation, such as the prefrontal cortex and amygdala. Understanding how these regional differences impact dopamine receptor function is vital for future scholarly work. Over time, the dynamic interactions between gut microbiota and dopamine receptors have not been fully investigated. Most existing studies are cross-sectional, making it difficult to determine the causal relationship between gut dysbiosis and changes in dopamine receptor function. Longitudinal studies tracking changes in microbiota composition and D2 receptor expression over time will offer stronger evidence and insights for potential therapeutic windows. Many studies have focused on relatively homogeneous populations, limiting the generalizability of research results. Studying the impact of gut microbiota on D2 receptor function in different populations (including different genetic backgrounds, age groups, and comorbidities) will improve the generalizability of the results to a broader population. Comprehensive microbial community analysis is required. Although some studies have linked specific bacterial species (such as Bacteroidetes and Prevotella) to neurological and psychiatric symptoms, there is a lack of comprehensive microbiota analysis that includes a broader scope of bacterial species and their metabolites. Future scholarly work should focus on expanding microbial community analysis to discover other potentially important microbial communities and their collective implications for dopamine receptor signaling. In the context of addressing these limitations, future research can obtain a clearer understanding of the complex interactions between D2 receptors and gut microbiota, and how these interactions promote emotional regulation and neuropsychiatric disorders. This will also pave the way for developing more effective and personalized treatment strategies.

4. Conclusion

In conclusion, the dopamine D2 receptor is a key part of the GBA, playing a vital role in the regulation of emotion and behavior. The gut microbiota modulates the D2 receptor’s function, influencing mood regulation and contributing to the development of mood disorders. While the interaction between the D2 receptor and gut microbiota is increasingly recognized, the exact molecular mechanisms remain to be fully elucidated. Given the complexity of psychiatric disorders, it is likely that multiple mechanisms coexist, and further research is needed to delve into these interactions comprehensively. This could lay the groundwork for the development of more targeted and effective therapeutic strategies for mood disorders.

Future treatment strategies should focus on combining D2 receptor-targeted therapies with interventions aimed at modulating the gut microbiota, such as probiotics or dietary adjustments. This integrated approach holds the potential to enhance treatment efficacy and minimize side effects, offering a promising direction for the future management of mood disorders. Additionally, further research should explore the bidirectional interactions between the D2 receptor and gut microbiota, in particular, how these interactions impact neurotransmitter systems and emotion regulation. Advancing new targeted interventions that modulate both the D2 receptor and gut microbiota could offer innovative treatments, in particular, in cases where current drug therapies are limited due to side effects or insufficient efficacy. Ultimately, modulating the gut microbiota may offer a safer and more effective treatment approach, improving patient outcomes in managing mood disorders.

References

[1] Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of Gastroenterology. 2015; 28: 203–209.

[2] Aljeradat B, Kumar D, Abdulmuizz S, Kundu M, Almealawy YF, Batarseh DR, et al. Neuromodulation and the Gut-Brain Axis: Therapeutic Mechanisms and Implications for Gastrointestinal and Neurological Disorders. Pathophysiology: the Official Journal of the International Society for Pathophysiology. 2024; 31: 244–268. https://doi.org/10.3390/pathophysiology31020019.

[3] Kasarello K, Cudnoch-Jedrzejewska A, Czarzasta K. Communication of gut microbiota and brain via immune and neuroendocrine signaling. Frontiers in Microbiology. 2023; 14: 1118529. https://doi.org/10.3389/fmicb.2023.1118529.

[4] Vasilev GV, Miteva D, Gulinac M, Chervenkov L, Kitanova M, Velikova T. Exploring Gut–Brain Interaction Disorders: Mechanisms and Translational Therapies Crossing Neurology to Gastroenterology. Gastroenterology Insights. 2024; 15: 555–573. https://doi.org/10.3390/gastroent15030041.

[5] Pinheiro CR, Moura EG, Manhães AC, Fraga MC, Claudio-Neto S, Younes-Rapozo V, et al. Maternal nicotine exposure during lactation alters food preference, anxiety-like behavior and the brain dopaminergic reward system in the adult rat offspring. Physiology & Behavior. 2015; 149: 131–141. https://doi.org/10.1016/j.physbeh.2015.05.040.

[6] Zhang X, Tsuboi D, Funahashi Y, Yamahashi Y, Kaibuchi K, Nagai T. Phosphorylation Signals Downstream of Dopamine Receptors in Emotional Behaviors: Association with Preference and Avoidance. International Journal of Molecular Sciences. 2022; 23: 11643. https://doi.org/10.3390/ijms231911643.

[7] Belujon P, Grace AA. Dopamine System Dysregulation in Major Depressive Disorders. The International Journal of Neuropsychopharmacology. 2017; 20: 1036–1046. https://doi.org/10.1093/ijnp/pyx056.

[8] Hamamah S, Aghazarian A, Nazaryan A, Hajnal A, Covasa M. Role of Microbiota-Gut-Brain Axis in Regulating Dopaminergic Signaling. Biomedicines. 2022; 10: 436. https://doi.org/10.3390/biomedicines10020436.

[9] Deidda G, Biazzo M. Gut and Brain: Investigating Physiological and Pathological Interactions Between Microbiota and Brain to Gain New Therapeutic Avenues for Brain Diseases. Frontiers in Neuroscience. 2021; 15: 753915. https://doi.org/10.3389/fnins.2021.753915.

[10] Arneth BM. Gut-brain axis biochemical signalling from the gastrointestinal tract to the central nervous system: gut dysbiosis and altered brain function. Postgraduate Medical Journal. 2018; 94: 446–452. https://doi.org/10.1136/postgradmedj-2017-135424.

[11] Bonaz B, Sinniger V, Pellissier S. The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract. Frontiers in Immunology. 2017; 8: 1452. https://doi.org/10.3389/fimmu.2017.01452.

[12] Warren A, Nyavor Y, Zarabian N, Mahoney A, Frame LA. The microbiota-gut-brain-immune interface in the pathogenesis of neuroinflammatory diseases: a narrative review of the emerging literature. Frontiers in Immunology. 2024; 15: 1365673. https://doi.org/10.3389/fimmu.2024.1365673.

[13] Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Frontiers in Endocrinology. 2020; 11: 25. https://doi.org/10.3389/fendo.2020.00025.

[14] Foster JA, Baker GB, Dursun SM. The Relationship Between the Gut Microbiome-Immune System-Brain Axis and Major Depressive Disorder. Frontiers in Neurology. 2021; 12: 721126. https://doi.org/10.3389/fneur.2021.721126.

[15] El Aidy S, Dinan TG, Cryan JF. Immune modulation of the brain-gut-microbe axis. Frontiers in Microbiology. 2014; 5: 146. https://doi.org/10.3389/fmicb.2014.00146.

[16] Chen Y, Xu J, Chen Y. Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders. Nutrients. 2021; 13: 2099. https://doi.org/10.3390/nu13062099.

[17] Yuan C, He Y, Xie K, Feng L, Gao S, Cai L. Review of microbiota gut brain axis and innate immunity in inflammatory and infective diseases. Frontiers in Cellular and Infection Microbiology. 2023; 13: 1282431. https://doi.org/10.3389/fcimb.2023.1282431.

[18] Lo BC, Chen GY, Núñez G, Caruso R. Gut microbiota and systemic immunity in health and disease. International Immunology. 2021; 33: 197–209. https://doi.org/10.1093/intimm/dxaa079.

[19] Stahl SM. Dazzled by the dominions of dopamine: clinical roles of D3, D2, and D1 receptors. CNS Spectrums. 2017; 22: 305–311. https://doi.org/10.1017/S1092852917000426.

[20] Zhang AQ, Ralph MR, Stinchcombe AR. A mathematical model for the role of dopamine-D2 self-regulation in the production of ultradian rhythms. PLoS Computational Biology. 2024; 20: e1012082. https://doi.org/10.1371/journal.pcbi.1012082.

[21] Oda Y, Kanahara N, Iyo M. Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia. International Journal of Molecular Sciences. 2015; 16: 30144–30163. https://doi.org/10.3390/ijms161226228.

[22] Stahl SM. Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes. CNS Spectrums. 2017; 22: 375–384. https://doi.org/10.1017/S1092852917000608.

[23] Lawford BR, Young R, Noble EP, Kann B, Ritchie T. The D2 dopamine receptor (DRD2) gene is associated with co-morbid depression, anxiety and social dysfunction in untreated veterans with post-traumatic stress disorder. European Psychiatry: the Journal of the Association of European Psychiatrists. 2006; 21: 180–185. https://doi.org/10.1016/j.eurpsy.2005.01.006.

[24] Peng B, Xu Q, Liu J, Guo S, Borgland SL, Liu S. Corticosterone Attenuates Reward-Seeking Behavior and Increases Anxiety via D2 Receptor Signaling in Ventral Tegmental Area Dopamine Neurons. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2021; 41: 1566–1581. https://doi.org/10.1523/JNEUROSCI.2533-20.2020.

[25] Zarrindast MR, Khakpai F. The Modulatory Role of Dopamine in Anxiety-like Behavior. Archives of Iranian Medicine. 2015; 18: 591–603.

[26] Zhang Y, Wang Y, Wang L, Bai M, Zhang X, Zhu X. Dopamine Receptor D2 and Associated microRNAs Are Involved in Stress Susceptibility and Resistance to Escitalopram Treatment. The International Journal of Neuropsychopharmacology. 2015; 18: pyv025. https://doi.org/10.1093/ijnp/pyv025.

[27] Sonnenschein SF, Gomes FV, Grace AA. Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia. Frontiers in Psychiatry. 2020; 11: 613. https://doi.org/10.3389/fpsyt.2020.00613.

[28] Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein HG, Steiner J, et al. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Frontiers in Psychiatry. 2014; 5: 47. https://doi.org/10.3389/fpsyt.2014.00047.

[29] Li M, Zhou L, Sun X, Yang Y, Zhang C, Wang T, et al. Dopamine, a co-regulatory component, bridges the central nervous system and the immune system. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2022; 145: 112458. https://doi.org/10.1016/j.biopha.2021.112458.

[30] Pan I, Issac PK, Rahman MM, Guru A, Arockiaraj J. Gut-Brain Axis a Key Player to Control Gut Dysbiosis in Neurological Diseases. Molecular Neurobiology. 2024; 61: 9873–9891. https://doi.org/10.1007/s12035-023-03691-3.

[31] Vasquez R, Oh JK, Song JH, Kang DK. Gut microbiome-produced metabolites in pigs: a review on their biological functions and the influence of probiotics. Journal of Animal Science and Technology. 2022; 64: 671–695. https://doi.org/10.5187/jast.2022.e58.

[32] Fock E, Parnova R. Mechanisms of Blood-Brain Barrier Protection by Microbiota-Derived Short-Chain Fatty Acids. Cells. 2023; 12: 657. https://doi.org/10.3390/cells12040657.

[33] de Wouters d’Oplinter A, Huwart SJP, Cani PD, Everard A. Gut microbes and food reward: From the gut to the brain. Frontiers in Neuroscience. 2022; 16: 947240. https://doi.org/10.3389/fnins.2022.947240.

[34] Scott SA, Fu J, Chang PV. Dopamine receptor D2 confluencers colonization resistance via gut microbiota metabolites. Nature. 2024; 628: 180–185. https://doi.org/10.1038/s41586-024-07179-5.

[35] Tennoune N, Andriamihaja M, Blachier F. Production of Indole and Indole-Related Compounds by the Intestinal Microbiota and Consequences for the Host: The Good, the Bad, and the Ugly. Microorganisms. 2022; 10: 930. https://doi.org/10.3390/microorganisms10050930.

[36] Zacharias HU, Kaleta C, Cossais F, Schaeffer E, Berndt H, Best L, et al. Microbiome and Metabolome Insights into the Role of the Gastrointestinal-Brain Axis in Parkinson’s and Alzheimer’s Disease: Unveiling Potential Therapeutic Targets. Metabolites. 2022; 12: 1222. https://doi.org/10.3390/metabo12121222.

[37] Schubert S. The effect of oral butyrate administration on the release of serotonin and dopamine in the gastrointestinal tract. Universityof Eastern Finland: Finland. 2021.

[38] Yang Y, Zhong Z, Wang B, Wang Y. Xiaoyao San ameliorates high-fat diet-induced anxiety and depression via regulating gut microbiota in mice. Biomedicine & Pharmacotherapy. 2022; 156: 113902. https://doi.org/10.1016/j.biopha.2022.113902.

[39] Margolis KG, Cryan JF, Mayer EA. The Microbiota-Gut-Brain Axis: From Motility to Mood. Gastroenterology. 2021; 160: 1486–1501. https://doi.org/10.1053/j.gastro.2020.10.066.

[40] Yu KB, Hsiao EY. Roles for the gut microbiota in regulating neuronal feeding circuits. The Journal of Clinical Investigation. 2021; 131: e143772. https://doi.org/10.1172/JCI143772.

[41] Bamicha V, Pergantis P, Drigas A. The effect of gut microbiome, neurotransmitters, and digital insights in autism. Applied Microbiology. 2024; 4: 114. https://doi.org/10.3390/applmicrobiol4040114.

[42] Qu S, Yu Z, Zhou Y, Wang S, Jia M, Chen T, et al. Gut microbiota modulates neurotransmitter and gut-brain signaling. Microbiological Research. 2024; 287: 127858. https://doi.org/10.1016/j.micres.2024.127858.

[43] Binda S, Tremblay A, Iqbal UH, Kassem O, Le Barz M, Thomas V, et al. Psychobiotics and the Microbiota-Gut-Brain Axis: Where Do We Go from Here? Microorganisms. 2024; 12: 634. https://doi.org/10.3390/microorganisms12040634.

[44] Zhao J, Liu J, Feng J, Liu X, Hu Q. The gut microbiota-brain connection: insights into major depressive disorder and bipolar disorder. Frontiers in Psychiatry. 2024; 15: 1421490. https://doi.org/10.3389/fpsyt.2024.1421490.

[45] Li J, Pu F, Peng C, Wang Y, Zhang Y, Wu S, et al. Antibiotic cocktail-induced gut microbiota depletion in different stages could cause host cognitive impairment and emotional disorders in adulthood in different manners. Neurobiology of Disease. 2022; 170: 105757. https://doi.org/10.1016/j.nbd.2022.105757.

[46] Li Z, Lai J, Zhang P, Ding J, Jiang J, Liu C, et al. Multi-omics analyses of serum metabolome, gut microbiome and brain function reveal dysregulated microbiota-gut-brain axis in bipolar depression. Molecular Psychiatry. 2022; 27: 4123–4135. https://doi.org/10.1038/s41380-022-01569-9.

[47] Góralczyk-Bińkowska A, Szmajda-Krygier D, Kozłowska E. The Microbiota-Gut-Brain Axis in Psychiatric Disorders. International Journal of Molecular Sciences. 2022; 23: 11245. https://doi.org/10.3390/ijms231911245.

[48] Ma Z, Zhao H, Zhao M, Zhang J, Qu N. Gut microbiotas, inflammatory factors, and mental-behavioral disorders: A mendelian randomization study. Journal of Affective Disorders. 2025; 371: 113–123. https://doi.org/10.1016/j.jad.2024.11.049.

[49] Mitrea L, Nemeş SA, Szabo K, Teleky BE, Vodnar DC. Guts Imbalance Imbalances the Brain: A Review of Gut Microbiota Association With Neurological and Psychiatric Disorders. Frontiers in Medicine. 2022; 9: 813204. https://doi.org/10.3389/fmed.2022.813204.

[50] Liu S, Cheng L, Liu Y, Zhan S, Wu Z, Zhang X. Relationship between Dietary Polyphenols and Gut Microbiota: New Clues to Improve Cognitive Disorders, Mood Disorders and Circadian Rhythms. Foods (Basel, Switzerland). 2023; 12: 1309. https://doi.org/10.3390/foods12061309.

[51] Toader C, Dobrin N, Costea D, Glavan LA, Covache-Busuioc RA, Dumitrascu DI, et al. Mind, Mood and Microbiota-Gut-Brain Axis in Psychiatric Disorders. International Journal of Molecular Sciences. 2024; 25: 3340. https://doi.org/10.3390/ijms25063340.

[52] Verma A, Inslicht SS, Bhargava A. Gut-Brain Axis: Role of Microbiome, Metabolomics, Hormones, and Stress in Mental Health Disorders. Cells. 2024; 13: 1436. https://doi.org/10.3390/cells13171436.

[53] Guney C, Bal NB, Akar F. The impact of dietary fructose on gut permeability, microbiota, abdominal adiposity, insulin signaling and reproductive function. Heliyon. 2023; 9: e18896. https://doi.org/10.1016/j.heliyon.2023.e18896.

[54] Bali P, Lal P, Sivapuram MS, Kutikuppala LVS, Avti P, Chanana A, et al. Mind over Microbes: Investigating the Interplay between Lifestyle Factors, Gut Microbiota, and Brain Health. Neuroepidemiology. 2024; 58: 426–448. https://doi.org/10.1159/000538416.

[55] Patel RA, Panche AN, Harke SN. Gut microbiome-gut brain axis-depression: interconnection. World J Biol Psychiatry. 2025; 26: 1–36. https://doi.org/10.1080/15622975.2024.2436854.

[56] Krsek A, Baticic L. Neutrophils in the Focus: Impact on Neuroimmune Dynamics and the Gut-Brain Axis. Gastrointestinal Disorders. 2024; 6: 557–606. https://doi.org/10.3390/gidisord6030039.

[57] Chandrasekaran P, Weiskirchen S, Weiskirchen R. Effects of Probiotics on Gut Microbiota: An Overview. International Journal of Molecular Sciences. 2024; 25: 6022. https://doi.org/10.3390/ijms25116022.

[58] Hrncir T. Gut Microbiota Dysbiosis: Triggers, Consequences, Diagnostic and Therapeutic Options. Microorganisms. 2022; 10: 578. https://doi.org/10.3390/microorganisms10030578.

[59] Pires L, Gonzalez-Paramás AM, Heleno SA, Calhelha RC. Gut Microbiota as an Endocrine Organ: Unveiling Its Role in Human Physiology and Health. Applied Sciences. 2024; 14: 9383. https://doi.org/10.3390/app14209383.

[60] Kawahata I, Finkelstein DI, Fukunaga K. Dopamine D1–D5 receptors in brain nuclei: Implications for health and disease. Receptors. 2024; 3: 155–181. https://doi.org/10.3390/receptors3020009.

[61] Peng HR, Qiu JQ, Zhou QM, Zhang YK, Chen QY, Yin YQ, et al. Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis. Immunity. 2023; 56: 2773–2789.e8. https://doi.org/10.1016/j.immuni.2023.10.016.

[62] Anand N, Gorantla VR, Chidambaram SB. The Role of Gut Dysbiosis in the Pathophysiology of Neuropsychiatric Disorders. Cells. 2022; 12: 54. https://doi.org/10.3390/cells12010054.

[63] Ghorbani M, Stephen Joseph G B, Mei Mei T, Salwa Ramly S, Muhamad Rasat MA, Croft L, et al. Functional associations of the gut microbiome with dopamine, serotonin, and BDNF in schizophrenia: a pilot study. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery, 2024; 60: 123.https://doi.org/10.1186/s41983-024-00901-0.

[64] Liu H, Li R, Su K, Yuan J, LI Q, FENG X. Latest Research on the Neuroprotective Mechanism of Short-chain fatty acids in Stroke and Its Relationship with Post stroke Cognitive Impairment. Chinese General Practice. 2022; 25: 380–386. (In Chinese)

[65] WANG Q, GAO H, HE M, BAI X, XI H, YANG Y. Gut microbiota in anxiety after spinal cord injury: a review. Microbiology China. 2023; 50: 5563–5573. (In Chinese)

[66] Hao W, Ma Q, Wang L, Yuan N, Gan H, He L, et al. Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3. Microbiome. 2024; 12: 34. https://doi.org/10.1186/s40168-024-01756-6.

[67] Xiong RG, Li J, Cheng J, Zhou DD, Wu SX, Huang SY, et al. The Role of Gut Microbiota in Anxiety, Depression, and Other Mental Disorders as Well as the Protective Effects of Dietary Components. Nutrients. 2023; 15: 3258. https://doi.org/10.3390/nu15143258.

[68] Hong D, Zhang C, Wu W, Lu X, Zhang L. Modulation of the gut-brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis. Frontiers in Neurology. 2023; 14: 1133546. https://doi.org/10.3389/fneur.2023.1133546.

[69] Liu LX, Wang HY, Xie P. Gut microbiota: a new insight into neuropsychiatric disorders. SCIENTIA SINICA Vitae. 2023; 53: 556–570. (In Chinese)

[70] Javurek AB, Suresh D, Spollen WG, Hart ML, Hansen SA, Ellersieck MR, et al. Gut Dysbiosis and Neurobehavioral Alterations in Rats Exposed to Silver Nanoparticles. Scientific Reports. 2017; 7: 2822. https://doi.org/10.1038/s41598-017-02880-0.

[71] Wenzel TJ, Gates EJ, Ranger AL, Klegeris A. Short-chain fatty acids (SCFAs) alone or in combination regulate select immune functions of microglia-like cells. Molecular and Cellular Neurosciences. 2020; 105: 103493. https://doi.org/10.1016/j.mcn.2020.103493.

[72] Pérez de la Mora M, Borroto-Escuela DO, Crespo-Ramírez M, Rejón-Orantes JDC, Palacios-Lagunas DA, Martínez-Mata MK, et al. Dysfunctional Heteroreceptor Complexes as Novel Targets for the Treatment of Major Depressive and Anxiety Disorders. Cells. 2022; 11: 1826. https://doi.org/10.3390/cells11111826.

[73] Hwang YK, Oh JS. Interaction of the Vagus Nerve and Serotonin in the Gut-Brain Axis. International Journal of Molecular Sciences. 2025; 26: 1160. https://doi.org/10.3390/ijms26031160.

[74] Di Vincenzo F, Del Gaudio A, Petito V, Lopetuso LR, Scaldaferri F. Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review. Internal and Emergency Medicine. 2024; 19: 275–293. https://doi.org/10.1007/s11739-023-03374-w.

[75] Costantino G. Unravelling neuroinflammatory pathways by using in vitro and in vivo models. Tesi Dottorato. 2024. Available at: https://hdl.handle.net/20.500.14242/164935. (Accessed: 01 February 2025).

[76] Zajkowska I, Niczyporuk P, Urbaniak A, Tomaszek N, Modzelewski S, Waszkiewicz N. Investigating the Impacts of Diet, Supplementation, Microbiota, Gut-Brain Axis on Schizophrenia: A Narrative Review. Nutrients. 2024; 16: 2228. https://doi.org/10.3390/nu16142228.

[77] Iasevoli F, Avagliano C, D’Ambrosio L, Barone A, Ciccarelli M, De Simone G, et al. Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal. Biomedicines. 2023; 11: 895. https://doi.org/10.3390/biomedicines11030895.

[78] Chojnacki J, Popławski T, Kaczka A, Romanowska N, Chojnacki C, Gąsiorowska A. Assessment of Urinary Dopamine and Serotonin Metabolites in Relation to Dysbiosis Indicators in Patients with Functional Constipation. Nutrients. 2024; 16: 2981. https://doi.org/10.3390/nu16172981.

[79] Kollaparampil Kishanchand D, K A AK, Chandrababu K, Philips CA, Sivan U, Pulikaparambil Sasidharan BC. The Intricate Interplay: Microbial Metabolites and the Gut-Liver-Brain Axis in Parkinson’s Disease. Journal of Neuroscience Research. 2025; 103: e70016. https://doi.org/10.1002/jnr.70016.

[80] Shenoy PA, Syed M, Nayak V. Can bugs be an alternative or adjuvant to drugs in schizophrenia? Journal of Applied Pharmaceutical Science. 2024; 14: 019–036.

[81] Afroz KF, Manchia M. Gut microbiome and psychiatric disorders. BMC Psychiatry. 2023; 23: 488. https://doi.org/10.1186/s12888-023-05003-4.

[82] Nagamine T. The Role of the Gut Microbiota in Individuals with Irritable Bowel Syndrome: A Scoping Review. Medicina (Kaunas, Lithuania). 2024; 60: 1895. https://doi.org/10.3390/medicina60111895.

[83] Sfera A. Six decades of dopamine hypothesis: is aryl hydrocarbon receptor the new D2?. Reports. 2023; 6: 36. https://doi.org/10.3390/reports6030036.

[84] Martin-Gallausiaux C, Marinelli L, Blottière HM, Larraufie P, Lapaque N. SCFA: mechanisms and functional importance in the gut. The Proceedings of the Nutrition Society. 2021; 80: 37–49. https://doi.org/10.1017/S0029665120006916.

[85] Dicks LMT. Gut Bacteria and Neurotransmitters. Microorganisms. 2022; 10: 1838. https://doi.org/10.3390/microorganisms10091838.

[86] McGuinness AJ, Davis JA, Dawson SL, Loughman A, Collier F, O’Hely M, et al. A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia. Molecular Psychiatry. 2022; 27: 1920–1935. https://doi.org/10.1038/s41380-022-01456-3.

[87] Menezes AA, Shah ZA. A review of the consequences of gut microbiota in neurodegenerative disorders and aging. Brain Sciences. 2024; 14: 1224. https://doi.org/10.3390/brainsci14121224.

[88] Borrego-Ruiz A, Borrego JJ. An updated overview on the relationship between human gut microbiome dysbiosis and psychiatric and psychological disorders. Progress in Neuro-psychopharmacology & Biological Psychiatry. 2024; 128: 110861. https://doi.org/10.1016/j.pnpbp.2023.110861.

[89] Huang F, Wu X. Brain Neurotransmitter Modulation by Gut Microbiota in Anxiety and Depression. Frontiers in Cell and Developmental Biology. 2021; 9: 649103. https://doi.org/10.3389/fcell.2021.649103.

[90] Suda K, Matsuda K. How Microbes Affect Depression: Underlying Mechanisms via the Gut-Brain Axis and the Modulating Role of Probiotics. International Journal of Molecular Sciences. 2022; 23: 1172. https://doi.org/10.3390/ijms23031172.

[91] Averina OV, Poluektova EU, Zorkina YA, Kovtun AS, Danilenko VN. Human Gut Microbiota for Diagnosis and Treatment of Depression. International Journal of Molecular Sciences. 2024; 25: 5782. https://doi.org/10.3390/ijms25115782.

[92] Delva NC, Stanwood GD. Dysregulation of brain dopamine systems in major depressive disorder. Experimental Biology and Medicine. 2021; 246: 1084–1093. https://doi.org/10.1177/1535370221991830.

[93] Ayano GJ. Dopamine: receptors, functions, synthesis, pathways, locations and mental disorders: review of literatures. Journal of Mental Disorders and Treatment. 2016; 2: 2.

[94] Day CV, Gatt JM, Etkin A, DeBattista C, Schatzberg AF, Williams LM. Cognitive and emotional biomarkers of melancholic depression: An iSPOT-D report. Journal of Affective Disorders. 2015; 176: 141–150. https://doi.org/10.1016/j.jad.2015.01.061.

[95] Matin S, Dadkhah M. BDNF/CREB signaling pathway contribution in depression pathogenesis: A survey on the non-pharmacological therapeutic opportunities for gut microbiota dysbiosis. Brain Research Bulletin. 2024; 207: 110882. https://doi.org/10.1016/j.brainresbull.2024.110882.

[96] Modoux M, Rolhion N, Lefevre JH, Oeuvray C, Nádvorník P, Illes P, et al. Butyrate acts through HDAC inhibition to enhance aryl hydrocarbon receptor activation by gut microbiota-derived ligands. Gut Microbes. 2022; 14: 2105637. https://doi.org/10.1080/19490976.2022.2105637.

[97] Molska M, Mruczyk K, Cisek-Woźniak A, Prokopowicz W, Szydełko P, Jakuszewska Z, et al. The Influence of Intestinal Microbiota on BDNF Levels. Nutrients. 2024; 16: 2891. https://doi.org/10.3390/nu16172891.

[98] Lin L, Fu XY, Zhou XF, Liu D, Bobrovskaya L, Zhou L. Analysis of blood mature BDNF and proBDNF in mood disorders with specific ELISA assays. Journal of Psychiatric Research. 2021; 133: 166–173. https://doi.org/10.1016/j.jpsychires.2020.12.021.

[99] Bairamian D, Sha S, Rolhion N, Sokol H, Dorothée G, Lemere CA, Krantic S. Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease. Molecular Neurodegeneration. 2022; 17: 19. https://doi.org/10.1186/s13024-022-00522-2.

[100] Aho VTE, Houser MC, Pereira PAB, Chang J, Rudi K, Paulin L, et al. Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson’s disease. Molecular Neurodegeneration. 2021; 16: 6. https://doi.org/10.1186/s13024-021-00427-6.

[101] Crine V, Papenberg G, Johansson J, Boraxbekk CJ, Wåhlin A, Lindenberger U, et al. Associations between inflammation and striatal dopamine D2-receptor availability in aging. Journal of Neuroinflammation. 2025; 22: 24. https://doi.org/10.1186/s12974-025-03355-0.

[102] Zareba MR, Pico-Perez M, Arino-Brana P. Noradrenergic and dopaminergic neural correlates of trait anxiety: unveiling the impact of maladaptive emotion regulation. bioRxiv. 2024. (preprint)

[103] Fu H, Liu Y. Complex gut–brain interactions underlying inflammatory bowel disease-related depression have translational implications in regenerative medicine: A narrative review. Regenerative Medicine Reports. 2024; 1: 59–75.

[104] Kumar A, Pramanik J, Goyal N, Chauhan D, Sivamaruthi BS, Prajapati BG, et al. Gut Microbiota in Anxiety and Depression: Unveiling the Relationships and Management Options. Pharmaceuticals (Basel, Switzerland). 2023; 16: 565. https://doi.org/10.3390/ph16040565.

[105] Jia L, Xiao L, Fu Y, Shao Z, Jing Z, Yuan J, et al. Neuroprotective effects of probiotics on anxiety- and depression-like disorders in stressed mice by modulating tryptophan metabolism and the gut microbiota. Food & Function. 2024; 15: 2895–2905. https://doi.org/10.1039/d3fo03897a.

[106] Tsujita N, Akamatsu Y, Nishida MM, Hayashi T, Moritani T. Effect of Tryptophan, Vitamin B₆, and Nicotinamide-Containing Supplement Loading between Meals on Mood and Autonomic Nervous System Activity in Young Adults with Subclinical Depression: A Randomized, Double-Blind, and Placebo-Controlled Study. Journal of Nutritional Science and Vitaminology. 2019; 65: 507–514. https://doi.org/10.3177/jnsv.65.507.

[107] Merkouris E, Mavroudi T, Miliotas D, Tsiptsios D, Serdari A, Christidi F, et al. Probiotics’ Effects in the Treatment of Anxiety and Depression: A Comprehensive Review of 2014-2023 Clinical Trials. Microorganisms. 2024; 12: 411. https://doi.org/10.3390/microorganisms12020411.

[108] Rantala MJ, Luoto S, Borráz-León JI, Krams I. Schizophrenia: The new etiological synthesis. Neuroscience and Biobehavioral Reviews. 2022; 142: 104894. https://doi.org/10.1016/j.neubiorev.2022.104894.

[109] Li S, Zhuo M, Huang X, Huang Y, Zhou J, Xiong D, et al. Altered gut microbiota associated with symptom severity in schizophrenia. PeerJ. 2020; 8: e9574. https://doi.org/10.7717/peerj.9574.

[110] Rawani NS, Chan AW, Dursun SM, Baker GB. The Underlying Neurobiological Mechanisms of Psychosis: Focus on Neurotransmission Dysregulation, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction. Antioxidants (Basel, Switzerland). 2024; 13: 709. https://doi.org/10.3390/antiox13060709.

[111] Szeligowski T, Yun AL, Lennox BR, Burnet PWJ. The Gut Microbiome and Schizophrenia: The Current State of the Field and Clinical Applications. Frontiers in Psychiatry. 2020; 11: 156. https://doi.org/10.3389/fpsyt.2020.00156.

[112] Ginovart N, Kapur S. Role of dopamine D(2) receptors for antipsychotic activity. Handbook of Experimental Pharmacology. 2012; 27–52. https://doi.org/10.1007/978-3-642-25761-2_2.

[113] Taniguchi K, Ikeda Y, Nagase N, Tsuji A, Kitagishi Y, Matsuda S. Implications of Gut-Brain axis in the pathogenesis of Psychiatric disorders. Aims Bioengineering. 2021; 8: 243–256. https://doi.org/10.3934/bioeng.2021021.

[114] Ju S, Shin Y, Han S, et al. The Gut-Brain Axis in Schizophrenia: The Implications of the Gut Microbiome and SCFA Production. Nutrients. 2023; 15: 4391. https://doi.org/10.3390/nu15204391.

[115] García Mansilla MJ, Rodríguez Sojo MJ, Lista AR, Ayala Mosqueda CV, Ruiz Malagón AJ, Gálvez J, et al. Exploring Gut Microbiota Imbalance in Irritable Bowel Syndrome: Potential Therapeutic Effects of Probiotics and Their Metabolites. Nutrients. 2024; 17: 155. https://doi.org/10.3390/nu17010155.

[116] Álvarez-Herms J, González A, Corbi F, Odriozola I, Odriozola A. Possible relationship between the gut leaky syndrome and musculoskeletal injuries: the important role of gut microbiota as indirect modulator. AIMS Public Health. 2023; 10: 710–738. https://doi.org/10.3934/publichealth.2023049.

[117] Slyepchenko A, Maes M, Jacka FN, Köhler CA, Barichello T, McIntyre RS, et al. Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities. Psychother Psychosom. 2017; 86: 31–46. https://doi.org/10.1159/000448957.

[118] González-Blanco L, Dal Santo F, García-Portilla MP, Alfonso M, Hernández C, Sánchez-Autet M, et al. Intestinal permeability biomarkers in patients with schizophrenia: Additional support for the impact of lifestyle habits. European Psychiatry: the Journal of the Association of European Psychiatrists. 2024; 67: e84. https://doi.org/10.1192/j.eurpsy.2024.1765.

[119] Kleinridders A, Pothos EN. Impact of Brain Insulin Signaling on Dopamine Function, Food Intake, Reward, and Emotional Behavior. Current Nutrition Reports. 2019; 8: 83–91. https://doi.org/10.1007/s13668-019-0276-z.

[120] Sharma G, Biswas SS, Mishra J, Navik U, Kandimalla R, Reddy PH, et al. Gut microbiota dysbiosis and Huntington’s disease: Exploring the gut-brain axis and novel microbiota-based interventions. Life Sciences. 2023; 328: 121882. https://doi.org/10.1016/j.lfs.2023.121882.

[121] Tian H, Wang Z, Meng Y, Geng L, Lian H, Shi Z, et al. Neural mechanisms underlying cognitive impairment in depression and cognitive benefits of exercise intervention. Behavioural Brain Research. 2025; 476: 115218. https://doi.org/10.1016/j.bbr.2024.115218.

[122] Paton SEJ, Solano JL, Coulombe-Rozon F, Lebel M, Menard C. Barrier-environment interactions along the gut-brain axis and their influence on cognition and behaviour throughout the lifespan. Journal of Psychiatry & Neuroscience: JPN. 2023; 48: E190–E208. https://doi.org/10.1503/jpn.220218.

[123] Escalante J, Artaiz O, Diwakarla S, McQuade RM. Leaky gut in systemic inflammation: exploring the link between gastrointestinal disorders and age-related diseases. GeroScience. 2025; 47: 1–22. https://doi.org/10.1007/s11357-024-01451-2.

[124] Nagao-Kitamoto H, Kitamoto S, Kuffa P, Kamada N. Pathogenic role of the gut microbiota in gastrointestinal diseases. Intestinal Research. 2016; 14: 127–138. https://doi.org/10.5217/ir.2016.14.2.127.

[125] Cao Y, Li Y, Wang X, Liu S, Zhang Y, Liu G, et al. Dopamine inhibits group 2 innate lymphoid cell-driven allergic lung inflammation by dampening mitochondrial activity. Immunity. 2023; 56: 320–335.e9. https://doi.org/10.1016/j.immuni.2022.12.017.

[126] Bertollo AG, Puntel CF, da Silva BV, Martins M, Bagatini MD, Ignácio ZM. Neurobiological Relationships Between Neurodevelopmental Disorders and Mood Disorders. Brain Sciences. 2025; 15: 307. https://doi.org/10.3390/brainsci15030307.

[127] Wang Y, Du W, Hu X, Yu X, Guo C, Jin X, et al. Targeting the blood-brain barrier to delay aging-accompanied neurological diseases by modulating gut microbiota, circadian rhythms, and their interplays. Acta Pharmaceutica Sinica. B. 2023; 13: 4667–4687. https://doi.org/10.1016/j.apsb.2023.08.009.

[128] Munteanu C, Galaction AI, Turnea M, Blendea CD, Rotariu M, Poștaru M. Redox Homeostasis, Gut Microbiota, and Epigenetics in Neurodegenerative Diseases: A Systematic Review. Antioxidants (Basel, Switzerland). 2024; 13: 1062. https://doi.org/10.3390/antiox13091062.

[129] Li SS, Li AQ, Liu ZY, Zhao XY, Wang GR, Deng Y, et al. Glutamine enhances sucrose taste through a gut microbiota-gut-brain axis in Drosophila. Life Sciences. 2024; 339: 122415. https://doi.org/10.1016/j.lfs.2024.122415.

[130] Zhang F, Pan L, Lian C, Xu Z, Chen H, Lai W, et al. ICAM-1 may promote the loss of dopaminergic neurons by regulating inflammation in MPTP-induced Parkinson’s disease mouse models. Brain Research Bulletin. 2024; 214: 110989. https://doi.org/10.1016/j.brainresbull.2024.110989.

[131] Mata-Bermudez A, Trejo-Chávez R, Martínez-Vargas M, Pérez-Arredondo A, Martínez-Cardenas MDLÁ Diaz-Ruiz A, et al. Dysregulation of the dopaminergic system secondary to traumatic brain injury: implications for mood and anxiety disorders. Frontiers in Neuroscience. 2024; 18: 1447688. https://doi.org/10.3389/fnins.2024.1447688.

[132] Carbone MG, Maremmani I. Chronic Cocaine Use and Parkinson’s Disease: An Interpretative Model. International Journal of Environmental Research and Public Health. 2024; 21: 1105. https://doi.org/10.3390/ijerph21081105.

[133] Thangaleela S, Sivamaruthi BS, Kesika P, Mariappan S, Rashmi S, Choeisoongnern T, et al. Neurological Insights into Sleep Disorders in Parkinson’s Disease. Brain Sciences. 2023; 13: 1202. https://doi.org/10.3390/brainsci13081202.

[134] Młynarska E, Jakubowska P, Frąk W, Gajewska A, Sornowska J, Skwira S, et al. Associations of Microbiota and Nutrition with Cognitive Impairment in Diseases. Nutrients. 2024; 16: 3570. https://doi.org/10.3390/nu16203570.

[135] Dziedzic A, Maciak K, Bliźniewska-Kowalska K, Gałecka M, Kobierecka W, Saluk J. The Power of Psychobiotics in Depression: A Modern Approach through the Microbiota-Gut-Brain Axis: A Literature Review. Nutrients. 2024; 16: 1054. https://doi.org/10.3390/nu16071054.