Over the last decades, the scientific research focus has been shifted to finding the connection between gut bacteria and brain health. The gut-brain axis connects the gastrointestinal tract (GIT) to the central nervous system (CNS), and this axis plays a critical role in neurodevelopment, mental health, and neurodegenerative disorders. The trillions of microorganisms present in the gut help to promote the health of both the digestive and nervous systems. Dysbiosis can lead to mental health disorders such as depression, anxiety, and neurodegenerative diseases like Alzheimer’s and Parkinson’s. In this review, methodologies used to provide valuable insights into how gut bacteria impact brain health are also included. It also emphasizes the therapeutic potential of probiotics, prebiotics, personalized treatment, and dietary modifications to maintain mental and neurological health. However, there are still issues to be resolved, such as the need for longitudinal studies, standardized research procedures, and an in-depth understanding of the mechanisms. The researcher should focus more on understanding the gut-brain axis and its utilization and finding therapeutic potential for medical breakthroughs in the treatment of various neurological disorders. This review emphasizes the importance of preserving a balanced gut microbiome for optimum brain health and identifies current research gaps and suggests future directions.

Gut-brain axis, Gut microbiota, Mental health, Neurodevelopment, Neurodegenerative diseases, Probiotics, Neurotransmitters.

The gut-brain axis is a complex and dynamic communication network connecting the GIT with the CNS. All neurological, hormonal, and immunological processes are influenced by the gut microbiota. Recent studies showed that the gut microbes are essential for physiological functions such as behavior and brain health [1,2]. Another research finding showed that gut microbes play a key role in modifying mental health conditions, the development of the brain, and slowing down neurodegenerative disorders [3,4].

Figure 1: Illustrative diagram depicts the bidirectional connection between the gut and brain through the vagal neuronal pathway.

The proposed bidirectional communication shows the hypothalamic-pituitary-adrenal (HPA) axis influencing the gut microbiota, which in turn stimulates the brain through neuropeptides, neurotransmitters, bacterial secretions, and metabolites.

The proper understanding of the gut-brain axis aids in developing possible therapeutic interventions for the treatment of brain diseases. Disorders such as depression, anxiety, stress, autism, Alzheimer’s, and Parkinson’s are linked to the imbalance in the gut microbiota [5,6]. The mechanisms by which gut microbes impact brain function are studied through germ-free animal models, clinical trials, and sequencing technologies. For instance, the analysis of specific microbial groups associated with mental health outcomes is done by utilizing 16S Ribosomal ribonucleic acid (rRNA) sequencing and metagenomics [7]. The causal effects of gut microbiota on brain development and behavior are demonstrated by using germ-free models [3,4]. Clinical trials have further highlighted the possibility of treating depression and anxiety through modifications in the gut microbiota [8].

The aim of this review is to reveal the connection between the gut and brain and to explore future research directions to find out the therapeutic potential of the gut microbiota. A detailed understanding of the gut microbiota and its influences on overall brain health could help in developing effective therapeutic strategies for myriad of neurological disorders.

Table 1: Key Mechanisms of Gut-Brain Communication

Key Concepts and Theories
Microbiota and Neurodevelopment: Research conducted using Germ-free animal models has illustrated a notable change in brain structure and behavior in the absence of gut microbiota during early life. A study conducted by Heijtz et al. [3] and Sampson & Mazmanian [4] has shown that conventionally raised mice have better neural development and behavioral patterns as compared to germ-free mice. These findings emphasize the influence of gut microbes on the developmental process of the brain through neurotransmitter production and immune system modulation.

Microbiota and Mental Health: There is strong proof of linkage between the composition of gut microbes and mental disorders such as depression and anxiety. Research conducted by Cryan & Dinan [1] and Kelly et al. [9] has shown neuroactive substances like serotonin and GABA are produced by gut microbes, and these substances regulate the mood and emotional responses. The increased susceptibility to psychiatric disorders has been associated with dysbiosis, or an imbalance in gut microbiota composition. A clinical trial conducted by Romijn et al. [8] demonstrated that probiotics can improve mood and reduce symptoms of depression. These findings highlight that the treatment of mental disorders can be done by modifying gut microbes.

Microbiota and Neurodegenerative Diseases: The neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, have been associated with imbalances in the gut microbiota. The neuronal inflammation, protein aggregation, and neuronal damage are associated with specific bacterial strains and microbial metabolites [6,10]. Scheperjans et al. [6] compared the gut microbiota composition between healthy controls and Parkinson’s disease patients and concluded that there is a difference in composition of the gut microbiota between these individuals and suggested a potential role of the microbiota in disease susceptibility. According to Agahi et al. [11], probiotics improve cognitive function in individuals with mild cognitive impairment. A study has suggested that the ecological balance of gut flora regulates neurotropic factor expression. It has also been shown that gut flora is involved in regulating the microbiota-gut-brain (MGB) axis and suppressing inflammation [20].

Table 2: Gut microbiota composition in patients with Alzheimer’s disease

Gut Microbiota and Brain-Gut Interactions: Collins et al. [13] reviewed the effects of the gut microbiome on brain-gut interactions, highlighting bidirectional interactions and suggesting that dysbiosis may contribute to the development of mental illness, including depression and anxiety.

Gut Microbiota’s Role in Anxiety and Mood Disorders: According to Bercik et al., gut microbiota can influence behavior in mice, suggesting that bacterial infections can induce anxiety-like behaviors, which can be reversed by antibiotic treatment [14].

Probiotics and Neuroplasticity: Neufeld et al. determined that Bifidobacterium longum, a probiotic, decreased anxiety-like behavior in mice and normalized brain-derived neurotrophic factor (BDNF) levels inside the hippocampus, indicating a connection between gut microbiota and neuroplasticity [15].

Gut Microbiota and Stress Regulation: Sudo et al. demonstrated that colonization of the gut with specific bacterial strains can modulate the body’s stress response. It suggests that to maintain a balanced HPA axis, a healthy gut microbiome is essential [16].

Probiotics and Mental Health: Research has shown that probiotics can improve mental health. A study by Bravo et al. [17] found that long-term treatment with Lactobacillus rhamnosus, a probiotic, reduced anxiety and depression-like behavior in mice by influencing GABA receptor expression in the brain. Similarly, Forsythe et al. [18] found that probiotics could attenuate inflammation and behavioral modifications induced by early life stress in animal models, suggesting that probiotics may also offer a promising healing pathway for treating mood disorders.

Gut Microbiota and Cognitive Function: The gut microbiota plays a significant role in cognitive function. Gareau et al. [19] observed that postnatal colonization of germ-free mice with gut microbiota from control animals has shown improvement in cognitive function and reduced anxiety-like behavior. This result indicates that a healthy gut microbiome is important for emotional regulation and cognitive development, and functioning.

Instruments and Methods
Germ-free (GF) Animal Models: GF models enable researchers to introduce specific microbes and examine their physiological and psychological effects. Research conducted by Heijtz et al. [3] has demonstrated that the conventionally raised mice have normal brain development and behavior as compared to germ-free mice. When these GF mice are introduced to a normal gut microbiota, their behavior is also normalized. Hence, this research suggests the importance of microbiota in the development of the brain and behavior. Sampson et al. [4] revealed that the introduction of microbiota from Parkinson’s disease patients into GF mice has developed motor deficits and neuroinflammation, concluding the role of microbiota in disease pathology. The impact of gut microbiota from depressed patients on GF rats was studied by Kelly et al. [9] who highlighted that GF rats showed depression-like behavior and suggested the direct influence of microbiota on mental health.

Fecal Microbiota Transplantation (FMT): FMT is a method of transferring the gut microbiota of a healthy donor to a recipient. Research carried out by Kang et al. [12] showed that autism spectrum disorder (ASD) is treatable. They observed an improvement in gastrointestinal symptoms and behavioral outcomes following transplantation in ASD patients. The study’s purpose is to establish the effectiveness of FMT in treating ASD symptoms. They suggest that FMT will also be beneficial for the treatment of other mental problems like depression, anxiety, and Parkinson’s.

Clinical Trials with Probiotics and Prebiotics: Recent clinical trials have demonstrated the benefit of probiotics and prebiotics in the treatment of depression and anxiety. Romijn et al. [8] conducted a controlled clinical trial to assess the efficacy of probiotics on depression and anxiety. The depression patients were administered probiotics containing Lactobacillus rhamnosus HN001 and Bifidobacterium lactis HN019. They found that symptoms of depression and anxiety decreased as compared to the placebo group. It is also observed that probiotics have anti-inflammatory and stress-reducing effects.

Sequencing Technologies: With the advancement in technologies, the study of gut microbiota to get insight into microbial diversity, their stability, and metabolic capabilities has become easier. The advanced sequencing technologies, such as 16S rRNA sequencing and metagenomics, are used for detailed examination of gut microbes. Valles-Colomer et al. [7] found that specific microbial species were associated with depression by utilizing metagenomic sequencing technologies. They also uncovered functional pathways related to neurotransmitter metabolism and inflammation through which gut microbes impact mental health.

Neuroimaging Assessments: The impact of the gut microbiota on brain structure and function is better understood with the utilization of neuroimaging techniques such as Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) scan. The proper investigation of the gut-brain axis requires advanced techniques, such as neuroimaging. Kelly et al. [9] used a neuroimaging technique and found that regions associated with mood regulation were impacted by changes in gut microbial composition.

Table 3: Key Findings and Methodology

Applications and Implications
Probiotics and Prebiotics: Promising treatments for brain health because they alter gut microbiota composition and alleviate symptoms of mental and neurological illnesses. Clinical trials have demonstrated that probiotic supplementation with strains can alleviate depression and anxiety symptoms. Prebiotics, which are present in fruits, vegetables, and whole grains, encourage the growth of healthy gut bacteria, improving overall gut health and indirectly enhancing brain function.

Dietary Treatments: Such as fiber-rich meals, fermented foods, and polyphenol-rich sources like green tea and berries have all been linked to a diverse and beneficial gut flora. These components act as substrates for microbial fermentation in the gut, creating metabolites such as Short-chain fatty acids (SCFAs) that have anti-inflammatory and neuroprotective properties.

Figure 2: Microbiota-targeting therapies and influencing factors

Traditional Chinese medicine (TCM): Treatments regulate the gut microbiota and are increasingly applied in clinical practice. Studies have demonstrated that traditional Chinese medicine modulates gut microbiota function and composition, benefiting overall brain health.

Table 3: TCM and its impact on gut microbiota and cognitive function

Weaknesses and Gaps in Research
Lack of Longitudinal Studies: Longitudinal studies are important to understand the relationship between gut bacteria and brain health because they track microbial changes over time and how they affect brain function. These studies contribute to the understanding of microbial dynamics throughout the life cycle and establish causal relationships.

Heterogeneity in Study Designs: Differences in study design, such as number of participants, sample size, and methods used to assess microbial composition, contribute to the diversity of study findings. Sample collection, methods, sequencing, and data analysis design standards are needed to ensure reproducibility and robustness in microbiological studies by addressing methodological inconsistencies and systematic review and weakening that evidence, and to elucidate the impact of gut microbiota on specific neurological conditions [1].

Mechanistic Understanding: Although links between the gut microbiota and brain health have been established, the mechanisms underlying these interactions are poorly understood. Mechanistic studies are needed to explain how metabolites are derived from microbial, immune, and neural signaling pathways and affect brain function and behavior. Advanced approaches such as microbiome metabolism and neuroimaging combined with genetic manipulation in animal models may provide mechanistic insights into the causal relationship between the gut microbiota and neurodegenerative disease [4].

Translation from Animal Models to Human Applications: Translation of findings from animal studies to human clinical applications represents a major challenge for microbiota research. While animal models, especially germ-free models, provide valuable insights into basic mechanisms, the human microbiome and environment are highly diverse and thus require rigorous clinical trials with well-defined patient cohorts to validate preclinical findings and evaluate the efficacy of microbiota-targeted interventions in larger populations. Establishing compelling evidence from human research can be essential for directing healthcare practices and regulatory decisions regarding microbiota-based treatment plans.

Future Trends and Challenges
Advanced Sequencing and Bioinformatics: The advancement of sequencing technologies, combined with advanced bioinformatics tools, will help to revolutionize our knowledge of microbiota composition and characteristics in relation to brain health. High-throughput sequencing techniques, together with metagenomics and transcriptomics, allow complete profiling of microbial communities and their genetic capabilities.

Translating Preclinical Findings: Translating findings from preclinical models to clinical applications represents a major challenge in microbiota research. Although animal studies provide fundamental insights into microbiota-brain interactions, species-specific differences in gut microbiota composition and immune response require caution while translating the interpretation in a human context. Future efforts should prioritize large, multicenter clinical trials with diverse patient populations to confirm preclinical findings and assess safety, efficacy, and the long-term effects of microbiome-based interventions.

Ethical and Regulatory Considerations: The implementation of microbiota-based therapies increases ethical considerations concerning consent, privacy, and the potential for accidental consequences. Agahi et al. [11] emphasized the need for effective oversight and strong regulatory frameworks to minimize the risks associated with microbial therapies, build public confidence, and facilitate accurate access to emerging therapies.

This review article on the gut-brain axis revealed profound links between gut bacteria and brain health. Utilization of technologies such as advanced sequencing, and neuroimaging techniques helps to understand in-depth gut microbiota composition and its relation to various neurological disorders. Extensive research took place to show that changes in the gut microbiota could affect cognitive functioning, psychological distress, and neurodevelopmental conditions. Clinical trials and studies have provided compelling evidence for the therapeutic potential of probiotics and dietary intervention to alter the gut microbiota to improve gastrointestinal symptoms, behavioral outcomes, and mental health. Advances in neuroimaging, such as MRI and PET scans, allow researchers to understand how microbial changes in the gut could impact brain structure and function. Future research should delve into the development of microbiota-based therapies for the treatment of brain-related disorders and to enhance the overall mental health of the individual.

First, we acknowledge the authors and researchers whose work has laid the foundation for this review. We express our gratitude for their contribution in the medical field and for playing a key role in advancing the understanding of the gut microbiota and its role in mental health. We would like to thank all contributors who supported completing this review article.

Lastly, we are grateful to our institution, mentors, colleagues, families, and friends for their unwavering support and encouragement. With their invaluable assistance only, we have successfully completed this endeavor.

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Corresponding Author:
Sannu Ahmed
Department of Pharmacy
National Academy for Medical Sciences, Old Baneshwor, Kathmandu, Nepal
Email: pr.sannu.ahmed@gmail.com

Co-Author:
Pradip Regmi
Department of Pharmacy
Nepal Institute of Health Sciences, Jorpati, Kathmandu, Nepal

All authors contributed to the conceptualization, investigation, and data curation by acquiring and critically reviewing the selected articles. They were collectively involved in the writing – original draft preparation, and writing – review & editing to refine the manuscript. Additionally, all authors participated in the supervision of the work, ensuring accuracy and completeness. The final manuscript was approved by all named authors for submission to the journal.

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https://doi.org/10.63096/medtigo3062236

Sannu A, Pradip R. Advancements in Gut Microbiota Research: A Critical Review. medtigo J Med. 2024;2(3):e3062236. doi:10.63096/medtigo3062236 Crossref