The Gut Microbiome and its Impact on Neurological Health: A Systematic Review

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The Gut Microbiome and its Impact on Neurological Health: A Systematic Review

   

Karthik Chintharala1* , Salwa Asif2, Niharika Reddy3, Binay Kumar Panjiyar4 and Meghana Adusumilli1

1NRI Medical College & General Hospital-Guntur

2Department of Medicine, Faculty of Medicine, Tbilisi State Medical University

3Kasturba Medical College, Manipal

4GSCRT PGME Harvard Medical School, Research Fellow, Texas Tech University Health Sciences Center   

*Corresponding author: Karthik Chintharala, NRI Medical College & General Hospital-Guntur

Citation: Chintharala K, Asif S, Reddy N, Panjiyar BK, Adusumilli M. The Gut Microbiome and its Impact on Neurological Health: A Systematic Review. J Neurol Sci Res. 4(1):1-19.

Received: April 30, 2024 | Published: May 15, 2024

Copyright©️ 2024 genesis pub by Chintharala K, et al.CC BY-NC-ND 4.0 DEED. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non-Commercial-No Derivatives 4.0 International License. This allows others distribute, remix, tweak, and build upon the work, even commercially, as long as they credit the authors for the original creation.

Abstract

In recent years, neurological health has emerged as a leading global concern. Scientific studies have demonstrated that the gut microbiota plays a crucial role in this. Researchers now understand that the microbiota-gut-brain axis is critical for the formation and function of neurons and the pathogenesis of numerous neurological diseases. Thus, the significance of the gut-brain axis, mitochondrial and microglial dysbiosis, and their connection to neurological disorders is underscored by this systematic review. This paper further explains the bidirectional communication of signals between the gut to the brain, facilitated by mechanisms such as the vagus nerve, neurotransmitter formation, and the influence of short-chain fatty acids.

Keywords

Gut-Brain axis; Gut microbiome; Neurology; Gut microbiota

Introduction

In the human body, trillions of microbes reside that are assumed to influence and regulate the physiology of the host. The stomach and intestines (gastrointestinal tract or GIT) are where most microbes live, often called as gut microbiota. The GM is comprised of four major (Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria) and two minor phyla (Verrucomicrobia and Fusobacteria) [1].

Good gut bacteria exhibit several beneficial effects on the host in a healthy state, but studies show that a disease state can lead to the development of various neurological disorders [1].

The maturation and development of the human central nervous system (CNS) is regulated by both intrinsic and extrinsic factors [2]. It has been found that the gut microbiota plays an important role in several physiological processes, such as the maintenance of homeostasis, immunomodulation, and regulation of the central nervous system (CNS) and enteric nervous system (ENS). Dysbiosis of the gut microbial communities is particularly associated with a variety of neurological disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), autism spectrum disorder (ASD), and Major depressive disorder (MDD) [4]. Therefore, this systematic review provides insight into the involvement of GM and its impact on neurological health by analyzing the relationship between the GB axis and neurological abnormalities (Figure 1).

Figure 1:  Shows a two-way connection between the enteric system and the brain in both healthy and sick individuals, Illustrated by Asif S.

The relationship between gut and CNS is complex as well as bidirectional anatomically also labelled as GB axis cross-talking each other in both health and disease contexts [1, 16]. With the help of this crosstalk, gut sensory visceral signals are allowed to travel through the vagus nerve so it may regulate the reflex and mind/mood changes by impacting the CNS, which in turn will allow the brain to lead the signals so it gut physiology and other functions can be modulated.

The GM also communicates with the brain through the vagus nerve, impacting gut motility and pain perception [1]. Furthermore, the microbiota's production of neurotransmitters influences the activity of the ENS [1]. It is critical to comprehend the mechanisms by which GM impacts cognitive function. To illustrate the point, specific bacterial byproducts, like SCFAs, influence the maturation of specific T cells and the production of different cytokines. Aryl hydrocarbon receptors can be activated by some bacteria in the gut, which astrocytes can subsequently use to produce anti-inflammatory effects [5]. Lipopolysaccharides (LPS) can cause neuroinflammation after migrating from the stomach to the brain, further demonstrating the connection between the two systems. The amygdala is a site of neurogenesis, and alterations in the gut microbiota can impact the integrity of the blood-brain barrier [6]. The vagus nerve plays a crucial role in this intricate process, whether it's through direct connections or enteric cells that are related to hormones and endocrine systems [3]. Notably, metabolites like glutamate and serotonin, influenced by the GM, exert physiological effects in both the gut and the brain [5].

The GB axis relies on a network of afferent and efferent neurons, encompassing various pathways such as the ENS, autonomic nervous system (ANS), sympatho-adrenal axis, hypothalamic-pituitary-adrenal (HPA) axis, and descending monoaminergic pathways [3]. This network integrates as well as monitors gut functions, connecting both cognitive and emotional centres in the brain with intestinal functions, including immune responses,entero-endocrine signalling, intestinal permeability and enteric reflexes[7]. The influence of GM on microglia and neurogenesis within the hippocampus is also a subject of intense research [4]. Dysfunctions in microglia have been linked to various neurodevelopmental and neurodegenerative diseases, with SCFAs, immune cells, and the vagus nerve playing integral roles in this complex interplay [7].

Furthermore, the intricate interplay between mitochondria and the GM has profound implications for overall health. Interestingly, mitochondria produce reactive oxygen species (ROS) that can have beneficial effects on specific cells. The GM also plays an active role in this interplay, with commensal bacteria releasing peptides that activate ROS in gut epithelial cells, aiding in the maintenance of the gut barrier and triggering anti-inflammatory responses. Gut dysbiosis, oxidative stress, and neuroinflammation significantly contribute to various neurodegenerative and autoimmune diseases [8]. In addition, recent studies have shown that GM has a major impact on the side effects and efficacy of several medications, including psychotropics. Mood and personality can be impacted by genetically modified substances, which encompass both antibiotics and non-antibiotic medications [9]. Polypharmacy, the use of multiple drugs simultaneously, has been associated with a decline in microbial diversity. Medications for depressive symptoms, proton pump inhibitors, and antipsychotics are examples of drugs that fall within this category. The action of some psychiatric medications is impeded by specific bacterial strains [10]. As a result, there are treatments and preventative methods that, with a better understanding of these intricate relationships, could be effective.

Methods

Neuroscience clinical studies involving the gut microbiota are the subject of this review. The review not only complies with the guidelines for Meta-Analyses (PRISMA) for 2020 and Preferred Reporting Items for Systematic Review in (Figure 2) but exclusively relies on data acquired from published studies, thereby the need for ethical approval being eliminated.

Figure 2: Haddaway, N. R., Page, M. J., Pritchard, C. C., & McGuinness, L. A. (2022). PRISMA2020: An R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimized digital transparency and Open Synthesis Campbell System.

Methodical Literature Review and Study

As part of our systematic research evaluation and study selection process, we ran comprehensive research for pertinent publications using PubMed, which includes Google Scholar and Frontline. We used PubMed to find studies that were mentioned in editorials, commentaries, and review articles. Nonetheless, we persisted in seeking out further publications to fulfil our inclusion criteria. Using predetermined criteria, such as the presence of a well-described clinical cohort and the application of gut microbiota to neuroscience, we separately evaluated papers for inclusion in the study. Disagreements were settled through conversation after a review by three individuals.

Inclusion and Exclusion Criteria

A specific criteria was established to include and exclude participants so our study goal could be achieved. As briefed in (Table 1).

Inclusion Criteria

Exclusion Criteria

Human studies and Animal studies.

 

From 2013 to 2023

Only clinical data, no full text access

English Text

Non-English texts

Gender: All

 

Age: > 19 years of age

Age:<=19 years

Free papers

Papers that needed to be purchased

Free full texts

Paid papers

 

Studies involving clinical data other than neurological disorders

Table 1: Showing the criteria adopted during the literature search process.

Search Strategy

The PICO framework—which stands for "population," "intervention," "condition," and "control" or "comparison"—was utilized for this extensive literature review. Searches were conducted in databases such as PubMed and Google Scholar, among other Medical Libraries using terms relating to gut microbiota, gut microbiome, and neurological disorders. A comprehensive search strategy was devised using the medical subject heading (MeSH) approach for PubMed and Google Scholar, as outlined in Table (2). Thirteen papers were finalized.

PubMed

(((((((microbiome[gut microbiota on neurological health [Title/Abstract]) OR (gut microbiota on neurological disorders [Title/Abstract])) OR (gut microbiome on neurological disorders[Title/Abstract])) AND (("2013/01/01"[Date - Publication] : "2023/09/01"[Date - Publication]))) OR (gut microbiota[MeSH Terms])) OR (gastrointestinal MeSH Terms])) OR (neurological disorders[MeSH Terms])) OR (neuropsychiatric disorders[MeSH Terms])

29,08,930

 

Filter Applied: Clinical trials, meta-analyses, randomized controlled trials, systematic reviews, and associated data over the last decade are all available for free in this abstract. English, All people, Person: 19 and up

 

 

Papers deleted by finding duplicates and irrelevant articles

11,062

 

Selected papers

10

Google Scholar

gut microbiota on neurological health or gut microbiota on neurological disorders or gut microbiome on neurological disorders

61,000

 

Time range 2013-2023

18,500

 

from 1-10 pages of Google scholar

105

 

Selected papers

3

Table 2: Details the search process, including the keywords and engines used, as well as the total number of results shown.

Quality Appraisal Tools

To ensure the articles we selected were of high quality, we utilized a range of assessment tools. Utilizing the PRISMA protocol and the Cochrane method for bias evaluation for controlled clinical trials, we carried out our comprehensive Meta-analyses as well as reviews. Clinical trials that did not use random assignment were evaluated using the Newcastle-Ottawa methodology. We checked the thoroughness of qualitative studies using the Critical Appraisal Standards Program (CASP) rubric. We assessed the article's quality using the SANRA scale, so any room for interpretation in the classification could be avoided as indicated in (Table 3).

Quality Appraisal Tools Used

Type of Studies

Cochrane Bias Tool Assessment

Randomized Control Trials

Newcastle-Ottawa Tool

Non-RCT and Observational Studies

PRISMA Checklist

 Systematic Review

AMSTAR

Systematic Review

Table 3: Showing quality appraisal tools used.

Results

After searching through two selected databases, PubMed and Google Scholar, we extracted 2,969,930 articles. Following a rigorous evaluation, 2,940,361 publications were excluded based on specific criteria. 28,407 papers out of the remaining 29,569 were not chosen due to them having unsatisfactory titles, abstracts or duplicates. 1,162 papers were thoroughly examined whereas 1,149 were excluded as the inclusion criteria were not met. Lastly, the remaining 13 papers were run through a detailed quality check all of which not only included in our final systematic review but also met our criteria. The (Table 4). below provides a detailed description of each.

    Country

  Study Design

 Database Used

Conclusion

 

Korea

Database Highlights

PubMed

This article emphasizes the importance of metabolites generated from the gut as critical components that cross the blood-brain barrier, activate microglia, and trigger inflammatory immunological pathways once they reach the brain.

 
 

 Korea

Review

PubMed

This article discusses how the MGB axis controls biological networks that govern brain development and function, and whether or not the MGB axis has a role in neurological illnesses associated with the immune system.

 
 

 USA

Review

PubMed

This article delves into the idea that genetic modifications have a significant role in how the nervous system develops and functions, as well as in maintaining a healthy equilibrium between mental illness and wellness.

 
 

Spain

Systematic Review

PubMed

This systematic review explains the correlation between GM dysbiosis and neurological or neuropsychiatric disorders such depression, Alzheimer's disease, and Parkinson's disease. It examines the possible advantages of supplemental psychobiotics for certain diseases.

 

Belgium

Systematic Review

PubMed

Neurological diseases such as Alzheimer's, Parkinson's, MS, and ALS are associated with altered gut flora, according to this comprehensive research.

 
 

Portugal

Systematic Review

PubMed

In an effort to prove that dysbiosis affects CNS disorders or that diseases induce dysbiosis, this comprehensive review looked at how GM affected brain function.

 

  Iran

Comprehensive Review

PubMed

This article gives a thorough synopsis of the possible role of those who are GM in the development of neurological disorders.

 

 Korea

Review

PubMed

The effects of genetic modification (GM) on mitochondrial function and exercise performance, as well as their interaction, are covered in this article.

 
 

 Spain

 Review

PubMed

This article examines neurological disorders where changes in the GM have been reported, as well as the function of the GM in the GB axis.

 
 

  China

Systematic Review

Google Scholar

Key regions highlighted by the research include the MGB nexus and neuroinflammation.

 

 Malaysia

Systematic Review

Google Scholar

This research delves into the GB center and its impact on various elements of communication, including anatomy, metabolism, the immune system, and endocrine function. Immune functioning, mood, cognition, and mental wellness are impacted by this communication, which is facilitated by the ANS, HPA axis, and gastrointestinal nerves.

 

   USA

Database Highlights

PubMed

This article explores how microglia in the brain are influenced by the GM, impacting neurological disorders.

 
 

Table 4: Summary of the outcomes of the articles that were chosen. ALS stands for Amyotrophic Lateral Sclerosis, and CNS is an abbreviation for the Central Nervous System.

Discussion

There is growing evidence from clinical trials, epidemiological studies, and immunological investigations indicating that the microbiota in the intestines affects the gut-brain axis, which includes cognitive function, emotional control, neuromuscular tone, and hypothalamus-pituitary-adrenal axis regulation [19]. The autonomic nervous system, hypothalamic-pituitary-adrenal axis, and vagus nerve connect the brain to the gut, enabling the former to affect the latter's functions, such as the activity of functional immunological effector cells [19]. However, scientists are still trying to figure out how gut microbiota works, but they know that it affects the brain’s emotion and cognition centres and that changes in these areas' communication circuits are associated with gut microbiota variations [19]. As an example, there are now well-established connections between changes in the gut microbiota and functional gastrointestinal disturbances in several mood disorders, including depression, anxiety, and autism spectrum disorders [19]. Disruption of the blood-brain barrier, activation of microglial cell populations and astrocytes, and neuroinflammation can occur when microbiota in unhealthy states produce more inflammatory cytokines, lipopolysaccharides, and T and B cells while decreasing the quantity of short-chain fatty acids [1]. Therefore, there is mounting evidence that changes in the makeup of gut bacteria may impact cerebral processes and vice versa, as a result of the two-way link [21].

Based on the connections between gut microbiota and neuronal function as well as cerebral processes, experimental and clinical data point to the intestinal microbiota as an essential component of the gut-brain axis. The cells of the intestinal tract and the enteric nervous system are local targets of its effects, but it also has direct communication with the central nervous system via endocrinology and metabolic pathways linked to memory, anxiety, and stress [7]. Crucially, the vagus nerve is the primary modulatory constitutive channel that links the brain to the microbiota, and it is involved in this communication [22]. The gut-brain axis is modulated by microbiota, which in turn, affects gut motility and pain perception by regulating afferent sensory nerves and increasing their excitability by blocking calcium-dependent potassium channels [23].

Expanding on the vast influence of bacteria on the enteric nervous system, their effect extends to the production of neurotransmitters, including acetylcholine, serotonin, melatonin, histamine, and gamma-aminobutyric acid [24]. An effective form of catecholamines is also generated in the gut lumen by these microbial populations [25]. Key bacterial metabolites, including butyric acid, propionic acid and acetic acid, impact memory and learning processes, stimulate the parasympathetic nervous system and influence the gut-brain axis via their metabolic byproducts and short-chain fatty acids (SCFAs) [26], [27]. The intestinal immune system’s impacts on the gut microbiota's ability to regulate the activity of the enteric nervous system is discussed in (Figure 3).