The gut–brain axis in neurodegenerative disorders: Evaluating the therapeutic potential of probiotic and fecal microbiota transplantation

The gut–brain axis in neurodegenerative disorders: Evaluating the therapeutic potential of probiotic and fecal microbiota transplantation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review The gut–brain axis in neurodegenerative disorders: Evaluating the therapeutic potential of probiotic and fecal microbiota transplantation Bhaskar Jyoti Sharma This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7608549/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : The gut-brain axis (GBA) is a two-way communication mechanism that links the enteric nervous system and the central nervous system. Studies suggest that dysbiosis in the gut microbiota has a role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Objective: This review aims to synthesize current studies on the impact of the gut-brain axis (GBA) on neurodegeneration and to evaluate the therapeutic potential of therapies aimed at microbiota, including probiotics and fecal microbiota transplantation (FMT). Methods : A comprehensive literature analysis was conducted utilizing the PubMed, Scopus, and Web of Science databases to ascertain pertinent preclinical and clinical research published between 2010 to 2024. Results : These findings suggest that dysbiosis in the gut microbiota may initiate neuroinflammation and aberrant protein folding, hence undermining the integrity of the blood-brain barrier. While probiotic research has shown moderate enhancements in cognitive metrics, fecal microbiota transplantation (FMT) presents a more extensive, yet little investigated, approach to altering gut microbiome composition and potentially impacting disease progression. Conclusion : Interventions aimed at the intestinal microbiota present significant novel therapeutic pathways for the management of neurodegenerative disorders. Nonetheless, it is imperative to conduct comprehensive, meticulously designed clinical studies to validate therapeutic efficacy, establish uniform treatment procedures, and guarantee patient safety over prolonged durations. Cognitive Neuroscience Gut–Brain Axis Neurodegeneration Microbiome Probiotics Fecal Microbiota Transplantation Figures Figure 1 1. Introduction Neurodegenerative disorders (NDs), such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), are rapidly emerging as significant global public health crises. These illnesses include loss of neural structure and function after a Neurodegenerative disorders (NDs), such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), are rapidly emerging as significant global public health crises. These illnesses include loss of neural structure and function after a few days, along with problems with movement, severe cognitive impairment, or a big drop in quality of life. The World Health Organization says that by 2050, 139 million people around the world will have dementia, mostly because of Alzheimer's disease. This is a big problem for health care systems all across the world. ² Furthermore, the incidence of Parkinson's Disease has more than doubled in the past generation, underscoring the critical necessity for effective therapy frameworks. ³ Pathogenic neurodegenerative syndromes arise from a confluence of variables, including hereditary genetic predisposition, senescence of the brain system, environmental exposure, and protein misfolding. ⁴ Over the last few decades, scientific research and pharmaceutical efforts have predominantly concentrated on the central nervous system (CNS), aiming to develop therapy alternatives that alleviate symptoms without disrupting or reversing the disease's progression. This constraint has necessitated a re-evaluation of neuroscience, prompting researchers to explore biological processes that may contribute to neurodegeneration. In this setting, the gut-brain axis has garnered unprecedented interest in contemporary science. This axis serves as a multifaceted bidirectional communication conduit linking the emotional and cognitive regions of the brain with peripheral intestine processes around the body. 7 These interactions are facilitated by several pathways: neural pathways (mainly via the vagus nerve), humoral pathways (such as the hypothalamic–pituitary–adrenal system and enteric hormone-related pathways), immune communication pathways (mediated by cytokines and chemokines), and metabolic cooperation pathways (involving products produced by microorganisms). 8 GBA functioning is all about the gut microbiome, which is a huge ecosystem of trillions of microorganisms, such as bacteria, viruses, and fungus, that are all very different from each other. 9 This microbiota does not just live in the host without doing anything; it actively helps keep homeostasis in the host. The microbiota affects how the brain grows, how people act, and how they deal with stress by controlling the immune system, making neuroactive substances like serotonin and γ-aminobutyric acid (GABA), and making important metabolites like short-chain fatty acids (SCFAs). Homeostasis, also known as eubiosis, is essential for proper functioning, whereas changes in microbial composition (dysbiosis) are increasingly associated with the pathophysiology of several neurological illnesses. ¹²,¹³ Despite substantial relevant research, an issue remains to be addressed: the existing medication treatments for AD (such as acetylcholinesterase inhibitors) and PD (such as levodopa) are mainly employed as palliatives for ameliorating symptoms rather than for interfering with basic disease mediators. ⁵,¹⁴ These substantial therapy limitations underscore the urgent need for innovative, disease-modifying strategies that facilitate intervention at the first phases of the illness trajectory. In this review, we aim to present a comprehensive analysis of the growing evidence that associates disturbances in the gut microbiome with the etiology of primary neurodegenerative illnesses, including Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to critically evaluate the increasing preclinical and clinical evidence supporting two proposed therapeutic strategies targeting the microbiota: probiotics, defined as viable beneficial bacterial organisms, and fecal microbiota transplantation (FMT), a procedure involving the transfer of entire microbial ecosystems from healthy individuals. This review seeks to elucidate the possible therapeutic advantages of gut microbiota manipulations in mitigating or treating neurodegeneration, based on the provided information.few days, along with problems with movement, severe cognitive impairment, or a big drop in quality of life. The World Health Organization says that by 2050, 139 million people around the world will have dementia, mostly because of Alzheimer's disease. This is a big problem for health care systems all across the world. ² Furthermore, the incidence of Parkinson's Disease has more than doubled in the past generation, underscoring the critical necessity for effective therapy frameworks. ³ Pathogenic neurodegenerative syndromes arise from a confluence of variables, including hereditary genetic predisposition, senescence of the brain system, environmental exposure, and protein misfolding. ⁴ Over the last few decades, scientific research and pharmaceutical efforts have predominantly concentrated on the central nervous system (CNS), aiming to develop therapy alternatives that alleviate symptoms without disrupting or reversing the disease's progression. This constraint has necessitated a re-evaluation of neuroscience, prompting researchers to explore biological processes that may contribute to neurodegeneration. In this setting, the gut-brain axis has garnered unprecedented interest in contemporary science. This axis serves as a multifaceted bidirectional communication conduit linking the emotional and cognitive regions of the brain with peripheral intestine processes around the body. 7 These interactions are facilitated by several pathways: neural pathways (mainly via the vagus nerve), humoral pathways (such as the hypothalamic–pituitary–adrenal system and enteric hormone-related pathways), immune communication pathways (mediated by cytokines and chemokines), and metabolic cooperation pathways (involving products produced by microorganisms). 8 GBA functioning is all about the gut microbiome, which is a huge ecosystem of trillions of microorganisms, such as bacteria, viruses, and fungus, that are all very different from each other. 9 This microbiota does not just live in the host without doing anything; it actively helps keep homeostasis in the host. The microbiota affects how the brain grows, how people act, and how they deal with stress by controlling the immune system, making neuroactive substances like serotonin and γ-aminobutyric acid (GABA), and making important metabolites like short-chain fatty acids (SCFAs). Homeostasis, also known as eubiosis, is essential for proper functioning, whereas changes in microbial composition (dysbiosis) are increasingly associated with the pathophysiology of several neurological illnesses. ¹²,¹³ Despite substantial relevant research, an issue remains to be addressed: the existing medication treatments for AD (such as acetylcholinesterase inhibitors) and PD (such as levodopa) are mainly employed as palliatives for ameliorating symptoms rather than for interfering with basic disease mediators. ⁵,¹⁴ These substantial therapy limitations underscore the urgent need for innovative, disease-modifying strategies that facilitate intervention at the first phases of the illness trajectory. In this review, we aim to present a comprehensive analysis of the growing evidence that associates disturbances in the gut microbiome with the etiology of primary neurodegenerative illnesses, including Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to critically evaluate the increasing preclinical and clinical evidence supporting two proposed therapeutic strategies targeting the microbiota: probiotics, defined as viable beneficial bacterial organisms, and fecal microbiota transplantation (FMT), a procedure involving the transfer of entire microbial ecosystems from healthy individuals. This review seeks to elucidate the possible therapeutic advantages of gut microbiota manipulations in mitigating or treating neurodegeneration, based on the provided information. 2. Materials and methods 2.1 Literature search methodology A comprehensive literature analysis was performed to locate all published papers concerning gut-brain/microbiome/ND/probiotic/FT protocols. The digital bibliographic databases utilized comprised PubMed, Scopus, and the Web of Science Core Collection. The study's scope was confined to material indexed from January 1, 2010, to May 31, 2024, to represent the latest advancements in this swiftly developing academic domain. 2.2 Search Keywords The search method included a mix of Medical Subject Headings (MeSH) and unstructured phrases that covered the main themes discussed in this review. We employed Boolean logic operators ("AND," "OR") to search for the terms directly in the databases and combine them. This made the search results more precise. The main search equation was: ("gut-brain axis" OR "microbiome" OR "microbiota" OR "gut flora") AND ("neurodegeneration" OR "neurodegenerative disease" OR "Alzheimer" OR "Parkinson" OR "dementia") AND ("probiotic" OR "fecal microbiota transplantation" OR "FMT" OR "microbial therapy") This formula was changed to fit the different ways that each database outputs data. We also manually searched the bibliographies of the review articles we found to find any other relevant studies that the first automated database search didn't find. 2.3 Inclusion and Exclusion Criteria • Inclusion criteria: (i) Original research article (including animal studies); (ii) review of research and statistical analysis of more than one study; (iii) research paper published in English; (iv) studies published to date focusing on biological mechanisms linking the gut microbiota and AD or PD; (v) studies focusing on the benefits of good bacteria, prebiotic compounds, combinations of probiotic prebiotic supplements, and the treatment potential of microbiota transplantation procedures for the treatment of neurodegenerative disorders. • Exclusion criteria: i) was composed in a non-English language; ii) presented an opinion, meeting summary, correspondence to the editor, or book chapter; iii) focused on brain degenerative diseases other than Alzheimer's Disease (AD) and Parkinson's Disease (PD), lacking a distinct comparative analysis; and iv) involved a research paper with an incomplete manuscript. 2.4 Data Extraction and Synthesis The titles and abstracts of all potentially discovered records were initially evaluated according to predetermined inclusion and exclusion criteria. The whole texts of potentially pertinent publications were later obtained and thoroughly examined. The data obtained from the chosen papers were compiled in a standardized format, encompassing investigator(s) information, year of publication, study design (in vitro, in vivo, or clinical), sample characteristics, intervention details, essential methodological aspects, and principal findings. A meta-analysis was unfeasible due to the diverse nature of the research, which spanned from fundamental animal mechanistic studies to clinical investigations including people. Consequently, the collected data underwent theme analysis. The results were arranged in a way that made sense: gut-brain channels of communication, proof of dysbiosis in certain disorders, and the effects of therapies that build up in a systematic and analytical look at the whole study landscape. 3. Results 3.1 The gut–brain axis: the key pathways of communication There are many ways for the gut and brain to talk to each other in both directions. The vagus nerve is in charge of much of the neural tract. It connects the enteric nervous system to the brainstem. Laboratory research has shown that cutting the vagus nerve can stop some probiotics from changing the brain and make Parkinson's disease in animals less severe, showing how important it is. The neuroendocrine pathway is facilitated by the hypothalamic-pituitary-adrenal (HPA) axis. Gut microorganisms can swiftly change the HPA axis, which can also change cortisol, which is a main product of the HPA axis and a critical stress hormone that can have big effects on brain function and make neuroinflammation worse when it goes wrong. ¹⁷ The immune system pathway is a significant way that an imbalance in the gut microbiota can make the intestinal wall more permeable, which is known as "leaky gut." This lets bacterial lipopolysaccharides (LPS) and other inflammatory substances into the circulation. This process causes the brain's immune cells, called microglia, to make cytokines including IL-1β, TNF-α, and IL-6. These cytokines can cross the BBB. ¹⁸ The metabolic pathway uses substances that gut microorganisms make. Short-chain fatty acids (SCFAs), including butyrate, propionate, and acetate, generated during dietary fiber fermentation, can traverse the blood–brain barrier and provide neuroprotective, anti-inflammatory, and epigenetic benefits. The gut microbiota also makes a lot of neuroactive chemicals, such as gamma-aminobutyric acid (GABA), serotonin, and dopamine, that could affect how the gut communicates with the central nervous system. ²⁰ 3.2 Imbalance of the gut microbiota in Alzheimer’s disease and Parkinson’s disease: Studies indicate that individuals with Alzheimer's disease (AD) and Parkinson's disease (PD) exhibit markedly distinct gut microbiota compositions compared to healthy individuals of comparable ages. There are certain basic patterns that have come out of the investigations, even though the precise microbial profiles differ depending on the location, eating habits, and study methods used. ²¹ For instance, individuals with Alzheimer’s disease typically display diminished bacterial diversity within their gut microbiome. Research has consistently demonstrated the reduction of bacteria that synthesize short-chain fatty acids (SCFAs), including Faecalibacterium prausnitzii , Eubacterium rectale , and many species within the Lachnospiraceae family. 22 Furthermore, bacterial groups that cause inflammation, including Escherichia/Shigella and Bacteroidetes, usually show a tendency that is opposite to the one that causes inflammation. ²³ Individuals with Parkinson's disease also display microbiome disturbances. Prior research has consistently shown a diminished prevalence of the Prevotellaceae genus, which plays a role in mucin breakdown and the maturation of Th17 cells24. Patients usually have more of the Enterobacteriaceae family of bacteria, and the more of these bacteria there are, the worse their balance problems and trouble walking are. ²⁵ Researchers have also discovered that the concentration of Akkermansia muciniphila , a mucin-degrading bacterium that may be related with poor intestinal barrier function, is larger in PSC patients. ²⁶ Table 1 shows a side-by-side comparison of the typical changes in microbes seen in people with AD and PD. Table 1 Characteristic gut microbiota alterations in Alzheimer's disease and Parkinson's disease Taxonomic Classification Alteration in AD Alteration in PD Suggested Functional Impact References Firmicutes/Bacteroidetes proportion Reduced/Inconsistent findings Reduced Broad marker of microbial imbalance 51,52,53 Faecalibacterium prausnitzii Reduced Reduced (Frequently) Diminished anti-inflammatory SCFA (Butyrate) synthesis 51,53,54,55 Eubacterium rectale Reduced - Lowered SCFA synthesis 54 Lachnospiraceae Reduced - Decreased SCFA synthesis 51,54 Prevotellaceae - Reduced Compromised mucin structure, modified immune function 53,56 Enterobacteriaceae Elevated Elevated Enhanced inflammation, LPS synthesis 52,53,56 Escherichia/Shigella Elevated - Enhanced inflammation, LPS synthesis 52 Akkermansia muciniphila - Elevated Enhanced mucin breakdown, possible connection to membrane permeability 53,57 Bifidobacterium Reduced (Frequently) Inconsistent findings Diminished beneficial resident bacteria 51,52,55 Bacteroides Elevated (Frequently) Inconsistent findings Situation-dependent inflammatory/anti-inflammatory function 52,55 3.3 Mechanisms linking dysbiosis to neurodegeneration: Parallel dysbiosis in neurodegenerative illnesses transcends mere correlations, establishing mechanistic connections with disease pathology through networks of interrelated pathways. Chronic brain inflammation is a key feature of this process. When the balance of microorganisms is off, the levels of LPS and other pathogen-associated molecular patterns (PAMPs) in the blood rise. This activates Toll-like receptors (TLRs) on microglia. This activation creates a long-lasting proinflammatory milieu that causes cytokines to be released, which hurt nerve cells and stop new nerve cells from forming. ²⁷ Microbial dysbiosis may also facilitate the aggregation of pathogenic proteins. Inflammatory signals from the gut may boost brain kinases that add too many phosphate groups to tau protein, which is a critical part of Alzheimer's disease. In Parkinson's disease (PD), gut inflammation triggers a process that leads to the misfolding of alpha-synuclein (α-syn) in the enteric nervous system, potentially propagating into the brain through the vagus nerve in a prion-like fashion. ²⁹ Oxidative and mitochondrial damage have been suggested as additional primary consequences. Changes in the gut microflora may change the creation of metabolites, which could then change how mitochondria work. Inflammation that spreads throughout the body makes reactive oxygen species (ROS), which can then cause neuronal degeneration. ³⁰ Lastly, dysbiosis could damage the gut and blood-brain barriers' structural integrity. When the gut barrier is compromised, bacterial byproducts infiltrate the bloodstream, disrupting the integrity of the blood-brain barrier. This facilitates the entry of harmful chemicals and immune cells into the brain, hence worsening neuroinflammation. Figure 1 shows a conceptual diagram that shows how various mechanisms are related 31 .A conceptual diagram illustrating these interconnected mechanisms is presented in Fig. 1 . 3.4 Probiotics: preclinical and clinical evidence Numerous preclinical investigations utilizing mouse models of Alzheimer's disease and Parkinson's disease have exhibited beneficial outcomes associated with probiotic administration. Transgenic AD model mice experiments showed that a multispecies probiotic mixture (made up of Lactobacillus and Bifidobacterium species) improved memory and learning tasks and lowered the levels of amyloid-beta plaques and inflammatory cytokines in the brain. 3² Likewise, in PD model mice, the injection of probiotics alleviates motor insufficiency symptoms while safeguarding DAT neurons and downregulating α-synuclein expression, frequently resulting in the restoration of gut barrier functioning. ³³ The findings from human studies are more accessible compared to other investigations, although the evidence remains promising. Numerous randomized controlled trials have predominantly involved participants with Alzheimer's disease and/or mild cognitive impairment. These publications typically report substantial improvements in cognitive diagnostic scores (e.g., MMSE) in those administered probiotics relative to those in the placebo groups. ³⁴ Additionally, numerous studies have indicated the advantageous impacts of metabolic indicators, including reduced inflammation (e.g., CRP and TNF-α), enhanced antioxidant status (e.g., GSH), and improved lipid profiles. However, some RCTs have shown little or no effect on primary cognitive outcomes. This is because the studies were set up differently, used different strains of bacteria, and had different doses and lengths of time for the intervention.³⁶ Table 2 shows the design and main results of some clinical trials that looked into probiotics for neurodegenerative disorders.³⁶ Table 2 summarizes the design and key outcomes of selected clinical trials investigating probiotics in neurodegenerative disorders. Table 2 Summary of selected clinical trials on probiotics in neurodegenerative disorders Source Patient Group Study Type & Length Treatment Primary Results Akbari et al. (2016)³⁴ 60 individuals with AD Randomized controlled trial, 12 weeks Four-strain probiotic blend: Lactobacillus acidophilus , L. casei, B. bifidum, L. fermentum (20 billion CFU daily) Notable enhancement in MMSE scores. Decreased MDA levels, elevated GSH levels, CRP changes were not statistically significant. Tamtaji et al. (2019)³⁵ 60 individuals with AD Randomized controlled trial, 12 weeks Selenium-enriched probiotic containing L. acidophilus , B. lactis, S. cerevisiae Enhanced MMSE performance and cognitive assessment results. Decreased insulin resistance and inflammatory markers. Agahi et al. (2018)³⁷ 72 individuals with PD Randomized controlled trial, 12 weeks Four-strain probiotic combination: L. acidophilus , L. reuteri, B. bifidum, L. fermentum (20 billion CFU daily) UPDRS scores showed no meaningful changes. Enhanced frequency of bowel movements observed. Ibrahim et al. (2023)³⁸ 45 individuals with PD Randomized controlled trial, 3 months Three-strain probiotic: Streptococcus thermophilus, L. delbrueckii, B. lactis Minor improvements in non motor manifestations including constipation relief and life quality enhancement. Motor function scores remained unchanged. Akbari et al. (2016)³⁴ 60 AD patients RCT, 12 weeks Lactobacillus acidophilus , L. casei , B. bifidum , L. fermentum (200亿 CFU/d) Significant improvement in MMSE score. Reduced MDA, increased GSH, CRP not significant. Tamtaji et al. (2019)³⁵ 60 AD patients RCT, 12 weeks Probiotic selenium ( L. acidophilus , B. lactis , S. cerevisiae ) Improved MMSE and cognitive test scores. Reduced insulin resistance, inflammation. Agahi et al. (2018)³⁷ 72 PD patients RCT, 12 weeks L. acidophilus , L. reuteri , B. bifidum , L. fermentum (200亿 CFU/d) No significant change in UPDRS. Improved bowel movement frequency. Ibrahim et al. (2023)³⁸ 45 PD patients RCT, 3 months Streptococcus thermophilus , L. delbrueckii , B. lactis Modest improvement in non motor symptoms (constipation, quality of life). No change in motor scores. 3.5 Fecal microbiota transplantation: evidence in human studies and not just a clever therapy in animals FMT leads to the formation of fully healthy microbial communities: Initial compelling data from animal studies of FMT suggests the establishment of comprehensive healthy microbial communities and has produced persuasive preliminary evidence for this potential in animal models. Fecal microbiota transplantation from healthy donors to AD model mice has been found to enhance cognitive function and mitigate Aβ levels and neuroinflammation. ³⁹ Conversely, transferring microbiota from an AD mouse model or human AD patients to germ-free or antibiotic-treated mice might result in cognitive deficits and neuropathological alterations, so indicating a significant causal relationship of the microbiome. 40 In Parkinson's disease (PD) models, fecal microbiota transplantation (FMT) from healthy persons enhances motor function, safeguards nigrostriatal dopaminergic neurons, and mitigates α-synuclein (α-syn) pathology, whereas FMT from PD patients aggravates inflammation and pathology. 41 In the domain of human fecal microbiota transplantation for neurodegenerative diseases, evidence remains in the nascent phase, characterized by first pilot investigations, individual case reports, and continuing clinical trials 42 . An open-label exploratory investigation in patients with Parkinson's disease demonstrated enhancements in both motor and non-motor symptoms post-fecal microbiota transplantation, correlated with alterations in the fecal microbiota. There are anecdotal accounts of the subjective exacerbation of constipation and tremors. 43 However, these are just initial findings, and more large-scale, randomized, double-blind, placebo-controlled studies are needed to prove that these treatments really work and are safe for these groups of people. 4. Discussion This thorough study looks at both existing research that shows how imbalances in gut microorganisms can lead to Alzheimer's and Parkinson's diseases, as well as the potential of microbiome-focused treatments like beneficial bacterial supplementation and FMT procedures. The data emphasize the intestinal-brain connection as a fundamental factor in brain degeneration, serving both as a secondary consequence and a direct cause of essential disease mechanisms. The consistent patterns of bacterial alterations identified in AD and PD patients, notwithstanding variations among studies, furnish compelling evidence for the reduction of beneficial, inflammation-suppressing microbes (notably those synthesizing short-chain fatty acids) concomitant with the proliferation of inflammation-inducing bacterial populations. This microbial imbalance appears to accelerate disease progression via multiple interconnected processes, including chronic brain inflammation, aberrant protein synthesis, and compromised protective barriers, as illustrated in our suggested molecular framework. (Fig. 1 ). 4.1 Therapeutic promise and mechanistic insights: The medical justification for using probiotics and FMT centers on their ability to correct microbial imbalances and disrupt harmful biological processes. Probiotics, which consist mainly of Lactobacillus and Bifidobacterium species, are believed to provide health benefits through multiple pathways: ( 1 ) preventing harmful bacteria from establishing themselves through competitive mechanisms; ( 2 ) reinforcing the gut lining to decrease the amount of toxic substances entering the bloodstream and reduce inflammation; ( 3 ) directing immune responses toward anti-inflammatory patterns; ( 4 ) generating neuroactive compounds such as SCFAs, GABA, and serotonin; and ( 5 ) providing antioxidant protection by neutralizing harmful free radicals.⁴⁴, 4 ⁵ Laboratory studies have consistently validated these mechanisms, demonstrating decreased brain inflammation, reduced disease progression, and enhanced behavioral performance. FMT offers a more complete strategy by attempting to rebuild the full microbial community instead of adding only a few bacterial strains. Strong evidence from animal research where transplants from healthy subjects prevent disease while transplants from sick subjects cause disease offers convincing evidence that a balanced microbiome can modify disease progression.⁴⁶ This effect likely occurs through reestablishing a stable, varied microbial population that can carry out essential functions—including efficient SCFA synthesis, bile acid processing, and immune system training—which probiotic supplements alone might not completely achieve.⁴⁷ 4.2 Challenges and limitations: While it is good to see positive results, it is crucial to recognize the major problems and limitations that exist. There is no uniformity in the field of probiotics. Because the results rely a lot on the specific strains of bacteria, the results from one product can't be used for other formulations.⁴⁸ There are still questions about the best doses, treatment times, and whether microorganisms stay active while being stored. Most importantly, human randomized controlled trials are usually small and short, and they use different methods that make it hard to tell if they are beneficial. Furthermore, numerous investigations have focused on laboratory data rather than definitive clinical outcomes. The challenges associated with FMT are significantly more intricate. It is impossible to get safety information for neurologically challenged patients over long periods of time. Comprehensive donor evaluation mitigates risks; however, the potential for the transmission of infectious agents cannot be completely eradicated. Standardized protocols for identifying optimal donors—based on bacterial diversity, short-chain fatty acid concentrations, or other desirable donor attributes—are lacking. The mode of distribution (colonoscopy, nasojejunal tubes, or oral pills) affects how well the medication works and how well the patient can handle it. Moreover, the application of intricate biological therapies for chronic brain illnesses elicits ethical concerns, especially when the associated risks and benefits are not clearly delineated. In human studies more generally, establishing direct cause-and-effect linkages is highly challenging. Animal studies can demonstrate causation through sterile conditions and transplant experiments, but human research primarily reveals connections. Different study subjects, microbiome assessment methods, and outcome measures make it further harder to put together useful research findings. 4.3 Future directions: To facilitate the progression of this promising topic towards clinical use, further studies must directly address the current limitations. The most important thing to do is to undertake well-planned, large, long-term, randomized, placebo-controlled clinical studies with well-defined patient groups. These investigations ought to utilize carefully delineated interventions (specific probiotic strains or standardized fecal microbiota transplantation preparations) and evaluate clinically significant effects alongside mechanistic biomarkers. In addition to traditional probiotics, researchers ought to explore advanced live biotherapeutics, including genetically modified bacterial strains engineered to synthesize specific neuroprotective molecules (such as BDNF and anti-inflammatory cytokines), and delineate bacterial communities that collectively emulate the essential functions of a balanced microbiome. Ultimately, future research directions should focus on individualized approaches. Considering the person‒to-person differences in gut bacterial composition, a universal treatment strategy may prove inadequate. Methods that customize treatments according to a person's initial microbiome profile, dietary patterns, and genetic makeup offer the greatest potential for achieving optimal results. This approach might include microbiome analysis to detect imbalanced bacterial patterns, followed by choosing targeted treatments to address those particular abnormalities. 5. Conclusion The fast growing amount of research on the gut-brain link has greatly improved our understanding of neurodegenerative illnesses. It has moved the focus away from just looking at the central nervous system and toward the important role that gut microbes play. This thorough study brings together strong evidence that an imbalance of microbes in the digestive tract is a common problem in Alzheimer's and Parkinson's disease and that it helps the disease get worse by causing brain inflammation, abnormal protein clustering, cellular damage from free radicals, and weaker protective barriers. Therapeutic manipulation of this connection via interventions such as beneficial bacterial supplementation and microbiome transplantation presents a novel and promising strategy for modifying disease progression, potentially offering a means to slow or halt the advancement of these debilitating conditions. Laboratory research utilizing animal models yield compelling preliminary evidence that restoring microbial equilibrium can mitigate disease-associated alterations and improve cognitive function and motor skills. Nonetheless, the translation of these findings to human therapies remains in the first stages. Some clinical trials have shown good results, especially when it comes to how bacteria can help with metabolic processes and signs of inflammation. However, the data that clearly illustrate how useful these bacteria are in the clinic is still not complete. It is necessary to deal with big problems with standards, patient safety, and the complicated nature of human research. So, focusing on gut bacteria is a big change in how we treat neurodegenerative diseases. Future research must encompass extensive, meticulously designed, and prolonged human investigations to validate these methodologies, standardize procedures, and ascertain long-term safety profiles. Ultimately, personalized microbiome therapies tailored to each individual's distinct microbial makeup and medical attributes hold significant promise, paving the way for a groundbreaking age in the prevention and treatment of neurodegeneration. Abbreviations Amyloid-Beta (Aβ), Alzheimer’s Disease (AD), Alpha-Synuclein (α-syn), Blood-Brain Barrier (BBB), Brain-Derived Neurotrophic Factor (BDNF), Central Nervous System (CNS), Dopamine Active Transporter (DAT), Fecal Microbiota Transplantation (FMT), γ-Aminobutyric Acid (GABA), Gut-Brain Axis (GBA), Hypothalamic-Pituitary-Adrenal (HPA), Interleukin-1 Beta (IL-1β), Interleukin-6 (IL-6), Lipopolysaccharides (LPS), Medical Subject Headings (MeSH), Mini-Mental State Examination (MMSE), Neurodegenerative Disease (ND), Pathogen-Associated Molecular Patterns (PAMPs), Parkinson’s Disease (PD), Randomized Controlled Trial (RCT), Reactive Oxygen Species (ROS), Short-Chain Fatty Acids (SCFAs), Toll-Like Receptors (TLRs), Tumor Necrosis Factor-Alpha (TNF-α), Unified Parkinson’s Disease Rating Scale (UPDRS).) Declarations Funding/ Conflict of interest This review did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors . 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Appl Sci. 2023;13(15):8928. Vogt NM, Kerby RL, Dill-McFarland KA. Gut microbiome alterations in Alzheimer's disease. Sci Rep. 2017;7(1):13537. Cattaneo A, Cattane N, Galluzzi S. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017;49:60-68. Scheperjans F, Aho V, Pereira PA. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord. 2015;30(3):350-358. Scheperjans F. Gut microbiota, 1013 new pieces in the Parkinson's disease puzzle. Curr Opin Neurol. 2016;29(6):773-780. Keshavarzian A, Green SJ, Engen PA. Colonic bacterial composition in Parkinson's disease. Mov Disord. 2015;30(10):1351-1360. Kowalski K, Mulak A. Brain-Gut-Microbiota Axis in Alzheimer's Disease. J Neurogastroenterol Motil. 2019;25(1):48-60. Sun Y, Sommerville NR, Liu JYH. Intragastrointestinal amyloid-β1-42 oligomers perturb enteric function and induce Alzheimer's disease pathology. J Physiol. 2020;598(19):4209-4223. Challis C, Hori A, Sampson TR. Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice. Nat Neurosci. 2020;23(3):327-336. Maiti P, Manna J, Dunbar GL. Current understanding of the molecular mechanisms in Parkinson's disease: Targets for potential treatments. Transl Neurodegener. 2017;6:28. Braniste V, Al-Asmakh M, Kowal C. The gut microbiota influences blood‒brain barrier permeability in mice. Sci Transl Med. 2014;6(263):263ra158. Abraham D, Feher J, Scuderi GL. Exercise and probiotics attenuate the development of Alzheimer's disease in transgenic mice: Role of microbiome. Exp Gerontol. 2019;115:122-131. Srivastav S, Neupane S, Bhurtel S. Probiotics mixture increases butyrate, and subsequently rescues the nigral dopaminergic neurons from MPTP and rotenone-induced neurotoxicity. J Nutr Biochem. 2019;69:73-86. Akbari E, Asemi Z, Daneshvar Kakhaki R. Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial. Front Aging Neurosci. 2016;8:256. Tamtaji OR, Heidari-Soureshjani R, Mirhosseini N. Probiotic and selenium cosupplementation, and the effects on clinical, metabolic and genetic status in Alzheimer's disease: A randomized, double-blind, controlled trial. Clin Nutr. 2019;38(6):2569-2575. Den H, Dong X, Chen M, Zou Z. Efficacy of probiotics on cognition, and biomarkers of inflammation and oxidative stress in adults with Alzheimer's disease or mild cognitive impairment - a meta-analysis of randomized controlled trials. Aging (Albany NY). 2020;12(4):4010-4039. Agahi A, Hamidi GA, Daneshvar R. Does Severity of Alzheimer's Disease Contribute to Its Responsiveness to Modifying Gut Microbiota? A Double Blind Clinical Trial. Front Neurol. 2018;9:662. Ibrahim A, Ali RAR, Mansour MKM. The effect of fermented milk containing Streptococcus thermophilus and Lactobacillus delbrueckii on clinical symptoms and gut microbiota in patients with Parkinson's disease: A randomized double-blind controlled trial. Front Aging Neurosci. 2023;15:1154489. Kim MS, Kim Y, Choi H. Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model. Gut. 2020;69(2):283-294. Minter MR, Zhang C, Leone V. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease. Sci Rep. 2016;6:30028. Sun MF, Zhu YL, Zhou ZL. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson's disease mice: Gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain Behav Immun. 2018;70:48-60. Kuai XY, Yao XH, Xu LJ. Evaluation of fecal microbiota transplantation in Parkinson's disease patients with constipation. Microb Cell Fact. 2021;20(1):98. Huang H, Xu H, Luo Q. Fecal microbiota transplantation to treat Parkinson's disease with constipation: A case report. Medicine (Baltimore). 2019;98(26):e16163. Cheng LH, Liu YW, Wu CC, Wang S, Tsai YC. Psychobiotics in mental health, neurodegenerative and neurodevelopmental disorders. J Food Drug Anal. 2019;27(3):632-648. Westfall S, Lomis N, Kahouli I, Dia SY, Singh SP, Prakash S. Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis. Cell Mol Life Sci. 2017;74(20):3769-3787. Sun MF, Zhu YL, Zhou ZL. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson's disease mice: Gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain Behav Immun. 2018;70:48-60. Vindigni SM, Surawicz CM. Fecal Microbiota Transplantation. Gastroenterol Clin North Am. 2017;46(1):171-185. Koutnikova H, Genser B, Monteiro-Sepulveda M. Impact of bacterial probiotics on obesity, diabetes and nonalcoholic fatty liver disease related variables: a systematic review and meta-analysis of randomized controlled trials. BMJ Open. 2019;9(3):e017995. Wang JW, Kuo CH, Kuo FC. Fecal microbiota transplantation: Review and update. J Formos Med Assoc. 2019;118 Suppl 1:S23-S31. Long-Smith C, O'Riordan KJ, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota-Gut-Brain Axis: New Therapeutic Opportunities. Annu Rev Pharmacol Toxicol. 2020;60:477-502. Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC. Gut microbiome alterations in Alzheimer’s disease. Sci Transl Med. 2017;9(377):eaao6461. Zhuang ZQ, Shen LL, Li WW, Fu X, Zeng F, Gui L. Gut microbiota is altered in patients with Alzheimer’s disease. J Alzheimers Dis. 2018;63(4):1337-46. Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord. 2015;30(3):350–8. Miquel S, Martín R, Rossi O, Bermúdez-Humarán LG, Chatel JM, Sokol H. Faecalibacterium prausnitzii and human intestinal health. Curr Opin Microbiol. 2013;16(3):255–61. Ling Z, Zhu M, Yan X, Cheng Y, Shao L, Liu X. Structural and functional dysbiosis of fecal microbiota in Chinese patients with Alzheimer’s disease. Front Cell Dev Biol. 2020;8:634. Hill-Burns EM, Debelius JW, Morton JT, Wissemann WT, Lewis MR, Wallen ZD. Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov Disord. 2017;32(5):739–49. Bedarf JR, Hildebrand F, Coelho LP, Sunagawa S, Bahram M, Goeser F. Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease. Genome Med. 2017;9(1):39. Miquel S, Martín R, Rossi O. Faecalibacterium prausnitzii and human intestinal health. Curr Opin Microbiol. 2013;16(3):255-261. Additional Declarations The authors declare no competing interests. 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Introduction","content":"\u003cp\u003eNeurodegenerative disorders (NDs), such as Parkinson\u0026rsquo;s disease (PD) and Alzheimer\u0026rsquo;s disease (AD), are rapidly emerging as significant global public health crises. These illnesses include loss of neural structure and function after a Neurodegenerative disorders (NDs), such as Parkinson\u0026rsquo;s disease (PD) and Alzheimer\u0026rsquo;s disease (AD), are rapidly emerging as significant global public health crises. These illnesses include loss of neural structure and function after a few days, along with problems with movement, severe cognitive impairment, or a big drop in quality of life. The World Health Organization says that by 2050, 139\u0026nbsp;million people around the world will have dementia, mostly because of Alzheimer's disease. This is a big problem for health care systems all across the world. \u0026sup2; Furthermore, the incidence of Parkinson's Disease has more than doubled in the past generation, underscoring the critical necessity for effective therapy frameworks. \u0026sup3;\u003c/p\u003e\u003cp\u003ePathogenic neurodegenerative syndromes arise from a confluence of variables, including hereditary genetic predisposition, senescence of the brain system, environmental exposure, and protein misfolding. ⁴ Over the last few decades, scientific research and pharmaceutical efforts have predominantly concentrated on the central nervous system (CNS), aiming to develop therapy alternatives that alleviate symptoms without disrupting or reversing the disease's progression. This constraint has necessitated a re-evaluation of neuroscience, prompting researchers to explore biological processes that may contribute to neurodegeneration. In this setting, the gut-brain axis has garnered unprecedented interest in contemporary science. This axis serves as a multifaceted bidirectional communication conduit linking the emotional and cognitive regions of the brain with peripheral intestine processes around the body. 7 These interactions are facilitated by several pathways: neural pathways (mainly via the vagus nerve), humoral pathways (such as the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal system and enteric hormone-related pathways), immune communication pathways (mediated by cytokines and chemokines), and metabolic cooperation pathways (involving products produced by microorganisms). 8\u003c/p\u003e\u003cp\u003eGBA functioning is all about the gut microbiome, which is a huge ecosystem of trillions of microorganisms, such as bacteria, viruses, and fungus, that are all very different from each other. 9 This microbiota does not just live in the host without doing anything; it actively helps keep homeostasis in the host. The microbiota affects how the brain grows, how people act, and how they deal with stress by controlling the immune system, making neuroactive substances like serotonin and γ-aminobutyric acid (GABA), and making important metabolites like short-chain fatty acids (SCFAs). Homeostasis, also known as eubiosis, is essential for proper functioning, whereas changes in microbial composition (dysbiosis) are increasingly associated with the pathophysiology of several neurological illnesses. \u0026sup1;\u0026sup2;,\u0026sup1;\u0026sup3;\u003c/p\u003e\u003cp\u003eDespite substantial relevant research, an issue remains to be addressed: the existing medication treatments for AD (such as acetylcholinesterase inhibitors) and PD (such as levodopa) are mainly employed as palliatives for ameliorating symptoms rather than for interfering with basic disease mediators. ⁵,\u0026sup1;⁴ These substantial therapy limitations underscore the urgent need for innovative, disease-modifying strategies that facilitate intervention at the first phases of the illness trajectory.\u003c/p\u003e\u003cp\u003eIn this review, we aim to present a comprehensive analysis of the growing evidence that associates disturbances in the gut microbiome with the etiology of primary neurodegenerative illnesses, including Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to critically evaluate the increasing preclinical and clinical evidence supporting two proposed therapeutic strategies targeting the microbiota: probiotics, defined as viable beneficial bacterial organisms, and fecal microbiota transplantation (FMT), a procedure involving the transfer of entire microbial ecosystems from healthy individuals. This review seeks to elucidate the possible therapeutic advantages of gut microbiota manipulations in mitigating or treating neurodegeneration, based on the provided information.few days, along with problems with movement, severe cognitive impairment, or a big drop in quality of life. The World Health Organization says that by 2050, 139\u0026nbsp;million people around the world will have dementia, mostly because of Alzheimer's disease. This is a big problem for health care systems all across the world. \u0026sup2; Furthermore, the incidence of Parkinson's Disease has more than doubled in the past generation, underscoring the critical necessity for effective therapy frameworks. \u0026sup3;\u003c/p\u003e\u003cp\u003ePathogenic neurodegenerative syndromes arise from a confluence of variables, including hereditary genetic predisposition, senescence of the brain system, environmental exposure, and protein misfolding. ⁴ Over the last few decades, scientific research and pharmaceutical efforts have predominantly concentrated on the central nervous system (CNS), aiming to develop therapy alternatives that alleviate symptoms without disrupting or reversing the disease's progression. This constraint has necessitated a re-evaluation of neuroscience, prompting researchers to explore biological processes that may contribute to neurodegeneration. In this setting, the gut-brain axis has garnered unprecedented interest in contemporary science. This axis serves as a multifaceted bidirectional communication conduit linking the emotional and cognitive regions of the brain with peripheral intestine processes around the body. 7 These interactions are facilitated by several pathways: neural pathways (mainly via the vagus nerve), humoral pathways (such as the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal system and enteric hormone-related pathways), immune communication pathways (mediated by cytokines and chemokines), and metabolic cooperation pathways (involving products produced by microorganisms). 8\u003c/p\u003e\u003cp\u003eGBA functioning is all about the gut microbiome, which is a huge ecosystem of trillions of microorganisms, such as bacteria, viruses, and fungus, that are all very different from each other. 9 This microbiota does not just live in the host without doing anything; it actively helps keep homeostasis in the host. The microbiota affects how the brain grows, how people act, and how they deal with stress by controlling the immune system, making neuroactive substances like serotonin and γ-aminobutyric acid (GABA), and making important metabolites like short-chain fatty acids (SCFAs). Homeostasis, also known as eubiosis, is essential for proper functioning, whereas changes in microbial composition (dysbiosis) are increasingly associated with the pathophysiology of several neurological illnesses. \u0026sup1;\u0026sup2;,\u0026sup1;\u0026sup3;\u003c/p\u003e\u003cp\u003eDespite substantial relevant research, an issue remains to be addressed: the existing medication treatments for AD (such as acetylcholinesterase inhibitors) and PD (such as levodopa) are mainly employed as palliatives for ameliorating symptoms rather than for interfering with basic disease mediators. ⁵,\u0026sup1;⁴ These substantial therapy limitations underscore the urgent need for innovative, disease-modifying strategies that facilitate intervention at the first phases of the illness trajectory.\u003c/p\u003e\u003cp\u003eIn this review, we aim to present a comprehensive analysis of the growing evidence that associates disturbances in the gut microbiome with the etiology of primary neurodegenerative illnesses, including Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to critically evaluate the increasing preclinical and clinical evidence supporting two proposed therapeutic strategies targeting the microbiota: probiotics, defined as viable beneficial bacterial organisms, and fecal microbiota transplantation (FMT), a procedure involving the transfer of entire microbial ecosystems from healthy individuals. This review seeks to elucidate the possible therapeutic advantages of gut microbiota manipulations in mitigating or treating neurodegeneration, based on the provided information.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Literature search methodology\u003c/h2\u003e\u003cp\u003eA comprehensive literature analysis was performed to locate all published papers concerning gut-brain/microbiome/ND/probiotic/FT protocols. The digital bibliographic databases utilized comprised PubMed, Scopus, and the Web of Science Core Collection. The study's scope was confined to material indexed from January 1, 2010, to May 31, 2024, to represent the latest advancements in this swiftly developing academic domain.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Search Keywords\u003c/h2\u003e\u003cp\u003eThe search method included a mix of Medical Subject Headings (MeSH) and unstructured phrases that covered the main themes discussed in this review. We employed Boolean logic operators (\"AND,\" \"OR\") to search for the terms directly in the databases and combine them. This made the search results more precise. The main search equation was:\u003c/p\u003e\u003cp\u003e(\"gut-brain axis\" OR \"microbiome\" OR \"microbiota\" OR \"gut flora\") AND (\"neurodegeneration\" OR \"neurodegenerative disease\" OR \"Alzheimer\" OR \"Parkinson\" OR \"dementia\") AND (\"probiotic\" OR \"fecal microbiota transplantation\" OR \"FMT\" OR \"microbial therapy\")\u003c/p\u003e\u003cp\u003eThis formula was changed to fit the different ways that each database outputs data. We also manually searched the bibliographies of the review articles we found to find any other relevant studies that the first automated database search didn't find.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Inclusion and Exclusion Criteria\u003c/h2\u003e\u003cp\u003e\u0026bull; Inclusion criteria: (i) Original research article (including animal studies); (ii) review of research and statistical analysis of more than one study; (iii) research paper published in English; (iv) studies published to date focusing on biological mechanisms linking the gut microbiota and AD or PD; (v) studies focusing on the benefits of good bacteria, prebiotic compounds, combinations of probiotic prebiotic supplements, and the treatment potential of microbiota transplantation procedures for the treatment of neurodegenerative disorders.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u0026bull; Exclusion criteria: i) was composed in a non-English language; ii) presented an opinion, meeting summary, correspondence to the editor, or book chapter; iii) focused on brain degenerative diseases other than Alzheimer's Disease (AD) and Parkinson's Disease (PD), lacking a distinct comparative analysis; and iv) involved a research paper with an incomplete manuscript.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Data Extraction and Synthesis\u003c/h2\u003e\u003cp\u003eThe titles and abstracts of all potentially discovered records were initially evaluated according to predetermined inclusion and exclusion criteria. The whole texts of potentially pertinent publications were later obtained and thoroughly examined. The data obtained from the chosen papers were compiled in a standardized format, encompassing investigator(s) information, year of publication, study design (in vitro, in vivo, or clinical), sample characteristics, intervention details, essential methodological aspects, and principal findings. A meta-analysis was unfeasible due to the diverse nature of the research, which spanned from fundamental animal mechanistic studies to clinical investigations including people. Consequently, the collected data underwent theme analysis. The results were arranged in a way that made sense: gut-brain channels of communication, proof of dysbiosis in certain disorders, and the effects of therapies that build up in a systematic and analytical look at the whole study landscape.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.1 The gut\u0026ndash;brain axis: the key pathways of communication\u003c/h2\u003e\u003cp\u003eThere are many ways for the gut and brain to talk to each other in both directions. The vagus nerve is in charge of much of the neural tract. It connects the enteric nervous system to the brainstem. Laboratory research has shown that cutting the vagus nerve can stop some probiotics from changing the brain and make Parkinson's disease in animals less severe, showing how important it is.\u003c/p\u003e\u003cp\u003eThe neuroendocrine pathway is facilitated by the hypothalamic-pituitary-adrenal (HPA) axis. Gut microorganisms can swiftly change the HPA axis, which can also change cortisol, which is a main product of the HPA axis and a critical stress hormone that can have big effects on brain function and make neuroinflammation worse when it goes wrong. \u0026sup1;⁷\u003c/p\u003e\u003cp\u003eThe immune system pathway is a significant way that an imbalance in the gut microbiota can make the intestinal wall more permeable, which is known as \"leaky gut.\" This lets bacterial lipopolysaccharides (LPS) and other inflammatory substances into the circulation. This process causes the brain's immune cells, called microglia, to make cytokines including IL-1β, TNF-α, and IL-6. These cytokines can cross the BBB. \u0026sup1;⁸\u003c/p\u003e\u003cp\u003eThe metabolic pathway uses substances that gut microorganisms make. Short-chain fatty acids (SCFAs), including butyrate, propionate, and acetate, generated during dietary fiber fermentation, can traverse the blood\u0026ndash;brain barrier and provide neuroprotective, anti-inflammatory, and epigenetic benefits. The gut microbiota also makes a lot of neuroactive chemicals, such as gamma-aminobutyric acid (GABA), serotonin, and dopamine, that could affect how the gut communicates with the central nervous system. \u0026sup2;⁰\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Imbalance of the gut microbiota in Alzheimer\u0026rsquo;s disease and Parkinson\u0026rsquo;s disease:\u003c/h2\u003e\u003cp\u003eStudies indicate that individuals with Alzheimer's disease (AD) and Parkinson's disease (PD) exhibit markedly distinct gut microbiota compositions compared to healthy individuals of comparable ages. There are certain basic patterns that have come out of the investigations, even though the precise microbial profiles differ depending on the location, eating habits, and study methods used. \u0026sup2;\u0026sup1;\u003c/p\u003e\u003cp\u003eFor instance, individuals with Alzheimer\u0026rsquo;s disease typically display diminished bacterial diversity within their gut microbiome. Research has consistently demonstrated the reduction of bacteria that synthesize short-chain fatty acids (SCFAs), including \u003cem\u003eFaecalibacterium prausnitzii\u003c/em\u003e, \u003cem\u003eEubacterium rectale\u003c/em\u003e, and many species within the Lachnospiraceae family. 22 Furthermore, bacterial groups that cause inflammation, including Escherichia/Shigella and Bacteroidetes, usually show a tendency that is opposite to the one that causes inflammation. \u0026sup2;\u0026sup3;\u003c/p\u003e\u003cp\u003eIndividuals with Parkinson's disease also display microbiome disturbances. Prior research has consistently shown a diminished prevalence of the Prevotellaceae genus, which plays a role in mucin breakdown and the maturation of Th17 cells24. Patients usually have more of the Enterobacteriaceae family of bacteria, and the more of these bacteria there are, the worse their balance problems and trouble walking are. \u0026sup2;⁵ Researchers have also discovered that the concentration of \u003cem\u003eAkkermansia muciniphila\u003c/em\u003e, a mucin-degrading bacterium that may be related with poor intestinal barrier function, is larger in PSC patients. \u0026sup2;⁶ Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows a side-by-side comparison of the typical changes in microbes seen in people with AD and PD.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristic gut microbiota alterations in Alzheimer's disease and Parkinson's disease\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTaxonomic Classification\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAlteration in AD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAlteration in PD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSuggested Functional Impact\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReferences\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirmicutes/Bacteroidetes proportion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReduced/Inconsistent findings\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBroad marker of microbial imbalance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e51,52,53\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eFaecalibacterium prausnitzii\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReduced (Frequently)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDiminished anti-inflammatory SCFA (Butyrate) synthesis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e51,53,54,55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eEubacterium rectale\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLowered SCFA synthesis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLachnospiraceae\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDecreased SCFA synthesis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e51,54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevotellaceae\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCompromised mucin structure, modified immune function\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e53,56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEnterobacteriaceae\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eElevated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eElevated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEnhanced inflammation, LPS synthesis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e52,53,56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eEscherichia/Shigella\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eElevated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEnhanced inflammation, LPS synthesis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e52\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAkkermansia muciniphila\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eElevated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEnhanced mucin breakdown, possible connection to membrane permeability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e53,57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBifidobacterium\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReduced (Frequently)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eInconsistent findings\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDiminished beneficial resident bacteria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e51,52,55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBacteroides\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eElevated (Frequently)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eInconsistent findings\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSituation-dependent inflammatory/anti-inflammatory function\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e52,55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Mechanisms linking dysbiosis to neurodegeneration:\u003c/h2\u003e\u003cp\u003eParallel dysbiosis in neurodegenerative illnesses transcends mere correlations, establishing mechanistic connections with disease pathology through networks of interrelated pathways. Chronic brain inflammation is a key feature of this process. When the balance of microorganisms is off, the levels of LPS and other pathogen-associated molecular patterns (PAMPs) in the blood rise. This activates Toll-like receptors (TLRs) on microglia. This activation creates a long-lasting proinflammatory milieu that causes cytokines to be released, which hurt nerve cells and stop new nerve cells from forming. \u0026sup2;⁷\u003c/p\u003e\u003cp\u003eMicrobial dysbiosis may also facilitate the aggregation of pathogenic proteins. Inflammatory signals from the gut may boost brain kinases that add too many phosphate groups to tau protein, which is a critical part of Alzheimer's disease. In Parkinson's disease (PD), gut inflammation triggers a process that leads to the misfolding of alpha-synuclein (α-syn) in the enteric nervous system, potentially propagating into the brain through the vagus nerve in a prion-like fashion. \u0026sup2;⁹\u003c/p\u003e\u003cp\u003eOxidative and mitochondrial damage have been suggested as additional primary consequences. Changes in the gut microflora may change the creation of metabolites, which could then change how mitochondria work. Inflammation that spreads throughout the body makes reactive oxygen species (ROS), which can then cause neuronal degeneration. \u0026sup3;⁰\u003c/p\u003e\u003cp\u003eLastly, dysbiosis could damage the gut and blood-brain barriers' structural integrity. When the gut barrier is compromised, bacterial byproducts infiltrate the bloodstream, disrupting the integrity of the blood-brain barrier. This facilitates the entry of harmful chemicals and immune cells into the brain, hence worsening neuroinflammation. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows a conceptual diagram that shows how various mechanisms are related\u003csup\u003e31\u003c/sup\u003e.A conceptual diagram illustrating these interconnected mechanisms is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Probiotics: preclinical and clinical evidence\u003c/h2\u003e\u003cp\u003eNumerous preclinical investigations utilizing mouse models of Alzheimer's disease and Parkinson's disease have exhibited beneficial outcomes associated with probiotic administration. Transgenic AD model mice experiments showed that a multispecies probiotic mixture (made up of Lactobacillus and Bifidobacterium species) improved memory and learning tasks and lowered the levels of amyloid-beta plaques and inflammatory cytokines in the brain. 3\u0026sup2; Likewise, in PD model mice, the injection of probiotics alleviates motor insufficiency symptoms while safeguarding DAT neurons and downregulating α-synuclein expression, frequently resulting in the restoration of gut barrier functioning. \u0026sup3;\u0026sup3;\u003c/p\u003e\u003cp\u003eThe findings from human studies are more accessible compared to other investigations, although the evidence remains promising. Numerous randomized controlled trials have predominantly involved participants with Alzheimer's disease and/or mild cognitive impairment. These publications typically report substantial improvements in cognitive diagnostic scores (e.g., MMSE) in those administered probiotics relative to those in the placebo groups. \u0026sup3;⁴ Additionally, numerous studies have indicated the advantageous impacts of metabolic indicators, including reduced inflammation (e.g., CRP and TNF-α), enhanced antioxidant status (e.g., GSH), and improved lipid profiles. However, some RCTs have shown little or no effect on primary cognitive outcomes. This is because the studies were set up differently, used different strains of bacteria, and had different doses and lengths of time for the intervention.\u0026sup3;⁶ Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the design and main results of some clinical trials that looked into probiotics for neurodegenerative disorders.\u0026sup3;⁶ Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes the design and key outcomes of selected clinical trials investigating probiotics in neurodegenerative disorders.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of selected clinical trials on probiotics in neurodegenerative disorders\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSource\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatient Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStudy Type \u0026amp; Length\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTreatment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePrimary Results\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAkbari et al. (2016)\u0026sup3;⁴\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60 individuals with AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRandomized controlled trial, 12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFour-strain probiotic blend: \u003cem\u003eLactobacillus acidophilus\u003c/em\u003e, L. casei, B. bifidum, L. fermentum (20\u0026nbsp;billion CFU daily)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNotable enhancement in MMSE scores. Decreased MDA levels, elevated GSH levels, CRP changes were not statistically significant.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTamtaji et al. (2019)\u0026sup3;⁵\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60 individuals with AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRandomized controlled trial, 12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSelenium-enriched probiotic containing \u003cem\u003eL. acidophilus\u003c/em\u003e, B. lactis, \u003cem\u003eS. cerevisiae\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEnhanced MMSE performance and cognitive assessment results. Decreased insulin resistance and inflammatory markers.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAgahi et al. (2018)\u0026sup3;⁷\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72 individuals with PD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRandomized controlled trial, 12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFour-strain probiotic combination: \u003cem\u003eL. acidophilus\u003c/em\u003e, L. reuteri, B. bifidum, L. fermentum (20\u0026nbsp;billion CFU daily)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUPDRS scores showed no meaningful changes. Enhanced frequency of bowel movements observed.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIbrahim et al. (2023)\u0026sup3;⁸\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45 individuals with PD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRandomized controlled trial, 3 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eThree-strain probiotic: Streptococcus thermophilus, L. delbrueckii, B. lactis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMinor improvements in non motor manifestations including constipation relief and life quality enhancement. Motor function scores remained unchanged.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAkbari et al. (2016)\u0026sup3;⁴\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60 AD patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT, 12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eLactobacillus acidophilus\u003c/em\u003e,\u0026nbsp;\u003cem\u003eL. casei\u003c/em\u003e,\u0026nbsp;\u003cem\u003eB. bifidum\u003c/em\u003e,\u0026nbsp;\u003cem\u003eL. fermentum\u003c/em\u003e\u0026nbsp;(200亿 CFU/d)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSignificant improvement in MMSE score. Reduced MDA, increased GSH, CRP not significant.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTamtaji et al. (2019)\u0026sup3;⁵\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60 AD patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT, 12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eProbiotic selenium (\u003cem\u003eL. acidophilus\u003c/em\u003e,\u0026nbsp;\u003cem\u003eB. lactis\u003c/em\u003e,\u0026nbsp;\u003cem\u003eS. cerevisiae\u003c/em\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eImproved MMSE and cognitive test scores. Reduced insulin resistance, inflammation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAgahi et al. (2018)\u0026sup3;⁷\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72 PD patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT, 12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eL. acidophilus\u003c/em\u003e,\u0026nbsp;\u003cem\u003eL. reuteri\u003c/em\u003e,\u0026nbsp;\u003cem\u003eB. bifidum\u003c/em\u003e,\u0026nbsp;\u003cem\u003eL. fermentum\u003c/em\u003e\u0026nbsp;(200亿 CFU/d)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo significant change in UPDRS. Improved bowel movement frequency.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIbrahim et al. (2023)\u0026sup3;⁸\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45 PD patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT, 3 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eStreptococcus thermophilus\u003c/em\u003e,\u0026nbsp;\u003cem\u003eL. delbrueckii\u003c/em\u003e,\u0026nbsp;\u003cem\u003eB. lactis\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eModest improvement in non motor symptoms (constipation, quality of life). No change in motor scores.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Fecal microbiota transplantation: evidence in human studies and not just a clever therapy in animals\u003c/h2\u003e\u003cp\u003eFMT leads to the formation of fully healthy microbial communities: Initial compelling data from animal studies of FMT suggests the establishment of comprehensive healthy microbial communities and has produced persuasive preliminary evidence for this potential in animal models. Fecal microbiota transplantation from healthy donors to AD model mice has been found to enhance cognitive function and mitigate Aβ levels and neuroinflammation. \u0026sup3;⁹ Conversely, transferring microbiota from an AD mouse model or human AD patients to germ-free or antibiotic-treated mice might result in cognitive deficits and neuropathological alterations, so indicating a significant causal relationship of the microbiome. \u003csup\u003e40\u003c/sup\u003e In Parkinson's disease (PD) models, fecal microbiota transplantation (FMT) from healthy persons enhances motor function, safeguards nigrostriatal dopaminergic neurons, and mitigates α-synuclein (α-syn) pathology, whereas FMT from PD patients aggravates inflammation and pathology. \u003csup\u003e41\u003c/sup\u003e In the domain of human fecal microbiota transplantation for neurodegenerative diseases, evidence remains in the nascent phase, characterized by first pilot investigations, individual case reports, and continuing clinical trials\u003csup\u003e42\u003c/sup\u003e. An open-label exploratory investigation in patients with Parkinson's disease demonstrated enhancements in both motor and non-motor symptoms post-fecal microbiota transplantation, correlated with alterations in the fecal microbiota. There are anecdotal accounts of the subjective exacerbation of constipation and tremors. \u003csup\u003e43\u003c/sup\u003e However, these are just initial findings, and more large-scale, randomized, double-blind, placebo-controlled studies are needed to prove that these treatments really work and are safe for these groups of people.\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis thorough study looks at both existing research that shows how imbalances in gut microorganisms can lead to Alzheimer's and Parkinson's diseases, as well as the potential of microbiome-focused treatments like beneficial bacterial supplementation and FMT procedures. The data emphasize the intestinal-brain connection as a fundamental factor in brain degeneration, serving both as a secondary consequence and a direct cause of essential disease mechanisms. The consistent patterns of bacterial alterations identified in AD and PD patients, notwithstanding variations among studies, furnish compelling evidence for the reduction of beneficial, inflammation-suppressing microbes (notably those synthesizing short-chain fatty acids) concomitant with the proliferation of inflammation-inducing bacterial populations. This microbial imbalance appears to accelerate disease progression via multiple interconnected processes, including chronic brain inflammation, aberrant protein synthesis, and compromised protective barriers, as illustrated in our suggested molecular framework. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Therapeutic promise and mechanistic insights:\u003c/h2\u003e\u003cp\u003eThe medical justification for using probiotics and FMT centers on their ability to correct microbial imbalances and disrupt harmful biological processes. Probiotics, which consist mainly of Lactobacillus and Bifidobacterium species, are believed to provide health benefits through multiple pathways: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) preventing harmful bacteria from establishing themselves through competitive mechanisms; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) reinforcing the gut lining to decrease the amount of toxic substances entering the bloodstream and reduce inflammation; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) directing immune responses toward anti-inflammatory patterns; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) generating neuroactive compounds such as SCFAs, GABA, and serotonin; and (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) providing antioxidant protection by neutralizing harmful free radicals.⁴⁴,\u003csup\u003e4\u003c/sup\u003e⁵ Laboratory studies have consistently validated these mechanisms, demonstrating decreased brain inflammation, reduced disease progression, and enhanced behavioral performance.\u003c/p\u003e\u003cp\u003eFMT offers a more complete strategy by attempting to rebuild the full microbial community instead of adding only a few bacterial strains. Strong evidence from animal research where transplants from healthy subjects prevent disease while transplants from sick subjects cause disease offers convincing evidence that a balanced microbiome can modify disease progression.⁴⁶ This effect likely occurs through reestablishing a stable, varied microbial population that can carry out essential functions\u0026mdash;including efficient SCFA synthesis, bile acid processing, and immune system training\u0026mdash;which probiotic supplements alone might not completely achieve.⁴⁷\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Challenges and limitations:\u003c/h2\u003e\u003cp\u003eWhile it is good to see positive results, it is crucial to recognize the major problems and limitations that exist. There is no uniformity in the field of probiotics. Because the results rely a lot on the specific strains of bacteria, the results from one product can't be used for other formulations.⁴⁸ There are still questions about the best doses, treatment times, and whether microorganisms stay active while being stored. Most importantly, human randomized controlled trials are usually small and short, and they use different methods that make it hard to tell if they are beneficial. Furthermore, numerous investigations have focused on laboratory data rather than definitive clinical outcomes.\u003c/p\u003e\u003cp\u003eThe challenges associated with FMT are significantly more intricate. It is impossible to get safety information for neurologically challenged patients over long periods of time. Comprehensive donor evaluation mitigates risks; however, the potential for the transmission of infectious agents cannot be completely eradicated. Standardized protocols for identifying optimal donors\u0026mdash;based on bacterial diversity, short-chain fatty acid concentrations, or other desirable donor attributes\u0026mdash;are lacking. The mode of distribution (colonoscopy, nasojejunal tubes, or oral pills) affects how well the medication works and how well the patient can handle it. Moreover, the application of intricate biological therapies for chronic brain illnesses elicits ethical concerns, especially when the associated risks and benefits are not clearly delineated.\u003c/p\u003e\u003cp\u003eIn human studies more generally, establishing direct cause-and-effect linkages is highly challenging. Animal studies can demonstrate causation through sterile conditions and transplant experiments, but human research primarily reveals connections. Different study subjects, microbiome assessment methods, and outcome measures make it further harder to put together useful research findings.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e4.3 Future directions:\u003c/h2\u003e\u003cp\u003eTo facilitate the progression of this promising topic towards clinical use, further studies must directly address the current limitations. The most important thing to do is to undertake well-planned, large, long-term, randomized, placebo-controlled clinical studies with well-defined patient groups. These investigations ought to utilize carefully delineated interventions (specific probiotic strains or standardized fecal microbiota transplantation preparations) and evaluate clinically significant effects alongside mechanistic biomarkers.\u003c/p\u003e\u003cp\u003eIn addition to traditional probiotics, researchers ought to explore advanced live biotherapeutics, including genetically modified bacterial strains engineered to synthesize specific neuroprotective molecules (such as BDNF and anti-inflammatory cytokines), and delineate bacterial communities that collectively emulate the essential functions of a balanced microbiome.\u003c/p\u003e\u003cp\u003eUltimately, future research directions should focus on individualized approaches. Considering the person‒to-person differences in gut bacterial composition, a universal treatment strategy may prove inadequate. Methods that customize treatments according to a person's initial microbiome profile, dietary patterns, and genetic makeup offer the greatest potential for achieving optimal results. This approach might include microbiome analysis to detect imbalanced bacterial patterns, followed by choosing targeted treatments to address those particular abnormalities.\u003c/p\u003e\u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThe fast growing amount of research on the gut-brain link has greatly improved our understanding of neurodegenerative illnesses. It has moved the focus away from just looking at the central nervous system and toward the important role that gut microbes play. This thorough study brings together strong evidence that an imbalance of microbes in the digestive tract is a common problem in Alzheimer's and Parkinson's disease and that it helps the disease get worse by causing brain inflammation, abnormal protein clustering, cellular damage from free radicals, and weaker protective barriers. Therapeutic manipulation of this connection via interventions such as beneficial bacterial supplementation and microbiome transplantation presents a novel and promising strategy for modifying disease progression, potentially offering a means to slow or halt the advancement of these debilitating conditions.\u003c/p\u003e\u003cp\u003eLaboratory research utilizing animal models yield compelling preliminary evidence that restoring microbial equilibrium can mitigate disease-associated alterations and improve cognitive function and motor skills. Nonetheless, the translation of these findings to human therapies remains in the first stages. Some clinical trials have shown good results, especially when it comes to how bacteria can help with metabolic processes and signs of inflammation. However, the data that clearly illustrate how useful these bacteria are in the clinic is still not complete. It is necessary to deal with big problems with standards, patient safety, and the complicated nature of human research.\u003c/p\u003e\u003cp\u003eSo, focusing on gut bacteria is a big change in how we treat neurodegenerative diseases. Future research must encompass extensive, meticulously designed, and prolonged human investigations to validate these methodologies, standardize procedures, and ascertain long-term safety profiles. Ultimately, personalized microbiome therapies tailored to each individual's distinct microbial makeup and medical attributes hold significant promise, paving the way for a groundbreaking age in the prevention and treatment of neurodegeneration.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAmyloid-Beta (A\u0026beta;), Alzheimer\u0026rsquo;s Disease (AD), Alpha-Synuclein (\u0026alpha;-syn), Blood-Brain Barrier (BBB), Brain-Derived Neurotrophic Factor (BDNF), Central Nervous System (CNS), Dopamine Active Transporter (DAT), Fecal Microbiota Transplantation (FMT), \u0026gamma;-Aminobutyric Acid (GABA), Gut-Brain Axis (GBA), Hypothalamic-Pituitary-Adrenal (HPA), Interleukin-1 Beta (IL-1\u0026beta;), Interleukin-6 (IL-6), Lipopolysaccharides (LPS), Medical Subject Headings (MeSH), Mini-Mental State Examination (MMSE), Neurodegenerative Disease (ND), Pathogen-Associated Molecular Patterns (PAMPs), Parkinson\u0026rsquo;s Disease (PD), Randomized Controlled Trial (RCT), Reactive Oxygen Species (ROS), Short-Chain Fatty Acids (SCFAs), Toll-Like Receptors (TLRs), Tumor Necrosis Factor-Alpha (TNF-\u0026alpha;), Unified Parkinson\u0026rsquo;s Disease Rating Scale (UPDRS).)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding/\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Conflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis review did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors\u003cstrong\u003e\u0026nbsp;.\u003c/strong\u003eThe authors declare that there is no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBhaskar Jyoti Sharma: Conceptualization, Writing \u0026ndash; original draft. Abu Saif Mustaque: Writing \u0026ndash; review \u0026amp; editing, Supervision, Project administration.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGitler AD, Dhillon P, Shorter J. Neurodegenerative disease: models, mechanisms, and a new hope. Dis Model Mech. 2017;10(5):499-502.\u003c/li\u003e\n\u003cli\u003eDorsey ER, Sherer T, Okun MS, Bloem BR. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022;7(2):e105-e125.\u003c/li\u003e\n\u003cli\u003eKovacs GG. Molecular Pathological Classification of Neurodegenerative Diseases: Turning toward Precision Medicine. Int J Mol Sci. 2016;17(2):189.\u003c/li\u003e\n\u003cli\u003eCummings J, Lee G, Ritter A, Zhong K. Alzheimer\u0026apos;s disease drug development pipeline: 2021. 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Impact of bacterial probiotics on obesity, diabetes and nonalcoholic fatty liver disease related variables: a systematic review and meta-analysis of randomized controlled trials. BMJ Open. 2019;9(3):e017995.\u003c/li\u003e\n\u003cli\u003eWang JW, Kuo CH, Kuo FC. Fecal microbiota transplantation: Review and update. J Formos Med Assoc. 2019;118 Suppl 1:S23-S31.\u003c/li\u003e\n\u003cli\u003eLong-Smith C, O\u0026apos;Riordan KJ, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota-Gut-Brain Axis: New Therapeutic Opportunities. Annu Rev Pharmacol Toxicol. 2020;60:477-502.\u003c/li\u003e\n\u003cli\u003eVogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC. Gut microbiome alterations in Alzheimer\u0026rsquo;s disease. Sci Transl Med. 2017;9(377):eaao6461.\u003c/li\u003e\n\u003cli\u003eZhuang ZQ, Shen LL, Li WW, Fu X, Zeng F, Gui L. Gut microbiota is altered in patients with Alzheimer\u0026rsquo;s disease. J Alzheimers Dis. 2018;63(4):1337-46.\u003c/li\u003e\n\u003cli\u003eScheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E. Gut microbiota are related to Parkinson\u0026rsquo;s disease and clinical phenotype. Mov Disord. 2015;30(3):350\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eMiquel S, Mart\u0026iacute;n R, Rossi O, Berm\u0026uacute;dez-Humar\u0026aacute;n LG, Chatel JM, Sokol H. Faecalibacterium prausnitzii and human intestinal health. Curr Opin Microbiol. 2013;16(3):255\u0026ndash;61.\u003c/li\u003e\n\u003cli\u003eLing Z, Zhu M, Yan X, Cheng Y, Shao L, Liu X. Structural and functional dysbiosis of fecal microbiota in Chinese patients with Alzheimer\u0026rsquo;s disease. Front Cell Dev Biol. 2020;8:634.\u003c/li\u003e\n\u003cli\u003eHill-Burns EM, Debelius JW, Morton JT, Wissemann WT, Lewis MR, Wallen ZD. Parkinson\u0026rsquo;s disease and Parkinson\u0026rsquo;s disease medications have distinct signatures of the gut microbiome. Mov Disord. 2017;32(5):739\u0026ndash;49.\u003c/li\u003e\n\u003cli\u003eBedarf JR, Hildebrand F, Coelho LP, Sunagawa S, Bahram M, Goeser F. Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-na\u0026iuml;ve Parkinson\u0026rsquo;s disease. Genome Med. 2017;9(1):39.\u003c/li\u003e\n\u003cli\u003eMiquel S, Mart\u0026iacute;n R, Rossi O. Faecalibacterium prausnitzii and human intestinal health. Curr Opin Microbiol. 2013;16(3):255-261.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gut–Brain Axis, Neurodegeneration, Microbiome, Probiotics, Fecal Microbiota Transplantation","lastPublishedDoi":"10.21203/rs.3.rs-7608549/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7608549/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: The gut-brain axis (GBA) is a two-way communication mechanism that links the enteric nervous system and the central nervous system. Studies suggest that dysbiosis in the gut microbiota has a role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease.\u003c/p\u003e\n\u003cp\u003eObjective: This review aims to synthesize current studies on the impact of the gut-brain axis (GBA) on neurodegeneration and to evaluate the therapeutic potential of therapies aimed at microbiota, including probiotics and fecal microbiota transplantation (FMT).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: A comprehensive literature analysis was conducted utilizing the PubMed, Scopus, and Web of Science databases to ascertain pertinent preclinical and clinical research published between 2010 to 2024.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: These findings suggest that dysbiosis in the gut microbiota may initiate neuroinflammation and aberrant protein folding, hence undermining the integrity of the blood-brain barrier. While probiotic research has shown moderate enhancements in cognitive metrics, fecal microbiota transplantation (FMT) presents a more extensive, yet little investigated, approach to altering gut microbiome composition and potentially impacting disease progression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Interventions aimed at the intestinal microbiota present significant novel therapeutic pathways for the management of neurodegenerative disorders. Nonetheless, it is imperative to conduct comprehensive, meticulously designed clinical studies to validate therapeutic efficacy, establish uniform treatment procedures, and guarantee patient safety over prolonged durations.\u003c/p\u003e","manuscriptTitle":"The gut–brain axis in neurodegenerative disorders: Evaluating the therapeutic potential of probiotic and fecal microbiota transplantation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-17 09:11:33","doi":"10.21203/rs.3.rs-7608549/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ec5bff93-f619-41c3-9eaa-9afbabf5d55a","owner":[],"postedDate":"September 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54672205,"name":"Cognitive Neuroscience"}],"tags":[],"updatedAt":"2025-09-17T09:11:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-17 09:11:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7608549","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7608549","identity":"rs-7608549","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}