Background: Neurodegenerative diseases (NDDs) are multifactorial disorders frequently associated with gut dysbiosis, oxidative stress, and inflammation; however, the pathophysiological mechanisms remain poorly understood. Methods: Using untargeted mass spectrometry-based metabolomics and 16S sequencing of human stool, we investigated bacterial and metabolic dyshomeostasis in the gut microbiome associated with early disease stages across three NDDs-amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD)-and healthy controls (HC). Results: We discovered a previously unrecognized link between a microbial-derived metabolite with an unknown role in human physiology, 2,3-dihydroxypropane-1-sulfonate (DHPS), and gut dysbiosis in NDDs. DHPS was downregulated in AD, ALS, and PD, while bacteria involved in DHPS metabolism, Eubacterium and Desulfovibrio, were increased in all disease cohorts. Additionally, select taxa within the Clostridia class had strong negative correlations to DHPS, suggesting a potential role in DHPS metabolism. A catabolic product of DHPS is hydrogen sulfide, and when in excess, it is known to promote inflammation, oxidative stress, mitochondrial damage, and gut dysbiosis, known hallmarks of NDDs. Conclusions: These findings suggest that cryptic sulfur metabolism via DHPS is a potential missing link in our current understanding of gut dysbiosis associated with NDD onset and progression. As this was a hypothesis generating study, more work is needed to elucidate the role of DHPS in gut dysbiosis and neurodegenerative diseases.

Huntington's disease (HD) is a currently incurable neurogenerative disorder and is typically characterized by progressive movement disorder (including chorea), cognitive deficits (culminating in dementia), psychiatric abnormalities (the most common of which is depression), and peripheral symptoms (including gastrointestinal dysfunction). There are currently no approved disease-modifying therapies available for HD, with death usually occurring approximately 10-25 years after onset, but some therapies hold promising potential. HD subjects are often burdened by chronic diarrhea, constipation, esophageal and gastric inflammation, and a susceptibility to diabetes. Our understanding of the microbiota-gut-brain axis in HD is in its infancy and growing evidence from preclinical and clinical studies suggests a role of gut microbial population imbalance (gut dysbiosis) in HD pathophysiology. The gut and the brain can communicate through the enteric nervous system, immune system, vagus nerve, and microbiota-derived-metabolites including short-chain fatty acids, bile acids, and branched-chain amino acids. This review summarizes supporting evidence demonstrating the alterations in bacterial and fungal composition that may be associated with HD. We focus on mechanisms through which gut dysbiosis may compromise brain and gut health, thus triggering neuroinflammatory responses, and further highlight outcomes of attempts to modulate the gut microbiota as promising therapeutic strategies for HD. Ultimately, we discuss the dearth of data and the need for more longitudinal and translational studies in this nascent field. We suggest future directions to improve our understanding of the association between gut microbes and the pathogenesis of HD, and other 'brain and body disorders'.

The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.

Metabolic alterations, including hypermetabolism, lipid imbalances, and glucose dysregulation, are pivotal contributors to the onset and progression of Amyotrophic Lateral Sclerosis (ALS). These changes exacerbate systemic energy deficits, heighten oxidative stress, and fuel neuroinflammation. Simultaneously, gastrointestinal dysfunction and gut microbiota (GM) dysbiosis intensify disease pathology by driving immune dysregulation, compromising the intestinal barrier, and altering gut-brain axis (GBA) signaling, and lastly advancing neurodegeneration. Therapeutic and preventive strategies focused on nutrition offer promising opportunities to address these interconnected pathophysiological mechanisms. Diets enriched with antioxidants, omega-3 fatty acids, and anti-inflammatory compounds-such as the Mediterranean diet-have shown potential in reducing oxidative stress and systemic inflammation. Additionally, microbiota-targeted approaches, including probiotics, prebiotics, postbiotics, and fecal microbiota transplantation, are emerging as innovative tools to restore microbial balance, strengthen gut integrity, and optimize GBA function. This review highlights the critical need for personalized strategies integrating immunonutrition and microbiota modulation to slow ALS progression, improve quality of life, and develop preventive measures for neurodegenerative and neuroinflammatory diseases. Future research should prioritize comprehensive dietary and microbiota-based interventions to uncover their therapeutic potential and establish evidence-based guidelines for managing ALS and related disorders.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the progressive loss of motor neurons. Recent insights into ALS pathogenesis underscore the pivotal role of the gut microbiome, prompting an investigation into the potential therapeutic impact of fecal microbiota transplantation (FMT) on sporadic ALS patients.

Conducted as a double-blind, placebo-controlled, parallel-group, randomized clinical trial, the study enrolled 27 participants from October 2022 to April 2023. The participants were followed up for 6 months from February 2023 to October 2023, during in-person visits at baseline, week 15, week 23, and week 35. The participants, evenly randomized, received either healthy donor FMT (FMT, n = 14) or a mixture of 0.9% saline and food coloring (E150c) as sham transplantation (placebo, n = 13). The primary outcome measured the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score from baseline to week 35. Secondary outcomes included changes in gastrointestinal and respiratory functions, muscle strength, autonomic function, cognition, quality of life, intestinal microbiome composition, and plasm neurofilament light chain protein (NFL). Efficacy and safety outcomes were assessed in the intention-to-treat population.

A total of 27 randomized patients (47% women; mean age, 67.2 years), 24 participants completed the entire study. Notably, ALSFRS-R score changes exhibited no significant differences between FMT (6.1 [SD, 3.11]) and placebo (6.41[SD, 2.73]) groups from baseline to week 35. Secondary efficacy outcomes, encompassing respiratory function, muscle strength, autonomic function, cognition, quality of life, and plasm NFL, showed no significant differences. Nevertheless, the FMT group exhibited improvements in constipation, depression, and anxiety symptoms. FMT induced a shift in gut microbiome community composition, marked by increased abundance of Bifidobacterium, which persisted until week 15 (95% CI, 0.04 to 0.28; p = 0.01). Gastrointestinal adverse events were the primary manifestations of FMT-related side effects.

In this clinical trial involving 27 sporadic ALS patients, FMT did not significantly slow the decline in ALSFRS-R score. Larger multicenter trials are needed to confirm the efficacy of FMT in sporadic ALS patients and to explore the underlying biological mechanisms.

Chinese Clinical Trial Registry Identifier: ChiCTR 2200064504.

The intestine, as a crucial organ of the human body, has remained enigmatic despite the remarkable advancements in modern medical technology. Over the past decades, the invention of endoscopic technology has made the noninvasive intervention of the intestine a reality, expanding diagnostic and therapeutic options for diseases. However, due to the single-treatment feature of endoscopic procedures, continuous or repeated medication administration, sampling, and decompression drainage within the intestine have yet to be fulfilled. These limitations persisted until the invention of colonic transendoscopic enteral tubing (TET) in 2014, which realized repeated fecal microbiota transplantation, medication administration, and decompression drainage for the treatment of colon perforation and intestinal obstruction, as well as in situ dynamic sampling. These breakthroughs have not gone unnoticed, gaining global attention and recommendations from guidelines and consensuses. TET has emerged as a novel microbial research tool that offers new paradigms for human microbiome research. This review aims to update the research progress based on TET.

Microbiota refers to a collection of living microorganisms, including bacteria, yeasts, and viruses, that coexist in various sites of the human body. Microbiota can perform multiple functions in the body, which have an essential effect on human health and homeostasis. For example, the microbiota can digest polysaccharides, produce vitamins, modulate the immune system, and protect the body against pathogens. Various factors can occasionally alter the microbiota population in the human body, a condition known as dysbiosis. Dysbiosis can disrupt the homeostasis of a person's body and cause disease. Recent years have witnessed efforts to restore the microbiota population of an individual's body to its original state and eradicate dysbiosis through microbiota transplantation. The noteworthy point is that different methods such as fecal microbiota transplantation, vaginal microbiota transplantation (VMT), skin microbiota transplantation (SMT), oral microbiota transplantation (OMT), washed microbiota transplantation (WMT), and sinonasal microbiota transplantation (SiMT) are used for microbiota transplantation (MT). According to the results of studies and the usefulness of MT in improving a person's health, the purpose of this study is to investigate different methods of MT to eliminate dysbiosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons. While there has been significant progress in defining the genetic contributions to ALS, greater than 90 ​% of cases are sporadic, which suggests an environmental component. The gut microbiota is altered in ALS and is an ecological factor that contributes to disease by modulating immunologic, metabolic, and neuronal signaling. Depleting the microbiome worsens disease in the SOD1 ALS animal model, while it ameliorates disease in the C9orf72 model of ALS, indicating critical subtype-specific interactions. Furthermore, administering beneficial microbiota or microbial metabolites can slow disease progression in animal models. This review discusses the current state of microbiome research in ALS, including interactions with different ALS subtypes, evidence in animal models and human studies, key immunologic and metabolomic mediators, and a path toward microbiome-based therapies for ALS.

Every facet of biological anthropology, including development, ageing, diseases, and even health maintenance, is influenced by gut microbiota's significant genetic and metabolic capabilities. With current advancements in sequencing technology and with new culture-independent approaches, researchers can surpass older correlative studies and develop mechanism-based studies on microbiome-host interactions. The microbiota-gut-brain axis (MGBA) regulates glial functioning, making it a possible target for the improvement of development and advancement of treatments for neurodegenerative diseases (NDDs). The gut-brain axis (GBA) is accountable for the reciprocal communication between the gastrointestinal and central nervous system, which plays an essential role in the regulation of physiological processes like controlling hunger, metabolism, and various gastrointestinal functions. Lately, studies have discovered the function of the gut microbiome for brain health-different microbiota through different pathways such as immunological, neurological and metabolic pathways. Additionally, we review the involvement of the neurotransmitters and the gut hormones related to gut microbiota. We also explore the MGBA in neurodegenerative disorders by focusing on metabolites. Further, targeting the blood-brain barrier (BBB), intestinal barrier, meninges, and peripheral immune system is investigated. Lastly, we discuss the therapeutics approach and evaluate the pre-clinical and clinical trial data regarding using prebiotics, probiotics, paraprobiotics, fecal microbiota transplantation, personalised medicine, and natural food bioactive in NDDs. A comprehensive study of the GBA will felicitate the creation of efficient therapeutic approaches for treating different NDDs.

Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024;95:635-652.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to respiratory failure, and eventually death. However, there is a lack of effective treatments for ALS. Here we report the results of fecal microbiota transplantation (FMT) in two patients with late-onset classic ALS with a Japan ALS severity classification of grade 5 who required tracheostomy and mechanical ventilation. In both patients, significant improvements in respiratory function were observed following two rounds of FMT, leading to weaning off mechanical ventilation. Their muscle strength improved, allowing for assisted standing and mobility. Other notable treatment responses included improved swallowing function and reduced muscle fasciculations. Metagenomic and metabolomic analysis revealed an increase in beneficial Bacteroides species (Bacteroides stercoris, Bacteroides uniformis, Bacteroides vulgatus), and Faecalibacterium prausnitzii after FMT, as well as elevated levels of metabolites involved in arginine biosynthesis and decreased levels of metabolites involved in branched-chain amino acid biosynthesis. These findings offer a potential rescue therapy for ALS with respiratory failure and provide new insights into ALS in general.

The gut-brain axis is an essential communication pathway between the central nervous system (CNS) and the gastrointestinal tract. The human microbiota is composed of a diverse and abundant microbial community that compasses more than 100 trillion microorganisms that participate in relevant physiological functions such as host nutrient metabolism, structural integrity, maintenance of the gut mucosal barrier, and immunomodulation. Recent evidence in animal models has been instrumental in demonstrating the possible role of the microbiota in neurodevelopment, neuroinflammation, and behavior. Furthermore, clinical studies suggested that adverse changes in the microbiota can be considered a susceptibility factor for neurological disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). In this review, we will discuss evidence describing the role of gut microbes in health and disease as a relevant risk factor in the pathogenesis of neurodegenerative disorders, including AD, PD, HD, and ALS.

Fecal microbiota transplantation (FMT) has emerged as a promising therapeutic approach for dysbiosis-related diseases. However, the clinical practice of crude fecal transplants presents limitations in terms of acceptability and reproductivity. Consequently, two alternative solutions to FMT are developed: transplanting bacteria communities or virome. Advanced methods for transplanting bacteria mainly include washed microbiota transplantation and bacteria spores treatment. Transplanting the virome is also explored, with the development of fecal virome transplantation, which involves filtering the virome from feces. These approaches provide more palatable options for patients and healthcare providers while minimizing research heterogeneity. In general, the evolution of the next generation of FMT in global trends is fecal microbiota components transplantation which mainly focuses on transplanting bacteria or virome.

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration with typical survival of only 2-5 years from diagnosis. The causes of ALS are multifactorial: known genetic mutations account for only around 70% of cases of familial ALS and 15% of sporadic cases, and heritability estimates range from 8% to 61%, indicating additional causes beyond genetics. Consequently, interest has grown in environmental contributions to ALS risk and progression. The gene-time-environment hypothesis posits that ALS onset occurs through an interaction of genes with environmental exposures during ageing. An alternative hypothesis, the multistep model of ALS, suggests that several hits, at least some of which could be environmental, are required to trigger disease onset, even in the presence of highly penetrant ALS-associated mutations. Studies have sought to characterize the ALS exposome - the lifetime accumulation of environmental exposures that increase disease risk and affect progression. Identifying the full scope of environmental toxicants that enhance ALS risk raises the prospect of preventing disease by eliminating or mitigating exposures. In this Review, we summarize the evidence for an ALS exposome, discussing the strengths and limitations of epidemiological studies that have identified contributions from various sources. We also consider potential mechanisms of exposure-mediated toxicity and suggest future directions for ALS exposome research.

The comprehensive narrative review conducted in this study delves into the mechanisms of communication and action at the molecular level in the human organism. The review addresses the complex mechanism involved in the microbiota-gut-brain axis as well as the implications of alterations in the microbial composition of patients with neurodegenerative diseases. The pathophysiology of neurodegenerative diseases with neuronal loss or death is analyzed, as well as the mechanisms of action of the main metabolites involved in the bidirectional communication through the microbiota-gut-brain axis. In addition, interventions targeting gut microbiota restructuring through fecal microbiota transplantation and the use of psychobiotics-pre- and pro-biotics-are evaluated as an opportunity to reduce the symptomatology associated with neurodegeneration in these pathologies. This review provides valuable information and facilitates a better understanding of the neurobiological mechanisms to be addressed in the treatment of neurodegenerative diseases.

The human gastrointestinal tract is home to trillions of microorganisms-collectively referred to as the gut microbiome-that maintain a symbiotic relationship with their host. This diverse community of microbes grows and changes as we do, with developmental, lifestyle, and environmental factors all shaping microbiome community structure. Increasing evidence suggests this relationship is bidirectional, with the microbiome also influencing host physiological processes. For example, changes in the gut microbiome have been shown to alter neurodevelopment and have lifelong effects on the brain and behavior. Age-related changes in gut microbiome composition have also been linked to inflammatory changes in the brain, perhaps increasing susceptibility to neurological disease. Indeed, associations between gut dysbiosis and many age-related neurological diseases-including Parkinson's disease, Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis-have been reported. Further, microbiome manipulation in animal models of disease highlights a potential role for the gut microbiome in disease development and progression. Although much remains unknown, these associations open up an exciting new world of therapeutic targets, potentially allowing for improved quality of life for a wide range of patient populations.

Although previously restricted to a limited number of medical conditions, there is a growing appreciation that 'autoimmune' (or immune-mediated) processes are important aspects of a wide array of diverse medical conditions, including cancers, neurodegenerative diseases and psychiatric disorders. All of these classes of medical conditions are associated with alterations in mitochondrial function across an array of diverse cell types. Accumulating data indicate the presence of the mitochondrial melatonergic pathway in possibly all body cells, with important consequences for pathways crucial in driving CD8⁺ T cell and B-cell 'autoimmune'-linked processes. Melatonin suppression coupled with the upregulation of oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising the levels of the major histocompatibility complex (MHC)-1, which underpins the chemoattraction of CD8⁺ T cells and the activation of antibody-producing B-cells. Many factors and processes closely associated with autoimmunity, including gut microbiome/permeability, circadian rhythms, aging, the aryl hydrocarbon receptor, brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) all interact with the mitochondrial melatonergic pathway. A number of future research directions and novel treatment implications are indicated for this wide collection of poorly conceptualized and treated medical presentations. It is proposed that the etiology of many 'autoimmune'/'immune-mediated' disorders should be conceptualized as significantly determined by mitochondrial dysregulation, with alterations in the mitochondrial melatonergic pathway being an important aspect of these pathoetiologies.

Amyotrophic lateral sclerosis is a rare disease that cannot be cured. We report a case of a patient with amyotrophic lateral sclerosis whose pulmonary function and quality of life were improved by a combined tui na treatment and Western medicine.

A 48-year-old male was diagnosed with ALS 1 year ago and was treated with western medicine and herbal medicine with no significant effect. This time, he was admitted to our department because of slurred speech, coughing and choking, and weakness of the left upper limb for more than 1 year.

After 1 month of treatment with tui na and traditional western medicine, the patient's lung function and quality of life improved and he was discharged from the hospital.

Motor neuron disease. Amyotrophic lateral sclerosis.

The physiological function of ALS patients can be improved through the intervention of tui na.

Neurodegenerative diseases are highly prevalent but poorly understood, and with few treatment options despite decades of intense research, attention has recently shifted toward other mediators of neurological disease that may present future targets for therapeutic research. One such mediator is the gut microbiome, which communicates with the brain through the gut-brain axis and has been implicated in various neurological disorders. Alterations in the gut microbiome have been associated with numerous neurological and other diseases, and restoration of the dysbiotic gut has been shown to improve disease conditions. One method of restoring a dysbiotic gut is via fecal microbiota transplantation (FMT), recolonizing the "diseased" gut with normal microbiome. Fecal microbiota transplantation is a treatment method traditionally used for Clostridium difficile infections, but it has recently been used in neurodegenerative disease research as a potential treatment method. This review aims to present a summary of neurodegenerative research that has used FMT, whether as a treatment or to investigate how the microbiome influences pathogenesis.

There are trillions of different microorganisms in the human digestive system. These gut microbes are involved in the digestion of food and its conversion into the nutrients required by the body. In addition, the gut microbiota communicates with other parts of the body to maintain overall health. The connection between the gut microbiota and the brain is known as the gut-brain axis (GBA), and involves connections via the central nervous system (CNS), the enteric nervous system (ENS), and endocrine and immune pathways. The gut microbiota regulates the central nervous system bottom-up through the GBA, which has prompted researchers to pay considerable attention to the potential pathways by which the gut microbiota might play a role in the prevention and treatment of amyotrophic lateral sclerosis (ALS). Studies with animal models of ALS have shown that dysregulation of the gut ecology leads to dysregulation of brain-gut signaling. This, in turn, induces changes in the intestinal barrier, endotoxemia, and systemic inflammation, which contribute to the development of ALS. Through the use of antibiotics, probiotic supplementation, phage therapy, and other methods of inducing changes in the intestinal microbiota that can inhibit inflammation and delay neuronal degeneration, the clinical symptoms of ALS can be alleviated, and the progression of the disease can be delayed. Therefore, the gut microbiota may be a key target for effective management and treatment of ALS.

The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage of ALS patients having a known genetic risk factor. The article looks to integrate wider bodies of data on the biological underpinnings of ALS, highlighting the integrative role of alterations in the mitochondrial melatonergic pathways and systemic factors regulating this pathway across a number of crucial hubs in ALS pathophysiology, namely glia, gut, and the muscle/neuromuscular junction. It is proposed that suppression of the mitochondrial melatonergic pathway underpins changes in muscle brain-derived neurotrophic factor, and its melatonergic pathway mimic, N-acetylserotonin, leading to a lack of metabolic trophic support at the neuromuscular junction. The attenuation of the melatonergic pathway in astrocytes prevents activation of toll-like receptor agonists-induced pro-inflammatory transcription factors, NF-kB, and yin yang 1, from having a built-in limitation on inflammatory induction that arises from their synchronized induction of melatonin release. Such maintained astrocyte activation, coupled with heightened microglia reactivity, is an important driver of motor neuron susceptibility in ALS. Two important systemic factors, gut dysbiosis/permeability and pineal melatonin mediate many of their beneficial effects via their capacity to upregulate the mitochondrial melatonergic pathway in central and systemic cells. The mitochondrial melatonergic pathway may be seen as a core aspect of cellular function, with its suppression increasing reactive oxygen species (ROS), leading to ROS-induced microRNAs, thereby altering the patterning of genes induced. It is proposed that the increased occupational risk of ALS in farmers, gardeners, and sportsmen and women is intimately linked to exposure, whilst being physically active, to the widely used glyphosate-based herbicides. This has numerous research and treatment implications.