Fecal Microbiota Transplantation in Neurodegenerative Diseases: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by R. M. Damian Holsinger.

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. 

  • fecal microbiota transplantation
  • neurodegenerative disease
  • Alzheimer’s disease
  • Parkinson’s disease
  • Amyotrophic Lateral Sclerosis
  • Multiple sclerosis

1. Introduction

Neurodegenerative diseases present a unique challenge in the modern research landscape. Despite decades of research, ourthe understanding of the causes and mechanisms underlying them is still limited, and very few effective treatments exist. Given the lack of progress, the focus of the research community is increasingly shifting to exploring new or alternative factors that could influence either the pathogenesis or treatment of these diseases. One such factor is the gut–brain axis, which encompasses the bidirectional interaction between the gut and brain through neural, immune, endocrine and metabolic channels [1,2,3,4][1][2][3][4]. Neurodegenerative diseases are often associated with abnormal gut microbiome compositions [5,6,7,8,9,10,11[5][6][7][8][9][10][11][12][13],12,13], and as such, it is not surprising that modifying the gut microbiome is quickly becoming an area of interest for future research.
An increasingly popular method of microbiome modification is fecal microbiota transplantation (FMT). This treatment involves the transfer of gut microbiota from a ‘healthy’ individual to one who has a “diseased” gut microbiome, typically with the goal of correcting dysbiosis in the recipient [14]. It is usually used to treat Clostridium difficile infection (CDI), for which it is remarkably effective [15]; however, it is increasingly being used to treat other gastrointestinal diseases [16]. In the past few years, it has emerged as an intriguing option for treating neurological disease as well, resulting in a rapidly growing pool of literature [17].

2. Alzheimer’s Disease

Alzheimer’s disease (AD) is the single most common form of dementia, affecting approximately 40 million individuals globally [18]. It is a progressive neurodegenerative disease known for gradual deterioration in cognitive ability, especially memory [19], and distinctive pathological characteristics such as amyloid-beta (Aβ) plaques [20,21[20][21][22],22], neurofibrillary tangles (NFTs) [20[20][21],21], and heightened neuroinflammation [23,24,25,26][23][24][25][26]. Alterations in the AD gut microbiome have been noted both in humans [27,28][27][28] and in animal models [29,30][29][30]; in fact, gut microbiome changes appear to precede neurological pathology in APP/PS1 [31] and ADLPAPT mice [29]. Probiotics [32] and antibiotics [33] have been associated with improvements in AD outcomes, suggesting that correcting gut microbiome abnormalities may be a viable target for AD treatment; since FMT involves more expansive modifications to the microbiome than either probiotics or antibiotics can achieve [16], FMT may be even more effective.

3. Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting 3–5% of the population over 65 [49][34]. It is characterized by gradual loss of dopaminergic cells in substantia nigra pars compacta combined with the aggregation of α-synuclein (αSyn) into Lewy bodies [49][34]. PD is predominantly associated with motor symptoms such as tremor or postural instability, but it also presents with several non-motor symptoms, including sleep disturbances, psychiatric conditions and sensory symptoms [50][35]. PD is also associated with significant alterations in the gut microbiome [51][36] and gastrointestinal dysfunction [52][37], with constipation specifically considered one of the earliest markers of prodromal PD [53][38]. Many treatments exist, including exercise therapy, dopamine replacement and other pharmacologic treatment, and deep brain stimulation. However, effectiveness varies, with the most effective treatment in the early stages of PD, levodopa (L-dopa), being associated with adverse side effects such as dyskinesias and lack of impulse control [54][39]. Hence, there is a need for additional treatment options that allow for symptom relief without significant adverse side effects. Given the link between gut symptoms and PD, adjustment of the gut microbiome using FMT may be one such treatment.

4. Multiple Sclerosis

Multiple Sclerosis (MS) is the single most common demyelinating disease, characterized by gradual loss of myelination throughout the nervous system [63][40]. Primary symptoms directly related to demyelination include weakness, sensory loss and impaired balance, whilst secondary and tertiary symptoms, such as urinary tract infections and social isolation, develop as a consequence [64][41]. MS is often considered to progress through multiple stages, with gradual worsening of symptoms over time. In most cases, MS first occurs as a clinically isolated syndrome (CIS) consisting of various neurological symptoms that present for a few days, usually followed by subsequent periods of relapse and remission characteristic of relapsing-remitting MS (RRMS). Within 10–15 years, RRMS typically progresses to secondary-progressive MS (SPMS), as symptoms shift from a pattern of relapses to gradual progression without remission [65][42]. A small proportion of patients develop primarily progressive MS (PPMS) from onset without relapses early in the disease [65][42]. It is generally accepted that MS is an autoimmune disease, given that localized invasion of immune cells and cytokines in the CNS is considered a primary cause of progressive damage [66][43]. While there is a genetic component to the disease, environmental factors such as smoking, geographical location, vitamin D intake, and infection with Epstein–Barr virus, suggest that other factors may play a role in its pathogenesis [67][44]. MS patients often present with specific differences in gut microbiome composition, including a decrease in the genus Prevotella or increase in Akkermansia [68[45][46],69], suggesting an interaction between the gut and brain in MS. Currently, there is no cure for MS and most therapeutics are aimed at providing symptomatic relief [64][41], with particular emphasis on treating primary symptoms as they appear to prevent the subsequent development of secondary or tertiary symptoms [70][47]. Therefore, potential new disease-modifying treatments are needed.

5. Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with progressive loss of upper and lower motor neurons, leading to gradual loss of motor function accompanied by cognitive and behavioral changes that are within the spectrum of frontotemporal dementia [81][48]. The exact mechanism underlying the disease is not well known, but toxic protein aggregation, mitochondrial dysfunction, excitotoxicity and other cellular and molecular processes have been implicated with its development [82][49]. There is currently no cure, and the disease is typically fatal within 2–4 years of diagnosis. Three drugs are currently approved for the treatment of ALS but are only able to extend life expectancy by 3–6 months or slow the rate of decline in patients. Other treatments are aimed at relieving individual symptoms of the disease [83][50]. As with other neurodegenerative diseases described, ALS is associated with altered gut microbiome composition in humans and animal models alike [5,84][5][51]. There is hope that the gut microbiome may therefore be an additional target in the search for disease-altering treatments.

6. Conclusions

Despite extensive research over a number of decades, disease-altering treatments for neurodegenerative diseases are not yet available. When they do exist, treatments are generally aimed at alleviating symptoms, and may come with significant adverse side effects, limiting their use. There is therefore a desperate need for new treatment options that improve quality of life or modify the disease itself in a meaningful way. The evidence summarized in this review suggests that FMT is a potential treatment for these diseases that has, to date, not been explored. It is important to note that this specific area of research is still in its infancy and there are still several limitations regarding the current pool of research. For instance, while case studies are valuable for providing inspiration for future studies, and animal studies can provide further insight, clinical trials are still either very limited or lacking entirely. Additionally, FMT protocols are rarely standardized across multiple studies, and it is therefore difficult to make meaningful inferences on a meta scale. As noted previously in the section on PD, different delivery routes (e.g., nasoduodenal tube or colonic delivery) can produce significantly different outcomes [62][52]. Some studies may administer antibiotics beforehand, others might not; some studies may use a single FMT infusion, others may use multiple. Guidelines do exist to aid researchers in selecting donors; however, standardized protocols are still not available [87][53]. Given this absence, it would be beneficial for future research to either establish standard procedures or examine the impact of factors such as those mentioned, so that comparison between studies may become possible.

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