Introduction
The term “gut microbiota” refers to the complex community of bacteria, fungi, archaea and eukarya that inhabit the human gastrointestinal (GI) system. The abundance and diversity of these microorganisms are vital for gut health and homeostasis, as they collectively harbor 100 times more genomic content than human cells [1]. It is estimated that over 1013 bacterial cells reside in the GI tract [2], with the most common phyla being Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria [3]. While some components of the microbiota are shared across people, the exact composition is host-specific beginning at birth or possibly even prenatally, according to some studies [4, 5]. Microbial diversity increases with age, stabilizes in adulthood and declines in older populations [6]. Nevertheless, age is not the only contributing factor; genetics, environment, antibiotic use, the immune system and diet also play significant roles. Recent discoveries have highlighted that even within identical bacterial strains, there are genetic differences – known as microbial genomic structural variants – that are unique to each host’s microbiota and correlate with its health [7]. Environmental factors, such as exercise and geographical location, also influence the composition of the microbiome, while prolonged stress can lead to dysbiosis [8, 9]. Antibiotic treatment is a well-known cause of reduced microbial diversity: although this effect is reversible over time. Prolonged use can result in various complications. For example, antibiotics can promote the growth of antibiotic-resistant species and pathobionts like Clostridioides difficile at the expense of beneficial strains. In infants, antibiotic use can delay the development of the microbiota and is speculated to conditions such as asthma and obesity later in life [10]. Diet also plays a critical role in shaping the microbiome, with the quantity and type of consumed sugars, fats and fiber significantly affecting the growth of certain bacterial populations as they adapt to the nutrients available in the GI tract [1, 11]. These changes are significant because the gut microbiota facilitates various metabolic functions including the fermentation of complex carbohydrates to produce short-chain fatty acids (SCFAs). SCFAs in turn regulate essential cellular processes in epithelial cells. Additionally, the gut microbiota is involved in the synthesis of vitamin B12 and folate and it performs many other vital functions in the human organism, such as maintaining mucosal barriers and contributing to the development of the immune and nervous systems.
In recent years, it has become increasingly evident that the gut microbiota plays a more significant role in human health than previously understood. Its involvement in neuropsychiatric disorders and its connection to brain function have led to a surge in research and the development of the term “gut-brain axis” (GBA). This concept describes a bidirectional communication network that integrates neural, immune and endocrine components. The autonomic nervous system (ANS), enteric nervous system (ENS) and hypothalamic-pituitary-adrenal (HPA) axis serve as the primary descending pathways of this network [12]. The brain influences intestinal motility, permeability and partially regulates food intake. It also affects the secretory functions of enteroendocrine, immune and Paneth cells in the GI tract [12, 13]. Furthermore, studies using animal models have demonstrated psychological stress can directly affect the gut microbiota through HPA axis activation. For example, O’Mahony et al. found that rodents exposed to stressors exhibited increased corticosterone levels and altered immune responses, along with concurrent changes in microbiome composition [14]. One study observed a decrease in bacteria from the genus Bacteroides, and an increase in those from the genus Clostridium in mice subjected to stress [15]. The gut microbiome begins influencing the development of the nervous system very early in life [16]. To demonstrate the role of the gut microbiome in the proper development of the HPA axis and subsequent stress responses, Sudo et al. showed that germ-free mice exhibited an exaggerated stress response compared to mice with a specific pathogen and this effect could be reversed by recolonization the GI tract, though only up to a certain point in life [17]. Although these upward regulatory mechanisms start developing prenatally, they continue to function throughout an individual’s lifespan, operating through the ENS, vagal afferent nerves (VAN), cytokines, immune mediators, and microbial and intestinal metabolites. The vagus nerve is the most direct communication pathway from the gut to the brain. While it is not directly affected by the microbiota, it responds to the release of serotonin and hormones such as peptide YY (PYY), glucagon-like peptide 1 (GLP-1), and cholecystokinin (CCK) by enteroendocrine cells (EECs). These cells possess toll-like receptors (TLRs) that can detect bacterial signals, such as the presence of lipopolysaccharide, peptidoglycan or SCFAs. Through this mechanism, EECs can distinguish the bacterial populations in the gut and subsequently influence the VAN, altering GI secretion, motility and food intake [13, 18]. SCFAs, such as acetate, propionate and butyrate, are produced by bacterial fermentation in the intestine and interact with receptors on EECs, stimulating the production of PYY, and other satiety peptides (GLP-1, CCK, and leptin) [12]. Notably, propionate administration has been shown to facilitate weight loss in obese patients and is thought to influence gene expression in the dorsal vagal complex of the brainstem and hypothalamus, illustrating the potential role of the gut microbiota in appetite regulation [19]. SCFAs also play a crucial role at the epigenetic level, inhibiting histone deacetylase and regulating the function of regulatory T cells (T-regs). This has led to research on the potential use of butyrate as a therapeutic agent for neuropsychiatric disorders [11, 20]. Other metabolites regulated by commensal organisms include serotonin, along with neurotransmitters such as glutamate, γ-aminobutyric acid (GABA), acetylcholine, and dopamine [13]. Interestingly about 50% of the body’s dopamine and 90% of its serotonin are synthesized in the gut. Although some of these neurotransmitters can be produced by bacteria in the GI tract, they cannot cross the blood-brain-barrier (BBB) and must be synthesized in the brain from locally available neurotransmitter precursors. These precursors are derived from the diet and are partly influenced by gut microbiota metabolism. For example, tryptophan, a precursor of serotonin, has its availability regulated by Clostridia species, illustrating one of the gut’s indirect effects on neural signaling [21]. In addition, the microbiota regulates the function of various immune cells influencing the levels of circulating inflammatory cytokines and the permeability of the BBB. The GI system maintains a delicate balance between immune responses to pathogens and tolerance of commensal bacteria [22]. This balance is achieved through the innate immune system, which uses pattern recognition receptors to identify pathogen-associated molecular patterns (PAMPs) e.g. lipopolysaccharides (LPS) from Gram-negative bacteria, lipoteichoic acids from Gram-positive bacteria and various lipoproteins and peptidoglycans. In response, immune cells can stimulate the production of pro-inflammatory mediators that promote the elimination of pathogens when necessary [23, 24]. However, prolonged activation of these immune responses can lead to gut dysbiosis and increased intestinal permeability, which can further contribute to systemic inflammation. This, in turn, increases BBB permeability and activates microglia, the brain’s immune cells, which regulate neuroinflammation, influence synaptic remodeling and are implicated in many neurodevelopmental and neurodegenerative diseases [25]. Some studies have even used LPS as an inducer of neuropsychiatric disease in animal models [26, 27].
As discussed, the composition of the gut microbiota is shaped by a multitude of innate and environmental factors, influencing a wide range of metabolic and immunological processes. These processes may contribute not only to the development of gastrointestinal conditions but also to neurological, metabolic and psychiatric diseases.
The aim of this work is to present the results of recent studies on the influence of intestinal microbiota in the progression of selected neurodegenerative diseases, including multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease (PD), as well as neurodevelopmental disorders such as autism and schizophrenia and the potential role of fecal microbiota transplantation (FMT) as a therapeutic intervention for these conditions.
Fecal microbiota transplantation
FMT, also known as stool transplant, bacteriotherapy or intestinal microbiota transplant, is a relatively new and effective treatment for conditions related to gut dysbiosis. This procedure involves transferring healthy microbiota from a donor directly into the patient’s gastrointestinal tract to restore or establish a stable microbial community. FMT was initially used to treat recurrent Clostridioides difficile infection (rCDI) and has since become a standard practice for this condition [28, 29]. Donor samples can be administered either orally in capsules or through transcolonoscopic, nasoduodenal or nasogastric infusions. However, the optimal protocol for transplantation, including the number of samples to be administered, is still under discussion. Compared to oral probiotics, FMT offers a quicker and longer-lasting restoration of gut microbiota, providing a broader variety of microbial species [30]. Long-term engraftment of these species into the recipient’s gut has been shown to last up to 4 months, based on comparisons of gut microbiota profiles between donors and patients after transplantation of frozen samples [31]. FMT has proven to be highly effective in treating rCDI, with an estimated 90% of patients experiencing a disease-free period ranging from 3 to 201 months, and in some cases even longer [32]. A double-blind randomized control trial found that FMT from a donor was more effective than autologous FMT. Donor samples resulted in a reduction of Proteobacteria and Verrucomicrobia and an increase in Bacteroidetes and Firmicutes, effectively restoring the proper gut microbial structure – an outcome not observed with autologous samples [33]. The success of FMT may be attributed to findings from a study on gnotobiotic mice, which showed that commensal microbes from donors had a greater potential to colonize niche spaces in the GI tract compared to the recipient’s native microbes [34]. Despite the confirmed efficacy of FMT, there remains the challenge of preparing fecal samples in a way that allows for easy availability and storage, which is not feasible with fresh donations. Several studies have compared fresh, frozen and lyophilized microbiota concluding that all forms are non-inferior to each other, although with lyophilized microbiota may be slightly less effective. The same holds true for colonoscopic and oral routes of administration, with results being comparable. However the colonoscopic approach is psychologically easier for patients [35–37]. To enhance the accessibility of FMT, several ready-to-use therapeutics are currently in development. For example, Gonzales-Luna et al. in their review, highlighted several agents that have advanced to Phase III clinical trials, including CP101 – an oral capsule containing lyophilized healthy donor stool [38]. The methods of FMT are rapidly evolving with the goal of establishing it as a standardized, widely available treatment for various conditions. The success of FMT in treating CDI has paved the way for its application to other intestinal diseases. Additionally, FMT shows potential in eradicating multidrug-resistant bacterial infections, as it has been demonstrated to reduce the number of antibiotic resistance genes in patients with rCDI [39]. FMT has also been used to treat irritable bowel syndrome (IBS), particularly in the constipation-predominant type. However, a meta-analysis on this subject showed no significant clinical difference between the control and intervention groups [40]. The same review examined the effects of FMT on inflammatory bowel diseases, such as ulcerative colitis (CU) and Crohn’s disease (CD). In both conditions, FMT was found to have therapeutic properties, reducing symptoms and inducing endoscopic and histological remission, though recurrent infusions were often required to achieve these results. Other GI conditions targeted for FMT therapy include metabolic syndrome and hepatic disorders, although research in these areas remains limited [30, 40]. Interestingly, a study by Kurokawa et al. found that patients with irritable bowel syndrome (IBS), functional diarrhea and functional constipation who underwent FMT experienced improvements in anxiety and depression symptoms, regardless of changes in their GI symptoms [41]. This finding further underscores the connection between gut microbiota and brain function, highlighting the topic of GBA. Although FMT initially emerged as a treatment for GI conditions, there is a growing interest in its potential application in neurodegenerative and neurodevelopmental diseases.
Influence of microbiota on neurodegenerative conditions
Multiple sclerosis (MS)
MS is an autoimmune disease characterized by inflammation leading to progressive demyelination within the central nervous system (CNS). The majority of patients exhibit a relapsing-remitting form of MS (RRMS), which may evolve into secondary progressive MS (SPMS) over time. While the exact cause of the disease remains unclear, both genetic and environmental factors are known to contribute to its development. Characteristic symptoms include neuritis, ataxia, spasticity, fatigue and cognitive impairment [42]. Additionally, up to two-thirds of patients report at least one persistent GI symptom, such as constipation, dyspepsia, dysphagia or incontinence [43]. These intestine symptoms are connected to the altered microbiome observed in MS patients as compared to healthy controls. A study by Chen et al. demonstrated minimal differences in the richness of microbiota within a Japanese population of MS patients; however there were significant and consistent changes in the overall structure of their microbiome. Specifically, fecal samples from RRMS patients showed a depletion of fourteen species belonging to Clostridia clusters XIVa and IV, which are known for their ability to produce SCFAs. There was also a reduction in genus Bacteroides, including B. stercoris, B. coprocola, and B. coprophilus. The dysbiosis observed in MS patients was moderate and far less pronounced compared to other conditions like IBS [44]. Similar findings were reported in another study, which showed a decreased species richness in patients with active MS as compared to those in remission and healthy controls, suggesting a possible link between gut microbiota and disease exacerbation [45]. Evidence for the influence of microbiota on the development of neurological symptoms in MS comes from studies using autoimmune encephalomyelitis (EAE) mouse models. Lee et al. demonstrated that germ-free animals developed a milder form of EAE compared to conventionally colonized mice, likely due to the absence of immune stimulation by gut bacteria. This was characterized by lower levels of interferon-γ and interleukin-17A (IL-17A) in the intestines and spinal cord, along with increased levels of CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) [46]. Additionally, in other studies, the transplantation of microbiota from MS patients into germ-free mice resulted in more severe EAE with reduced numbers of IL-10+ Tregs compared to mice colonized with microbiota from healthy controls. The role of IL-10 in CNS autoimmunity is further highlighted by findings that administration of anti-IL-10 antibody increased the incidence of EAE. Researchers have also identified bacterial taxa, such as Akkermansia muciniphila associated with MS that are capable of inducing pro-inflammatory response [47, 48]. Some success has been reported in altering the microbiota of MS patients using probiotics, with the aim of slowing disease progression and alleviating some of the symptoms. MS patients who received long-term multi-strain probiotic treatment showed a decrease in their Expanded Disability Status Scale (EDSS) scores, alleviation of depression symptoms and overall improvement in general health. Additionally, there was a notable reduction in levels of inflammatory markers such as IL-6 and C-reactive protein (CRP), along with an increase in IL-10 [49, 50].
FMT remains a largely unexplored alternative for treating MS, but there are encouraging signs that it could be a viable option. One case study reported on an SPMS patient who underwent FMT for rCDI. The treatment not only stabilized the patient’s EDSS score but also led to further improvement over a 10-year period [51]. Similarly, a 52-year-old woman with a 20-year history of RRMS experienced improved muscle strength and a slight decrease in her EDSS score following FMT infusion [52]. In another case series, a prolonged remission and reversal of neurological symptoms were also noted in MS patients who received FMT for gastrointestinal conditions. A 30 year-old man regained the ability to walk and remained in remission for at least 15 years, while an 80-year-old woman became asymptomatic for over 2 years after receiving infusions [53]. One proof-of-concept single-subject study investigated the effects of FMT on a patient with a 2-year history of RRMS and walking difficulties. Engen et al. found that after 10 FMT infusions, the patient showed significant improvements in gait metrics, including stride distance, cadence and walking speed. These improvements were confirmed at the 12-month follow-up and no relapses were reported during that period. Moreover, changes in the patient’s gut microbiota were observed, including an increase in SCFAs, α-diversity and the abundance of butyrate-producing bacteria (Faecalibacterium prausnitzii) [54]. A randomized controlled pilot study was also conducted to assess the safety and tolerability of FMT in MS patients, but it was terminated early, rendering the results inconclusive. While the study suggested that FMT might improve small intestinal permeability and lead to beneficial alterations in patients’ microbiota, it did not show changes in MRI results or EDSS scores [55]. Despite the challenges, the findings from these studies offer hope that FMT could become a new treatment option for MS, and further research in this area is warranted.
Alzheimer’s disease (AD)
AD is a neurodegenerative disorder primarily characterized by cognitive impairment especially in its early stages. The disease is marked by neuronal and synaptic loss, the presence of β-amyloid (Aβ) protein aggregates, and the accumulation of hyperphosphorylated and misfolded tau protein in the brain [56]. Emerging evidence suggests that the gut microbiota may play a role in the pathogenesis of AD. Notably, studies have demonstrated a significant Aβ plaques reduction in a mouse model that achieved germ-free status following antibiotic treatment. This reduction was partially reversed after FMT from AD mice, and to a lesser extent, from wild-type mice. Unfortunately, the precise mechanism underlying these observations remains speculative [57, 58]. Additionally, there is substantial evidence indicating that the gut microbiota of AD patients differs from that of healthy individuals. In AD patients, microbial diversity is altered with increased levels of genera such as Escherichia, Bacteroides, and Ruminococcus and decreased levels of the species Eubacterium rectale, genus Bifidobacterium and members of the Firmicutes phylum. It is important to note that some of the more abundant bacterial strains in AD patients are known for their pro-inflammatory properties, such as Bacteroides, coated with LPS, that have been shown to accelerate amyloid deposition. On the other hand, the less abundant bacteria in this patients tend to exert anti-inflammatory effects. For example, Bifidobacterium species are involved in maintaining gut barrier integrity and reducing bacterial translocation from the gut to systemic circulation [59–61]. These shifts in microbial composition may influence the progression of AD, as there is a positive correlation between the prevalence of pro-inflammatory microbes and cerebrospinal fluid markers of AD pathology, including amyloid and tau protein [60]. In fact brain amyloidosis has been linked to gut microbiota composition. When comparing cognitively impaired patients with (Amy+) and without (Amy-) amyloidosis it was found that Amy+ patients exhibited greater gut dysbiosis. This dysbiosis was positively correlated with increased levels of pro-inflammatory cytokines, such as IL-6, CXCL2, NLR family pyrin domain containing 3 (NLRP3) and IL-1β, and decreased levels of the anti-inflammatory cytokine IL-10 [59]. The NLRP3 inflammasome is particularly interesting due to its role in promoting the aggregation of misfolded proteins. In animal models of AD, NLRP3 inflammasome deficiency has been associated with reduced deposition of Aβ plaques and enhanced phagocytosis of these plaques [62]. Additionally, abnormalities in the gut microbiota of Alzheimer’s patients, such as perturbations in SCFAs and tryptophan levels, have been identified. SCFA levels are often lower in AD patients, likely due to a decreased abundance of SCFA-producing bacteria from the Firmicutes phylum. Since SCFAs can cross the BBB and induce the maturation of glial cells, their reduced levels may serve as a predictor of conversion from amnestic mild cognitive impairment to AD [63, 64]. In the case of tryptophan, fecal metabolomic analyses have shown that reduced levels of 5-hydroxytryptophan are positively correlated with cognitive impairment in AD and gut dysbiosis [64]. These correlations suggest that gut microbiota may influence AD symptoms, making probiotic treatment a promising therapeutic intervention. Numerous studies in rat models have demonstrated that supplementation with Lactobacillus and Bifidobacterium can improve learning and memory, as well as decrease the number of Aβ conglomerates [65–67]. In human trials, as little as 12 weeks of probiotic treatment has shown a favorable effect on cognitive functions [68, 69].
Several studies have explored the efficacy of FMT in animal models of AD. These studies have demonstrated that FMT can reduce amyloid deposition in transgenic mice, potentially by inhibiting the activity of C-Jun N-terminal kinase. Moreover, FMT has been shown to reverse the decrease in levels of PSD-95 and synapsin 1 in AD mice, both of which are crucial markers of abnormal synaptic plasticity and are often altered in AD. Another promising aspect of FMT is its potential to mitigate neuroinflammation, as it may reduce the levels of cyclooxygenase-2, an enzyme involved in activating pro-inflammatory signaling pathways [70]. In a study by Kim et al., the transplantation of microbiota from healthy mice into AD mouse models was found to have beneficial effects. This treatment led to a significant decrease in β-amyloid plaque burden and tau pathology, along with improvements in cognitive function. Furthermore, studies have demonstrated an association between amyloid plaques and increased intestinal permeability, likely resulting from dysfunction in macrophage-mediated barrier integrity. Diseased mice exhibited altered colonic gene expression, characterized by the downregulation of genes involved in intestinal macrophage activity, the monocyte-macrophage axis and cell proliferation. Notably, these gene abnormalities, which contribute to chronic inflammation, were found to be reversible after FMT [71]. Additionally, there is also evidence suggesting that the donor’s age is a crucial factor when considering treatments of age-related diseases like Alzheimer’s. Cognitive improvement was more pronounced in mice that received transplants from younger rodents compared to those matched for age. This restoration of hippocampal function was associated with a reduction in plaque load [72]. While these results in animal models are promising, large-scale studies in human population are still lacking. However, there are two significant case reports involving patients with AD who were treated for rCDI, and subsequently experienced considerable improvements in cognitive function, memory and mood following FMT. In the first case the patient was initially diagnosed with cognitive impairment scoring 20 points on the Mini-Mental State Examination (MMSE). Remarkably, this score improved to 26 points just 2 months after a single FMT infusion. At a 6-month follow-up visit the patient reported a subjective improvement in mood and achieved a score of 29 points on the MMSE, indicating a return to normal cognitive function [73]. In the second case study, a female patient with moderate cognitive impairment (MMSE 15) and severe depression, as indicated by a Geriatric Depression Scale (GDS) score of 23, underwent FMT treatment. One month after the first FMT, her MMSE score improved to 18, and after 2 additional months it reached 20, indicating a shift to mild cognitive impairment. This improvement was sustained 1 week after the second FMT and was accompanied by reduction in depression severity, with her GDS score decreasing to 17, indicating mild depression. Additionally, there were notable changes in patient’s microbiota composition and SCFA levels following the treatment [74]. Despite encouraging findings, much research is still needed to fully understand the role of gut microbiota in the development and progression of AD and other age-related cognitive impairments. Our current knowledge is not yet sufficient to draw definitive conclusions. Nevertheless, the preliminary evidence suggests that FMT holds potential as a treatment option for cognitive impairments associated with aging. For example, Chen et al. have shown that FMT can improve cognition in patients with mild cognitive impairment and does not lead to decline in cognitive scores in patients with severe cognitive impairment. These improvements were measured using the Montreal Cognitive Assessment-Basic (MoCA-B), Activities of Daily Living (ADL), and the cognitive section of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) [75].
Parkinson’s disease (PD)
PD is characterized by the accumulation of α-synuclein aggregates, known as “Lewy bodies” within midbrain dopamine neurons, leading to neurodegeneration. The progressive loss of these neurons, which connect the midbrain to the striatum, results in the primary symptoms of the disease, including bradykinesia, muscle stiffness, and asymmetric tremor [76]. Interestingly, alfa-synuclein aggregates have also been identified in the ENS, suggesting a potential link between the brain and gut in PD [77]. This connection is further supported by the fact that the majority of PD patients experience GI symptoms, which often manifest years before the onset of motor symptoms [76, 78]. To reinforce this brain-gut hypothesis, studies using mouse models of PD have demonstrated that α-synuclein can originate in the gut, cross the BBB and subsequently spread to the brain [79]. In line with this evidence and the recognized influence of the microbiome on neurodegenerative diseases, significant alterations in the gut microbiome have been observed in PD patients compared to healthy controls. One of the pioneering studies on the gut microbiota in Parkinson’s disease was conducted by Scheperjans et al. They found a significantly lower prevalence of the Prevotellaceae family in PD patients, a change that was independent of the Wexner constipation score. In addition, the study revealed that postural instability and gait difficulty in PD patients were positively associated with an increased population of the Enterobacteriaceae family, suggesting a potential correlation between microbiota composition and disease progression [80]. Further research has identified gut microbiota alterations at a genus level in PD patients. Specifically, there were numbers of Dorea, Bacteroides, Prevotella, and Faecalibacterium genera, coupled with a higher abundance of Christensenella, Catabacter, Oscillospira, Bifidobacterium and Lactobacillus genera in PD patients [81]. The Lactobacillaceae family, known for its ability to interact with ENS neurons, has been implicated in the regulation of α-synuclein secretion. The increased abundance of Lactobacillaceae observed in PD patients was associated with decreased levels of ghrelin, a gut hormone known to regulate nigrostriatal dopamine function [80]. However, the findings across different studies are not consistent, underscoring the need for further research with larger populations to draw more definitive conclusions regarding microbiota composition in PD. For instance Hill-Burns et al. reported elevated levels of Akkermansia, Lactobacillus, and Bifidobacterium genera in PD patients, along with reduced levels of the Lachnospiraceae family. Interestingly, they did not observe any significant differences in the Prevotellaceae family [82]. Still, the gut microbiota seems to play a significant role in the progression of PD. For example, in a study involving α-synuclein-expressing mice, the transplantation of microbiota from PD patients caused a deterioration in motor symptoms, while the depletion alleviated these symptoms, reduced α-synuclein aggregation and mitigated constipation [83]. Similarly, FMT from PD donors to healthy recipients was found to induce PD symptoms, promote dopaminergic neuronal death and increase LPS levels [84, 85]. Another study explored the use of osteocalcin injections to prevent motor deficits and dopaminergic neuron loss in a mouse model of PD. Interestingly, the protective effects of osteocalcin were only observed in mice with an existing gut microbiota, whether native or transplanted; no protective effects were noted in mice treated with antibiotics. This protective function was associated with increased levels of propionate. Moreover, oral administration of propionate also conferred beneficial effects on PD mice, suggesting its potential as a therapeutic target [86].
The application of FMT in PD research is still relatively novel and underexplored. In a study using a rotenone-induced PD mouse model, significant alterations in the gut microbiome were observed, including an increase in the Verrucomicrobia phylum, particularly the Akkermansia genus and a decrease in the Bacteroidetes phylum and in Helicobacter pylori. FMT treatment resulted in a microbiota composition that closely resembled that of the donor group, most importantly reducing the abundance of the Akkermansia genus – bacteria that is known for its ability to degrade the intestinal mucosal barrier. In addition to alleviating GI and motor symptoms, FMT lowered LPS levels, which in turn suppressed inflammation signaling pathways and improved gut permeability [85]. Furthermore, this treatment was associated with decreased microglial activation in the substantia nigra and increased concentrations of striatal dopamine and 5-HT in the treated mice [84]. Interest in the efficacy of FMT for treating PD in humans has been steadily increasing, with research ranging from small case reports to large-scale clinical trials emerging in recent years. In a case series published in 2021, 6 patients underwent FMT and after 4 weeks, 5 of them reported improvements in the Unified Parkinson’s Disease Rating Scale (UPDRS-III), the Non-Motor Symptoms Scale (NMSS) and constipation scores. Notably, at week 24 both motor and non-motor benefits were sustained in the majority of these patients [87]. Another case study reported on a single patient treated with FMT primarily for constipation. The patient experienced significant improvements in constipation scales, which persisted for up to 3 months of follow-up, alongside a reduction in UPDRS scores. Remarkably, his leg tremor nearly ceased 1 week after transplantation, although the tremor returned after 2 months, it was considerably less severe than before [88]. A preliminary study involving 15 patients reported promising results after a 3-month follow-up period, including a reduction in UPDRS-III scores, improved sleep quality, and partial alleviation of depression and anxiety symptoms. Interestingly, these positive results were observed only in the group that received colonic FMT, as opposed to the nasointestinal approach. During an extended follow-up, 2 patients from the colonic group maintained a satisfactory response for up to 24 months, while none in the nasointestinal group experienced benefits beyond 3 months of satisfaction [89]. In an effort to understand the effects of FMT on microbiota composition in PD patients who experienced improvements in constipation, motor and non-motor symptoms, researchers compared microbiota profiles before and after treatment. The analysis revealed that patients had a lower overall abundance of fecal microbiota in both before and after FMT compared to healthy controls. However, specific genera such as Blautia and Faecalibacterium and members of Lachnospiraceae family increased after treatment. Initially, Bacteroides was the dominant genus in PD patients, but its abundance gradually decreased up to 12 weeks post-transplantation, with a corresponding rise in genera such as Collinsella, Eubacterium hallii group, Ruminococcus 1, Dorea, Blautia and Romboutsia. Additionally, a decline in Escherichia-Shigella was observed, which coincided with improvements in postural instability and gait difficulties [90]. In recent years, several randomized clinical trials have been conducted to evaluate the use of FMT in PD, with their findings now published. In one smaller study, DuPont et al. recruited 12 patients with mild to moderate Parkinson’s disease and administered either an orally delivered FMT product or a placebo. Approximately 10 weeks after treatment, patients who received the FMT reported subjective improvements in various symptoms, including constipation, falls, sleep disturbances, motor deficits, and overall Parkinson’s symptoms. Additionally, their motility index showed significant improvement. Analysis of gut microbiota revealed notable changes, particularly an increase in specific families within the phylum Firmicutes [91]. Bruggeman et al. recently published the findings of the GUT-PARFECT trial, a double-blind, placebo-controlled, phase 2 trial conducted at Ghent University Hospital with 46 participants. The results suggest that a single FMT can induce mild, but long-lasting improvements in motor symptoms in patients with early-stage PD. Specifically, patients showed significant improvements in their Movement Disorder Society-UPDRS-III scores at the 12-month follow-up [92]. Similar outcomes were obtained in another placebo-controlled study involving 56 participants. In this study, total MDS-UPDRS scores were significantly reduced in both the treatment and placebo groups at weeks 4 and 8. However, while the placebo effect wore off by week 12, the benefits in the FMT group persisted. Notably, the MDS-UPDRS part 1 score showed a more pronounced decrease in the treatment group as early as week 4, suggesting that FMT can improve the quality of life for PD patients. Additionally, improvements in non-motor aspects, including cognitive function, were evidenced by a significant decrease in the MOCA scores. Researchers also identified specific bacteria from the phylum Firmicutes, such as Eubacterium eligens, Eubacterium ventriosum, and Roseburia, which showed positive correlations with improvements in the gastrointestinal function and PD symptoms. These findings suggest that combining FMT with conventional PD treatments may lead to more substantial symptom relief [93]. However, contrasting results were reported by Scheperjans et al., who found no significant difference in MDS-UPDRS (I-III) scores between patients who received FMT and those in the placebo group at the 6-month follow-up [94]. Despite these mixed results, the examples above demonstrate the strong potential of FMT as a treatment for alleviating both motor and non-motor deficits in PD.
Influence of microbiota on neurodevelopmental conditions
Autism
Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by difficulties in social interactions, communication challenges, and stereotypic behaviors. In the United States, nearly 1% of children are diagnosed with ASD and a significant number of them experience GI issues, most commonly constipation [95, 96]. The prevalence suggest a potential link between gut microbiota and ASD, yet research findings on this connection have been inconsistent. Some studies report no significant differences in the diversity or composition of microbiota between ASD patients with and without GI symptoms, as well as compared to healthy controls and neurotypical siblings. The changes reported in abundance of phyla such as Firmicutes, Bacteroidetes and Proteobacteria have been contradictory, with none achieving statistical significance. Moreover, findings on microbiota richness and diversity in ASD have been conflicting, with reports indicating both increases and decreases [97–100]. Despite these inconsistencies, some research has identified correlations between GI symptoms, autism severity, and alterations in the gut microbiome. Adams et al. observed that children with ASD had lower levels of beneficial bacteria such as Bifidobacterium and Enterococcus genera alongside a higher abundance of the Lactobacillus genus [101]. Additionally, an increased abundance of the genus Suterella has been noted in ASD children [102, 103], and a correlation between higher levels of Ruminococcus torques and GI disorders in ASD patients has been established [103]. The results concerning a higher incidence of several Clostridium clusters in ASD patients seem to be in agreement with each other. What is more, patients with GI symptoms exhibited an even more pronounced increase in these clusters, especially in the population of Clostridium perfringens and its associated toxins [104–106]. However, despite these observations, the overall, microbial gut composition in ASD patients does not appear to follow a clear global pattern. A statistical analysis of the available data indicates that only a few bacteria, such as the genus Prevotella, the phylum Firmicutes at l, Clostridiales clusters and selected Bifidobacterium species show a somewhat consistent configuration across studies [107]. In autism spectrum disorder, “leaky gut” and other GI disorders are very common, and a correlation between these conditions and ASD has been shown by Hsiao et al. Using a maternal immune activation (MIA) model, they showed that offspring of MIA-exposed mice exhibit both ASD-like behaviors and concurrent alterations in gut microbiota, alongside defects in gut permeability. These intestinal barrier integrity issues emerged very early, being detectable in 3-week-old mice. The offspring exhibited an increased abundance of Prevotellaceae, Bacteroidales and Lachnospiraceae, suggesting that these microbial changes contribute to gut health issues associated with ASD [108]. Furthermore, even colonization of germ-free mice with microbiota derived from ASD patients has been shown to independently promote ASD-like symptoms, including increased repetitive behavior, decreased sociability, and reduced locomotion [109, 110]. These microbiota-induced changes affect metabolic pathways that regulate alternative splicing of mRNA, gene expression and the production of taurine and 5-aminovaleric acid. Both of these amino acids act as GABAA receptor agonists and their levels were found to be decreased in recipient mice, indicating that gut microbiota can influence inhibitory GABA signaling [110]. In rat models receiving FMT from ASD patients, elevated levels of 5-HT – a neurotransmitter linked to autism that plays an important part in neuronal development, were observed [109]. Additionally, alterations were observed in tryptophan metabolism and the serotonergic synapse pathway, which were positively correlated with several genera within the order Clostridiales [111]. Deficient tryptophan metabolism was also associated with a reduction in species such as Bifidobacterium and Blautia [112].
Despite the uncertainty surrounding the involvement of gut microbiota in autism, there have been promising results from studies using FMT in autistic patients. In a mouse model, FMT from healthy donors to affected mice led to a normalization of A. muciniphila abundance, improved memory and social behavior and decreased levels of TNF-α in the brain [113]. Similarly, using in vitro cultured human gut microbiota as transplants also had a significantly positive effect on anxiety-like and repetitive behaviors, as well as chemokine levels. This approach also resulted in the normalization of microbiota composition, with a relative decrease in key taxa including Clostridiaceae and Prevotella, producing outcomes comparable to those achieved with donor-derived microbiota [114]. In human studies, the effects of FMT appear to be significant as well. Two case reports have documented a significant improvement in autism symptoms following FMT treatment. In 1 case report, a 19-year-old patient experienced a significant reduction in aggression, improved sleep patterns, and spoke his first two words 1 month after undergoing FMT. His gastrointestinal symptoms, including bloating, constipation, and diarrhea, also showed marked improvement. At 16 months post-FMT, the patient’s Childhood Autism Rating Scale (CARS) score had significantly decreased, indicating an overall reduction in autism severity [115]. The other case involved a 7-year-old child who received five rounds of FMT. Following treatment, both the CARS and Social Responsiveness Scale (SRS) scores decreased, reflecting improvements in social skills. Additionally, there was noticeable progress in gross motor skills, adaptive behavior, and language development [116]. In a study by Kang et al., 18 children with ASD underwent an 8-week FMT treatment which led to significant improvements in GI symptoms such as abdominal pain, reflux, indigestion, diarrhea, and constipation. Notably, there was also an alleviation of many autistic symptoms as measured by the Parent Global Impressions-III scale. These improvements persisted for the entire 8-week follow-up period and were associated with notable alterations in the gut microbiota of the recipients. Specifically, there was an overall increase in bacterial diversity, with a marked elevation in the relative abundance of genera such as Bifidobacterium, Prevotella and Desulfovibrio. The shift brought the recipient’s microbiota composition closer to that of the donors, suggesting a strong engraftment of the introduced microbial communities [117]. The authors conducted a 2-year follow-up and reported that the positive effects of the treatment persisted, with autism-related symptoms continuing to improve steadily from the end of the trial up to the 2-year mark. This finding underscores the long-term effect of FMT in managing ASD symptoms [118]. Similarly, another study administered oral lyophilized FMT treatment to 38 children with ASD and observed a significant reduction in autism-related symptoms. At the 20-week follow-up, scores on the Autism Behavior Checklist (ABC), CARS and SRS decreased, alongside an improvement in sleep disturbances. Although there was no significant change in overall microbiota biodiversity, specific alterations were noted: levels of Blautia, Sellimonas, Saccharomycopsis, and Cystobasidium decreased, while levels of Dorea increased after FMT [119]. Other authors have reported similar improvements in both GI and autism-related symptoms, though with different shifts in bacterial populations, such as a decrease in Bacteroides fragilis and Bacteroides vulgatus after treatment [120]. In one study, a lower abundance of Eubacterium coprostanoligenes prior to FMT was found to correlate with a better response to treatment, and its subsequent increase after FMT was associated with a reduction in GI symptoms. The influence of FMT on ASD severity may also extend to neurotransmitter regulation. Researchers observed that FMT treatment decreased serum concentrations of both 5-HT and GABA while increasing dopamine levels. Interestingly 5-HT showed a negative correlation, and GABA a positive correlation with the Bristol stool score, indicating a potential link between neurotransmitter levels and gastrointestinal function [121]. These findings suggest that FMT may have a consistent and beneficial impact on ASD symptoms, reinforcing its potential as a therapeutic option. The consistent results across different studies highlight the promising role of FMT in managing both the gastrointestinal and neurological aspects of autism spectrum disorder.
Schizophrenia
Schizophrenia is a mental disorder that causes abnormal social behavior, with symptoms that include delusions, hallucinations, disorganized speech and behavior. Patients may also exhibit negative symptoms, such as diminished emotional expression or avolition [122]. The disorder is characterized by dysfunction in the dopaminergic system [123], its pathophysiology remains complex and not fully understood, involving a variety of epigenetic and environmental factors that could impact its development [124]. The connection between schizophrenia and gut microbiota is an emerging area of research. The concept of GBA, along with data indicating that prenatal microbial infections significantly increase the risk of developing schizophrenia [125], suggest that dysbiosis associated with the disease could impact its progression. Schwarz et al. were among the first to demonstrate that gut microbiota composition differs significantly between patients experiencing first-episode psychosis and non-psychiatric controls. Patients exhibited a particularly increased abundance of the Lactobacillaceae family, which positively correlated with the severity of the disease and with global assessment of functioning scores. Conversely, a negative correlation was observed with the Ruminococcaceae family and Bacteroides spp. both of which were found in lower abundance in patients. Additionally, there were changes in the relative proportions of other bacterial families [126]. However, subsequent studies have reported mixed, and in some cases contradictory results. Four studies identified β-diversity differences between patients with schizophrenia and control groups. Of these, two studies reported reduced alpha diversity in patients [127, 128], while the other two found reporting nonsignificant differences in microbial richness [129, 130]. At the family level, one study reported increased abundances of Veillonellaceae, Prevotellaceae, Bacteroidaceae and Coriobacteriaceae in patients, while Lachnospiraceae, Ruminococcaceae, Norank, and Enterobacteriaceae were found to be decreased [127]. Inconsistencies were noted regarding the abundance of Proteobacteria, which was reported as decreased in one study [130] and increased in another [128]. At the genus level, specific results regarding bacterial prevalence in schizophrenia on the genus level also varied among researchers. Two studies found higher representations of Succinivibrio, Anaerococcus and Megasphaera in patients, whereas a decrease was observed in the genera Haemophilus, Sutterella, Blautia, Coprococcus and Roseburia [129, 130]. Some of these findings were corroborated by another research team that evaluated Blautia, Ruminococcus, and Coprococcus. However, they noted a contrasting increase in Sutterella, along with elevated levels of the phyla Prevotella and Parabacteroides. Additionally, this study reported a decrease in the genera such as Corynebacterium, Adlercreutzia and Faecalibacterium [128]. Correlations between certain bacteria and disease severity have been observed. Zheng et al. have established that Veillonellaceae was negatively correlated with both positive and negative symptom scales. At the family level Bacteroidaceae, Streptococcaceae, and two Lachnospiraceae were positively correlated with symptom severity. Notably, Ruminococcaceae exhibited both positive and negative correlations, depending on the operational taxonomic unit [127]. According to Nguyen et al., an increased abundance of the genus Bacteroides was associated with greater severity of depressive symptoms, while mental well-being was positively correlated with the phylum Verrucomicrobia. Additionally, a decreased abundance of the family Ruminococcaceae was linked to increased negative symptoms of schizophrenia [130].
In a study investigating the impact of microbiota on schizophrenia symptoms, a FMT was performed from drug-free patients to germ-free mice. This procedure had a significant effect as the mice exhibited symptoms similar to those of the donors, including psychomotor hyperactivity, impaired spatial learning and memory deficits, after transplantation. In addition to these clinical changes, the transplanted mice displayed abnormalities in serotonin metabolic pathways. Specifically, they had lower levels of tryptophan in the GI system compared to controls, which was correlated with cognitive impairments observed in the mice. Furthermore, serum levels of 5-HT decreased while kynurenine and kynurenic acid levels increased, indicating a shift in tryptophan metabolism favoring the latter. This dysregulation in serotonin production known to be a factor in many psychiatric disorders, appears to be mediated by microbiota in this case. The mice also exhibited elevated levels of dopamine in the prefrontal cortex and striatum [131]. In a separate study using a mouse model, similar psychomotor symptoms were observed, along with reductions in anxiety and depression. Notably, the study found that the abundance of Aerococcaceae and Rikenellaceae families after transplantation could discriminate between schizophrenia model mice and healthy controls with 100% accuracy. Additionally, changes in neurotransmitter levels included elevated glutamine and GABA in the hippocampus, and decreased glutamate in this region. The hippocampus, typically rich in glutamate, is implicated in the pathogenesis of schizophrenia [127]. Also, the levels of glycerophospholipids, which are crucial in dendrite elongation, were reduced in the hippocampus, cortex, cerebellum and striatum of the recipient mice [127, 132]. Interestingly, transplantation of the single species, Streptococcus vestibularis alone was sufficient to induce schizophrenia-like social behaviors in recipient mice, along with alterations in GABA, tryptophan and dopamine pathways. This finding highlights the influence of specific bacterial compositions on symptoms and neurotransmitter synthesis [133]. Given these research findings, it is clear that gut microbiota is altered in schizophrenia and may influence its progression. However, current therapeutic efforts are primarily focused on probiotics [134–136]. Further research is needed, such as studies using rat models of schizophrenia, to determine whether FMT could serve as an effective adjunctive treatment for this disease.
Conclusions
The research results discussed above emphasize the significant relationship between gut microbiota and neurological diseases, presenting promising avenues for novel therapeutic strategies. Disruption in intestinal microbiota have been linked to symptoms severity and disease progression in a range of neurodegenerative and neurodevelopmental disorders such as MS, AD, PD, autism spectrum disorders and schizophrenia. An increasing body of evidence suggests the potential therapeutic value of targeting gut microbiota in these conditions. Continued research, particularly large-scale clinical trials, is essential to fully elucidate the mechanisms of the gut-brain axis and develop microbiota-related therapeutic options. Among these, FMT is emerging as a promising approach not only for restoring microbial balance in gastrointestinal disorders but also for addressing neurological and psychiatric conditions.
