Next Article in Journal
The Determinants of Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus
Next Article in Special Issue
Neurosensory Alterations in Retinopathy of Prematurity: A Window to Neurological Impairments Associated to Preterm Birth
Previous Article in Journal
Pathogenesis of Paradoxical Reactions Associated with Targeted Biologic Agents for Inflammatory Skin Diseases
Previous Article in Special Issue
CT-Detected MTA Score Related to Disability and Behavior in Older People with Cognitive Impairment
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 10
Issue 7
10.3390/biomedicines10071486
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Gut Microbiome–Brain Crosstalk in Neurodegenerative Diseases

by
Laura Ghezzi
1,*,
Claudia Cantoni
1,
Emanuela Rotondo
2 and
Daniela Galimberti
2,3
1
Department of Neurology, School of Medicine, Washington University, St. Louis, MO 63110, USA
2
Neurodegenerative Diseases Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20100 Milan, Italy
3
Department of Biomedical, Surgical and Dental Sciences, University of Milan, Centro Dino Ferrari, 20100 Milan, Italy
*
Author to whom correspondence should be addressed.
Biomedicines 2022, 10(7), 1486; https://doi.org/10.3390/biomedicines10071486
Submission received: 5 May 2022 / Revised: 20 May 2022 / Accepted: 25 May 2022 / Published: 23 June 2022
(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)
Browse Figure
Versions Notes

Abstract

:
The gut–brain axis (GBA) is a complex interactive network linking the gut to the brain. It involves the bidirectional communication between the gastrointestinal and the central nervous system, mediated by endocrinological, immunological, and neural signals. Perturbations of the GBA have been reported in many neurodegenerative diseases, suggesting a possible role in disease pathogenesis, making it a potential therapeutic target. The gut microbiome is a pivotal component of the GBA, and alterations in its composition have been linked to GBA dysfunction and CNS inflammation and degeneration. The gut microbiome might influence the homeostasis of the central nervous system homeostasis through the modulation of the immune system and, more directly, the production of molecules and metabolites. Small clinical and preclinical trials, in which microbial composition was manipulated using dietary changes, fecal microbiome transplantation, and probiotic supplements, have provided promising outcomes. However, results are not always consistent, and large-scale randomized control trials are lacking. Here, we give an overview of how the gut microbiome influences the GBA and could contribute to disease pathogenesis in neurodegenerative diseases.

1. Introduction

The gut–brain axis (GBA) refers to a complex network of bidirectional interactions between the gut microbiome and the central nervous system (CNS). The GBA involves multiple biological systems and is crucial in maintaining the overall body homeostasis [1]. Signals travel from the gut to the CNS and vice versa, either directly through the autonomic nervous system or indirectly through metabolites and chemical transmitters [1,2]. Both of these interactions can modulate and be influenced by the gut microbiome composition. The GBA has recently attracted interest due to its emerging role in mediating health and disease and potential use as a therapeutic target. The gut microbiome impacts many aspects of brain development and function, including microglia and astrocyte maturation and polarization, blood–brain barrier (BBB) formation and permeability, neurogenesis, and myelination [3,4,5,6,7,8,9]. GBA disruption may participate in the pathophysiology of several brain disorders, including neurodegenerative diseases [5,10,11,12]. However, controversy exists surrounding the extent and the exact mechanisms through which an altered gut microbiome may influence the development of CNS inflammation and degeneration. This review summarizes the current literature exploring the GBA’s role in neurodegenerative diseases, focusing on current and potential therapeutic strategies targeting the GBA.

2. The Gut Microbiome in CNS Homeostasis

The gut microbiome is constituted by a huge community of bacteria, archaea, fungi, and viruses [13], with a great deal of variability among individuals. Unfortunately, there is no agreement on which populations should prevail in a healthy adult microbiome. Cross-sectional studies have shown that gut microbiome composition in individuals with various neurological diseases is different compared to healthy controls [1] (Table 1). Moreover, preclinical studies in animal disease models have confirmed that the gut microbiome obtained from patients with neurological diseases can precipitate brain pathology and behavioral changes in mice [14]. Gut microorganisms can influence CNS functions by producing metabolites, neuroactive molecules, and hormones [15] (Figure 1).
Short-chain fatty acids (SCFAs) are the main products of anaerobic fermentation of indigestible polysaccharides such as dietary fibers and resistant starch by the microbiome in the large intestine [40]. They comprise mainly acetate, propionate, and butyrate, and their quantity varies depending on diet and the gut microbiome composition [41]. SCFAs improve gut health by maintaining the intestinal barrier, mucus production, and immunoregulation [42]. Although the exact mechanisms of action of SCFAs remain unknown, it is known that SCFAs bind to G protein-coupled receptors (GPCRs). The best-studied SCFAs receptors are G-protein coupled receptors 41 and 42 (GPR42 and GRP41), also known as free-fatty acid receptors 2 and 3 (FFAR2 and FFAR3), which are expressed on a wide variety of cells and whose activation determines a different effect based on the cell type harboring them [43]. Besides exerting local effects, SCFAs can cross the BBB and play an important role in the microbiome–brain crosstalk. In animal models, the brain uptake of SCFAs has been demonstrated following the injection of 14C-SCFAs into the carotid artery. In humans, detectable levels of SCFAs in cerebrospinal fluids (CSF) have been reported [44]. SCFAs seem to contribute to BBB integrity. Supporting this notion, germ-free (GF) mice show reduced expression of tight junction proteins such as claudin and occludin, leading to increased permeability of the BBB from intrauterine life to adulthood [4]. Recolonization of these mice with SCFA-producing bacterial strains rescues the phenotype [4]. Glial cells, especially microglia, play a pivotal role in sculpting neuronal networks and shaping circuits. Normal microglial functions are fundamental for the elimination of excess or unnecessary synaptic connection during CNS development [45]. The microbiome influences microglial maturation and function, as demonstrated by the immature microglia phenotype described in GF mice [46]. It is interesting to note that SCFA supplementation can reverse microglia defects [46]. Although the mechanisms involved in controlling the maturation and function of microglia by SCFAs remain unknown, the activation of FFAR2 seems to be involved, since FFAR2-deficient mice displayed the same microglia defect as GF mice [47].
Secondary bile acids are another category of microbial-derived metabolites that has recently attracted a lot of attention in the context of the GBA. Bile acids are endogenous molecules synthesized by the liver from cholesterol and further metabolized by the gut microbiome. Primary bile acids are secreted in the intestine where they are either reabsorbed by the ileum mucosa or deconjugated by the gut microbiome [48]. It is known that microbial deconjugation prevents bile acid reuptake, but studies on GF mice showed how the gut microbiome is also fundamental to regulating primary bile acid reabsorption at the ileum level [49]. In addition, both conjugated and unconjugated bile acids have been demonstrated to cross the BBB, and bile acid receptors are present in the CNS [50]. Alterations in bacterial-associated bile acids have been reported in human studies and mouse models of PD, AD, and other neurological diseases [51,52]. However, the exact function of bile acids in the GBA crosstalk has not been elucidated yet.
Lipopolysaccharide (LPS) is a large molecule present in the outer membrane of Gram-negative bacteria. In the CNS, released LPS is recognized by toll-like receptors 4 (TLR4), primarily expressed by microglia with subsequent production of proinflammatory cytokine and proliferation [53]. The opposite effect can be exerted by polysaccharide A, secreted by B. fragilis and recognized by toll-like receptors 2 (TLR2), whose activation induces a protective CNS immunoregulatory response [54].
Gut hormones are also important to consider in gut–brain signaling. Obesity has been correlated to mood disorders, and several gut hormones (i.e., cholecystokinin, ghrelin, and serotonin) have been linked to anxiety and depression [55].
Gut microbes can either modulate or directly synthesize neuroactive substances such as dopamine, noradrenaline, acetylcholine, histamine, melatonin, and gamma-aminobutyric acid (GABA) [15]. GABA-producing pathways are expressed by Bacteroides, Parabacteroides, and Escherichia species [56]. Evidence of their influence on CNS synaptic transmission, through the gut–brain axis, is derived from studies on subjects with major depressive disorder (MDD), a disease strongly associated with GABA dysregulation. In MDD patients, the relative abundance of fecal Bacteroides is inversely correlated with the functional connectivity between the dorsolateral prefrontal cortex and the default mode network [56]. Furthermore, modulation of the gut microbiome composition has been demonstrated to influence both circulating and central levels of GABA [57,58]. Treatment of mice with the probiotic strain Lactobacillus rhamnosus (JB-1) showed a reduction of stress and depression-like behavior (assessed by the forced-swim test), associated with the modulation of GABA receptor expression in the prefrontal cortex, the amygdala, and the hippocampus [57]. In another study, the administration of Lactobacillus and Bifidobacterium increased the levels of GABA inside the CNS and ameliorated memory performances in mice [59]. Gut bacteria and enteroendocrine cells (EECs) are also important in the production of serotonin (5-HT), and even if the majority of 5-HT is produced in the gut and cannot bypass the BBB, GF mice have decreased concentrations of 5-HT and tryptophan in the CNS, suggesting a modulating role of the gut microbiome on central serotonin levels [60]. The production of 5-HT by EECs is influenced by the levels of secondary bile acids [61].

3. The Gut Microbiome and Cognition

Microbiome composition is age-sensitive, and humans show marked differences in microbial profiles during infancy, adolescence, adulthood, and aging [62,63,64]. Many factors shape the developing microbiome: Genetics [65], stress [66], mode of birth [67], diet [68], medication [69], and the environment [70]. Before birth, bacteria present in the placenta, amniotic cavity, umbilical cord, and meconium start to shape the characteristics of the future microbiome [71].
After birth, and during the first years of life, the gut microbiome of infants experiences significant changes, mainly influenced by feeding patterns (breast vs. artificial milk and, later, solid food). However, diet remains the main determinant of the gut microbiome composition in adults.
The gut microbiome has an intrinsic role in aging-related cognitive impairment. The dysbiotic status, characteristic of the aging microbiome, influences cognition through multiple pathways. The prevalence of bacteria considered proinflammatory, at the expense of more immunoregulatory microbial populations, can promote the release of pro-inflammatory cytokines and bacterial toxins, inhibit the transmission of the regulatory neural signal via the vagus nerve, and suppress the production and release of microbial metabolites and hormones [72,73].
From a neuropsychological point of view, several studies found a correlation between the gut microbiome composition and performance on cognitive tests (motor speed, attention, memory). For example, the relative abundance of Actinobacteria phylum has been linked to better performance in tests of attention, working memory, and paired-associate learning tasks [74]. In a mouse model, the administration of two Bifidobacterium strains improved memory and learning [75]. In humans, the administration of B. longum for 4 weeks was associated with reduced stress and improved visuospatial memory performance [76]. However, in another study, administration of the probiotic Lactobacillus casei Shirota to a cohort of healthy middle-aged subjects determined an improvement in mood but a parallel slight decrease in memory performance in neurocognitive tests [77]. Therefore, it is currently far from clear whether supplementation with psychobiotics, i.e., probiotics with an effect on the CNS, can exert any consistent effects on cognition in humans.
Furthermore, many of the benefits observed in learning and memory after the administration of probiotics occurred alongside reductions in biomarkers of stress (glucocorticoids) or inflammation (proinflammatory cytokines) [76]. Both glucocorticoids and proinflammatory cytokines impair cognitive performance under numerous conditions [78]. As stated above, dysbiosis is associated with impaired gut barrier function that allows bacteria or bacterial products to infiltrate into systemic circulation [79]. The resulting inflammatory states have been associated with behaviors such as social isolation, depression, apathy, and attentional impairments.

4. The Gut Microbiome and Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra and striatum, with abnormal accumulation of α-synuclein in the brain. The main symptoms of PD are resting tremors, stiffness, bradykinesia, and postural instability [80]. With disease progression, cognitive decline might ensue [81]. In addition, non-motor symptoms such as behavioral changes, sleep disorders, and gastrointestinal and autonomic dysfunction may precede the motor symptoms [82]. More than 80% of patients with PD experience gastrointestinal symptoms [83]. As in other neurodegenerative diseases, PD has been associated with inflammation, specifically the inflammatory state resulting from the senescence of the immune system, defined as inflammaging [84]. In 2003, Braak and collaborators introduced the hypothesis that PD originates in the gut [85] and dysbiosis and gut inflammation are now considered important contributors to the disease pathogenesis [86,87]. Inflammatory responses have been described in the colonic tissues of animal models of the disease, including the elevation of proinflammatory cytokines and chemokines such as TNF-α, IL-1b, and leukocyte infiltration and activation [88,89]. In people with PD, serum levels of calprotectin, a marker of intestinal inflammation, were reported elevated compared to healthy controls (HCs) and correlated with monocyte count in the peripheral blood [90]. In another study, calprotectin, alpha-1-antitrypsin, and zonulin were also increased in people with PD [91]. Studies focused on gut microbiome changes in people with PD described a significant increase in the proinflammatory bacteria Ralstonia, Akkermansia, Oscillospira, and Bacteriodes [26]. Bacteroides and Verrucomicrobiaceae abundance have also been associated with plasma TNF-α and IFN-γ levels, respectively [33]. Another consistently reported alteration in PD patients is a decrease in Roseburia abundance [12]. Roseburia can enhance intestinal barrier function and reduce intestinal inflammation by upregulating antimicrobial peptide genes and toll-like receptor (TLR)-related genes, such as TLR5, and downregulating the NF-kB pathway [92]. Consistently, sigmoid mucosa biopsies obtained from patients with PD showed an increase in the expression of TLR4 mRNA compared to HCs [93]. In the rotenone mouse model, loss of the TLR4 gene significantly improved intestinal barrier integrity and reduced intestinal and CNS inflammation, α-synuclein aggregation, and dopaminergic cell loss in the substantia nigra, thus alleviating the impairment of motor function [93].
Several animal studies have reported the spread of α-synuclein pathology from the gut to the brain, and pathological changes in the CNS can be observed after the injection of α-synuclein into the intestinal wall [94,95,96]. However, the exact route through which pathological deposits of α-synuclein may spread to the brain remains vastly hypothetical. According to Braak’s original hypothesis, environmental factors may contribute, triggering the pathological process via the olfactory bulb or the intestinal nerve plexus [97]. Supporting this theory, vagotomy can prevent the transmission of pathological alpha-synuclein to the CNS in animal models [95].

5. The Gut Microbiome and Alzheimer’s Disease

AD is the most common cause of cognitive decline worldwide [98]. It is characterized by the deposition of Amyloid beta (Aβ) plaques and hyperphosphorylated tau protein tangles, leading to neuroinflammation, synaptic dysfunction and, ultimately, neuronal loss [98]. As with PD, AD pathogenesis has also been linked to GBA dysfunction and increased intestinal inflammation [99]. The evidence of the possible role of the gut microbiome in AD pathogenesis came from the mouse model of the disease. GF APPPS1 mice showed a reduction in Aβ pathology compared to specific pathogen-free (SPF) mice [100]. Moreover, some recent studies have reported an altered gut microbiome composition in people with AD compared to HCs [10,17,18,19]. Aging itself impacts the gut microbiome composition, favoring proinflammatory bacteria, such as Bacillus fragilis, Bacteroides fragilis, and Faecalibacterium prausnitzii, to the detriment of more immune-regulatory bacteria [101]. Indeed, in patients with evidence of amyloid deposition, an increase in the proinflammatory taxa Escherichia and Shigella was associated with an increase in peripheral inflammatory markers such as interleukin-1β, NLR Family Pyrin Domain Containing 3, and C-X-C Motif Chemokine Ligand 2 (IL-1β, NLRP3, and CXCL2) [16,17,18]. The alterations most consistently reported by other studies include a decrease in Firmicutes and Bifidobacteria, together with an increase in Proteobacteria and Enterobacteria [16,17,18]. However, the results regarding Bacteroidaceae abundance seem to be less reproducible, with studies reporting either a decrease [22] or an increase [21], variably associated with alteration in Actinobacteria or Prevotella. The lack of consistency can be explained by the different geographical origins of the participants and the difference in comorbidities [102]. Interestingly, a pronounced difference in Enterobacteriaceae abundance between AD and MCI has been reported, suggesting the changes in gut microbiome composition might be gradual during disease progression [19].
As far as gut microbial products are concerned, an alteration in the gut’s production of SCFAs, including butyrate, propionate, and acetate, has been repeatedly reported in patients with AD [101]. A decrease in SCFAs has been associated with increased epithelial leakage and bacterial translocation, with a consequent increase in circulating Gram-negative bacteria and LPS [103], microglia activation, and Aβ deposition in the CNS [104,105]. Moreover, a lower abundance of the butyrate-producing genus Butyrivibrio has been linked to a reduction in the intestinal expression of the transporter P-glycoprotein in AD patients [18]. Intestinal P-glycoprotein has been demonstrated to be essential for maintaining gut homeostasis and controlling intestinal inflammation [106]. Butyrate seems to have a protective effect against neuroinflammation in animal models of disease [107]. However, studies on the effect of SCFA supplementation reported contrasting results, with an even higher Aβ burden after treatment with butyrate in one study [104]. Besides acting locally, gut-derived metabolites can penetrate the CNS [108]. Elevated levels of trimethylamine N-oxide have been reported in people with AD and MCI compared to HCs and are correlated with Aβ and p-tau levels [109].
Lastly, as outlined in the previous paragraph, strains of bacteria derived from the gut microbiome can produce amyloids and favor Aβ peptide aggregation [101]. The proteins curli, TasA, CsgA, FapC, and phenol soluble modulins produced by E. coli, B. subtilis, S. typhymurium, E. fluorescens, and S. aureus, respectively, are only some of the bacteria-derived amyloids with the ability to promote the formation of Aβ oligomers and fibrils in vitro [110]. Bacterial-derived amyloids can act in concert with other bacterial-derived products, such as LPS, to trigger inflammation and increase Aβ deposition in the CNS, as it has been extensively demonstrated in animal models of AD [111,112,113].

6. The Gut Microbiome and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Compared to other neurodegenerative disorders, little evidence supports the implication of the gut microbiome in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTD).
ALS is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons [114]. One of the most common mutations associated with familial ALS is found in the superoxide dismutase 1 gene (SOD1) [114]. By looking at humanized SOD1 mutated mice (G93A), researchers found that these mice had decreased intestinal integrity, increased intestinal permeability, and abnormal Paneth cells, an important cluster of cells implicated in autophagy host–pathogen interactions. Moreover, G93A mice showed an atypical intestinal microbiome, meager in SCFA-producing bacteria such as Butyrivibrio fibrisolvens [115]. Interestingly, butyrate supplementation successfully restored intestinal eubiosis and prolonged G93A mouse life spans [116].
Besides SCFA, nicotinamide supplementation also helps the improvement of ALS symptoms in the mouse model. In particular, the lack of Akkermansia muciniphila, a bacterium that produces a high quantity of nicotinamide, has been associated with a worse clinical course, and nicotinamide supplementation produced a partial improvement. Notably, changes in the gut microbiome composition were reported in the mouse model before clinical onset, opening the possibility of using the gut microbiome as an early biomarker of disease. Unfortunately, studies on people with ALS led to inconsistent results, possibly due to differences in sample size and patient characteristics [35,36]. However, recent studies seem to agree that ALS patients show a noticeable change in the gut microbial structure when compared to healthy controls, consisting of the increased abundance of the Bacteroidetes phylum, together with a decrease in Firmicutes [37], Roseburia intestinalis and Eubacterium rectale, two dominant butyrate-producing species [38].
Frontotemporal dementia (FTD) is a term referring to a wide variety of syndromes, including the behavioral variant frontotemporal dementia and the non-fluent and semantic variants of primary progressive aphasia, each of which can also be accompanied by ALS [117]. Studies on the GBA in people with FTD are scarce and limited to the animal model of the disease. FTD is a multifactorial disease with a solid genetic contribution and a variable degree of environmental influence. The three most common genes involved in the development of the disease are Chromosome 9 Open Reading Frame (C9ORF)72, Microtubule-Associated Protein Tau (MAPT), and Progranulin (GRN). The expansion of C9ORF72 is considered the most common genetic cause of FTD and ALS [118]. As with GRN mutations, another less common genetic cause of FTD, C9ORF72 expansion, is always associated with TAR DNA binging Protein (TDP)-43 pathology. MAPT mutations are invariably associated with Tau pathology [117].
While the loss of C9ORF72 function in humans is associated with neurodegeneration, C9ORF72 reduction or complete deletion in knockout mice (C9orf72−/−) does not trigger ALS or FTD-like disease [119]. C9orf72−/− present an inflammatory phenotype characterized by cytokine storm, splenomegaly, and neuroinflammation [120]. Remarkably, antibiotic treatment or fecal transplantation from an anti-inflammatory environment-associated mouse phenotype was able to rescue the phenotype [120].
Finally, microbiome studies on Drosophila flies carrying the transgenic mutant human FTDP-17-associated tau showed reduced gut motility and subsequently increased gut bacterial load in aged tau transgenic compared to control flies [121].

7. The Gut Microbiome and Other Forms of Dementia

Alterations in the GBA have been reported in Lewy body dementia (LBD), Huntington’s disease (HD), and Creutzfeldt–Jakob disease (CJD). LBD is associated with impaired control of gastrointestinal and cardiac functions that might be linked to the loss of cholinergic dorsal vagal nucleus (DMV) neurons. The degree of DMV cell loss has been found to be similar in LBD patients with or without gastrointestinal symptoms [122].
HD is an inherited neurodegenerative disease that causes progressive motor decline, cognitive dysfunction, and neuropsychiatric symptoms. In addition to the neurological decline and similar to LBD, HD is associated with gastrointestinal disturbances, nutrient deficiencies, gastritis, and weight loss [123]. As reported in PD, AD, and ALS, one study found lower alpha and beta diversity, indicating less healthy baseline richness and altered microbial gut composition in HD patients than HCs [124].
Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases affecting humans and animals. Studies from three decades ago showed how germ-free mice infected with prions have increased survival compared to conventional mice, suggesting a role of microbes in enhancing the disease [125]. Moreover, the prion disease mouse microbiome is significantly different from non-infected mice, alongside SCFA and bile acid production [126].

8. Therapeutic Approaches

8.1. Fecal Microbiome Transplantation

Fecal microbiome transplantation (FMT) is a procedure where a solution of fecal material from a donor is transferred, through colonoscopy, nasogastric tubes, or oral pills, into the intestinal tract of a recipient, aimed at directly changing the gut microbiome composition [127]. FMT has shown promising results in C. difficile infection [128] and could potentially be applied to all the diseases associated with gut microbiome dysbiosis, including neurodegenerative diseases. The most robust results on the effects of FMT on neurodegenerative diseases have been obtained from studies on animal models [101]. FMT from mouse models of AD to GF or antibiotic-treated specific-pathogen-free (SPF) recipient mice resulted in impaired neurogenesis, memory impairment, increased levels of proinflammatory cytokines, and Aβ plaque deposition [129,130]. Furthermore, when FMT was carried out from people with AD to GF mice, an accelerated cognitive decline was observed [131]. On the contrary, ADLPAPT and APPswe/PS1dE9 Tg mice receiving FMT from WT mice showed less cognitive decline, lower Aβ burden, and lower levels of systemic inflammation [132,133,134]. In humans, only two single-case report studies have been published so far. Both showed improvement in cognitive function in people with AD receiving FMT from HCs [135,136].
FMT from animal models of PD into healthy mice could induce synaptic loss and motor dysfunction. On the contrary, FMT from healthy mice to MTPT-treated mice showed a neuroprotective effect and suppressed the activation of TLR4/TNF-α pathway in the gut and the brain [137]. Moreover, α-synuclein-overexpressing mice colonized with the gut microbiome of people with PD showed exacerbated motor dysfunctions [138]. Based on the few case reports published, FMT is reported to be safe and effective at reducing constipation and temporally relieving motor symptoms in people with PD [139,140,141]. Despite promising results in preliminary studies on animal models and human subjects, caution is needed when drawing conclusions, and future randomized clinical trials are needed to clarify the role of FMT in neurodegenerative diseases. FMT is associated with minor adverse events and side effects, including diarrhea, abdominal pain, fever, and flatulence [139,140,141]. However, the exact mechanisms behind its effects on the CNS are still poorly understood and the effect of a single treatment is only temporary. Significant challenges include the timing of transplantation, the high costs of sample preparation and preservation, and the difficulties in defining the criteria to select fecal donors [12].

8.2. Probiotics

Probiotics are defined as non-viable food components that confer health benefits to the host and are associated with modulating the microbiome [12]. Studies on human and animal models have shown that probiotics can help maintain intestinal homeostasis, by stabilizing the epithelial barrier, increasing the production of SCFAs, modulating the mucosal immune system towards a more immunoregulatory response, and inhibiting the production of proinflammatory cytokines [101]. In animal models of AD, the administration of a probiotic mixture showed enhancement of cognitive functions, modulation of the gut microbiome composition, and reduction of oxidative stress and CNS inflammation [142,143,144]. In addition, the administration of a probiotic mixture of Lactobacillus and Bifidobacterium has proven capable of influencing the concentration of neurotransmitters, such as GABA and glutamate, directly in the CNS [145]. In a recent randomized trial on people with AD, the daily administration of a probiotic mixture of Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum for 12 weeks determined a statistically significant improvement in the mini-mental state exam (MMSE) score compared to controls. Positive changes in plasma metabolic markers were also reported [146]. Again, another recent meta-analysis reported positive effects on the cognitive function of probiotic administration in people with AD [147]. However, another recent study reported contrasting results. The authors did not observe any effect of a 12-week probiotic treatment in people with AD in terms of either cognitive functions or inflammatory markers [148].
Probiotics also showed promising results in people with PD. Recent studies have confirmed a possible positive role of the probiotic mixture in relieving constipation and motor symptoms [149,150,151]. In addition, even though the exact mechanism of action is unknown, probiotic treatment has been shown to modulate intestinal permeability, mucosal inflammation, and stimulate the production of SCFAs [152].
Finally, in a study on ALS patients, the Rikenellaceae family, belonging to Bacteroidales phylum, significantly increased after 6 months of probiotic administration [153].

8.3. Diet

Diet is a rapid and direct way to modify the gut microbiome composition and function. With diet alteration, the gut microbiome composition and the abundance of SCFAs and gut metabolites can change drastically [154]. Diet can influence inflammation inside the CNS through the GBA, and many different types of diets have been proposed as beneficial in preventing or ameliorating neurodegenerative diseases [154,155]. Among them, the Mediterranean diet is a well-known healthy diet rich in vegetables, whole grains, low in dairy, with olive oil as the main source of fat [156]. Recent studies reported how adherence to a Mediterranean diet can improve motor and cognitive symptoms in PD [157]. Moreover, a Mediterranean diet seems to reduce the risk of PD [158]. The Mediterranean diet has also shown beneficial effects on other forms of neurodegeneration, such as AD. Many, but not all, epidemiological studies confirmed a protective effect of the Mediterranean diet on neurodegeneration [101]. However, only a few large randomized clinical trials have been conducted so far, often with contrasting results [101].
A ketogenic diet is a nutritional program rich in fats and low in carbohydrates, developed in the 1900s as a treatment for epilepsy [159]. Recently, a ketogenic regimen has been investigated in neurodegenerative diseases, such as AD and PD, with promising results [160,161,162,163].
Lastly, as has been extensively reviewed elsewhere, a calorie restriction (CR) regimen has been shown to have beneficial effects on both neuroinflammation and neurodegeneration [157].

9. Conclusions

Studies in human and animal models of neurodegenerative diseases showed how the GBA might be involved in disease pathogenesis and a target for possible therapeutic approaches. The evidence linking the gut microbiome to neurodegeneration is compelling. However, studies on possible therapeutic manipulations of the gut microbiome are scarce and lack consistency. Despite being promising, this field is in its infancy, and more randomized clinical trials are needed to really understand its entire potential.

Author Contributions

Conceptualization L.G.; writing—review and editing L.G., C.C., E.R. and D.G. All authors have read and agreed to the published version of the manuscript.

Funding

NAAPC funded by Italian Ministry of Health (Ricerca Corrente).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

L.G. is supported by the National MS Society Postdoctoral fellowship (FG1907-34474). C.C. is supported by the Career Transitional Fellowship from the NMSS (TA-1805-31003), U.S. Department of Defense-Defense Health Program Exploration-Hypothesis Development (MS200066) and generous donations from the Whitelaw Terry, Jr./Valerie Terry Fund.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Morais, L.H.; Schreiber, H.L.; Mazmanian, S.K. The gut microbiota-brain axis in behaviour and brain disorders. Nat. Rev. Microbiol. 2021, 19, 241–255. [Google Scholar] [CrossRef] [PubMed]
  2. Wehrwein, E.A.; Orer, H.S.; Barman, S.M. Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System. Compr. Physiol. 2016, 6, 1239–1278. [Google Scholar] [PubMed]
  3. Bercik, P.; Denou, E.; Collins, J.; Jackson, W.; Lu, J.; Jury, J.; Deng, Y.; Blennerhassett, P.; Macri, J.; McCoy, K.D.; et al. The Intestinal Microbiota Affect Central Levels of Brain-Derived Neurotropic Factor and Behavior in Mice. Gastroenterology 2011, 141, 599–609. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Braniste, V.; Al-Asmakh, M.; Kowal, C.; Anuar, F.; Abbaspour, A.; Tóth, M.; Korecka, A.; Bakocevic, N.; Ng, L.G.; Kundu, P.; et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med. 2014, 6, 263ra158. [Google Scholar] [CrossRef] [Green Version]
  5. Carlson, A.; Xia, K.; Azcarate-Peril, M.A.; Goldman, B.D.; Ahn, M.; Styner, M.A.; Thompson, A.L.; Geng, X.; Gilmore, J.H.; Knickmeyer, R.C. Infant Gut Microbiome Associated with Cognitive Development. Biol. Psychiatry 2017, 83, 148–159. [Google Scholar] [CrossRef] [PubMed]
  6. Gao, W.; Salzwedel, A.P.; Carlson, A.L.; Xia, K.; Azcarate-Peril, M.A.; Styner, M.A.; Thompson, A.L.; Geng, X.; Goldman, B.D.; Gilmore, J.H.; et al. Gut microbiome and brain functional connectivity in infants-a preliminary study focusing on the amygdala. Psychopharmacology 2019, 236, 1641–1651. [Google Scholar] [CrossRef]
  7. Heijtz, R.D.; Wang, S.; Anuar, F.; Qian, Y.; Björkholm, B.; Samuelsson, A.; Hibberd, M.L.; Forssberg, H.; Pettersson, S. Normal gut microbiota modulates brain development and behavior. Proc. Natl. Acad. Sci. USA 2011, 108, 3047–3052. [Google Scholar] [CrossRef] [Green Version]
  8. Hoban, A.E.; Stilling, R.M.; Ryan, F.J.; Shanahan, F.; Dinan, T.G.; Claesson, M.J.; Clarke, G.; Cryan, J.F. Regulation of prefrontal cortex myelination by the microbiota. Transl. Psychiatry 2016, 6, e774. [Google Scholar] [CrossRef] [Green Version]
  9. Sudo, N.; Chida, Y.; Aiba, Y.; Sonoda, J.; Oyama, N.; Yu, X.-N.; Kubo, C.; Koga, Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. 2004, 558, 263–275. [Google Scholar] [CrossRef]
  10. Jiang, C.; Li, G.; Huang, P.; Liu, Z.; Zhao, B. The Gut Microbiota and Alzheimer’s Disease. J. Alzheimer’s Dis. 2017, 58, 1–15. [Google Scholar] [CrossRef]
  11. Klingelhoefer, L.; Reichmann, H. Pathogenesis of Parkinson disease—The gut-brain axis and environmental factors. Nat. Rev. Neurol. 2015, 11, 625–636. [Google Scholar] [CrossRef] [PubMed]
  12. Wang, Q.; Luo, Y.; Chaudhuri, K.R.; Reynolds, R.; Tan, E.-K.; Pettersson, S. The role of gut dysbiosis in Parkinson’s disease: Mechanistic insights and therapeutic options. Brain 2021, 144, 2571–2593. [Google Scholar] [CrossRef] [PubMed]
  13. Lloyd-Price, J.; Mahurkar, A.; Rahnavard, G.; Crabtree, J.; Orvis, J.; Hall, A.B.; Brady, A.; Creasy, H.H.; McCracken, C.; Giglio, M.G.; et al. Strains, functions and dynamics in the expanded Human Microbiome Project. Nature 2017, 550, 61–66. [Google Scholar] [CrossRef] [PubMed]
  14. Jiang, H.; Ling, Z.; Zhang, Y.; Mao, H.; Ma, Z.; Yin, Y.; Wang, W.; Tang, W.; Tan, Z.; Shi, J.; et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav. Immun. 2015, 48, 186–194. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Liu, L.; Huh, J.R.; Shah, K. Microbiota and the gut-brain-axis: Implications for new therapeutic design in the CNS. eBioMedicine 2022, 77, 103908. [Google Scholar] [CrossRef]
  16. Cattaneo, A.; Cattane, N.; Galluzzi, S.; Provasi, S.; Lopizzo, N.; Festari, C.; Ferrari, C.; Guerra, U.P.; Paghera, B.; Muscio, C.; et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol. Aging 2017, 49, 60–68. [Google Scholar] [CrossRef] [Green Version]
  17. Vogt, N.M.; Kerby, R.L.; Dill-McFarland, K.A.; Harding, S.J.; Merluzzi, A.P.; Johnson, S.C.; Rey, F.E.; Carlsson, C.M.; Asthana, S.; Zetterberg, H.; et al. Gut microbiome alterations in Alzheimer’s disease. Sci. Rep. 2017, 7, 13537. [Google Scholar] [CrossRef]
  18. Haran, J.P.; Bhattarai, S.K.; Foley, S.E.; Dutta, P.; Ward, D.V.; Bucci, V.; McCormick, B.A. Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway. mBio 2019, 10, e00632-19. [Google Scholar] [CrossRef] [Green Version]
  19. Liu, P.; Wu, L.; Peng, G.; Han, Y.; Tang, R.; Ge, J.; Zhang, L.; Jia, L.; Yue, S.; Zhou, K.; et al. Altered microbiomes distinguish Alzheimer’s disease from amnestic mild cognitive impairment and health in a Chinese cohort. Brain Behav. Immun. 2019, 80, 633–643. [Google Scholar] [CrossRef]
  20. Ling, Z.; Zhu, M.; Yan, X.; Cheng, Y.; Shao, L.; Liu, X.; Jiang, R.; Wu, S. Structural and Functional Dysbiosis of Fecal Microbiota in Chinese Patients with Alzheimer’s Disease. Front. Cell Dev. Biol. 2021, 8, 63406. [Google Scholar] [CrossRef]
  21. Zhuang, Z.-Q.; Shen, L.-L.; Li, W.-W.; Fu, X.; Zeng, F.; Gui, L.; Lü, Y.; Cai, M.; Zhu, C.; Tan, Y.-L.; et al. Gut Microbiota is Altered in Patients with Alzheimer’s Disease. J. Alzheimer’s Dis. 2018, 63, 1337–1346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Guo, M.; Peng, J.; Huang, X.; Xiao, L.; Huang, F.; Zuo, Z. Gut Microbiome Features of Chinese Patients Newly Diagnosed with Alzheimer’s Disease or Mild Cognitive Impairment. J. Alzheimer’s Dis. 2021, 80, 299–310. [Google Scholar] [CrossRef] [PubMed]
  23. Li, C.; Cui, L.; Yang, Y.; Miao, J.; Zhao, X.; Zhang, J.; Cui, G.; Zhang, Y. Gut Microbiota Differs between Parkinson’s Disease Patients and Healthy Controls in Northeast China. Front. Mol. Neurosci. 2019, 12, 171. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Barichella, M.; Severgnini, M.; Cilia, R.; Cassani, E.; Bolliri, C.; Caronni, S.; Ferri, V.; Cancello, R.; Ceccarani, C.; Faierman, S.; et al. Unraveling gut microbiota in Parkinson’s disease and atypical parkinsonism. Mov. Disord. 2019, 34, 396–405. [Google Scholar] [CrossRef]
  25. Aho, V.T.E.; Pereira, P.A.B.; Voutilainen, S.; Paulin, L.; Pekkonen, E.; Auvinen, P.; Scheperjans, F. Gut microbiota in Parkinson’s disease: Temporal stability and relations to disease progression. eBioMedicine 2019, 44, 691–707. [Google Scholar] [CrossRef] [Green Version]
  26. Keshavarzian, A.; Green, S.J.; Engen, P.A.; Voigt, R.M.; Naqib, A.; Forsyth, C.B.; Mutlu, E.; Shannon, K.M. Colonic bacterial composition in Parkinson’s disease. Mov. Disord. 2015, 30, 1351–1360. [Google Scholar] [CrossRef]
  27. Scheperjans, F.; Aho, V.; Pereira, P.A.; Koskinen, K.; Paulin, L.; Pekkonen, E.; Haapaniemi, E.; Kaakkola, S.; Eerola-Rautio, J.; Pohja, M.; et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov. Disord. 2015, 30, 350–358. [Google Scholar] [CrossRef]
  28. Unger, M.M.; Spiegel, J.; Dillmann, K.U.; Grundmann, D.; Philippeit, H.; Bürmann, J.; Faßbender, K.; Schwiertz, A.; Schäfer, K.H. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Park. Relat. Disord. 2016, 32, 66–72. [Google Scholar] [CrossRef]
  29. Bedarf, J.R.; Hildebrand, F.; Coelho, L.P.; Sunagawa, S.; Bahram, M.; Goeser, F.; Bork, P.; Wüllner, U. Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients. Genome Med. 2017, 9, 39. [Google Scholar] [CrossRef]
  30. Hill-Burns, E.M.; Debelius, J.W.; Morton, J.T.; Wissemann, W.T.; Lewis, M.R.; Wallen, Z.D.; Peddada, S.D.; Factor, S.A.; Molho, E.; Zabetian, C.P.; et al. Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov. Disord. 2017, 32, 739–749. [Google Scholar] [CrossRef]
  31. Hopfner, F.; Künstner, A.; Müller, S.H.; Künzel, S.; Zeuner, K.E.; Margraf, N.G.; Deuschl, G.; Baines, J.F.; Kuhlenbäumer, G. Gut microbiota in Parkinson disease in a northern German cohort. Brain Res. 2017, 1667, 41–45. [Google Scholar] [CrossRef] [PubMed]
  32. Heintz-Buschart, A.; Pandey, U.; Wicke, T.; Sixel-Döring, F.; Janzen, A.; Sittig-Wiegand, E.; Trenkwalder, C.; Oertel, W.H.; Mollenhauer, B.; Wilmes, P. The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder. Mov. Disord. 2018, 33, 88–98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Lin, C.H.; Chen, C.C.; Chiang, H.L.; Liou, J.M.; Chang, C.M.; Lu, T.P.; Wu, M.S.; Chuang, E.Y.; Tai, Y.-C.; Cheng, C.; et al. Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson’s disease. J. Neuroinflamm. 2019, 16, 129. [Google Scholar] [CrossRef] [PubMed]
  34. Pietrucci, D.; Cerroni, R.; Unida, V.; Farcomeni, A.; Pierantozzi, M.; Mercuri, N.B.; Biocca, S.; Stefani, A.; Desideri, A. Dysbiosis of gut microbiota in a selected population of Parkinson’s patients. Park. Relat. Disord. 2019, 65, 124–130. [Google Scholar] [CrossRef]
  35. Fang, X.; Wang, X.; Yang, S.; Meng, F.; Wang, X.; Wei, H.; Chen, T. Evaluation of the Microbial Diversity in Amyotrophic Lateral Sclerosis Using High-Throughput Sequencing. Front. Microbiol. 2016, 7, 1479. [Google Scholar] [CrossRef] [Green Version]
  36. Brenner, D.; Hiergeist, A.; Adis, C.; Mayer, B.; Gessner, A.; Ludolph, A.C.; Weishaupt, J.H. The fecal microbiome of ALS patients. Neurobiol. Aging 2018, 61, 132–137. [Google Scholar] [CrossRef]
  37. Zeng, Q.; Shen, J.; Chen, K.; Zhou, J.; Liao, Q.; Lu, K.; Yuan, J.; Bi, F.-F. The alteration of gut microbiome and metabolism in amyotrophic lateral sclerosis patients. Sci. Rep. 2020, 10, 12998. [Google Scholar] [CrossRef]
  38. Nicholson, K.; Bjornevik, K.; Abu-Ali, G.; Chan, J.; Cortese, M.; Dedi, B.; Jeon, M.; Xavier, R.; Huttenhower, C.; Ascherio, A.; et al. The human gut microbiota in people with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Front. Degener. 2020, 22, 186–194. [Google Scholar] [CrossRef]
  39. Hertzberg, V.S.; Singh, H.; Fournier, C.N.; Moustafa, A.; Polak, M.; Kuelbs, C.A.; Torralba, M.G.; Tansey, M.G.; Nelson, K.E.; Glass, J.D. Gut microbiome differences between amyotrophic lateral sclerosis patients and spouse controls. Amyotroph. Lateral. Scler. Frontotemporal. Degener. 2022, 23, 91–99. [Google Scholar] [CrossRef]
  40. Dalile, B.; Van Oudenhove, L.; Vervliet, B.; Verbeke, K. The role of short-chain fatty acids in microbiota–gut–brain com-munication. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 461–478. [Google Scholar] [CrossRef]
  41. Macfarlane, S.; Macfarlane, G.T. Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 2003, 62, 67–72. [Google Scholar] [CrossRef] [PubMed]
  42. O’Keefe, S.J.D. Diet, microorganisms and their metabolites, and colon cancer. Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 691–706. [Google Scholar] [CrossRef] [PubMed]
  43. Bolognini, D.; Tobin, A.B.; Milligan, G.; Moss, C.E. The Pharmacology and Function of Receptors for Short-Chain Fatty Acids. Mol. Pharmacol. 2015, 89, 388–398. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Liu, J.; Sun, J.; Wang, F.; Yu, X.; Ling, Z.; Li, H.; Xu, J.; Zhang, H.; Jin, J.; Chen, W.; et al. Neuroprotective Effects of Clostridium butyricum against Vascular Dementia in Mice via Metabolic Butyrate. Biomed Res. Int. 2015, 2015, 412946. [Google Scholar] [CrossRef] [Green Version]
  45. Wilton, D.K.; Dissing-Olesen, L.; Stevens, B. Neuron-Glia Signaling in Synapse Elimination. Annu. Rev. Neurosci. 2019, 42, 107–127. [Google Scholar] [CrossRef]
  46. Erny, D.; Hrabě de Angelis, A.L.; Jaitin, D.; Wieghofer, P.; Staszewski, O.; David, E.; Keren-Shaul, H.; Mahlakoiv, T.; Jakobshagen, K.; Buch, T.; et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 2015, 18, 965–977. [Google Scholar] [CrossRef]
  47. Gautier, E.L.; Shay, T.; Miller, J.; Greter, M.; Jakubzick, C.; Ivanov, S.; Helft, J.; Chow, A.; Elpek, K.G.; Gordonov, S.; et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 2012, 13, 1118–1128. [Google Scholar] [CrossRef] [Green Version]
  48. Wahlström, A.; Sayin, S.I.; Marschall, H.-U.; Bäckhed, F. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab. 2016, 24, 41–50. [Google Scholar] [CrossRef] [Green Version]
  49. Sayin, S.I.; Wahlström, A.; Felin, J.; Jäntti, S.; Marschall, H.U.; Bamberg, K.; Bäckhed, F.; Angelin, B.; Hyötyläinen, H.; Orešič, M.; et al. Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-beta-muricholic Acid, a Naturally Occurring FXR Antagonist. Cell Metab. 2013, 17, 225–235. [Google Scholar] [CrossRef] [Green Version]
  50. Kiriyama, Y.; Nochi, H. The Biosynthesis, Signaling, and Neurological Functions of Bile Acids. Biomolecules 2019, 9, 232. [Google Scholar] [CrossRef] [Green Version]
  51. Hertel, J.; Harms, A.C.; Heinken, A.; Baldini, F.; Thinnes, C.C.; Glaab, E.; Vasco, A.D.; Pietzner, M.; Stewart, I.; Wareham, N.; et al. Integrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-Host Interactions on Sulfur Metabolism in Parkinson’s Disease. Cell Rep. 2019, 29, 1767–1777. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Nho, K.; Kueider-Paisley, A.; MahmoudianDehkordi, S.; Arnold, M.; Risacher, S.L.; Louie, G.; Blach, C.; Baillie, R.; Han, X.; Kastenmüller, G.; et al. Altered bile acid profile in mild cognitive impairment and Alzheimer’s disease: Relationship to neuroimaging and CSF biomarkers. Alzheimer’s Dement. 2018, 15, 232–244. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Zhao, J.; Bi, W.; Xiao, S.; Lan, X.; Cheng, X.; Zhang, J.; Lu, D.; Wei, W.; Wang, Y.; Li, H.; et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci. Rep. 2019, 9, 5790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Wang, Y.; Telesford, K.M.; Ochoa-Re, J.; Haque-Begum, S.; Christy, M.; Kasper, E.J.; Wang, L.; Wu, Y.; Robson, S.C.; Kasper, D.L.; et al. An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling. Nat. Commun. 2014, 5, 4432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Jenkins, T.A.; Nguyen, J.C.D.; Polglaze, K.E.; Bertrand, P.P. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients 2016, 8, 56. [Google Scholar] [CrossRef]
  56. Strandwitz, P.; Kim, K.H.; Terekhova, D.; Liu, J.K.; Sharma, A.; Levering, J.; McDonald, D.; Dietrich, D.; Ramadhar, T.R.; Lekbua, A.; et al. GABA-modulating bacteria of the human gut microbiota. Nat. Microbiol. 2019, 4, 396–403. [Google Scholar] [CrossRef]
  57. Bravo, J.A.; Forsythe, P.; Chew, M.V.; Escaravage, E.; Savignac, H.M.; Dinan, T.G.; Bienenstock, J.; Cryan, J.F. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl. Acad. Sci. USA 2011, 108, 16050–16055. [Google Scholar] [CrossRef] [Green Version]
  58. Kootte, R.S.; Levin, E.; Salojärvi, J.; Smits, L.P.; Hartstra, A.V.; Udayappan, S.D.; Hermes, G.; Bouter, K.E.; Koopen, A.M.; Holst, J.J.; et al. Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition. Cell Metab. 2017, 26, 611–619. [Google Scholar] [CrossRef] [Green Version]
  59. Mao, J.-H.; Kim, Y.-M.; Zhou, Y.-X.; Hu, D.; Zhong, C.; Chang, H.; Brislawn, C.J.; Fansler, S.; Langley, S.; Wang, Y.; et al. Genetic and metabolic links between the murine microbiome and memory. Microbiome 2020, 8, 53. [Google Scholar] [CrossRef]
  60. Clarke, G.; Grenham, S.; Scully, P.; Fitzgerald, P.; Moloney, R.D.; Shanahan, F.; Dinan, T.G.; Cryan, J.F. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 2013, 18, 666–673. [Google Scholar] [CrossRef] [Green Version]
  61. Yano, J.M.; Yu, K.; Donaldson, G.P.; Shastri, G.G.; Ann, P.; Ma, L.; Hsiao, E.Y.; Nagler, C.R.; Ismagilov, R.F.; Mazmanian, S.K.; et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015, 161, 264–272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Kundu, P.; Blacher, E.; Elinav, E.; Pettersson, S. Our Gut Microbiome: The Evolving Inner Self. Cell 2017, 171, 1481–1493. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Eastwood, J.; Walton, G.; Van Hemert, S.; Williams, C.; Lamport, D. The effect of probiotics on cognitive function across the human lifespan: A systematic review. Neurosci. Biobehav. Rev. 2021, 128, 311–327. [Google Scholar] [CrossRef] [PubMed]
  64. Gao, W.; Baumgartel, K.L.; Alexander, S.A. The Gut Microbiome as a Component of the Gut–Brain Axis in Cognitive Health. Biol. Res. Nurs. 2020, 22, 485–494. [Google Scholar] [CrossRef]
  65. Goodrich, J.K.; Davenport, E.R.; Beaumont, M.; Jackson, M.A.; Knight, R.; Ober, C.; Spector, T.D.; Bell, J.T.; Clark, A.G.; Ley, R.E. Genetic Determinants of the Gut Microbiome in UK Twins. Cell Host Microbe 2016, 19, 731–743. [Google Scholar] [CrossRef] [Green Version]
  66. Kim, D.R.; Bale, T.L.; Epperson, C.N. Prenatal Programming of Mental Illness: Current Understanding of Relationship and Mechanisms. Curr. Psychiatry Rep. 2015, 17, 5. [Google Scholar] [CrossRef]
  67. Stewart, C.J.; Ajami, N.J.; O’Brien, J.L.; Hutchinson, D.S.; Smith, D.P.; Wong, M.C.; Ross, M.C.; Lloyd, R.E.; Doddapaneni, H.; Metcalf, G.A.; et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 2018, 562, 583–588. [Google Scholar] [CrossRef]
  68. Johnson, A.; Vangay, P.; Al-Ghalith, G.A.; Hillmann, B.M.; Ward, T.L.; Shields-Cutler, R.R.; Kim, A.D.; Shmagel, A.K.; Syed, A.N.; Walter, J.; et al. Daily Sampling Reveals Personalized Diet-Microbiome Associations in Humans. Cell Host Microbe 2019, 25, 789–802.e5. [Google Scholar] [CrossRef]
  69. Mortensen, M.S.; Jensen, B.H.; Williams, J.; Brejnrod, A.D.; Andersen, L.O.; Röser, D.; Andreassen, B.U.; Petersen, A.M.; Stensvold, C.R.; Sørensen, S.J.; et al. Stability and resilience of the intestinal microbiota in children in daycare—A 12 month cohort study. BMC Microbiol. 2018, 18, 223. [Google Scholar] [CrossRef] [Green Version]
  70. Rothschild, D.; Weissbrod, O.; Barkan, E.; Kurilshikov, A.; Korem, T.; Zeevi, D.; Costea, P.I.; Godneva, A.; Kalka, I.N.; Bar, N.; et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 2018, 555, 210–215. [Google Scholar] [CrossRef]
  71. Collado, M.C.; Rautava, S.; Aakko, J.; Isolauri, E.; Salminen, S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci. Rep. 2016, 6, 23129. [Google Scholar] [CrossRef] [Green Version]
  72. Li, H.; Ni, J.; Qing, H. Gut Microbiota: Critical Controller and Intervention Target in Brain Aging and Cognitive Im-pairment. Front. Aging Neurosci. 2021, 13, 671142. [Google Scholar] [CrossRef] [PubMed]
  73. Halverson, T.; Alagiakrishnan, K. Gut microbes in neurocognitive and mental health disorders. Ann. Med. 2020, 52, 423–443. [Google Scholar] [CrossRef]
  74. Fernández-Real, J.M.; Serino, M.; Blasco, G.; Puig, J.; Daunis-I-Estadella, P.; Ricart, W.; Burcelin, R.; Fernández-Aranda, F.; Portero-Otin, M. Gut Microbiota Interacts with Brain Microstructure and Function. J. Clin. Endocrinol. Metab. 2015, 100, 4505–4513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Savignac, H.M.; Tramullas, M.; Kiely, B.; Dinan, T.G.; Cryan, J.F. Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav. Brain Res. 2015, 287, 59–72. [Google Scholar] [CrossRef] [PubMed]
  76. Allen, A.P.; Hutch, W.; Borre, Y.E.; Kennedy, P.J.; Temko, A.; Boylan, G.; Clarke, G.; Murphy, E.; Cryan, J.F.; Dinan, T.G. Bifidobacterium longum 1714 as a translational psychobiotic: Modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl. Psychiatry 2016, 6, e939. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Benton, D.; Williams, C.; Brown, A. Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur. J. Clin. Nutr. 2006, 61, 355–361. [Google Scholar] [CrossRef] [Green Version]
  78. Donzis, E.J.; Tronson, N.C. Modulation of learning and memory by cytokines: Signaling mechanisms and long term consequences. Neurobiol. Learn. Mem. 2014, 115, 68–77. [Google Scholar] [CrossRef] [Green Version]
  79. Sarkar, A.; Harty, S.; Lehto, S.; Moeller, A.H.; Dinan, T.G.; Dunbar, R.I.; Cryan, J.F.; Burnet, P. The Microbiome in Psychology and Cognitive Neuroscience. Trends Cogn. Sci. 2018, 22, 611–636. [Google Scholar] [CrossRef]
  80. Obeso, J.A.; Stamelou, M.; Goetz, C.G.; Poewe, W.; Lang, A.E.; Weintraub, D.; Burn, D.; Halliday, G.M.; Bezard, E.; Przedborski, S.; et al. Past, present, and future of Parkinson’s disease: A special essay on the 200th Anniversary of the Shaking Palsy. Mov. Disord. 2017, 32, 1264–1310. [Google Scholar] [CrossRef]
  81. Aarsland, D.; Creese, B.; Politis, M.; Chaudhuri, K.R.; Weintraub, D.; Ballard, C. Cognitive decline in Parkinson disease. Nat. Rev. Neurol. 2017, 13, 217–231. [Google Scholar] [CrossRef] [Green Version]
  82. Pfeiffer, R.F. Non-motor symptoms in Parkinson’s disease. Park. Relat. Disord. 2016, 22, S119–S122. [Google Scholar] [CrossRef]
  83. Cersosimo, M.G.; Raina, G.B.; Pecci, C.; Pellene, A.; Calandra, C.R.; Gutiérrez, C.; Micheli, F.E.; Benarroch, E.E. Gastrointestinal manifestations in Parkinson’s disease: Prevalence and occurrence before motor symptoms. J. Neurol. 2012, 260, 1332–1338. [Google Scholar] [CrossRef]
  84. Tansey, M.G.; Wallings, R.L.; Houser, M.C.; Herrick, M.K.; Keating, C.E.; Joers, V. Inflammation and immune dysfunction in Parkinson disease. Nat. Rev. Immunol. 2022, 4, 1–17. [Google Scholar] [CrossRef]
  85. Braak, H.; Del Tredici, K.; Rüb, U.; de Vos, R.A.; Steur, E.N.J.; Braak, E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 2003, 24, 197–211. [Google Scholar] [CrossRef]
  86. Houser, M.C.; Chang, J.; Factor, S.A.; Molho, E.S.; Zabetian, C.P.; Hill-Burns, E.M.; Tansey, M.G.; Payami, H.; Hertzberg, V.S. Stool Immune Profiles Evince Gastrointestinal Inflammation in Parkinson’s Disease. Mov. Disord. 2018, 33, 793–804. [Google Scholar] [CrossRef]
  87. Dumitrescu, L.; Marta, D.; Dănău, A.; Lefter, A.; Tulbă, D.; Cozma, L.; Manole, E.; Gherghiceanu, M.; Ceafalan, L.C.; Popescu, B.O. Serum and Fecal Markers of Intestinal Inflammation and Intestinal Barrier Permeability Are Elevated in Parkinson’s Disease. Front. Neurosci. 2021, 15, 738. [Google Scholar] [CrossRef]
  88. Morais, L.H.; Hara, D.B.; Bicca, M.A.; Poli, A.; Takahashi, R.N. Early signs of colonic inflammation, intestinal dysfunction, and olfactory impairments in the rotenone-induced mouse model of Parkinson’s disease. Behav. Pharmacol. 2018, 29, 199–210. [Google Scholar] [CrossRef]
  89. Pellegrini, C.; Fornai, M.; Colucci, R.; Tirotta, E.; Blandini, F.; Levandis, G.; Cerri, S.; Segnani, C.; Ippolito, C.; Bernardini, N.; et al. Alteration of colonic excitatory tachykininergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration. J. Neuroinflam. 2016, 13, 146. [Google Scholar] [CrossRef] [Green Version]
  90. Hor, J.W.; Lim, S.-Y.; Khor, E.S.; Chong, K.K.; Song, S.L.; Ibrahim, N.M.; Teh, C.S.J.; Chong, C.W.; Hilmi, I.N.; Tan, A.H. Fecal Calprotectin in Parkinson’s Disease and Multiple System Atrophy. J. Mov. Disord. 2021. online ahead of print. [Google Scholar] [CrossRef]
  91. Schwiertz, A.; Spiegel, J.; Dillmann, U.; Grundmann, D.; Bürmann, J.; Fassbender, K.; Schäfer, K.-H.; Unger, M. Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson’s disease. Park. Relat. Disord. 2018, 50, 104–107. [Google Scholar] [CrossRef]
  92. Patterson, A.M.; Mulder, I.E.; Travis, A.; Lan, A.; Cerf-Bensussan, N.; Gaboriau-Routhiau, V.; Garden, K.; Logan, E.; Delday, M.I.; Coutts, A.G.P.; et al. Human Gut Symbiont Roseburia hominis Promotes and Regulates Innate Immunity. Front. Immunol. 2017, 8, 1166. [Google Scholar] [CrossRef]
  93. Terán-Ventura, E.; Aguilera, M.; Vergara, P.; Martínez, V. Specific changes of gut commensal microbiota and TLRs during indomethacin-induced acute intestinal inflammation in rats. J. Crohn’s Colitis 2014, 8, 1043–1054. [Google Scholar] [CrossRef] [Green Version]
  94. Challis, C.; Hori, A.; Sampson, T.; Yoo, B.B.; Challis, R.C.; Hamilton, A.M.; Mazmanian, S.K.; Volpicelli-Daley, L.A.; Gradinaru, V. Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice. Nat. Neurosci. 2020, 23, 327–336. [Google Scholar] [CrossRef]
  95. Kim, S.; Kwon, S.H.; Kam, T.I.; Panicker, N.; Karuppagounder, S.S.; Lee, S.; Ko, H.S.; Lee, J.H.; Kook, M.; Foss, C.A.; et al. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease. Neuron 2019, 103, 627–641. [Google Scholar] [CrossRef]
  96. Uemura, N.; Yagi, H.; Uemura, M.T.; Hatanaka, Y.; Yamakado, H.; Takahashi, R. Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve. Mol. Neurodegener. 2018, 13, 21. [Google Scholar] [CrossRef] [Green Version]
  97. Braak, H.; Rüb, U.; Gai, W.P.; Del Tredici, K. Idiopathic Parkinson’s disease: Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural. Transm. 2003, 110, 517–536. [Google Scholar] [CrossRef]
  98. Hodson, R. Alzheimer’s disease. Nature 2018, 559, S1. [Google Scholar] [CrossRef] [Green Version]
  99. Sochocka, M.; Donskow-Łysoniewska, K.; Diniz, B.S.; Kurpas, D.; Brzozowska, E.; Leszek, J. The Gut Microbiome Altera-tions and Inflammation-Driven Pathogenesis of Alzheimer’s Disease-a Critical Review. Mol. Neurobiol. 2019, 56, 1841–1851. [Google Scholar] [CrossRef] [Green Version]
  100. Harach, T.; Marungruang, N.; Duthilleul, N.; Cheatham, V.; Mc Coy, K.D.; Frisoni, G.B.; Neher, J.J.; Fåk, F.; Jucker, M.; Lasser, T.; et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci. Rep. 2017, 7, 41802. [Google Scholar] [CrossRef]
  101. Varesi, A.; Pierella, E.; Romeo, M.; Piccini, G.B.; Alfano, C.; Bjørklund, G.; Oppong, A.; Ricevuti, G.; Esposito, C.; Chirumbolo, S.; et al. The Potential Role of Gut Microbiota in Alzheimer’s Disease: From Diagnosis to Treatment. Nutrients 2022, 14, 668. [Google Scholar] [CrossRef] [PubMed]
  102. He, Y.; Wu, W.; Zheng, H.-M.; Li, P.; McDonald, D.; Sheng, H.-F.; Chen, M.-X.; Chen, Z.-H.; Ji, G.-Y.; Zheng, Z.-D.; et al. Regional variation limits applications of healthy gut microbiome reference ranges and disease models. Nat. Med. 2018, 24, 1532–1535. [Google Scholar] [CrossRef] [PubMed]
  103. Kohler, A.C.; Maes, M.; Slyepchenko, A.; Berk, M.; Solmi, M.; Lanctôt, L.K.; Carvalho, F.A. The Gut-Brain Axis, Including the Microbiome, Leaky Gut and Bacterial Translocation: Mechanisms and Pathophysiological Role in Alzheimer’s Disease. Curr. Pharm. Des. 2016, 22, 6152–6166. [Google Scholar] [CrossRef] [PubMed]
  104. Colombo, A.V.; Sadler, R.K.; Llovera, G.; Singh, V.; Roth, S.; Heindl, S.; Monasor, L.S.; Verhoeven, A.; Peters, F.; Parhizkar, S.; et al. Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition. eLife 2021, 10, e59826. [Google Scholar] [CrossRef]
  105. Wenzel, T.J.; Gates, E.J.; Ranger, A.L.; Klegeris, A. Short-chain fatty acids (SCFAs) alone or in combination regulate select immune functions of microglia-like cells. Mol. Cell. Neurosci. 2020, 105, 103493. [Google Scholar] [CrossRef]
  106. Szabady, R.L.; Louissaint, C.; Lubben, A.; Xie, B.; Reeksting, S.; Tuohy, C.; McCormick, B.A.; Demma, Z.; Foley, S.E.; Faherty, C.S.; et al. Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeosta-sis. J. Clin. Investig. 2018, 128, 4044–4056. [Google Scholar] [CrossRef]
  107. Sun, J.; Xu, J.; Yang, B.; Chen, K.; Kong, Y.; Fang, N.; Gong, T.; Wang, F.; Ling, Z.; Liu, J. Effect of Clostridium butyricum against Microglia-Mediated Neuroinflammation in Alzheimer’s Disease via Regulating Gut Microbiota and Metabolites Butyrate. Mol. Nutr. Food Res. 2019, 64, e1900636. [Google Scholar] [CrossRef]
  108. Del Rio, D.; Zimetti, F.; Caffarra, P.; Tassotti, M.; Bernini, F.; Brighenti, F.; Zini, A.; Zanotti, I. The Gut Microbial Metabolite Trimethylamine-N-Oxide Is Present in Human Cerebrospinal Fluid. Nutrients 2017, 9, 1053. [Google Scholar] [CrossRef] [Green Version]
  109. Vogt, N.M.; Romano, K.A.; Darst, B.F.; Engelman, C.D.; Johnson, S.C.; Carlsson, C.M.; Asthana, S.; Blennow, K.; Zetterberg, H.; Bendlin, B.B.; et al. The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimer’s Res. Ther. 2018, 10, 124. [Google Scholar] [CrossRef] [Green Version]
  110. Kesika, P.; Suganthy, N.; Sivamaruthi, B.S.; Chaiyasut, C. Role of gut-brain axis, gut microbial composition, and probiotic intervention in Alzheimer’s disease. Life Sci. 2021, 264, 118627. [Google Scholar] [CrossRef]
  111. Hauss-Wegrzyniak, B.; Vraniak, P.D.; Wenk, G.L. LPS-induced neuroinflammatory effects do not recover with time. NeuroReport 2000, 11, 1759–1763. [Google Scholar] [CrossRef] [PubMed]
  112. Kahn, M.S.; Kranjac, D.; Alonzo, C.A.; Haase, J.H.; Cedillos, R.O.; McLinden, K.A.; Boehm, G.W.; Chumley, M.J. Prolonged elevation in hippocampal Aβ and cognitive deficits following repeated endotoxin exposure in the mouse. Behav. Brain Res. 2012, 229, 176–184. [Google Scholar] [CrossRef] [PubMed]
  113. Asti, A.; Gioglio, L. Can a Bacterial Endotoxin be a Key Factor in the Kinetics of Amyloid Fibril Formation? J. Alzheimer’s Dis. 2014, 39, 169–179. [Google Scholar] [CrossRef] [PubMed]
  114. van Es, M.A.; Hardiman, O.; Chio, A.; Al-Chalabi, A.; Pasterkamp, R.J.; Veldink, J.H.; Van den Berg, L.H. Amyotrophic lateral sclerosis. Lancet 2017, 390, 2084–2098. [Google Scholar] [CrossRef]
  115. Wu, S.; Yi, J.; Zhang, Y.-G.; Zhou, J.; Sun, J. Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model. Physiol. Rep. 2015, 3, e12356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Zhang, Y.; Ogbu, D.; Garrett, S.; Xia, Y.; Sun, J. Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis. Gut Microbes 2021, 13, 1996848. [Google Scholar] [CrossRef] [PubMed]
  117. Boeve, B.F.; Boxer, A.L.; Kumfor, F.; Pijnenburg, Y.; Rohrer, J.D. Advances and controversies in frontotemporal dementia: Diagnosis, biomarkers, and therapeutic considerations. Lancet Neurol. 2022, 21, 258–272. [Google Scholar] [CrossRef]
  118. Abramzon, Y.A.; Fratta, P.; Traynor, B.J.; Chia, R. The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Front. Neurosci. 2020, 14, 42. [Google Scholar] [CrossRef] [Green Version]
  119. Moens, T.G.; Partridge, L.; Isaacs, A.M. Genetic models of C9orf72: What is toxic? Curr. Opin. Genet. Dev. 2017, 44, 92–101. [Google Scholar] [CrossRef]
  120. Burberry, A.; Suzuki, N.; Wang, J.-Y.; Moccia, R.; Mordes, D.A.; Stewart, M.H.; Suzuki-Uematsu, S.; Ghosh, S.; Singh, A.; Merkle, F.T.; et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci. Transl. Med. 2016, 8, 347ra93. [Google Scholar] [CrossRef] [Green Version]
  121. Rydbom, J.; Kohl, H.; Hyde, V.R.; Lohr, K.M. Altered Gut Microbial Load and Immune Activation in a Drosophila Model of Human Tauopathy. Front. Neurosci. 2021, 15, 731602. [Google Scholar] [CrossRef] [PubMed]
  122. Benarroch, E.E.; Schmeichel, A.M.; Sandroni, P.; Low, P.A.; Parisi, J.E. Involvement of vagal autonomic nuclei in multiple system atrophy and Lewy body disease. Neurology 2006, 66, 378–383. [Google Scholar] [CrossRef] [PubMed]
  123. McColgan, P.; Tabrizi, S.J. Huntington’s disease: A clinical review. Eur. J. Neurol. 2017, 25, 24–34. [Google Scholar] [CrossRef] [PubMed]
  124. Wasser, C.I.; Mercieca, E.C.; Kong, G.; Hannan, A.J.; McKeown, S.J.; Glikmann-Johnston, Y.; Stout, J.C. Gut dysbiosis in Huntington’s disease: Associations among gut microbiota, cognitive performance and clinical outcomes. Brain Commun. 2020, 2, fcaa110. [Google Scholar] [CrossRef] [PubMed]
  125. Lev, M.; Raine, C.S.; Levenson, S.M. Enhanced survival of germfree mice after infection with irradiated scrapie brain. Experientia 1971, 27, 1358–1359. [Google Scholar] [CrossRef] [PubMed]
  126. Yang, D.; Zhao, D.; Shah, S.Z.A.; Wu, W.; Lai, M.; Zhang, X.; Li, J.; Guan, Z.; Zhao, H.; Li, W.; et al. Implications of gut microbiota dysbiosis and metabolic changes in prion disease. Neurobiol. Dis. 2019, 135, 104704. [Google Scholar] [CrossRef]
  127. Gupta, S.; Allen-Vercoe, E.; Petrof, E.O. Fecal microbiota transplantation: In perspective. Ther. Adv. Gastroenterol. 2015, 9, 229–239. [Google Scholar] [CrossRef] [Green Version]
  128. Surawicz, C.M.; Brandt, L.J.; Binion, D.G.; Ananthakrishnan, A.N.; Curry, S.R.; Gilligan, P.H.; Zuckerbraun, B.S.; McFarland, L.V.; Mellow, M.; Zuckerbraun, B. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am. J. Gastroenterol. 2013, 108, 478–498. [Google Scholar] [CrossRef]
  129. Kim, N.; Jeon, S.H.; Ju, I.G.; Gee, M.S.; Do, J.; Oh, M.S.; Kil Lee, J. Transplantation of gut microbiota derived from Alzheimer’s disease mouse model impairs memory function and neurogenesis in C57BL/6 mice. Brain Behav. Immun. 2021, 98, 357–365. [Google Scholar] [CrossRef]
  130. Wang, M.; Cao, J.; Gong, C.; Amakye, W.K.; Yao, M.; Ren, J. Exploring the microbiota-Alzheimer’s disease linkage using short-term antibiotic treatment followed by fecal microbiota transplantation. Brain Behav. Immun. 2021, 96, 227–238. [Google Scholar] [CrossRef]
  131. Fujii, Y.; Nguyen, T.T.T.; Fujimura, Y.; Kameya, N.; Nakamura, S.; Arakawa, K.; Morita, H. Fecal metabolite of a gnotobiotic mouse transplanted with gut microbiota from a patient with Alzheimer’s disease. Biosci. Biotechnol. Biochem. 2019, 83, 2144–2152. [Google Scholar] [CrossRef]
  132. Kim, M.-S.; Kim, Y.; Choi, H.; Kim, W.; Park, S.; Lee, D.; Kim, D.K.; Kim, H.J.; Choi, H.; Hyun, D.-W.; et al. Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model. Gut 2020, 69, 283–294. [Google Scholar] [CrossRef] [PubMed]
  133. Sun, J.; Xu, J.; Ling, Y.; Wang, F.; Gong, T.; Yang, C.; Ye, S.; Ye, K.; Wei, D.; Song, Z.; et al. Fecal microbiota transplantation alleviated Alzheimer’s disease-like pathogenesis in APP/PS1 transgenic mice. Transl. Psychiatry 2019, 9, 189. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Dodiya, H.B.; Kuntz, T.; Shaik, S.M.; Baufeld, C.; Leibowitz, J.; Zhang, X.; Gottel, N.; Zhang, X.; Butovsky, O.; Gilbert, J.A.; et al. Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. J. Exp. Med. 2019, 216, 1542–1560. [Google Scholar] [CrossRef] [Green Version]
  135. Park, S.-H.; Lee, J.H.; Shin, J.; Kim, J.-S.; Cha, B.; Lee, S.; Kwon, K.S.; Shin, Y.W.; Choi, S.H. Cognitive function improvement after fecal microbiota transplantation in Alzheimer’s dementia patient: A case report. Curr. Med. Res. Opin. 2021, 37, 1739–1744. [Google Scholar] [CrossRef] [PubMed]
  136. Hazan, S. Rapid improvement in Alzheimer’s disease symptoms following fecal microbiota transplantation: A case report. J. Int. Med. Res. 2020, 48, 0300060520925930. [Google Scholar] [CrossRef] [PubMed]
  137. Sun, M.F.; Zhu, Y.L.; Zhou, Z.L.; Jia, X.B.; Xu, Y.D.; Yang, Q.; Shen, Y.Q.; Cui, C. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: Gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain. Behav. Immun. 2018, 70, 48–60. [Google Scholar] [CrossRef] [PubMed]
  138. Sampson, T.R.; Debelius, J.W.; Thron, T.; Janssen, S.; Shastri, G.G.; Ilhan, Z.E.; Challis, C.; Schretter, C.E.; Rocha, S.; Gradinaru, V.; et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell 2016, 167, 1469–1480.e12. [Google Scholar] [CrossRef] [Green Version]
  139. Huang, H.; Xu, H.; Luo, Q.; He, J.; Li, M.; Chen, H.; Zhou, Y.; Tang, W.; Nie, Y. Fecal microbiota transplantation to treat Parkinson’s disease with constipation: A case report. Medicine 2019, 98, e16163. [Google Scholar] [CrossRef]
  140. Xue, L.J.; Yang, X.Z.; Tong, Q.; Shen, P.; Ma, S.J.; Wu, S.N.; Wang, H.G.; Zheng, J.-L. Fecal microbiota transplantation therapy for Parkinson’s disease: A preliminary study. Medicine 2020, 99, e22035. [Google Scholar] [CrossRef]
  141. Kuai, X.-Y.; Yao, X.-H.; Xu, L.-J.; Zhou, Y.-Q.; Zhang, L.-P.; Liu, Y.; Pei, S.-F.; Zhou, C.-L. Evaluation of fecal microbiota transplantation in Parkinson’s disease patients with constipation. Microb. Cell Factories 2021, 20, 98. [Google Scholar] [CrossRef] [PubMed]
  142. Distrutti, E.; O’Reilly, J.-A.; McDonald, C.; Cipriani, S.; Renga, B.; Lynch, M.A.; Fiorucci, S. Modulation of Intestinal Microbiota by the Probiotic VSL#3 Resets Brain Gene Expression and Ameliorates the Age-Related Deficit in LTP. PLoS ONE 2014, 9, e106503. [Google Scholar] [CrossRef]
  143. Bonfili, L.; Cecarini, V.; Cuccioloni, M.; Angeletti, M.; Berardi, S.; Scarpona, S.; Rossi, G.; Eleuteri, A.M. SLAB51 Probiotic Formulation Activates SIRT1 Pathway Promoting Antioxidant and Neuroprotective Effects in an AD Mouse Model. Mol. Neurobiol. 2018, 55, 7987–8000. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Kobayashi, Y.; Sugahara, H.; Shimada, K.; Mitsuyama, E.; Kuhara, T.; Yasuoka, A.; Xiao, J.Z.; Kondo, T.; Abe, K. Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alz-heimer’s disease. Sci. Rep. 2017, 7, 13510. [Google Scholar] [CrossRef]
  145. O′Hagan, C.; Li, J.; Marchesi, J.; Plummer, S.; Garaiova, I.; Good, M.A. Long-term multi-species Lactobacillus and Bifidobacterium dietary supplement enhances memory and changes regional brain metabolites in middle-aged rats. Neurobiol. Learn. Mem. 2017, 144, 36–47. [Google Scholar] [CrossRef] [PubMed]
  146. Akbari, E.; Asemi, Z.; Daneshvar Kakhaki, R.; Bahmani, F.; Kouchaki, E.; Tamtaji, O.R.; Salami, M.; Hamidi, G.A. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: A randomized, double-blind and controlled trial. Front. Aging Neurosci. 2016, 8, 256. [Google Scholar] [CrossRef] [Green Version]
  147. Den, H.; Dong, X.; Chen, M.; Zou, Z. Efficacy of probiotics on cognition, and biomarkers of inflammation and oxidative stress in adults with Alzheimer’s disease or mild cognitive impairment–A meta-analysis of randomized controlled trials. Aging 2020, 12, 4010–4039. [Google Scholar] [CrossRef]
  148. Agahi, A.; Hamidi, G.A.; Daneshvar, R.; Hamdieh, M.; Soheili, M.; Alinaghipour, A.; Esmaeili Taba, S.M.; Salami, M. Does Severity of Alzheimer’s Disease Contribute to Its Responsiveness to Modifying Gut Microbiota? A Double Blind Clinical Trial. Front. Neurol. 2018, 9, 662. [Google Scholar] [CrossRef] [Green Version]
  149. Barichella, M.; Pacchetti, C.; Bolliri, C.; Cassani, E.; Iorio, L.; Pusani, C.; Cereda, E.; Pinelli, G.; Privitera, G.; Cesari, I.; et al. Probiotics and prebiotic fiber for constipation associated with Parkinson disease: An RCT. Neurology 2016, 87, 1274–1280. [Google Scholar] [CrossRef]
  150. Cassani, E.; Privitera, G.; Pezzoli, G.; Pusani, C.; Madio, C.; Iorio, L.; Barichella, M. Use of probiotics for the treatment of constipation in Parkinson’s disease patients. Minerva Gastroenterol. Dietol. 2011, 57, 117–121. [Google Scholar]
  151. Tan, A.H.; Lim, S.-Y.; Chong, K.K.; Manap, M.A.A.; Hor, J.W.; Lim, J.L.; Low, S.C.; Chong, C.W.; Mahadeva, S.; Lang, A.E. Probiotics for constipation in Parkinson’s disease: A randomized placebo-controlled study. Neurology 2020, 96, e772–e782. [Google Scholar] [CrossRef] [PubMed]
  152. Ghyselinck, J.; Verstrepen, L.; Moens, F.; Abbeele, P.V.D.; Bruggeman, A.; Said, J.; Smith, B.; Barker, L.A.; Jordan, C.; Leta, V.; et al. Influence of probiotic bacteria on gut microbiota composition and gut wall function in an in-vitro model in patients with Parkinson’s disease. Int. J. Pharm. X 2021, 3, 100087. [Google Scholar] [CrossRef] [PubMed]
  153. Di Gioia, D.; Bozzi Cionci, N.; Baffoni, L.; Amoruso, A.; Pane, M.; Mogna, L.; Mazzini, L.; Lucenti, M.A.; Bersano, E.; Cantello, R.; et al. A prospective longitudinal study on themicrobiota composition in amyotrophic lateral sclerosis. BMC Med. 2020, 18, 153. [Google Scholar] [CrossRef] [PubMed]
  154. Wilson, A.S.; Koller, K.R.; Ramaboli, M.C.; Nesengani, L.T.; Ocvirk, S.; Chen, C.; Flanagan, C.A.; Sapp, F.R.; Merritt, Z.T.; Bhatti, F.; et al. Diet and the Human Gut Microbiome: An International Review. Am. J. Dig. Dis. 2020, 65, 723–740. [Google Scholar] [CrossRef] [Green Version]
  155. Fontana, L.; Ghezzi, L.; Cross, A.H.; Piccio, L. Effects of dietary restriction on neuroinflammation in neurodegenerative diseases. J. Exp. Med. 2021, 218, e20190086. [Google Scholar] [CrossRef]
  156. Mazzocchi, A.; Leone, L.; Agostoni, C.; Pali-Schöll, I. The Secrets of the Mediterranean Diet. Does [Only] Olive Oil Matter? Nutrients 2019, 11, 2941. [Google Scholar] [CrossRef] [Green Version]
  157. Paknahad, Z.; Sheklabadi, E.; Derakhshan, Y.; Bagherniya, M.; Chitsaz, A. The effect of the Mediterranean diet on cognitive function in patients with Parkinson’s disease: A randomized clinical controlled trial. Complement. Ther. Med. 2020, 50, 102366. [Google Scholar] [CrossRef]
  158. Maraki, M.I.; Yannakoulia, M.; Stamelou, M.; Stefanis, L.; Xiromerisiou, G.; Kosmidis, M.H.; Dardiotis, E.; Hadjigeorgiou, G.M.; Sakka, P.; Anastasiou, C.A.; et al. Mediterranean diet adherence is related to reduced probability of prodromal Parkinson’s disease. Mov. Disord. 2019, 34, 48–57. [Google Scholar] [CrossRef]
  159. Ułamek-Kozioł, M.; Czuczwar, S.J.; Januszewski, S.; Pluta, R. Ketogenic Diet and Epilepsy. Nutrients 2019, 11, 2510. [Google Scholar] [CrossRef] [Green Version]
  160. Włodarek, D. Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease). Nutrients 2019, 11, 169. [Google Scholar] [CrossRef] [Green Version]
  161. Broom, G.M.; Shaw, I.C.; Rucklidge, J.J. The ketogenic diet as a potential treatment and prevention strategy for Alz-heimer’s disease. Nutrition 2019, 60, 118–121. [Google Scholar] [CrossRef] [PubMed]
  162. Rusek, M.; Pluta, R.; Ułamek-Kozioł, M.; Czuczwar, S.J. Ketogenic Diet in Alzheimer’s Disease. Int. J. Mol. Sci. 2019, 20, 3892. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Phillips, M.C.L.; Murtagh, D.K.J.; Gilbertson, L.J.; Asztely, F.J.S.; Lynch, C.D.P. Low-fat versus ketogenic diet in Parkinson’s disease: A pilot randomized controlled trial. Mov. Disord. 2018, 33, 1306–1314. [Google Scholar] [CrossRef] [PubMed]
Biomedicines 10 01486 g001 550
Figure 1. The gut microbiome influences the gut–brain axis through the production of SCFAs, amyloid proteins, LPS, bile acids, and neurotransmitters. SCFAs and bile acids can enter the circulation and have been demonstrated to have an important effect on maintaining BBB homeostasis. Amyloid proteins and LPS can increase local inflammation, promoting further local and systemic protein deposition (A). On the other hand, the CNS can control epithelial permeability, gut motility, and inflammation through the autonomic nervous system and the hypothalamus–pituitary axis (B). Created with Biorender.Com.
Figure 1. The gut microbiome influences the gut–brain axis through the production of SCFAs, amyloid proteins, LPS, bile acids, and neurotransmitters. SCFAs and bile acids can enter the circulation and have been demonstrated to have an important effect on maintaining BBB homeostasis. Amyloid proteins and LPS can increase local inflammation, promoting further local and systemic protein deposition (A). On the other hand, the CNS can control epithelial permeability, gut motility, and inflammation through the autonomic nervous system and the hypothalamus–pituitary axis (B). Created with Biorender.Com.
Biomedicines 10 01486 g001
Table
Table 1. Human studies on the gut microbiome in neurodegenerative diseases. AD: Alzheimer’s disease, PD: Parkinson’s disease; ALS: Amyotrophic lateral sclerosis; HCs: Healthy controls; MCI: Mild cognitive impairment.
Table 1. Human studies on the gut microbiome in neurodegenerative diseases. AD: Alzheimer’s disease, PD: Parkinson’s disease; ALS: Amyotrophic lateral sclerosis; HCs: Healthy controls; MCI: Mild cognitive impairment.
Study DesignAnalysisResultsRef
AD
Case control (40 Amyloid+, 33 Amyloid3− subjects and 10 HCs)Microbial DNA qPCR Assay KitAmyloid+ subjects: ↓ E. rectale and ↑ Escherichia/Shigella comapred to Amyloid− and HCs[16]
Case control (25 AD and 25 HCs)16S rRNA sequencingAD: ↓ Firmicutes and Actinobacteria and ↑ Bacteroides[17]
Case control (24 AD, 33 other dementia, 51 HCs)Shotgun metagenomic sequencingAD: ↑ Bacteroides spp., Alistipes spp., Odoribacter spp., Barnesiella spp.; ↓ Lachnoclostridium spp.compared to HCs[18]
Case-control (33 AD, 32 aMCI and 32 HCs)16S rRNA sequencingAD: ↓ Firmicutes, increased Proteobacteria compared to HCs
aMCI: ↑ Bacteroides compared to AD		[19]
Case control (100 AD, 71 HCs)16S rRNA sequencingAD: ↓ Faecalibacterium, Roseburia, Clostridium sensu stricto, Gemmiger, Dialister, Romboutsia, Coprococcus, and Butyricicoccus[20]
Case-control (43 AD and 43 HCs)16S rRNA sequencingAD: ↓ in Bacteroides and increase in Actinobacteria[21]
Case-control (18 AD, 20 MCI, 18 HCs)16S rRNA sequencingAD: ↑ Prevotella and ↓ Bacteroides, Lachnospira compare to HCs
MCI: ↑ Prevotella compared to HCs		[22]
PD
Case-control (51 PD, 48 HCs)16S rRNA sequencingPD: ↑ Akkermansia and Prevotella; ↓ Lactobacillus[23]
Case-control (193 PD, 22 PSP, 22 MSA and 113 HCs)16S rRNA sequencingPD: ↑ Akkermansia compared to HCs[24]
Case-control (76 PD, 76 HCs)16S rRNA sequencingPD: ↓ Prevotella and Clostridium XIV [25]
Case control (38 PD, 34 HCs)16S rRNA sequencingPD: ↑ Roseburia, Blautia and Coprococcus, ↓ Faecalibacterium[26]
Case-control (72 PD, 73 HCs)16S rRNA sequencingPD: ↑ Prevotellaceae[27]
Case-control (34 PD, 34 HCs)16S rRNA sequencingPD: ↓ Bacteroidetes and Prevotellaceae, ↑ Enterobacteriaceae[28]
Case-control (31 PD, 28 HCs)Metagenomic shotgun sequencingPD: ↑ Akkermansia muciniphila, ↓ Prevotella copri and Eubacterium biforme[29]
Case-control (197 PD, 130 HCs)16S rRNA sequencingPD: ↑ Actinobacteria, Bacteroidetes and Firimicutes[30]
Case-control (29 PD, 29 HCs)16S rRNA sequencingPD: ↑ Lactobacillaceae, Bernesiellaceae and Enterococcaceae[31]
Case-control (76 PD, 78 HCs)16S and 18S rRNA sequencingPD: ↑ Akkermansia[32]
Case-control (75 PD, 45 HCs)16S rRNA sequencingPD: ↓ Lachnospiraceae, increased Bifidobacteriaceae[33]
Case-control (80 PD, 72 HCs)16S rRNA sequencingPD: ↑ Lactobacillaceae, Enterococcaceae and Enterobacteriaceae; ↓ Lachnospiraceae[34]
ALS
Case-control (6 ALS, 5 HCs)16S rRNA sequencingALS: ↓ Bacteroides, Prevotella and Escherichia; increased Faecalibacterium, Anaerosipes and Lachnospira[35]
Case-control (25 ALS, 32 HCs)16S rRNA sequencingNo significant difference[36]
Case-control (20 ALS, 20 HCs)16S rRNA sequencingALS: ↑ Bacterodetes, ↓ Firmicutes[37]
Case-control (66 ALS, 61 HCs)Metagenomic shotgun sequencingALS: ↓ Eubacterium rectale and Roseburia intestinalis[38]
Case-control (10 ALS, 10 HCs)16S rRNA sequencingALS: ↓ Prevotella[39]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ghezzi, L.; Cantoni, C.; Rotondo, E.; Galimberti, D. The Gut Microbiome–Brain Crosstalk in Neurodegenerative Diseases. Biomedicines 2022, 10, 1486. https://doi.org/10.3390/biomedicines10071486

AMA Style

Ghezzi L, Cantoni C, Rotondo E, Galimberti D. The Gut Microbiome–Brain Crosstalk in Neurodegenerative Diseases. Biomedicines. 2022; 10(7):1486. https://doi.org/10.3390/biomedicines10071486

Chicago/Turabian Style

Ghezzi, Laura, Claudia Cantoni, Emanuela Rotondo, and Daniela Galimberti. 2022. "The Gut Microbiome–Brain Crosstalk in Neurodegenerative Diseases" Biomedicines 10, no. 7: 1486. https://doi.org/10.3390/biomedicines10071486

APA Style

Ghezzi, L., Cantoni, C., Rotondo, E., & Galimberti, D. (2022). The Gut Microbiome–Brain Crosstalk in Neurodegenerative Diseases. Biomedicines, 10(7), 1486. https://doi.org/10.3390/biomedicines10071486

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop