Probiotics for Neurodegenerative Diseases: Comparison
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Please note this is a comparison between Version 5 by Jessie Wu and Version 4 by Prashant Kaushik.

Neurodegenerative disorders (ND) are a group of conditions that affect the neurons in the brain and spinal cord, leading to their degeneration and eventually causing the loss of function in the affected areas. These disorders can be caused by a range of factors, including genetics, environmental factors, and lifestyle choices. Major pathological signs of these diseases are protein misfolding, proteosomal dysfunction, aggregation, inadequate degradation, oxidative stress, free radical formation, mitochondrial dysfunctions, impaired bioenergetics, DNA damage, fragmentation of Golgi apparatus neurons, disruption of axonal transport, dysfunction of neurotrophins (NTFs), neuroinflammatory or neuroimmune processes, and neurohumoral symptoms. According to studies, defects or imbalances in gut microbiota can directly lead to neurological disorders through the gut-brain axis. Probiotics in ND are recommended to prevent cognitive dysfunction, which is a major symptom of these diseases. 

  • probiotics
  • neurodegenerative diseases
  • gut microbiota
  • aging
  • microglia

1. Relation of Gut Microbiota with Neurodegenerative Disorders

The health of the brain is synchronized or regulated by the GI tract or it is directly proportional to the microbiome present in the human gut. Imbalance in the microbial community is associated with many diseases, but in the brain, it was responsible for neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and others disorders [1]. Brain and gut microbiota can interrelate with each other through several pathways such as neuroendocrine, neuroimmune, and autonomic nervous systems. Interactive partners that perform the mechanisms are the cell wall, neurotransmitters, vagus nerves, and metabolites [2]. The microbiome of the gut can synthesize the neurotransmitter that may help to maintain the homeostasis of the central nervous system, which can influence neurodegeneration, examples are tryptophan, brain-derived neurotrophic factor (BDNF), Gama-aminobutyric acid (GABA), and short-chain fatty acid (SCFA) [3]. Neurotrophins have a neuroprotective property that is important for the growth, development, and synaptic plasticity along with the differentiation and survival of the neuron. The decreased level of BDNF influences the neurodegenerative disease related to the cerebral cortex and directly relates to the gut-brain axis, which triggers other diseases too [4]. Gut microbes such as Faecalibacterium prausnitzil, Clostridium leptum and Eubacterium rectala, etc. produce short-chain fatty acids through a down regulation of pro-inflammatory cytokines that play a major role in neurodegeneration. Microbial-derived SCFAs are produced by bacterial fermentation and have neuro-active functions, they act as a modulator for serotonin (neurotransmitter) and some neuropeptides which help to facilitate the gut-brain axis at various stages. During the release mechanism which influences neuronal health and behavioral response [5]. Excessive release of SCFAs is responsible for neuronal health and behavioral responses. An essential amino acid called tryptophan plays an important role in the synthesis of serotonin and other neurotransmitters in the CNS. Imbalance in their levels leads to brain and gastrointestinal disturbances that may cause neurodegeneration, cognitive impairment, and mood disorders [6][7]. An important inducer that administered the excitation of the neurons, is a by-product of bacterial metabolism called GABA. Deregulation of GABA leads to various pathological imbalances that play a major role in neuro-cytotoxicity which accelerates several chronic neurological disorders. GABA is an example that proves how gut microbiota regulates brain chemistry [8].

1.1. Alzheimer’s Disease (AD)

People with gut disorders more prone to have AD in the future. Changes in complex ecosystems are co-related with many gastrointestinal disturbances that can implicate many inflammatory diseases including obesity, diabetes and inflammatory bowel disease. The dysbiosis of gut microbiota has an impact on the synthesis of proteins and metabolic processes which are related to the progression of the disease such as AD. Aging changes the gut microbial concentration which enhances pro-inflammatory bacterial growth more than anti-inflammatory bacteria that deteriorates the permeability of the blood-brain barrier and GIT (Gastro Intestinal Tract) functions [9]. Pro-inflammatory phylum such as Proteobacteria, Verrucomicrobia, genera such as Escherichia/Shigella, and species such as Pseudomonas aeruginosa, anti-inflammatory species are Clostridium spp., and Ruminococcaceae. Some study reveals that increased mRNA encoding initiates the release of pro-inflammatory cytokines such as, IL6, CXCL2, and NLRP3, Escherichia/Shigella are related to pro-inflammatory taxon [6]. The presence of Helicobacter pylori in the gut microbiota increases the release of inflammatory mediators which increases the amyloid β 40/42 ratio in the serum, other bacteria such as Borrelia burgdorferi and Chlamydia pneumoniae also participate in the hyper phosphorylation of tau which is an important hallmark of AD. IL-10 is an anti-inflammatory cytokine Eubacterium rectale is associated with an anti-inflammatory taxon [10].

1.2. Parkinson’s Disease

PD is a multifocal neuronal disease that is distinguished by tremors, slow movement, akinesia, muscular rigidity, gait, and difficulty in walking. Instead of these symptoms, PD patients suffer from constipation which is one of the causes of increased intestinal permeability and inflammation that is directly related to the microbiota community of the small intestine [11]. Small intestinal bacterial outgrowth and helicobacter pylori infection has seen in diseased person that causes motor impairment and problem-related with stool [12]. In most cases, patients suffer from increased mucosal permeability and endo-toxic exposure caused by Coliform bacteria [13]. Comparably, some bacteria are reduced in feces such as Roseburia intestinalis, Roseburia hominis, Coprococcus eutactus, and Blautia faecis dysregulate the biosynthesis of lipopolysaccharides and are also responsible for GABA deregulation [14]. Escherichia coli is a Gram-negative bacteria that releases amyloidogenic protein which induces alpha-synuclein aggregation and which regulates disease in the gut and neurodegeneration in the brain [15].

1.3. Huntington’s Disease

HD is a genetic disease caused by overexpression of the huntingtin coding gene, new research suggests that an imbalance in gut microbiota dysregulates the cytokine levels and excessive production of hydrogen sulfide that negatively affects gut health [16][17]. Imbalance is seen in two microbial communities such as increased the majority of the bacterial phyla Bacteroidetes (4%) and Firmicutes (83%) which causes mortality and motor ability-related problems in HD conditions. Research suggests that irregular intestinal biomicrome decreases mucosal thickness and decreased neuropeptide formation with abnormal endocrine hormonal conditions [18][19][20]. ATP levels are associated with Prevotella scopos which has negative effects and also has a co-relation with decreased butyrate formation affected by Blautia producta [21].

1.4. Other Neurological Disorders

In neurological disorders, the nerve function and structure become affected badly, causes of neuronal cell death, are Amyotrophic lateral sclerosis, Friedreich ataxia, Lewy body disease, spinal muscular atrophy, and Epilepsy, etc. Epilepsy, a neuro-psychiatric disorder is a result of environmental and genetic imbalance, several studies implicated dysbiosis of gut microbiota correlated with the disease, and imbalance of microbiome increases the pro, and anti-inflammatory effects, which leads to chronic inflammation and progression of the disease [22][23]. Bacteria out-growth downregulates lipid and glucose metabolism which disturbs the ATP binding cassette and transporter-associated pathways [24]. Amyotrophic lateral sclerosis is a degenerative condition that is caused by the mutation in dozens of genes which produces a misfolded protein that is found in motor neurons, responsible for voluntary muscular movement [25]. Bulbar function slowly deteriorated with the progression of the disease, and dysphagia (because of aspiration pneumonia and weight loss) have seen [26]. ALS is implicated by the deregulation of the resident and peripheral immune system. Gut microbiota connected with the intestinal immune system, because of invasion or dysbiotic leaky gut and disturbed molecular patterns, provoke cells to release pro-inflammatory cytokines that deregulate the Firmicutes/Bacteroidetes ratio [27]. Bacteroidetes are good gut bacteria, that are decreasing at the diseased condition that imbalances the cell homeostasis, is regarded as dysbiosis and several reviews suggest that the gut plays an impotent role in the progression of Lewy body disease, and intestinal pro-inflammation is the cause of the chronic phase of the disease. An imbalance in microbiota and translocation of the lumen through a leaky gut are key mechanisms of the disease [28].

2. Recent Evidence for Probiotics and Neurodegenerative Disorders

In neurodegenerative disorders, neuroinflammation plays a very crucial role in pathogenesis, which has been proven through various studies. That may further drive the progressive loss of dopaminergic neurons. Therefore, increasing efforts on anti-inflammation approaches are being made in developing a cure for neurodegenerative disorders (ND) [29]. Different probiotics such as E. coli, Lactiplantibacillus plantarum, Bifidobacterium pseudocatenulatum and other combinations of probiotics capsules or tablets can useful as anti-inflammatory, anti-oxidant, or anti-pro inflammatory cytokines release and reduce the chances of occurring ND in patients [30]. Numerous neurological and psychiatric illnesses are linked to altered amounts of 5-HT (5-hydroxytryptamine-Serotonin) and DA (dopamine) to regulate this signaling molecule VSL#3 such as complex probiotic (consists of eight bacterial strains) VSL#3 interacts with mesenchymal stromal cells (hMSCs) to reduce neurodegeneration and inhibit NOD-like receptor protein-3, which mediated inflammation without altering the effects of hMSCs [31]. Cognitive processes, learning, memory, and emotional changes can all be modulated by NA. The two major inhibitory and excitatory chemicals are GABA and ACh. With respect to a single strain Bifidobacterium longum improve the cognitive function in healthy Balb/c mice, another context of using a multistrain probiotic, including different species of Lactobacilli and Bifidobacterium in the adult population, demonstrated improved cognition [32]. In accordance with the recent study to analyze the effect of a diet containing appropriate bacteria, participants were asked to consume two capsules after the meal in the morning and evening, which made a total of four capsules (a total of 1 × 109 colony-forming a unit of Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI in soybean oil) to be taken per day for 12 days and then the relative abundance at genus level of Clostridiales and Prevotellaceae has been observed [33].

2.1. Invertebrate System Studies

The beneficial effect of probiotics for neurodegenerative disease can be studied through an invertebrate model system, which is quite cheaper, and translational. Because of the complexity of the human nervous system and microbiota, identifying the primary microbial proteins or metabolites that have a direct influence on host neurons during neurodegeneration is usually difficult [34]. Simpler organisms like C. elegans were utilized in order to better understand the microbe-host interaction in the context of NDs. A recent study of the effect of probiotics on invertebrate models shows that, protein aggregation of α-synuclein, movement analysis, or locomotor analysis were restored with the help of a single bacterial strain (Lactobacillus plantarum) or multiple bacterial strains (E. coli OP50 and B. subtilis NCIB3610) [35]. In the PD model (C. elegans), expression of α-synuclein was expressed in disease the condition [36]. The Caldwell lab used a genome-wide RNAi screen to identify the role of the endocytic pathway in reducing α-synuclein toxicity in order to identify genetic variables that influence α-synuclein-mediated proteotoxicity and treated C. elegans with B. subtilis PB6 and Bifidobacterium dentium respectively that regulate the endocytic pathway through degradation of α-synuclein aggregates [37]. The PXN21 protein from B. subtilis prevents and prevents α-synuclein from aggregating [38]. The adult-onset loss of the dopaminergic neurons and locomotor dysfunction were induced by Ala-53-Thr, Ala-30-Pro, or Gln-46-Tyr mutations in the α-synuclein gene in the D. melanogaster variant of the UAS-Synuclein experiment, this locomotor dysfunction was restored by B. subtilis PXN21 and Lactobacillus plantarum within 4–12 days [39]. In the D. melanogaster strains of UAS-BACE/UAS-APP, L. brevis and Bifidobacterium dentium are less prevalent in the gut, and GABA levels are decreased in the CNS [40]. Similarly for AD model, uncoordinated locomotion, the buildup of insoluble tau, and age-related neuronal loss and deterioration are all present in C. elegans (A53T) mutant [41]. Although, Tan et al. found that Lactobacillus, particularly the L. plantarum DR7 strain, restores the rough eye phenotype in D. melanogaster GMR-A42 AD flies. The L. plantarum DR7 can restore the gut microbiota diversity in flies by increasing the abundance of Stenotrophomonas and Acetobacter, with reducing Wolbachia [42]. Although in other ND, like ALS; the generation of SOD1 (G85R) mutations in C. elegans led to severe locomotor defects and the formation of insoluble SOD1 aggregates in the perinuclear region of motor neurons [43]. In a demethylase-dependent manner, the KDM5 protein controls the immune deficiency (IMD) signaling pathway and maintains bacterial balance in D. melanogaster [44].

2.2. Vertebrate System Studies

The prevalence of ND is on the increase worldwide as the population ages, posing a serious danger to human health. Probiotics, live microorganisms that help the host’s health, may hold promise in the treatment and prevention of these crippling diseases, according to a recent study. Vertebrate models have become an important resource in this context for understanding the fundamental processes of neurodegeneration and evaluating the effectiveness of probiotics in reversing it. With respect to AD, according to Webberley et al.’s 2022 research in 3xTg mice, the Lab4b probiotic acts as a neuroprotective agent through an anti-inflammatory cytokine, and it has also been demonstrated that IL-10 absence lessens disease pathology in AD animals [45]. Similarly, Yang et al. discuss the importance of Acidophillus-KAL4 in reducing gut barrier damage and inflammation in elderly SAMP8 mouse models, as well as lowering levels of LPS and γ-H2AX, 8-OHdG, TLR4, RIG-I, and NF-κβ nuclear translocation in the brain [46]. In respect to PD, Sun et al. created male C57BL/6 (MPTP initiated) mice, and they investigated whether reversing gut microbiome dysbiosis was possible and Clostridium butyricum therapy for four weeks resulted in reduced amounts of colonic GLP-1, colonic GPR41/43, and cerebral GLP-1 receptor in MPTP-induced rodents [47]. By shedding light on the underlying mechanisms of these conditions and testing the efficacy of probiotics in vertebrate models, researchers might develop treatments that fight against these terrible illnesses Table 1.
Table 1. Study of neurodegenerative diseases and their mediation with probiotics on different invertebrate and vertebrate model systems.
Model System ND Mediation Outcome Refs.
Study History in an Invertebrate Model System
C. elegans PD B. subtilis PXN21

Lactobacillus plantarum		 Inhibits and reverses α-syn aggregation,

improved locomotion and reduced dopaminergic neuron degeneration		 [48]
AD E. coli OP50

B. subtilis NCIB3610		 Alleviated the paralysis phenotype, behavioral deficits, and aggravate lifespan [49]
ALS Lacticaseibacillus rhamnosus HA-114 Suppresses the progression of motor neuron degeneration [50]
HD Bacillus subtilis Extends longevity through downregulation of the insulin-like signaling pathway [51]
D. melanogaster

Park25 flies		 AD Lactobacillus plantarum DR7 Ameliorate the AD effects [52]
Bifidobacterium longum ssp. infantis NCIM 702 255 Rescued amyloid beta deposition and acetylcholinesterase activity [53]
Lactobacillus spp. Improved gene expression related to insulin signaling, fat metabolism [54]
PD Acetobacter tropicalis Reduced mitochondrial function and disrupted insulin-like signaling and glucose regulation [55][56]
ALS Lactobacillus plantarum Degeneration of motor nerve cells [57]
HD E. coli Regulating HTT aggregates and motor defects [58]
Study history in vertebrate model system
3 × Tg AD † mice AD Lactobacillus plantarum PS128 Regulated glycogen synthase kinase 3 beta activity [59]
Bifidobacterium breve A1 Reduce the expression of Aβ gene [60]
SLAB51 It degrade Aβ plaque through CathepsinD [61]
5× FAD Tg mice L. plantarum C29

Bifidobacterium lactis CUL 34		 Decrease the expression of Caspase 3 and increase the activation of microglial [62]
Wistar rats L. plantarum MTCC 1325 Increase the concentration of ACh in hippocampus [63]
C57BL/6 mice MPTP † -induced PD
Streptococcus thermophilus CRL808
Increase pro-inflammatory receptors concentration (IL10)
Bifidobacterium bifidum

Lactobacillus reutri

Lactobacillus fermentum		 Increase PPARγ
6-OHDA † induced PD † in C57BL/6 mice SLAB51:

Streptococcus thermophilus,

Bifidobacterium longum,

Bifidobacterium breve,

Bifidobacterium infantis,

Lactobacillus acidophilus,

Lactobacillus plantarum,

Lactobacillus paracasei,

Lactobacillus delbrueckii sub sp. bulgaricus, Lactobacillus brevis		 Induces hippocampal long-term

potentiation through BDNF		 [69]
PD patients Streptococcus salivarius sub sp. thermophilus, Enterococcus faecium,

Lactobacillus rhamnosus GG,

Lactobacillus acidophilus		 Decrease IL1, IL8 and TNFα [70]
Bifidobacterium infantis Reduce abdominal pain and constipation
Mice ALS Lacticaseibacillus rhamnosus HA-114 Through mitochondrial β-oxidation restores lipid equilibrium and energy balance [71]
C57BL/6 mice HD Bifidobacterium spp. decreased Il-1β and Il-6 and increased TGF-β and Il-10 expression [72]
BALB/c mice L. casei IMV B-7280 Inhibiting NF-κB pathway [73]
C57/BL6 mice L. lactis NZ9000SHD5 reduced colonic glandular structure,

downregulated expression of inflammatory molecule		 [72]
(† = Disease induced mice model).

3. Mechanism of Action and Therapeutic Effect of Probiotics in Combatting Neurological Disorders

Probiotics, which have been shown to have health benefits when consumed, have drawn a lot of interest in recent years because of their ability to treat and avoid a variety of diseases. While the exact mechanism of action of probiotics is not yet fully understood, growing evidence suggests that they act through various pathways to regulate immune function, improve gut barrier function, modulate the gut-brain axis and neurological complications [74].
Based on the results of both the animal and human studies, the consumption of probiotics has a significant beneficial effect on AD Table 1. WResearchers can conclude that most of the study is based on Bifidobacterium and Lactobacillus and as an outcome this research reveals that probiotics can improve memory dysfunction and cognitive dysfunction in similar to neurodegenerative diseases [38][75]. With respect to AD, the CNS’s inflammatory reaction to damage or infection is called neuroinflammation, which is accompanied by an accumulation of glial cells. Activated microglia and astrocytes generate pro-inflammatory cytokines like IL6, IL8, and IL10, and these cytokines directly cause neuronal injury [76]. According to studies, probiotics can restore chronic inflammation, the function of clearing abnormal proteins, and synaptic dysfunction. Neurodegeneration and brain loss are caused by all of these occurrences. To understand and solve the puzzle of how probiotics were beneficial in AD, there have primarily been four clinical trials, which are mentioned in Table 2, below. Regarding PD, a new clinical trial of probiotic capsules (containing Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum) demonstrates the same effects as the MDS-UPDRS [77]. Another 2019 research demonstrates that the major pro- and anti-inflammatory cytokines, as well as ROS, are produced by Lactobacillus and Bifidobacterium genus when peripheral blood mononuclear cells (PBMCs) isolated from people with Parkinson’s disease (PD) are compared to healthy participants [78]. In relation to other ND Lacticaseibacillus rhamnosus HA-114 can improve the energy balance and cholesterol homeostasis in ND animals [71]. In relation to neurodegenerative disease, only 10% of the research concentrates on Streptococcus and Clostridium species. So on, wresearchers give a summary of the literature in this systematic reviewsearch by using data that was extracted from different sources.
Table 2. Recent clinical studies of ND with combination or singular probiotic with their therapeutic effect and mechanism of action.
ND Probiotics Duration Mechanism Therapeutic Effect Ref.
AD L. acidophilus

L. cases

B. bifidum

L. fermentum		 12 weeks Management of metabolic deviation Decreased level of triglyceride in blood

Decreased serum malondialdehyde

Unproductive on antioxidant capacity.		 [79]
L. fermentum

L. plantarum

B. lactis

L. acidophilus

B. bifidum

B. longum		 12 weeks Management of Urea and Glucose level Improved cognitive function.

Unproductive on antioxidant capacity. Improved level of Glutathione

Reduced level of Deoxyguanosine.		 [80]
L. acidophilus

B. bifidum

B. longum

selenium		 12 weeks Metabolic deviation and oxidative stress balancing Decreased level of triglyceride in blood

Improved the level of Glutathione

Improved antioxidant capacity.		 [81]
L. casei W56

L. lactis W19

L. acidophilus W22

B. lactis W52

L. paracasei W20

L. plantarum W62

B. lactis W51

B. bifidum W23

L salivarius W24		 28 days Simulating the microbiota gut brain axis and active immune cells Improved Faecalibacterium concentration in faecal.

High concentration of kynurenine in blood.

Improved RNA concentration in faecal bacteria.		 [82]
PD Blautia

Roseburia,

Coprococcus

Firmicutes

Proteobacteria

Verrucomicrobia, Oscillospira

Bacteroides		 NA Maintaining level of fecal microbiota and mucosal level Pro inflammatory dysbiosis,

trigger inflammation

Induced misfolding of α synuclein.		 [83]
B. bifidum NA Regulation of neuronal inflammation Reduced neuroinflammation. [84]
L. salivarius

L. plantarum

L. acidophilus

L. rhamnosus

B. animalis subsp.

B. breve		 NA- Monitoring the production of cytokine, superoxide anions (O2-);

Proliferation of E. coli and K. pneumoniae DNA for tyrosine decarboxylase		 Reduced ROS generation, improved constipation, and inhibition of E. coli and K. pneumonia all contribute to anti-inflammatory activity. [85]
Multiple Sclerosis B. animalis NA Regulation of gut barrier permeability Improved gut barrier function and reduced inflammation. [86]
ALS L. rhamnosus NA Regulation of behavioral changes Improved behavior and social interaction. [87]
B. longum NA Regulation of stress and anxiety level Reduced anxiety and depressive symptoms. [88]
Patient (Infant aged < 7 months)
B. breve M-16V
No effect on AD marker [64]
Pregnant woman B. longum BB536 Prevent eczema and AD in their offspring [65]
Children aged (1–3 years) L. fermentum

L. plantarum CJLP133		 Decrease IFNγ and IL4 [66]
Adult patients B. animalis LKM512 Reduce the cumulative incidence of AD [67]
MitoPark PD † mice PD Lactobacillus rhamnosus GG

Bifidobacterium bifidum		 Decrease the level of dopaminergic neuronal loss [68]

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