Insights into Emerging Trends of Gut Dysbiosis in Alzheimer’s Disease: Exploring Potential of Pre and Probiotics

 

 

Table 1: Common species of gut microbiota and effects of their metabolites on the central nervous system

Gut microbiota	Metabolites	Effects on the central nervous system function	Ref.
Lactobacillus, Bifidobacterium	Gamma-aminobutyric acid (GABA)	The primary inhibitory neurotransmitter is responsible for controlling mood, behavioural and cognitive processes.	(49)
Bifidobacterium infantis, Streptococcus, Escherichia, Enterococcus, Lactococcus, Lactobacillus,)	Candida Serotonin (5-HT	Neurotransmitters, control emotional responses.	(50)
Escherichia, Bacillus, Lactococcus, Lactobacillus, Streptococcus	Dopamine	Regulate both mental and physical activities, including cognitive functions like learning and memory.	(50)
Lactobacillus, Bacillus	Acetylcholine	Cognitive, memory, social interaction, self-care capacity, and emotional well-being.	(51)
Bacteroides, Bifidobacterium, Propionibacterium, Eubacterium, Lactobacillus, Clostridium, Roseburia, Prevotella	Short-chain fatty acids (SCFA)	Enhance the blood-brain barrier's permeability reduction, stimulate the production and release of neurotransmitters.	(52)
Lactococcus, Lactobacillus, Streptococcus, Enterococcus	Histamine	Manage sleep patterns and cognitive functions.	(53) (54)

Additionally, the human gastrointestinal tract is a hospitable environment that is home to more than 100 trillion microbes, thereby classifying the microbiome as the body's largest "virtual organ." This, in turn, affects and regulates the host's overall fitness, appearance, and well-being [48]. As a result, significant efforts have been focused on countering the impact of intestinal dysbiosis in neurodegenerative disease.

 

Gut -Brain Axis:

Through microbial–metabolite, immunological, endocrine, and neurological pathways, the “gut–brain axis” is a two-way communication system that connects the central nervous system and the gastrointestinal tract.  It affects behavior, emotions, and thought processes in addition to coordinating intestinal processes including motility and secretion.  Intestinal permeability modulation, enteroendocrine hormone secretion, immunological activation with cytokine release, vagal and enteric nervous system signalling, and microbial synthesis of neuroactive metabolites such short-chain fatty acids are important pathways.  A disturbance of this intricately regulated network leads to neuroinflammation, barrier dysfunction, and altered neurotransmission—processes that are becoming more and more linked to neurodegenerative diseases like Alzheimer's [55]. Within this communication network, the brain influences gut movement, sensory, and secretion processes, while signals from the gut in turn impact brain function [56]. Maintaining gut homeostasis relies heavily on this relationship, which has also been linked to the development of various metabolic and mental health issues, including psychiatric and neurological disorders [57, 58].

 

Different routes of communication between the gut microbiota and the brain have been proposed:

·     The vagus nerve serves as the primary modulatory pathway, with its influence exerted through both incoming and outgoing branches [59, 60].

·     Through the production of metabolites and bioactive peptides, including short-chain fatty acids, as well as the regulation of neurotransmitters, like serotonin and acetylcholine, the gut microbiota affects the host [59-61].

·     The HPA system releases cortisol in response to stress, which can affect intestinal motility, health, and mucus production. Ultimately, this can lead to changes in the gut microbiota's composition.  By altering the levels of stress hormones, this alteration may have an impact on the central nervous system. [61].

·     The immune response is mediated through the release of pro-inflammatory cytokines and chemokines [62].

·     Immunity plays a critical role in this process. Specifically, toll-like receptors (TLRs) and peptidoglycans (PGNs) act as sensors of microbial components, mediating the immune response towards microbes [63, 64].

 

Local immune activation can, through various pathways, result in immune activation in different organs, including the brain [65]. This low-grade immune activation has been linked to the underlying causes of certain forms of depression and neurodegenerative disorders, including AD and Parkinson's disease (PD) [59]. The intricate relationship between various factors is not unexpected, considering that the gut–brain axis is directly or indirectly linked to neuropsychiatric illnesses, with the gut microbiota serving as a primary component of this communication [66].

 

Gut dysbiosis & AD

The role of gut microbiota and GMBA in AD is of utmost importance. GM plays a crucial role in overall health and function of the brain, and alterations in the GM have been linked to various neurological disorders, including AD. GMBA, a member of the gut microbiota, has been shown to have a significant impact on the development and progression of AD [67]. Gut bacteria composition has a dramatic impact on any age-related neurological disorder. External factors such as diet, lifestyle, and pro-inflammatory insults, as well as internal components including genetic variations, the immune system, metabolites, and hormones, significantly impact the makeup of the gut microbiome, which subsequently produces signalling compounds viz., SCFAs, tryptophan, choline, and hormones (including ghrelin, leptin) in the gastrointestinal tract capable of regulating central nervous system functions [68]. Aging has a significant impact on the composition of GM, which tends to favor the development of pro-inflammatory bacteria. These include Bacillus fragilis, Faecalibacteriumprausnitzii, Eubacterium rectale, Eubacterium hallii, and Bacteroides fragilis. Local and systemic inflammation come from the reduction of anti-inflammatory bacterial numbers.  This inflammation damages the blood-brain barrier (BBB) and increases the permeability of the gastrointestinal system.  A compromised blood-brain barrier encourages neuroinflammation. 

 

According to research by Cattaneo et al., patients with amyloid-positive illnesses have more pro-inflammatory microorganisms than healthy individuals [69]. Although infection with Salmonella enterica or Candida albicans enhanced susceptibility to subsequent infections in transgenic mice expressing mutant human APP and in Caenorhabditis elegans models harboring human Aβ42, these animals outlived wild-type controls with prolonged survival.  Aβ's antibacterial qualities are responsible for this contradiction, as its heparin-binding motif makes it easier for it to interact with the glycosylated parts of microbial cell walls.  By promoting microbial agglutination and disrupting pathogen adherence to host cells, this binding helps the host defend against infection even if the host is generally more susceptible [70]. Bacteria-derived amyloids have been identified as potential causative factors for Aβ peptide aggregation in AD. Specifically, amyloids produced by certain bacteria, such as curli from E. coli, TasA from Bacillus subtilis, CsgA from S. Typhimurium, FapC from Pseudomonas fluorescens, and phenol soluble modulins from Staphylococcus aureus, have been shown to contribute to the development of Alzheimer's disease pathology by promoting the formation of Aβ oligomers and fibrils [71].

 

Amyloids originating from bacteria, other factors are involved in the onset and progression of Alzheimer's disease. The administration of lipopolysaccharides (LPS) from bacteria to experimental animals in the fourth ventricle of the brain resulted in a symptom profile that closely resembled Alzheimer's disease [72]. Even the injection of LPS in mice leads to an increase in Aβ levels in the hippocampal area, resulting in cognitive defects. This supports the role of LPS in the formation of amyloid fibrils [73,74]. Upon being in use, LPS has been discovered to initiate the TLR4 pathway, causing immune cells to produce pro-inflammatory cytokines and IgM/IgA, leading to an intensification of systemic inflammation [75-78]. From this viewpoint, gut inflammation could be a reason why AD develops. The connection between the GM’s composition, inflammation, additional neuroinflammation, and the onset of AD, is a key point of contention in understanding the causes of Alzheimer's disease. Several investigations have found pathogens in the brain tissue of patients who died from AD [79-82].

 

Among the viruses and bacteria that have been linked to AD are herpes simplex virus type 1 and various bacterial species, including Chlamydophila pneumoniae, Borrelia burgdorferi, and other spirochetes [83-85]. Evidence also indicates a substantial rise in levels of Helicobacter pylori-specific IgG antibodies in both the cerebrospinal fluid and the serum of individuals with AD [86]. New therapeutic strategies may be developed by exploring the key function of specific gut microbiota compositions associated with AD, in an effort to increase the presence of beneficial microorganisms, while also modifying both dietary habits and lifestyle, which could help to prevent the progression of AD as shown in (Figure 1) [87-89].

Figure 1: Depicts the effects of an imbalance in the gut microbiome in AD. Gut dysbiosis results in a decrease of beneficial compounds, including SCFAs and H2, and an increase of harmful compounds, such as amyloids and Trimethylamine N-oxide (TMAO), which leads to increased permeability of the intestinal mucosal barrier and BBB, activation of peripheral immune responses, and elevated levels of peripheral and central oxidative stress. The progression of AD pathology is furthered by gut dysbiosis, which leads to enhanced amyloid plaque formation, increased neuroinflammation, SGs, and IR.

 

Probiotics and Prebiotics as a Potential treatment strategy for AD:

Probiotics:

First used in 1974, the term "probiotics" today refers to "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host." Immune response modulation, stress protection, pathogen colonization inhibition, and intestinal epithelial barrier function augmentation are some of their positive benefits. In models of neurodegenerative diseases, probiotic supplementation has been demonstrated to improve spatial memory, lower the load of amyloid plaque in the hippocampus, and restore synaptic plasticity and long-term potentiation in rats treated with Aβ [90-93]. These effects are partially mediated by the brain's inhibition of NF-κB signaling that is dependent on TLR4 and RIG-I.  There isn't much clinical data, but one randomized study found that probiotics helped AD patients' cognitive performance and lipids and malondialdehyde levels, two plasma indicators.  Although these results point to the therapeutic potential of probiotics in halting or reducing the course of AD, there is currently not enough clinical evidence to support their routine usage in AD care [94-95].

 

The exact mechanism by which probiotics display effects in AD remains unclear. According to 16s rRNA sequencing, supplementation with probiotics in humans did not appear to alter the types of bacteria in the intestinal flora, yet it did cause the benefits of probiotics to manifest on behaviour by temporarily modifying the state of gene expression in the collective microbiome, a phenomenon that was later validated in germ-free mice and identical twins [96]. Therefore, metatranscriptomic and metabolomic technologies are needed to assess the effects of probiotic intervention on gut microbiota in the host. Although probiotics have been widely promoted among the general public, many probiotic strains and formulations have yielded contradictory clinical results [91]. More attention should be paid to the adverse effects of probiotics. These include: - Systemic infection, GI side effects, Gene transfer from probiotics to normal microbiota, Harmful metabolic effects of probiotics, Immune system stimulation and other potential negative consequences [97]. However, future probiotic treatments for Alzheimer's disease necessitate the creation of methods to overcome colonization resistance [91].

 

Prebiotics:

The existing definition of prebiotics is "a substrate that selectively benefits from being used by the host's micro-organisms and can lead to a reduction in cognitive impairments and decreased Aβ deposition in the brains of animals with Alzheimer's disease" [98]. Prebiotics are non-digestible organic compounds, specifically short-chain carbohydrates that can selectively promote the growth and/or activity of one or a small set of beneficial gut bacteria [99]. The gut microbiota serves as a source of food, which in turn triggers the production of short-chain fatty acids (SCFAs), ultimately impacting both gastrointestinal and extra intestinal functions [100]. A body of research is indicating their potential usefulness as additional therapy options for various neurological and psychiatric disorders, including anxiety, depression, and Parkinson's disease [101]. Current research into AD prevention and treatment is also exploring the potential benefits of prebiotics, yielding encouraging outcomes [99,101-110]. Yeast beta glucans administration to mouse models of Alzheimer's disease (AD) has been shown to be effective in several ways. It helps to re-establish a balance between pro-inflammatory and anti-inflammatory gut microbiome species. This balance is crucial for the production of short-chain fatty acids (SCFAs), which in turn limits neuroinflammation and insulin resistance [102]. Reduced neuroinflammation and improved short-term memory and cognitive ability in mice that resembled features of Alzheimer's disease were also reported after pre-treatment with lactulose and melibiose, two trehalose analogues. This improvement may be attributed to enhanced autophagy function [104].     Furthermore, 5xFAD mice that were fed a diet supplemented with mannan oligosaccharide for eight weeks were able to promote the growth of Lactobacillus species and reduce the abundance of Helicobacter. This resulted in a decrease in LPS leakage and helped to prevent dysfunctions in the intestinal epithelial barrier and the blood-brain barrier. This prebiotic-driven reshaping of the gut microbiota was accompanied by several notable effects, including reduced Aβ accumulation in various brain regions such as the cortex, hippocampus, and amygdala, reestablishment of redox homeostasis, and increased levels of butyrate [105]. Comparable outcomes were achieved in both rat and mouse models of Alzheimer's disease through the oral administration of oligosaccharides derived from Marinda officinalis, which resulted in enhanced memory and learning capabilities, as well as reduced plaque formation, oxidative stress, and overall inflammation [109-110].

 

The exact mechanism by which the aforementioned prebiotics work is still unclear, but their ability to maintain a diverse and stable gut microbiota may underlie these observed benefits [102, 107, 109]. Recent studies support this hypothesis by indicating that the combination of probiotics and prebiotics, often referred to as synbiotics, appears to be more beneficial than prebiotics alone in promoting neurogenesis and decreasing both local and systemic inflammation, with its effects being more pronounced [107]. Findings from a large, multi-ethnic longitudinal study involving 1837 elderly individuals without signs of neurodegeneration have demonstrated that regular consumption of fructan, a well-established prebiotic, decreases the likelihood of developing AD, supporting previous research conducted in mice [106].  Despite the study's comprehensive normalization for factors such as age, gender, recruitment time, ethnicity, daily caloric intake, education, and APOE genotype, other authors argue that the evidence supporting the use of prebiotics in clinical practice remains insufficient [108]. These data collectively imply that prebiotics could be beneficial as a preventative or supplementary treatment for AD, but further human clinical trials are required to form a definitive conclusion illustrated in (Table 2).

 

 

 

 

Table 2: Effects of probiotics/prebiotics on AD

SR.NO.	GUT MICROBIOTA[Probiotics/Prebiotics]	MODEL	FINDING	Ref.
1.	Collinsella	PRS mode [PRSice-2 software]	Previous research has linked certain microorganisms to neuroinflammatory processes within the MGBA, whereas protective species such as Gordonibacter are understood to produce metabolites that foster gut and brain well-being.	111
2.	C rodentium	female germ-free Swiss Webster mice[Study design C57BL/6 mice were]	Observations in this study showed a decrease in BDNF levels within the hippocampi of mice infected with C rodentium, implying that an enteric bacterial infection can negatively affect memory by decreasing hippocampal BDNF.	112
3.	a Lactobacillus, L. rhamnosus	BALB/c mice	The administration led to a decrease in both anxiety and stress response, accompanied by alterations in central gamma-aminobutyric acid (GABA) receptors expression.	113
4.	Bifidobacterium infantis, 552 Lactobacillus rhamnosus strain R0011 (95%) and 553 L. helveticus strain R0052 (5%), L. rhamnosus (JB-1), 554 and Lactobacillus farciminis	RAT MODEL	An imbalance has developed between the 565 pro-inflammatory and anti-inflammatory responses, with the entire immune system now predominantly shifting 566 toward inflammation. This shift is characterised by a significant 567 increase in the release of pro-inflammatory cytokines and a corresponding 568 decrease in the release of anti-inflammatory cytokines, leading to 569 further exacerbation of the inflammation.	114
5.	L. acidophilus, Bifidobacterium langum, and L. case	CLINICAL TRAIL	In individuals who are overweight, levels of inflammatory cytokines have decreased.	115
6.	Erysipelatoclostridium	AD model mice (i.e., APP/PS1 mice),	Erysipelatoclostridium plays a crucial role in the development of AD, acting as microorganisms associated with inflammation.54 In mice with AD, they act as a central bacterial taxon, significantly contributing to the synthesis of DCA in the gut.	116
7.	Dubosiella	wild-type (WT) mice	Dubosiella exhibits anti-aging effects in AD mice by enhancing the bacterial genus, which includes reducing oxidative stress, improving endothelial function, and modifying the GM.	116
8	Gram-negative bacilli, and Escherichia coli (E. coli)	Drosophila as a Model	Researchers led by Zhan et al. discovered that fragments from Escherichia coli (E. coli) and lipopolysaccharide, a compound produced by certain bacteria, were found together in areas of the brain known as A plaques in deceased Alzheimer's disease (AD) patients. Additionally, lipopolysaccharide was found in the brain's perivascular areas, which suggests that the breakdown of the blood-brain barrier due to microbial activity may be contributing to the neurodegeneration seen in AD.Reports suggest that systemic inflammation and gut permeability are significant factors in the development of Alzheimer's disease.	117
9.		Mouse model	Research utilizing mouse models has shown the effects of gut microbiota on amyloid-beta accumulation, neuroinflammation, and cognitive deterioration. Evidence from these results suggests a link between the gut microbiome and the development of dementia.	118
10.	C. butyricum	AD animal models	Butyricum triggers the release of GLP-1, which safeguards the BBB, possibly through the regulation of tight junctions. Similarly, C. butyricum has been shown to prevent brain endothelial barrier dysfunction, as indicated by reduced brain water content and the reinstatement of normal tight junction protein levels.	119
11.	Lactobacillus plantarum MTCC 1325	3-month-old male albino rats (Wistar strain)	The following effects have been observed: 1. Improved spatial memory. 2. Enhanced gross behavioral activity. 3. The formation of hyperchromatic nuclear chromatin in the cytoplasm. 4. An increased level of acetylcholine (Ach) in the hippocampus and cerebral cortex. 5. A decreased level of amyloid plaques and neurofibrillary tangles (NFT) in the hippocampus and cerebral cortex.	120
12.	Lactobacillus acidophilus, Bifidobacterium bifidum and Bifidobacterium longum	Adult normal reared male Wistar rats	The provided data lists several benefits associated with a particular treatment or intervention. These benefits include: 1. Improved spatial learning and memory. 2. Restoration of synaptic plasticity in the brain's hippocampus. 3. Prevention of the accumulation of Aβ peptide in the brain's hippocampus. 4. Decrease in malondialdehyde (MDA) levels in the brain. 5. Increase in total antioxidant capacity in the plasma.	121
13.	SLAB51	3xTg-AD mice	The analysis of brain homogenates revealed several key findings: 1. A decrease in p53 levels was observed. 2. An increase in RARβ levels was detected. 3. Elevated levels of antioxidant enzymes were found, including:   - Glutathione S-transferase (GST)   - Glutathione peroxidase (GPx)   - Superoxide dismutase (SOD)   - Catalase (CAT) 4. A decrease in poly-ADP ribose polymerase (PARP) levels was observed. 5. A decrease in 8-Oxoguanine glycosylase (OGG1) levels was detected in the brain.	122
14.	SLAB51 (Streptococcus thermophilus, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium infantis, Lactobacillus acidophilus, lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. bulgaricus and Lactobacillus brevis)	8-week-old male 3xTg-AD mice	There are several key findings related to glucose and insulin signaling in the brain: 1.  Increased levels of glucose transporter 3 (GLUT3) and glucose transporter 1 (GLUT1) were observed in the hippocampal CA1 region. 2.  Reduced levels of phosphorylated tau protein were found in the brain, which may indicate a decrease in tau aggregation. 3.  Elevated levels of HbA1c, a marker of long-term glucose control, were detected in the plasma. 4.  Increased expression of the insulin-like growth factor-I receptor (IGF-IRβ) was observed in the brain.	123
15.	Lactobacillus plantarum, Lactobacillus delbrueckii subsp. Bulgaricu, Lactobacillus paracasei, Lactobacillus acidophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis and Streptococcus salivarius subspecies, thermophilus	6–8-month-old female AppNL−G−F and C57BL/6 (wild type	The provided data suggests several key findings related to the effects of a particular treatment or intervention. These findings include: 1. Elevated levels of short chain fatty acids (SCFAs) in the brain's hippocampus, specifically:   - Acetate   - Butyrate   - Lactate 2. Increased levels of SCFAs in the serum, including:   - Propionate   - Isobutyrate 3. Enhanced c-fos immunoreactivity in the brain, which is indicative of increased neuronal activity. 4. Reduced anxiety-like behavior in individuals undergoing this treatment or intervention.	124
16.	Lactobacillus acidophilus, Bifidobacterium bifidum and Bifidobacterium longum	Male Sprague-Dawley rats	The following effects have been observed: 1. Enhanced spatial learning and memory capabilities. 2. An increase in the amplitude of field excitatory postsynaptic potentials (fEPSPs) within the hippocampus. 3. An increase in long-term potentiation in the CA1 region of the hippocampus. 4. Reduced paired-pulse facilitation in neurons. 5. Lower levels of nitric oxide in the serum.	125
17.	Lactobacillus reuteri, Lactobacillus rhamnosus and Bifidobacterium infantis	Male Wistar rats	The following effects have been observed: 1. Improved spatial learning and memory. 2. Reduced accumulation of Aβ (amyloid-beta) in the hippocampus. 3. Lower levels of MDA (malondialdehyde), a marker of oxidative stress, in the brain. 4. Increased levels of SOD (superoxide dismutase), an antioxidant enzyme, in brain homogenates. 5. Decreased levels of IL-1β (interleukin-1 beta) and α-TNF (tumor necrosis factor-alpha) in hippocampal tissue.	126
18.	Bifidobacterium breve strain A1	10-week-old male ddY mice	The effects of the treatment on cognitive function and related biological markers include: 1. Enhanced spatial learning and memory capabilities. 2. Elevated plasma acetate levels. 3. Reduced expression of genes induced by amyloid beta (Aβ) in the hippocampus. 4. Prevention of cognitive dysfunction caused by amyloid beta (Aβ).	127
19.	Lactobacillus acidophilus 1688FL431-16LA02, Lactobacillus fermentum ME3, Bifidobacterium lactis 1195SL609-16BS01 and Bifidobacterium longum 1152SL593-16BL03	8-week-old male Wistar rats	The following effects have been observed: 1. Enhanced memory and spatial learning abilities. 2. An increase in superoxide dismutase (SOD) levels in hippocampal tissue. 3. A decrease in malondialdehyde (MDA) levels in the hippocampus. 4. A reduction in the number and size of amyloid-beta (Aβ) plaques in the brain.	128
20.	Lactobacillus rhamnosus UBLR-58	Female Swiss albino mice	Observations in Brain Tissue: 1. Decreased MDA level:   MDA (Malondialdehyde) is a marker of lipid peroxidation, which is a process that can lead to cell damage. A decrease in MDA level suggests a reduction in oxidative stress in the brain. 2. Increased SOD level:   SOD (Superoxide Dismutase) is an enzyme that helps to neutralize superoxide radicals, which are a type of free radical that can cause cell damage. An increase in SOD level indicates an enhanced ability to counteract oxidative stress in the brain. 3. Increased GPx level:   GPx (Glutathione Peroxidase) is an enzyme that helps to reduce oxidative stress by neutralizing hydrogen peroxide and other peroxides. An increase in GPx level suggests an improved ability to mitigate oxidative damage in the brain. 4. Increased CAT level:   CAT (Catalase) is an enzyme that helps to break down hydrogen peroxide into water and oxygen, thereby reducing oxidative stress. An increase in CAT level indicates an enhanced ability to neutralize hydrogen peroxide in the brain. 5. Reduced amyloid plaques deposition:   Amyloid plaques are abnormal protein deposits that are associated with neurodegenerative diseases such as Alzheimer's. A reduction in amyloid plaques deposition suggests a decrease in the progression of neurodegenerative disease in the brain.	129
21.	Bacillus subtilis NCIB3610 and Escherichia coli OP50	Not relevent	The provided data appears to describe several potential benefits of a particular treatment or intervention. These benefits include: 1. Improved cognitive function 2. Reduced expression of Aβ peptides 3. Relief from behavioral deficits 4. Enhanced chemotactic response	130
22.	Bifidobacterium longum, Lactobacillus acidophilus lysates, vitamins A, vitamin D, omega 3 fatty acids in cod liver oil, vitamins B1, B3, B6, B9, B12, and Interval treadmill running	Male APP/PS1 transgenic mice (B6C3- Tg(APPswe, PSEN1dE9)85Dbo/Mmjax; APP/PS1TG)	Observations Indicative of Potential Neuroprotective Effects: 1. Increased exploratory activity 2. Reduced Aβ plaques in the hippocampus 3. Increased microglia in the brain 4. Elevated OGG1 levels in the brain 5. Increased presence of Lactobacillus reuteri in the gut 6. Enhanced cognitive performance	131
23.	Bifidobacterium longum, Lactobacillus acidophilus lysates, vitamins A, vitamin D, omega 3 fatty acids in cod liver oil, vitamins B1, B3, B6, B9, B12, and Interval treadmill running	3-month-old, male APP/PS1 transgenic mice (B6C3-Tg (APPswe, PSEN1dE9) 85Dbo/Mmjax; APP/PS1TG) and six wild types	Observations of Oxidative Stress Markers: 1. Elevated levels of Superoxide Dismutase (SOD) were found in the hippocampus. 2. An increase in the concentration of Nuclear Factor-Erythroid Factor 2-Related Factor 2 (NRF-2) was observed in the liver. 3. A higher level of 8-oxodG, a marker of oxidative DNA damage, was detected in the hippocampus.	132
24.	Lactobacillus helveticus IDCC3801	Male Sprague Dawley rats and ICR mice	The following effects have been observed: 1. An increase in memory and cognitive function. 2. A decrease in the activity of β-secretase in the brain. 3. A decrease in the amount of intracellular APPβ. 4. An increase in the amount of intracellular APPα. 5. A decrease in the production of Aβ40 in the brain.	133
25.	Lactobacillus Pentosus and Lactobacillus plantarum C29.	Male ICR mice	Research has shown several key effects of a particular treatment or intervention: 1. Enhanced spatial learning and memory capabilities. 2. Elevated levels of cAMP response element-binding protein (CREB) in the hippocampus. 3. Increased activation of brain-derived neurotrophic factor (BDNF) in the hippocampus.	134
26.	Lactobacillus casei, Lactobacillus plantarum, Lactobacillus salivarius, Lactobacillus acidophilus, Lactobacillus rhamnosus, Streptococcus thermophilus, Bifidobacterium bifidum, Bifidobacterium infantis, Bifidobacterium longum, and Bifidobacterium breve	male and female 3xTg mice	The study revealed several key findings related to cognitive function and neurodegeneration. These include: 1. Enhanced spatial learning and memory capabilities. 2. Reduced levels of Aβ40 and Aβ42 peptides in the hippocampus. 3. Decreased levels of amyloid and tau proteins in the basal forebrain and frontal cortices. 4. Lower expression of the microglial marker arginase 1 (ARG1) in the brain.	135
27.	Prebiotic mannan oligosaccharide	5XFADmice	There is a reduction observed in cognitive deficits, amyloid plaques, oxidative stress, and microglial activation, accompanied by changes in the gut microbiome.	136
28.	Prebiotic R13		TrkB receptor kinase blocked the pro-inflammatory pathway in the gut, resulting in decreased amyloid production and oxidative stress.	137
29.	prebiotic sodium oligo-mannate (GV-971)		The goal is to improve mental faculties and manage mild to moderate Alzheimer's disease. Studies indicate that GV-971 has the potential to counteract cognitive decline by correcting gut imbalances; reducing brain inflammation; and crossing the blood-brain barrier to directly interact with Aβ, preventing the formation of Aβ fibrils.	138

 

Our knowledge of health, illness, and the creation of innovative biotherapeutics has significantly increased as a result of research on the human microbiota.  Considerable advancements have been made in the identification and characterization of particular probiotic strains and prebiotics, as well as in the validation of their possible health benefits.  Despite these developments, there is still mistrust in the medical world, mostly because of the shortcomings of recent studies.  Variability in illness models frequently affects results, and there are still few large-scale, randomized, controlled clinical trials that support the purported advantages of probiotics and prebiotics. Live probiotic cells' ability to survive and operate is further hampered by the harsh circumstances of the gastrointestinal track.  Although it is frequently challenging to demonstrate their specificity, prebiotics get around this problem by preventing enzymatic breakdown and favorably encouraging the growth of good gut microorganisms.  Microencapsulation of probiotics is one of the newer techniques that optimizes delivery selectivity and cell viability throughout gastrointestinal transit.  Future approaches are probably going to combine prebiotics (synbiotics) and microencapsulated probiotics, which will have synergistic effects.  Creating physiologically appropriate models to investigate host-microbiota interactions and designing targeted delivery systems that guarantee effectiveness and repeatability in clinical settings are two of the major challenges that lie ahead.

 

Conflict of Interest: No Conflict of interest

Funding Declaration: No Funding

Ethics declaration: Not applicable

 

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