Impact of Gut Microbiome Lactobacillus spp. in Brain Function and its Medicament towards Alzheimer’s Disease Pathogenesis

Alzheimer’s disease is neurodegenerative dementia which has significant health complications in the old age group. An imbalance in gut microbiota can influence to cause several diseases like chronic disorders, depression, type II diabetics, and neurological disorders like AD. Aging is one of the major causes of the development of neurodegenerative disease due to the decreasing levels of neurotransmitters, oxidative stress, chronic inflammation, and apoptosis. These harmful effects of aging can be prevented by probiotics usage. The gut-microbiota is capable to control the brain function through the gut-brain axis. Lactobacillus strains are considered as beneficial microorganism because of its importance of the maintenance in healthy intestinal microflora, immunomodulation, and intestinal pathogenic intervention. They have diverse applications in the medical field with properties like antioxidant, anticancer, anti-inflammatory, anti-proliferative, anti-obesity, and anti-diabetic activities. Probiotic supplementation with Lactobacillus strains shows an optimistic trend to use it as a significant therapy for cognitive symptoms. This review article put forwards the significance of the gut-brain axis and the contribution of Lactobacillus strains as a probiotic supplement and its therapeutic innovations for future aspects and the limitation to treat AD-related pathogenesis are briefly elucidated.

γ-secretase but causes serious side effects like blindness and large catalytic pocket 7,9 . The tau is a microtubule-binding protein that helps in stabilizing and providing flexibility to the microtubules 10 . In pathological condition, the tau will get disintegrated from the microtubules and forms tau aggregations causing intracellular deposition of neurofibrillary tangles causes impairment in neuronal axons and therefore causes neurodegeneration 7 . Due to the incomplete understanding of AD, the tau-targeted treatment stays challenging 7 . oxidative stress is another significant factor of AD pathogenesis brought about by the imbalance between Reactive Oxygen species (ROS) production and antioxidants levels making harm to the cells by excessive production of ROS 11 .
Based on different strategies, different drugs are used for the treatment of AD. which includes Aβ plagues inhibitors (Tramiprosate and ALZ-801), anti-tau (EpoD), anti-inflammatory (NSAID) and cholinergic enhancement drug (Donepezil, Galantamine, Rivastigmine, and Tacrine) which inhibits the acetylcholinesterase (AChE) 12,13 but these drugs can cause serious side effects like nausea, vomiting, muscle cramps, increased bowel movement frequencies, loss of appetite, dizziness, confusion, constipation 14 .
Various studies showed that the loss of biodiversity in the gastrointestinal tract of humans can lead to AD. The gut microbiota can maintain the homeostasis of the brain by producing neurotransmitters, nerve signals, and metabolites transmitted along the gut-brain axis 15 . Human lifestyle changes contributed a depletion in gut microbiota which could lead to a high risk of AD pathogenesis 15 . So, an alteration in gut microbiota through a probiotic supplementation with beneficial microorganisms could reduce the risk of AD pathogenesis and also side effects associated with the AD drugs.

The Gut microbiota and the Gut-Brain Axis
The gut microbiota consists of numerous bacterial species dwelling inside the gastrointestinal tract (GIT) existing as symbionts with the human host 16 and is believed to play an essential role in physiology 17,18 . A 51% of gut microbiota are belonging to the Firmicutes phyla comprising the groups of Clostridium coccoides and Clostridium leptum and the most acknowledged Lactobacillus genera and 48% consists of the Bacteroidetes phyla comprising well recognized genera of Prevotella and Bacteroides 19,20 . The remaining 1% of microbiota is the less-known phyla, comprising Proteobacteria, Actinobacteria, Bifidobacteria, Fusobacteria, Spirochaetes, Verrucomicrobia, and Lentispaerae 19,21 .
The gut microbiota got recognition due to its connectedness to the body parts remarkably the brain. The GIT is connected with the Central nervous system (CNS) through a signaling pathway of networks including the autonomic, immune systems, neuroendocrine, bacterial metabolites, and neuromodulatory molecules are collectively called as the "gut-brain axis" 19,22,23 . The regulatory factors are mainly common in between enteric nervous system (ENS) and CNS 19,24 .
T h e m i c ro b i o t a a n d i n t e s t i n a l enterochromaffin (EC) cells secreted hormones and metabolites cross with several biochemical pathways influencing the CNS processing creating a way to communicate between the external environment in link with the gut microbiota and brain 19 . The enteric nervous system formed by millions of nerves end in the GIT mucosa, helps to control the functions of the intestine and communicates with the brain through the nerve vagus and is responsible for the transmission of signals from the brain to GIT through the autonomic nervous system 23 . Studies suggest that an imbalance in the gut microbiota can influence the progression of neurological disorder and can initiate disease onset and also collapses the permeability of the intestine which leads to inflammatory conditions in both gut and brain, because of the proinflammatory cytokines which can enter into the bloodstream and reach the brain 19,25,26 . Evidence suggests that the importance of inflammation should not be underrated, since it plays a critical role in various chronic disorders, like type II diabetes 27 , AD 28 , and depression 23,29 .

the genus lactobacillus
The lactobacilli are Gram-positive, rods or coccobacilli non-spore formers, strict fermentative, aero-tolerant, or anaerobic with complex nutritional requirements like carbohydrates, amino acids, peptides, fatty acid esters, salts, nucleic acid derivatives, and vitamins 30 . Lactobacilli are either homofermentative (yielding lactic acid more than 85%) or heterofermentative (yielding lactic acid, carbon dioxide, and ethanol/acetic acid) depends upon a carbon source as glucose 30 . The strains of Lactobacillus are referred to as safe consumption bacteria because of their efficiency in gut defense mechanisms 31 . Lactobacillus is a genuine member of lactic acid bacteria (LAB) and other genera includes Streptococcus, Pediococcus, Lactococcus, Leuconostoc, Bifidobacterium, Carnobacterium, Enterococcus and Sporolactobacillus 32 .
A probiotic is a supplementary diet consist of beneficial living microorganisms which is found as normal flora with little or no pathogenicity 33,34 . These probiotics are believed to have an effect on preventing or treating diseases like gastrointestinal sickness, diarrhoea, irritatable bowel syndrome, and inflammatory bowel disease (IBD) 35 , and also possess anticancer, antioxidant, anti-obesity, antidiabetic, and antihyperlipidemic activities 1 . Using of Lactobacilli as a probiotic strain have a long history of safe use because of its normal inhabit in human and animal GIT 36 and also considered as a beneficial microorganism because of its roles in immunomodulation, enteric pathogenic intervention, and healthy intestinal microflora maintenance 37 . Due to the attractiveness of "all-natural" products to treat diseases, Lactobacillus sp. (Table 1) supplemented products received popularity 35 .

Lactobacillus sp. studies in Alzheimer's disease
The gut microbiota's contribution to AD pathogenesis is well studied in human and animal models. Most of the studies on probiotics were associated with its effects on oral bacteriotherapy in numerous neurological diseases and function, and only a few examines have been done to find the relationship between probiotic treatment and the mechanisms connected with AD 48 . The scientists have shown the benefits of probiotics to improve cognitive impairment in humans. The probiotics are hypothesized to be a cognition booster because of its two-way communication between gut microbiota, the GIT, and the brain through the immune system, nervous system, and hormones 49 . The contribution of Lactobacillus strains to the AD pathogenesis is well depicted in AD models (Table 2).

DISCuSSION
The relationship between the brain and the gut is a rapidly emerging field of study due to Obligatory homofermentative   suggesting that inflammation can be induced induced aging Treatment with C29 increased the suppressed by D-galactose by activating M1 macrophages. expression of DCX, BDNF, and CREB in the The expression of autophagy proteins was hippocampus region of the mouse. The findings influenced by neither C29 nor D-galactose.
of the study suggest that C29 can be used to inhibit inflammaging.  the importance of a healthy gut specifically for immune systemic functions as well as for mental health. Once the most ignored area (the gut) has now become the most appreciated area because of its effects on most chronic diseases including neurodegenerative diseases. Lactobacillus strains as a probiotic supplement got a long history of safe uses because of their normal inhabit in the gastrointestinal tract of human beings. The studies on probiotic supplementation with Lactobacillus strains showed a decrease in the neuroinflammation responses stimulated by lipopolysaccharides (LPS) which produce proinflammatory cytokines 48 . L. plantarum MTCC 1325 was reported to produce acetylcholine (Ach) neurotransmitter which has properties against D-galactose induced AD impairment 1 . L. paracasei BD87E6 was reported to produce (S)-rivastigmine, an anticholinesterase inhibitor that serves the cholinergic hypothesis 20 . A dysregulation in the gut microbiota can lead to AD by regulating short-chain fatty acid (SCFA) 53 . Lactobacillus strains can be used as a preventive measure to treat AD, cognitive enhancer, memory enhancer, and safe treatment for chronic-stress-induced depression. Studies on AD mice models treated with Lactobacillus strains proved that the modification on the gut microbiota can affect the various pathways which can result in the delaying of AD progression. The treatment with probiotic supplements showed a reduction in Aβ load and an improvement in cognitive function which supports the idea of modulation of gut microbiota for the treatment and prevention of AD 62 .

L. fermentum, In vitro
A study from the University of Geneva, Switzerland confirms the correlation between an imbalance of gut microbiota linked to the Aβ plaques development in the brain 65 . Studies on the links between metabolic and AD demonstrate an increment in Type 3 diabetes due to the unhealthy nutrigenomic diets down-regulated brain and hepatic Sirt1 (Sirtuin 1) related with insulin resistance, aggregation of α-synuclein and, Aβ dyshomeostasis in AD and PD 66 . Increased exposure to Gram-negative bacterial derived LPS can cause dysbiosis in gut microbiota which may initiate metabolic and liver diseases and promote systemic chronic low-grade inflammation. In vitro studies on investigating the Lactobacillus and Bifidobacterium probiotics on colonic LPS and inflammatory cytokine concentrations using human colonic microbiota models uncovered that the particular probiotic strains can diminish the concentrations of colonic LPS, which may further reduce the secretion of inflammatory cytokines in macrophage cells 67 . LPS alters the cell phospholipid dynamics associated with the recruitment of the Aβ peptide with the advancement of toxic Aβ oligomers. With the induction of a neuroinflammatory response, LPS can act on Blood-Brain Barrier (BBB) with BBB disruption or through receptors 68 . Through the inflammatory process, the bacterial LPS corrupts asterocyte which thus delays Aβ clearance in the brain with an increased amyloid plaque formation in different networks related to excessive feeding and abnormal liver metabolism 69 . Researchers have been now recognized that the gene Sirt 1 to be defective and has been linked to genetic disease, non-alcoholic fatty liver disease (NAFLD), diabetics, and neurodegenerative diseases and the bacterial LPS may act as a competitive inhibitor to Sirt 1 with glucose and cholesterol toxicity to different cells and tissues 70 . To reactivate Sirt 1 and to improve drug-induced toxicity nutritional diets are required. For early identification of AD, researchers are working to identify the specific bacterial strains that produce inflammatory LPS and short-chain fatty acids (SCFAs). Understanding these underlying factors may give a new point of view on novel therapeutic strategies for AD and pathologies.

CONCluSION
Biotherapy with Lactobacillus strains shows an enormous ability to treat against ADrelated pathogenesis. Thus, Modulation of the gut with a personalized diet can become a treatment for various disorders including AD with decreased or no side effects. Further research to confirm the gut-microbiota and related linkages to the gutbrain axis are required to completely understand the scope of probiotics to treat these impaired diseases with a good safety profile. Researchers have been identified the inflammatory molecules LPS, from bacteria been linked to AD and chronic gut inflammation, and SCFAs. The increased degrees of LPS are identified with chronic diseases such as NAFLD, diabetics, obesity, and neurodegenerative disease. The interest in probiotics treatments for AD is quite compelling with importance to its interaction with LPS. LPS is associated with the aggregation of Aβ with impacts on nuclear and cell receptors prompts to neurotoxicity and Aβ plaque formation. In future researchers can contribute to the perspective of probiotic therapy with Lactobacillus strains and interaction with LPS to prevent Aβ aggregation and neurodegeneration as a safe and effective therapy.

ACKNOWleDGMeNtS
We would like to thank the Department of Biotechnology, Karunya Institute of Technology and Sciences.