The gut microbiome is a diverse and metabolically active population of organisms that has an impact on the host's phenotype [1]. The major function of gut microbiota is to balance metabolic homeostasis as well as the functioning of the immune system, regulate inflammation, increase mineral bioavailability, synthesize neurotransmitters, and control appetite and blood sugar [2]. The beneficial functions of normal gut microbes have been demonstrated by various high-quality data from the Human Microbiome Project (HMP) and European Metagenomics of the Human Intestinal Tract (MetaHIT) [3]. The intestinal community has more microbes in comparison to the stomach due to the harsh acidic gastric mucosa of the stomach. The beneficial bacteria of the gut microbiota are represented by Cytophaga-Flavobacterium-Bacteroides (CFB) and Firmicutes. While Firmicutes are categorized into Bacilli, Clostridia, Erysipelotrichia, Limnochordia, Negativicutes, Thermolithobacteria, and Tissierellia, whereas the CFB group constitutes Bacteroides with the majority of Prevotella and Porphyromonas [4]. Organisms of these communities produce several metabolites like short-chain fatty acids (SCFAs) including butyrate, propionate, and acetate which are key sources of energy and they also maintain tissue integrity for the peripheral and colorectal tissues. Bifidobacterium produces vitamin B complexes, vitamin K, folic acid, etc. and also synthesizes acetates which help in preventing pathogenic infections. Faecalibacterium prausnitzii produces butyrate which in turn produces compounds that inhibit or slow down the inflammation process [5]. In addition to vitamin synthesis and regulating the motility of the gut, the microbiota also modulates the development and activity of microglia in the central nervous system [6].

The “gut-brain axis” links the microbiome of the gut with the CNS via hormones, cytokines, and neurotransmitters. The idea of the gut-brain axis is a bidirectional communication pathway between the “little brain” or enteric nervous system in the gut and the "large brain" in the cranium, connected via neurons in the sympathetic and parasympathetic nervous systems as well as by circulatory hormones and other neuromodulatory agents [7]. The two-way communication takes place via several pathways involving the enteric nervous system, circulatory system, immune system, vagus nerve, and neuroendocrine system. Interestingly, these pathways also contain microbiota-related neuroactive compounds such as gut hormones, peptides and microbiota-derived metabolites. When these metabolites enter the brain, they influence neurodegenerative as well as neurodevelopmental and neuropsychiatric diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, autism, depression, stroke, CNS malignancies, stress, schizophrenia and anxiety [8]. Reports suggest that low brain-derived neurotrophic factor (BDNF) expression in the cortex, hippocampus, and amygdala in germ-free mice, also had impaired neurogenesis in the hippocampus and altered amygdala neuronal morphology [9].

In addition to the intestine, the mouth and stomach also play integral roles in the gut-brain axis. As the mouth serves as the access point to the enteric system, hence microbial colonization in the mouth also impacts systemic health [4]. The imbalance of gut microorganisms is known as gut dysbiosis. Dysbiosis of the oral microbiome such as the abundance of Streptococcus mutans, and Porphyromonas gingivalis can disrupt the blood-brain barrier, cause the production of pro-inflammatory cytokines, neuroinflammation and neurodegeneration through deposition of toxic byproducts [10]. The crosstalk between the stomach and CNS involves spinal and vagus nerves. Moreover, the HPA axis, Thyrotropin-releasing hormone (TRH)-containing nerve fibres, capsaicin-sensitive nerves and various peptides modulate gastric mucosa [11]. The stomach microbiota consists low abundance of micro-organisms due to the acidic pH of the organ and is mainly inhabited by Streptococcus and Prevotella. The disruption of the microbial balance disturbs immune responses [12] and hampers gastric mucosa attributable to the gut-brain axis [11]. Various risk factors associated with gut dysbiosis are dietary habits, use of antibiotic medication, age, genetics, circadian rhythm, baby delivery route and other lifestyle-related factors like cigarette smoking and environmental factors (Heavy metals like Arsenic, Cadmium, Lead, persistent organic pollutants, pesticides, and nanomaterial) [13].

In this regard, the relationship between the consumption of functional foods, phytonutrients and nutraceuticals with CNS health is gaining research attention. One such important phytochemical that has currently piqued the interest of researchers is dietary polyphenol. Polyphenols are the phytochemicals identified by the presence of many phenolic hydroxyl groups present in the compound [14]. These are the secondary metabolites produced by plants (fruits and vegetables) in response to exogenous stress factors such as reactive oxygen species (ROS), pathogens, parasites, ultraviolet radiation (UV) and plant predators. Polyphenols present in grapes, blueberries, tea, cocoa, walnuts exert a positive effect on the functioning of the CNS, improve brain and cerebrovascular blood flow as well as improve cognitive performance [15]. Polyphenols can exhibit neuroprotective activities through the generation of neurotrophic factors including BDNF, nerve growth factor (NGF), as well as glial cell line-derived neurotrophic factor (GDNF). These factors can exhibit neurotrophic function by interacting with the appropriate receptors and activating the downstream neuroprotective pathways. Polyphenolic compounds can modify the gut microbiota compositions or metabolites generated and can prevent neurodegeneration by stimulating gut microbial growth or by possessing an antimicrobial effect. In addition, polyphenols have anti-inflammatory, anti-mutagenic, and antioxidant properties. It has been discovered that polyphenols influence the "gut-brain axis" in a certain way [14].

Neurodegenerative disorders have been imposing major medical burdens on the society. Although the precise processes underlying neurodegeneration are not yet fully understood, oxidative stress and neuroinflammation are thought to be the key contributors to the process. Gut dysbiosis has been discovered to have a causal relationship with neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, autism spectrum disorder, Huntington's disease, etc. [7]. Since polyphenols show neuroprotective effects and also have intricate relationships with gut dysbiosis, thus this systematic review focuses on mechanisms and molecular pathways through which dietary polyphenols may modulate gut microbiota. Further links between observable alterations in the metabolites of the microbial species with plausible neuroprotective effects have also been discussed through a structured search of the literature.