Background: The gut microbiota (GM) of the human body comprises several species of microorganisms. This microorganism plays a significant role in the physiological and pathophysiological processes of various human diseases. Methods: The literature review includes studies that describe causative factors that influence GM. The GM is sensitive to various factors like circadian rhythms, environmental agents, physical activity, nutrition, and hygiene that together impact the functioning and composition of the gut microbiome. This affects the health of the host, including the psycho-neural aspects, due to the interconnectivity between the brain and the gut. Hence, this paper examines the relationship of GM with neurodegenerative disorders in the context of these aforesaid factors. Conclusion: Future studies that identify the regulatory pathways associated with gut microbes can provide a causal link between brain degeneration and the gut at a molecular level. Together, this review could be helpful in designing preventive and treatment strategies aimed at GM, so that neurodegenerative diseases can be treated.

Joshua Lederberg, a molecular biologist, referred to “gut microbiota” (GM) as the totality of microorganisms, such as bacteria, viruses, protozoa, and fungi, and their collective genetic material that inhabits the gastrointestinal tract (GIT) [1]. There are approximately 100 trillion microorganisms within the GIT of humans [2]. Various functions of these microorganisms include anaerobic metabolism of indigestible carbohydrates, biogenesis of short-chain fatty acids (SCFAs), processing of essential molecules (bile acids, steroids and their derivatives, and various drugs), and defense against external pathogens [3]. In nature, literature suggests intestinal microbiota as one of the richest ecosystems [4].

The neonatal gut is sterile and harbors no microorganisms. The growth and maintenance of enteric microbiota in humans depend on the growth, development, and patterns related to the gestational period, mode of delivery, habits related to diet, nutrition, sanitation practices, and use of antibiotics [5, 6]. The GM contributes to several crucial roles in human health and contributes in the pathophysiology of many diseases. In humans, it may be classified as beneficial, essential, or resident microbiota (referred sometimes to as housekeepers of the gut) and opportunistic bacteria. The overgrowth of the latter leads to a decrease in the resident microbiota, thereby impacting the pathogenesis of diseases such as pseudomembranous colitis, caused by an opportunistic pathogen, Clostridium difficile [7, 8].

The most common phyla of GM present in the intestine of humans include Bacteroides and Firmicutes [9]. The first group includes Bacteriodes, Enterobacteria, Staphylococci, Clostridia, Bacilli. The second group comprises Lactobacteria species (such as rhamnosus, acidophilus, plantarum, etc.), Bifidobacterium bifidum, Enterococci, and Peptostreptococci [9, 10]. Any change in the number or composition of the organisms in the microbiota of the gut causes a state of impaired gut microbiological system which could be associated with the pathogenesis of many chronic disorders like metabolic syndrome, Crohn’s disease (CD), ulcerative colitis, and colorectal cancers [11].

An ever-increasing amount of evidence supports the intimate relationship shared by the GIT and the CNS, including the neural connections called the gut-brain axis (GBA) [12]. The afferents from the sympathetic and parasympathetic nervous systems, respectively, ascend up to the CNS, while the latter sends neuronal signals through both afferent and efferent pathways governing the autonomic nervous system. This system is within the muscular myenteric plexus that mediates gut motility and mucosal Auerbach’s plexus, which sends signals that produce secretions in the intestinal mucosa [13]. Thus, the brain intimately helps in the modulation of gut motility, immune defense, intestinal brush border permeability, and regulation of secretions produced by the gut. Simultaneously, the gut also communicates with the hypothalamic-pituitary-adrenal axis (HPA axis) [14, 15]. This axis can significantly impact the GBA as it is involved directly in the release of cortisol, a hormone that regulates the stress response [16].

Further, GM has also been shown to have an effect on the growth, regulation, and modulation of the immune system-CNS communication [17]. The GM may also play a key role in the biosynthesis of molecules and metabolites, which possess the ability to cause neuromodulation. This may thus play a role in the pathogenesis of several neurodegenerative disorders (NDs) such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) [18].

This paper presents a synthesis of findings related to the role of GM and its crosstalk with the nervous systems – both the enteric nervous system and the CNS. It also reviews the studies that describe causative factors (shown in Fig. 1). The paper discusses several possible causative factors like diet, physical activity, exposure to pathogens, age, alcohol consumption, medication/drug use, and psychological stress/anxiety (Table 1). Further, links and relationships to the pathogenesis of NDs and dysregulation are explored.

Fig. 1.

Schematic of causative factors affecting GM.

Fig. 1.

Schematic of causative factors affecting GM.

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Table 1.

Relationships between GM and lifestyle factors

Aim of the studyArticle typeConclusionReference
Diet 
To understand the complex relationship between dietary fiber consumption and GM in relation to human health Review GM response may vary depending upon the type, duration, and amount of dietary fiber consumption Fu et al. [67] (2022) 
To understand the relationship between prebiotics and probiotics Review Both probiotics and prebiotics have demonstrated a remarkable capacity to modulate human health, particularly the intestinal flora You et al. [68] (2022) 
Investigating the role of artificial sweetener on pathogenicity and interaction of GM Original research The artificial sweeteners are reported to induce glucose intolerance by altering the GM Shil and Chichger [71] (2021) 
Transkingdom network analysis to model host-microbe interactions under Western diet Original research Two species of lactobacilli, i.e., Lactobacillus gasseri and Lactobacillus johnsonii, improve lipid metabolism by acting on liver mitochondria Rodrigues et al. [77] (2021) 
Sleep 
Better understanding of the relationship between the GM and sleep disorders Review Sleep disorders are associated with alterations in the intestinal bacterial composition, particularly an increase in the Firmicutes/Bacteroidetes ratio and a disruption of the intestinal barrier Neroni et al. [108] (2021) 
To assess the impact of intermittent hypoxia (OSA) on murine model Original research Intermittent hypoxia resulted into alteration of the microbiota composition and its diversity Moreno-Indias et al. [109] (2015) 
Effect of chronic sleep fragmentation (CSF) on GM and its downstream metabolic implications Original research Prolonged sleep disruption causes an increase in fat mass and selective changes in the GM which result in increased gut permeability and adipose tissue inflammatory changes followed by insulin resistance Poroyko et al. [110] (2016) 
To quantify sleep measures coupled with GM Original research Sleep efficiency was positively correlated with an increase in the abundance population of Bacteroidetes and Firmicutes, whereas sleep fragmentation was negatively correlated with Bacteroidetes in humans Smith et al. [111] (2019) 
Physical activity 
Role of exercise in altering the microbial composition Review Exercise can influence the GM in a number of ways, like by increasing the diversity of microflora, increasing the number of beneficial microbial species, and promoting the growth of commensal bacteria Monda et al. [144] (2017) 
10 To evaluate the effect of probiotics among athletes and a range of outcomes Review May enhance the physical performance and promote health in athletes Marttinen et al. [177] (2020) 
11 To establish a relationship between the GM and exercise in endurance sports Review Exercise intensity and duration determine the microbial diversity and composition in endurance sports Clauss et al. [178] (2021) 
12 How diet and physical activity modulate GM Review Physical activity induces changes in intestinal microbial composition by improving B/F ratio or by improving barrier function Campaniello et al. [149] (2022) 
Social isolation 
13 To investigate the link between the social interaction and GM composition Original research The sustained interaction somewhat close relationship influences the GM and greater diversity Dill-McFarland et al. [181] (2019) 
14 To evaluate the changes in the GM over time during adolescence through social deprivation model in rats Original research Social isolation caused short-term changes in the GM in females. Also, in these socially isolated rats, inflammatory response in the dorsal and ventral hippocampus was found to be correlated with the GM composition Lopizzo et al. [185] (2021) 
15 To understand the changes in GM in rodent model (monogamous prairie vole) of social isolation Original research Prolonged isolation is involved in altered neuronal activity and neurochemical expression in different brain regions Donovan et al. [186] (2020) 
16 To study intestinal permeability in maternally separated Wistar rats Original research Increased intestinal permeability in the neonatal stage may be linked to the long-term HPA axis-altered response Rincel et al. [188] (2019) 
Aim of the studyArticle typeConclusionReference
Diet 
To understand the complex relationship between dietary fiber consumption and GM in relation to human health Review GM response may vary depending upon the type, duration, and amount of dietary fiber consumption Fu et al. [67] (2022) 
To understand the relationship between prebiotics and probiotics Review Both probiotics and prebiotics have demonstrated a remarkable capacity to modulate human health, particularly the intestinal flora You et al. [68] (2022) 
Investigating the role of artificial sweetener on pathogenicity and interaction of GM Original research The artificial sweeteners are reported to induce glucose intolerance by altering the GM Shil and Chichger [71] (2021) 
Transkingdom network analysis to model host-microbe interactions under Western diet Original research Two species of lactobacilli, i.e., Lactobacillus gasseri and Lactobacillus johnsonii, improve lipid metabolism by acting on liver mitochondria Rodrigues et al. [77] (2021) 
Sleep 
Better understanding of the relationship between the GM and sleep disorders Review Sleep disorders are associated with alterations in the intestinal bacterial composition, particularly an increase in the Firmicutes/Bacteroidetes ratio and a disruption of the intestinal barrier Neroni et al. [108] (2021) 
To assess the impact of intermittent hypoxia (OSA) on murine model Original research Intermittent hypoxia resulted into alteration of the microbiota composition and its diversity Moreno-Indias et al. [109] (2015) 
Effect of chronic sleep fragmentation (CSF) on GM and its downstream metabolic implications Original research Prolonged sleep disruption causes an increase in fat mass and selective changes in the GM which result in increased gut permeability and adipose tissue inflammatory changes followed by insulin resistance Poroyko et al. [110] (2016) 
To quantify sleep measures coupled with GM Original research Sleep efficiency was positively correlated with an increase in the abundance population of Bacteroidetes and Firmicutes, whereas sleep fragmentation was negatively correlated with Bacteroidetes in humans Smith et al. [111] (2019) 
Physical activity 
Role of exercise in altering the microbial composition Review Exercise can influence the GM in a number of ways, like by increasing the diversity of microflora, increasing the number of beneficial microbial species, and promoting the growth of commensal bacteria Monda et al. [144] (2017) 
10 To evaluate the effect of probiotics among athletes and a range of outcomes Review May enhance the physical performance and promote health in athletes Marttinen et al. [177] (2020) 
11 To establish a relationship between the GM and exercise in endurance sports Review Exercise intensity and duration determine the microbial diversity and composition in endurance sports Clauss et al. [178] (2021) 
12 How diet and physical activity modulate GM Review Physical activity induces changes in intestinal microbial composition by improving B/F ratio or by improving barrier function Campaniello et al. [149] (2022) 
Social isolation 
13 To investigate the link between the social interaction and GM composition Original research The sustained interaction somewhat close relationship influences the GM and greater diversity Dill-McFarland et al. [181] (2019) 
14 To evaluate the changes in the GM over time during adolescence through social deprivation model in rats Original research Social isolation caused short-term changes in the GM in females. Also, in these socially isolated rats, inflammatory response in the dorsal and ventral hippocampus was found to be correlated with the GM composition Lopizzo et al. [185] (2021) 
15 To understand the changes in GM in rodent model (monogamous prairie vole) of social isolation Original research Prolonged isolation is involved in altered neuronal activity and neurochemical expression in different brain regions Donovan et al. [186] (2020) 
16 To study intestinal permeability in maternally separated Wistar rats Original research Increased intestinal permeability in the neonatal stage may be linked to the long-term HPA axis-altered response Rincel et al. [188] (2019) 

The literature search was done using scientific search tools like PubMed and Google Scholar. Only articles published in English were considered for the review. Original articles, review articles, editorials, and commentaries with full-text or institutional subscriptions were included, whereas any unpublished content, web links, or newspaper content were excluded. Search keywords included GM, neurodegeneration, microbiome, gut-brain axis, and brain health. The selection of keywords was based on previously published literature. Relevant publications after the 1980s were considered for writing the article.

GM comprises a diverse community of microorganism, which includes bacteria, viruses, and eukaryote that resides in the GIT of humans. Altogether, this complex community of microbes influences several physiological processes, like modulating metabolism and immune system, helping in digestion, and maintaining brain health [19, 20].

Initially, it was thought that the bacteria present in the GIT are commensals and harmless, but studies have shown that these microorganisms show a symbiotic (mutually beneficial) relationship with the host (human) and also impact long-term health parameters of the hosts [21, 22]. It is estimated that the human GIT comprises around 1014 to 1015 microorganisms, which is almost equal to the combined human cells with a weight of 0.2 kg [23]. However, some studies state that the estimates of the GM are 10 times more than the combined human cells [24].

Human GM plays a significant role in the immune response, absorption, processing of nutrients from the diet, and maintaining the homeostasis of the intestine [24]. Recent studies also show an association between human microbiota and brain health [25]. Emerging literature suggests the association of GM to several health ailments. Any alterations in the microbiota are referred as dysbiosis and tend to show an increased risk of disorders such as inflammatory bowel disease, obesity, mood disorders like anxiety, cancer, asthma, and also ND like PD and AD [26, 27]. Further, it may be noted that through the bidirectional pathway, i.e., the GBA, microbiota has an impact on the brain health and behavior [28].

Interventions that focus on the consumption of prebiotics/probiotics or fecal microbiome transplantation have shown promising results in improving the health conditions and treating some disorders [29, 30]. Therefore, better understanding of the complex link between the gut microbiome and human biology could be of potential revolution for personalized medicine and treatment strategies [31].

The bidirectional information network is the communication system that exists between the two, i.e., the brain and the GM. This axis allows a constant crosstalk between the two that influences both physiological and behavioral responses. This bidirectional information communicates “from brain to GM (top-down) and from gut to brain (bottom-up)” [14, 15]. The regulation through brain occurs via the neuroanatomical pathway, immunological pathway, and neuroendocrine-HPA axis pathway, i.e., in a top-down manner, whereas the GM influences the brain in a bottom-up manner. All these communications are established through neurotransmitters, peptides, or microbial-derived products [32, 33]. There are five different routes through which GM communicates with the CNS. This includes the neuroendocrine-HPA axis, neuroanatomical pathway, microbiota metabolism pathway, immune system, blood-brain barrier, and intestinal mucosal barrier [34]. Several preclinical studies show that bidirectional communication prevails between brain-GM axis. In transkingdom symbiosis, the GM establishes a dynamic bidirectional communication [35]. The gut bacteria work in concert with the host body to manage the function and growth of the immunological, metabolic, and neurological systems [36].

The initial preclinical studies that led to the understanding of the involvement of GM and its role in the development of brain function were conducted on postnatal colonization of microbiota in germ-free (GF) and specific pathogen-free mice by Sudo et al. [37]. With the colonization of the bacterial species Bifidobacterium infantis among GF mice, it led to the reversal of the HPA axis and enhanced response toward stress with the entero-pathogenic Escherichia coli. However, the mutant strain in the bacteria was removed in the case of entero-pathogenic E.coli that showed the association between the GM and the postnatal stress response [37]. These preclinical studies showed the involvement of the external environment and GM in the change observed in brain behavior. Hence, these experiments suggest the understanding at a much deeper level of the bidirectional involvement of the gut and its microbiota with the brain. According to Morais et al. [35], the bidirectional communication is mediated by both the direct and indirect pathways in the brain-gut axis. The communication channels involve various systems, including the autonomic nervous system, HPA axis, neuroendocrine, immunological, and metabolic pathways. The GM produces neuroactive compounds, like GABA, dopamine, or 5-HT, amino acids (like tryptophan and tyramine), and metabolites (like SCFAs and 4-ethylphenylsulfate) [35]. These can affect metabolism, interact with the host immune system, or affect cells of the regional enteric nervous system and the afferent pathways of the vagus nerve, which send messages directly to the brain, all through portal system [35]. Stress conditions can activate the HPA axis, stimulate the secretion of corticotropin receptor hormone, and trigger the release of ACTH that leads to the synthesis and release of stress hormone, i.e., cortisol. Along with cortisol, various immune mediators and neurotransmitters of CNS can stimulate ENS and vagus nerve afferent that can alter the microbiota composition and its environment [38].

However, the exact communication between the two is still debatable. Moreover, the following intrinsically connected evidence-based communication pathways exist between GM and the brain.

Neuro-Anatomical Pathway

It has been indicated in many studies that the vagus nerve and its pathways (10th cranial nerve) are associated with the gut and the brain [39]. Also, the vagus nerve has both afferent and efferent communication with the gut and microbiota [40]. Studies suggest that the vagus nerve has the potential to differentiate between pathogenic and non-pathogenic bacteria and induce both anxiolytic as well as anxiogenic effects on it [41, 42]. The establishment of this connection between the two involves complex mechanisms.

Neuroendocrine – HPA Axis Pathway

The HPA axis is one of the major neuroendocrine systems. In response to the external stimuli, corticotrophin-releasing factor and vasopressin are synthesized and secreted by the neurons of neuroendocrine in the paraventricular nucleus. Later, these two stimulate the production of ACTH, which results in the secretion of cortisol by the adrenal cortex. Further, this glucocorticoid hormone acts via a negative feedback cycle [33]. The principal coordinator of the stress response is the HPA axis, which also regulates several other functions in the body, like digestion, immunity, temper, etc. In case a threat is sensed, re-establishing the organism’s homeostatic balance is done through the HPA axis [33, 43].

Plausible Role of Immune System for Gut-Brain Association

The immune system of our body acts as a significant coordinator of the gut-brain association [44]. GM also modulates the brain-resident immune cells. The activities of immune cells in both regions are implicated in response to inflammation in the brain or injury or any issue with neurogenesis and plasticity [44, 45]. This may later contribute to the pathology of neurological illnesses. The expression of toll-like receptors by immune cells recognizes the microbe-associated molecular patterns (MAMPs), leading to the activation of the immune cells. These activated cells produce some proinflammatory cytokines (e.g., TNF-α and interleukins [IL-1β, IL-17A, and IL-6]) [46‒49]. By crossing the BBB, these cells enter into the brain circulation, which may lead to the progression of neurological issues. It has also been seen that GF mice, which are devoid of the gut immune system, when introduced to certain specific selected bacteria, were able to restore the entire gut immune system and its function [36]. Examples of such instances are seen, where the introduction of segmented filamentous bacteria in the gut of those animals showed the restoration of B cells and T cells in the large and small intestines [50, 51]. Hence, such studies indicate that the immune system is plausibly a crucial player in the association of neurodegeneration with GM. Additionally, the gut microbiome can also affect the CNS-resident immune cells directly. The gut-microbiome-derived molecules in the brain can pass through the BBB and can play a crucial role in the maturation and activation of astrocytes and microglia [52].

Chemicals Released by the GM

The various chemicals released by the GM include neurotransmitters, neuropeptides, and other microbial products [53]. GM produces neurotransmitters such as gamma amino butyric acid produced by the Lactobacilli, serotonin, melatonin, catecholamines, histamine, and acetylcholine [54, 55]. The microbial products such as SCFAs and butyrate have shown an impact on the etiology of mood disorders and show its correlation between the GM and the brain axis [56]. Additionally, certain bacteria are known to encode genes for certain enzymes that can catalyze the conversion of substrates into their associated neurotransmitters [54]. The precursors of these neurotransmitters are primarily amino acids like tyrosine and tryptophan, which are derived from food. The neurotransmitter-producing cells take up these precursors and are then converted into functional neurotransmitters via intermediate steps [54].

Lifestyle as a Modulator of GM

Little is known about how lifestyle choices and environmental variables affect the microbiome. Several factors are known to influence the GM and its balance, among which lifestyle is one of the key factors. Studies have confirmed a direct link between physical activity and feeding habits [57]. Besides the dietary lifestyle factors, several non-dietary lifestyle factors like smoking and physical inactivity can have an impact on the large bowel [58]. People with active lifestyles eat healthier meals that are higher in fiber, vegetables, and fruits. In contrast, sedentary people tend to consume diets that are lower in fiber and higher in fat [59]. Eating habits and regular physical activity influence the diversity of microorganisms in our bodies, as well as the existence of bacteria that are good for our health. The physiological status of an individual (illness or health, old or young, and leanness or obesity) determines the impact of these associated factors. Stress, a common lifestyle factor, influences colonic motor activity and may alter the microbiota profile, including a decrease in the number of lactobacilli. IBS can result due to stress and changes associated with microbe population through the CNS [58]. Other environmental factors, travel, and working shifts also influence gut health. Frequent travel may increase the chances of contracting infectious diseases, and in some cases, it may get undiagnosed, which may cause GI problems in the long run [58, 60].

Dietary Factors

The GM present in the stomach is regulated by many factors, and the food consumed plays a major role [23]. In addition to its fundamental role as a source of energy, nutrition has a significant and long-lasting effect on brain function [61]. The association between better brain development in childhood and breastfeeding is directly linked, and the benefits last during adulthood [62]. The ability of diet to bring firm epigenetic alterations on neurons, necessary for appropriate nervous system development, may help explain its long-term impacts [63, 64]. Its effects start directly from the breast milk that humans consume. A number of differences have been observed between breast milk and formula-fed milk [65]. The positive and negative effects are seen not only with regard to the breast milk and formula feed but also with various other dietary components such as fat, dietary fiber, cheese, artificial sweeteners, and probiotics [65, 66]. These dietary components play an important role; for example, with the intake of dietary fiber, there is a reduction in the development of cardiovascular phenotypes and type 2 diabetes mellitus (T2DM). This is due to the human GM, which offers protection by the synthesis of SCFAs and butyric acid [67].

Diet-based processes like probiosis and prebiosis are used to promote host health by enhancing the intestinal microbiota composition [58]. Both pre- and probiotics have been shown to influence a number of bacteria, typically Lactobacillus and Bifidobacterium [68, 69]. Prebiotics promote the growth of beneficial bacteria that are indigenous to the colon. The probiotics are usually live bacteria which are consumed along with yogurt [68]. Cheese helps in the increased production of the SCFA, which helps against pathogens [70]. In vitro studies on artificial sweetener reported increased in the ability of E. coli and Enterococcus faecalis to form a biofilm. These sweeteners are reported to induce glucose intolerance by altering the GM [71, 72].

The increasing research highlights the significance of GM in the overall metabolic integrity, health, and disease of human beings [73]. T2DM is a highly prevalent and most common metabolic disorder globally [74‒76]. The Western diet consists of high-refined sugars and high-saturated fats, which have been identified as one of the major contributing factors to T2DM, with the microbiota of the gut playing an essential role in modulating the effects and outcomes of diet [73]. A study was performed by using transkingdom network analysis, wherein a data-driven approach of biology was used for modeling the microbe and host interactions that were under the influence of Western diet [77]. An analysis was done of the individual components of GM, and their interaction was noted which led to alterations in the host metabolism induced by the Western diet. The transkingdom network investigation spiked toward the discrete microbes with the possible and potential causal effects on the glucose and lipid metabolism of the host. This study demonstrated the deleterious effect of Western diet on metabolism, which can result from the reduction in beneficial microbes such as Lactobacilli and increase of pathobionts such as Romboutsia ilealis in the GM, acting through various host pathways. The microscopy and gene expression data revealed that two species of Lactobacilli, i.e., Lactobacillus gasseri and Lactobacillus johnsonii, improve lipid metabolism by acting on liver mitochondria. Further, it was found that reduced glutathione may be a mediator of these effects, according to metabolomics investigations [77]. Moreover, it also uncovered the possible role of probiotic strains in the treatment of T2DM and deeper insights into their mechanism of action, providing a better chance to develop focused therapies against T2DM in order to restore healthy microbiota completely. Therefore, it can be concluded that the damaging impact of Western diets in GM could be partially due to the increase in R. ilealis and decrease in Lactobacilli, both of them functioning through distinct host pathways [77]. These gut bacteria can produce SCFAs by metabolizing the indigestible dietary fibers, which may get absorbed from intestinal mucosa and later used as source of energy for water and mineral absorption, epithelial growth, and mucus secretion [78].

In addition to this, vitamins and minerals also have an impact on the neuronal signaling. Vitamin E is a potent antioxidant that supports mitochondrial function in cells, whereas B vitamins are crucial for fiber myelination and neuronal survival [79]. A dietary reduction in calories intake can cause neurons to stimulate a modest chronic stress response, which favors the upregulated production of brain-derived neurotrophic factor (BDNF) and chaperones, which has a protective effect against neuronal death and protein aggregation [80]. The CNS is highly dependent on energy, and it consumes around 20% of the body’s demand for oxygen and glucose [81]. Therefore, to fulfill this demand for energy, the CNS is constantly engaged in crosstalk with the gut and other organs involved in metabolism. This facilitates the adaptive response to dietary modifications [82]. Fibroblast growth factor 21 enables the refinement of food selection and its metabolism according to dietary modifications [83]. Other factors like IGF-1 have an essential role in the development survival of the neurons [84]. Adiposity and fat accumulation are modulated by CNS insulin sensitivity [84]. These communication networks are deeply influenced by diet and GM along the brain-periphery signaling pathway via communication mechanisms like CNS-diet interactions, microbiota-CNS interactions, and interaction with the immune system [42]. Significant modification in the lifestyle pattern or dietary intake can influence several important mechanisms (like the Wnt/β catenin system) in the brain and gut [85].

Can Intermittent Fasting Influence the GM?

Recent studies indicate intermittent fasting (IF) may alter the GM and this could be due to increased microbial remodeling and taxonomic diversity. This is presented by a growing number of evidences, where timing of the diet is also seen [86]. A study carried out by Ozkul et al. [87] showed the effect of religious fasting on the health of GM. This fasting is a type of IF where the intake of food is restricted from sunrise to sunset. Considering the time gap of 17-h restricted food intake, it can be classified as IF. In the study, IF was done for a 29-day period and the results of the GM before and after fasting were analyzed. It has shown a positive effect and increase of bacteria Akkermansia muciniphila and Bacteroides fragilis [87, 88]. There is also a decreasing trend but not significant decrease that is seen in Faecalibacterium prausnitzii and Enterobacteriaceae which have obesity inducing and endotoxin production properties [89, 90]. Recent studies have also shown the use of IF as one of the treatment adjuvants for many diseases such as T2DM [91], MS [92], and promoting the browning of the white adipose tissue [93]. Similar to the abovementioned IF, different cultures have such similar fasting examples, such as “Navaratri fasting” which is popularly followed in the Indian subcontinent, wherein there is a continuous fasting of 9 days [94, 95]. Similarly, Ramadan is practiced in Islam. Many religions perform IF for different purposes like spiritual and physical [96]. Previous literature states there is an increase in the alpha diversity of the bacteria and the stabilization in the ratio of Firmicutes and Bacteroidetes [97]. IF programs contribute to balancing the GM composition [96]. A study by Mesnage et al. [98] found a decrease in bacterial species of Lachnospiraceae and Ruminococcaceae, whereas increase in Bacteroidetes was seen. These findings suggest that such change in composition is part of physiological adaptations. IF regimens that restrict food intake to daytime may leverage circadian rhythm to enhance metabolic health. By creating an internal circadian clock, organisms have evolved to limit their activity to the day or night in order to ensure that physiological processes occur at the optimal times [99]. Most of the studies on diet, timing, and circadian rhythm are based upon animal research. However, data on human indicate shift-based occupation disrupts circadian biology and is linked with several metabolic disorders. Both the composition and interactions of GM, as well as eating habits and a wide variety of gut functions, are all influenced by circadian rhythmicity [100]. Further, long-term studies are needed to investigate the role of IF on GM and its influence on neurodegenerative disease profile [101]. A study designed to analyze the pathological changes in brain and gut tissues (from the brain bank) and its co-relation with the eating style of the individual is imperative.

Effect of Circadian Rhythm on the GM

The GM helps the human body digest nutrients derived through the diet and produce the metabolites, which are microbiota-derived to assist the host’s metabolism [102]. Similarly, the host’s circadian rhythm optimizes the body’s physiology toward a favorable environment by regulating the coordination and timing of the various metabolic processes [103]. Apart from the dietary quality, the host-microbe interactions influence the timing as well as the regular dark and light cycles defined as circadian rhythms in the host [104]. The microbiota of the gut and the circadian rhythm collectively synchronize the metabolic and neural pathways, pathogenesis, and disease progression [105]. The interactions among the GM, circadian rhythm, and metabolic pathways of the host have a significant impact on the energy homeostasis, pathogenesis, and progression of obesity [106] and, consequently, neurodegenerative diseases [107].

Sleep

There is a linkage between sleep disorders and alterations in the composition of the GM demonstrated through human and animal studies [108]. Reduced sleep timing or poor sleep quality has been linked with alternated GM. There are a very limited number of studies that have examined GM composition and sleep. Mice model study on sleep apnea reported intermittent hypoxia (obstructive sleep apnea) modifies the diversity of the GM. The study showed an increased number of Firmicutes and decreased levels of Bacteroidetes and Proteobacteria phyla in the fecal samples of mice with OSA [109]. Another study by Poroyko et al. [110] in 2016 reported that mice that were exposed to chronic sleep fragmentation induced systemic inflammation, increased gut permeability, thereby altering the GM. In a study by Smith et al. [111] (2019), sleep efficiency was positively correlated with an increase in the population of Bacteroidetes and Firmicutes, whereas sleep fragmentation was negatively correlated with Bacteroidetes in humans.

Exposure to Pathogens

Through its epithelial lining, the human gut is constantly exposed to pathogenic organisms that can range from bacteria, viruses, and fungi to parasites associated with the GM [27]. These pathogens serve their existence by translocating the effector proteins into the host (human) cells affecting the gut integrity and function and posing a risk to the intestine’s immune system. Through mechanisms like immune modulation and colonization resistance, the GM plays a protective role during infections [112]. These mechanisms, in some inappropriate conditions, can also serve as a reservoir for opportunistic pathogens, which can thrive and cause undesirable outcomes like severe dysbiosis of the GM [113].

From the existing literature, it is obvious that any shift in the host GM can have a defining effect on the pathogenic process and clearance of viral, bacterial, and parasitic infections [114]. C. difficile is one of the most prominent pathogens that can exploit the antibiotic-mediated alteration of the GM [115]. Viruses like hepatitis B, hepatitis C, or influenza viruses can have an immunomodulatory effect leading to the metabolic alteration of GM [116]. Another virus called Epstein-Barr virus (EBV), present in almost 95% of the adult population, is considered a common component of the human commensal microbiome. There is evidence linking EBV to the etiology of degenerative diseases, such as MS. Inflammation and immune activation induced due to dysbiosis may worsen the neurological symptoms in EBV-infected individuals. Infection with EBV can alter brain homeostasis, resulting in inflammatory brain disorders like MS, GBS, etc. Any manipulation in neural homeostasis occurring via alteration in glial functioning is unclear [117].

Studies point toward the co-infection, which provides a suitable environment for several diseases. In the case of multifactorial diseases, like cancer, exposure to Helicobacter pylori is linked with reactivation of EBV. A study by Kashyap et al. [118], 2021, showed that co-culturing of H. pylori with EBV resulted in increased expression of H. pylori pathogenic genes (cagA and babA). In contrast, EBV-associated genes (gp350, bzlf1, ebna1, ebna3c, lmp1, lmp2a, and lmp2b) were also highly expressed. Jakhmola and Jha, 2021, showed enhanced expression of inflammatory cytokine IL-6 in glial cells infected directly with EBV and EBV-infected lymphocytes (PBMCs). Migration and invasion of PBMCs during these infections probably occurred, which suggested the EBV provided aid in neuroinflammatory response via PBMC infiltration [119]. Parasites can markedly alter both the immune and physical outlook of the gut and its microbiota, generating a space for them to interact, which in turn leads to the further alteration of the infection outcomes, impacting the overall health and well-being of the individual. Parasitic protozoa and helminths can cause trans-domain interaction in the gut, leading to physical and immunomodulatory alteration in the microbiota. The GM also has a role in the immune response resolution followed by a pathogenic infection. If there is any disturbance to the advantageous microbiota diversity of the gut, it can advance to the advent of opportunistic pathogens (which can turn pathogenic under special conditions) [120].

Age

The GM diversity declines with age, which may result from various lifestyle changes in the human body. It is observed that microbiota diversity starts increasing in early childhood, reaches maximum level, and attains stability by 3 years of age [121, 122]. It is essential to maintain microbial diversity when aging progresses (important for healthy living), which can be brought about by a healthy diet and lifestyle [123]. With increasing age, especially in aged people, the GM shows signs of dysbiosis, and a decrease in the population of proinflammatory commensals and other beneficial microbes has also been observed [124].

Pediatric Gut Health and Disease

Several factors appear to affect the development of a child’s microbiome. Some of the most important ones are maternal GM, antibiotic exposure of mother during pregnancy as well as exposure to the child during the first year of life, mode of delivery [125], maternal vaginal colonization of group B Streptococcus [126], and exposure to complementary feeds after 6 months. C-section delivery appears to affect the microbial composition by facilitating gut dysbiosis by delayed colonization of Bifidobacterium sp. It also appears to reduce IgA levels in breast milk [127].

Higher socio-economic status is also associated with increased abundance of Lactobacilli and Bacteroides-Prevotella. Formula feeding is linked with reduced Bifidobacterium and increased Enterobacteriacae [128]. Gut dysbiosis in a child produces defective immune programming and is implicated in a number of diseases like necrotizing enterocolitis, coeliac disease, inflammatory bowel disease, obesity, and even asthma and psychiatric disorders like ADHD. The clinical studies have shown that breast milk oligosaccharides preferentially increase Bifidobacterium and activate genes, which reduce inflammation in NEC. Oral probiotics in very low birth weight infants have shown to reduce the incidence as well as the severity of NEC [129‒131].

Consumption of highly processed foods during childhood triggers a low-grade inflammatory state in the gut; a state of “metabolic endotoxemia” ensues, rendering the child susceptible to lipopolysaccharide. Upon binding to toll-like receptor-4, LPS induces a proinflammatory state, which promotes insulin resistance. A study showed that a perinatally administered combination of Bifidobacteria and Lactobacillus led to improved glucose control and insulin sensitivity in both the mother and the child. Hence, probiotic supplementation during pregnancy might reduce the risk of gestational diabetes [58, 132]. Ingestion of prebiotic fiber has been shown to reduce symptoms of pouchitis in patients of IBD in a randomized, double-blind, crossover, and clinical trial [133]. Oral intake of inulin and oligofructoses has a dual effect both at the level of the gut mucosa by increasing the integrity of the epithelium and in the lumen as well by increasing the number of beneficial bacteria (Bifidobacteria) [134].

Psychological Stress and Anxiety

Psychological stress, anxiety, and depression can alter the levels of gastric secretions and even increase highly palatable food consumption, which can influence and affect the GM’s survival and function [135]. Furthermore, depression, anxiety, and stress can alter the composition of GM through stress hormones (cortisol, catecholamines, etc.) and autonomic and inflammatory alterations. As a result, the GM may release metabolically active substances, neurohormones, and toxins that can affect eating attitudes and dietary patterns [135]. The microbiota of the gut not only produce but also can respond to the same neurochemical substances such as serotonin, GABA, dopamine, norepinephrine, melatonin, and acetylcholine, which are required by the brain for regulating cognition, behavior, mood, and emotions. Hence, the GM can act as a feedback channel for brain function through their response to these neurochemical substances [136‒138]. From the previous studies, it is observed that the complexes generated by the gut during the time of infection, known as “inflammatory cytokines,” alter the neurochemistry of the brain, making the individual susceptible to stress, depression, and anxiety [139, 140].

The amygdala and prefrontal cortex are engaged in the processing and expression of signals that are related to fear and anxiety. Preclinical studies have demonstrated the altered transcriptional networks within the prefrontal cortex and amygdala [141]. miRNAs have been linked to anxiety-like behaviors and regulate gene translation through translational repression [141]. A study on GF mice demonstrated that retention of cued fear memory depended on the presence of a functional microbiome during neurodevelopment. Transcriptome analysis confirmed functional hyperactivity in the amygdala region of GF mice [142]. A study by Hoban et al. [143] found the involvement of a large proportion of miRNAs, which was dysregulated in the amygdala (103 miRNA) and prefrontal cortex (31 miRNA). Altered expression of BDNF has also been seen in these mice. This implies that these miRNAs might have a role in the neurodevelopment. The amygdala’s apparent hyperactivity at baseline may eventually prime these GF mice to react to outside stimuli differently. Future research should emphasize examining alterations in gene expression over a range of time points to assess a temporal response in the amygdala more precisely. Lifestyle modifications with gentle exercise patterns like yoga are found to be effective in reducing psychological stress and depression, which is correlated with increased microbiota diversity with higher amounts of healthy strains of GM [144].

Effect of Nutrition on Psychiatric Disorders

Nutrition influences not only diverse aspects of health, like supporting normal growth and development, healthy body weight maintenance, and reducing chronic disease risk, but also mental health in a significant manner [145]. A type of nutrition intake, which includes amino acids, lipids, minerals, and vitamins, determines the growth and development of the brain [146]. Undoubtedly, having a high-energy output, the human brain relies upon an incessant supply of energy acquired through nutrition [147]. A conventional nutritious diet with wholesome foods, including fruit, vegetables, whole grains, fish, lean meat, seafood, and nuts, is a good option for treating several diseases, including psychiatric disorders [148]. The dietary habits of a person can modulate and regulate the microbiota of the gut and other associated components like the immune system and mediators of inflammation that are observed to have a role in psychiatric disorders [149]. The elements present in the diet can also modify various neurotrophic factors, like the BDNF, that are crucial for mechanisms such as neuronal plasticity [150].

The determinants of mental health are composite, and the growing evidence suggests a strong association between an imperfect diet and the augmentation of mood disorders, besides other neuropsychiatric circumstances [145]. According to the recent literature, the inflammatory processes sustain the evolution of neuropsychiatric symptoms, revealing the causative association between the psychopathology and immune system. The lifestyle components like nutrition and exercise can influence psychopathology that may happen through a bidirectional interconnection [151]. A large number of evidence corresponds toward the role of diet and GM in psychiatric disorders, for example, anxiety, depression, and autism. Modifications of lifestyle intended for better nutrition are shown to be therapeutically beneficial for patients with psychiatric disorders [152]. Another study reported an altered GM diversity in these children with Bacteroidetes present in large quantity in severe autism cases [153]. Besides this, bacteria corresponding to the genus, Ruminococcus, Lactobacillus, Bifidobacterium, and Prevotella, are also reported to be altered in few cases [154, 155].

In case of depression, significant alteration in GM has been reported having richness of Firmicutes, Actinobacteria, and Bacteroidetes [156]. Also, it has been shown that the patients with depression had increased richness of alpha diversity [157]. Similarly, the relation of GM to the anxiety disorders has been studied in animal models [158]. Two days post-infection with Campylobacter jejuni reported elevated anxiety behavior in mice model [159]. Similar observations were shown by Tzounis et al. [160] (2008), when 8-h post-infection study was done by infecting with two strains, i.e., Citrobacter rodentium and C. jejuni.

Dietary alteration toward improving mental health and well-being is a cost-effective, non-pharmacological, and practical intervention for individuals with psychiatric disorders. Applying these nutritional interventions in the psychiatry setting offers an optimistic tool for therapists in managing psychiatric disorders. Apart from psychotherapy, pharmacological therapy, and physical activity, nutritional interventions are essential in managing biopsychosocial and multifactorial components of psychiatric disorders [161].

Medication/Drug Use

As the microbiota of gut is a complex ecosystem, it can even mediate the interaction between the human body and the medications or drugs used. This gut microbe-drug interaction is complex as the composition and integrity of GM can be affected by certain drugs or medications, and conversely, the GM can also affect the drug response of the individual by enzymatical transformation of the drug structure, thereby changing its bioactivity, bioavailability, or toxicity [162]. Both antibiotic and non-antibiotic drugs also possess the potential to influence and change the integrity of GM, leading to the compromised health outcomes [163]. The mechanism of drug impact on GM can be either translocation or bidirectional [162]. The translocation of the microbiota can be explained by the proton pump inhibitor group of drugs, where the microbiota is displaced from the other parts of the body to the gut and by reducing the acidic nature of the stomach; these proton pump inhibitors permit oral microbes to pass through the stomach into the gut, provoking the microbial dysbiosis and damaging the integrity of GM [164]. The other dominant mechanism is a bidirectional one, in which the drugs can promote growth of some bacteria and inhibit growth of certain other bacteria of the GM. Anti-diabetic drug metformin is shown to have a positive impact on the growth of SCFA producers of the GM, which contribute toward the therapeutic effect of the drug in maintaining the glucose homoeostasis and correcting the insulin resistance [165]. Drugs like antineoplastic drugs (5-fluorouracil, floxuridine, daunorubicin), antirheumatic drug (diacerein), antigout drug (benzbromarone), and peptic ulcer disease treating drug (oxethazaine) are found to be toxic to the microbiota of gut damaging the integrity and composition [162, 166‒169].

Alcohol Consumption and Tobacco Use

Smoking and alcohol consumption have a potential to alter the microbiota of gut extensively, resulting in dysbiosis with a modified immune response. Tobacco and alcohol cause degradation of microbiota with anti-inflammatory activity and modifications of the GM [170]. Chronic alcohol intake and smoking can cause dysbiosis of the gut, leading to the etiopathogenesis of various liver diseases through alteration of intestinal barrier function. This alteration of intestinal barrier causes gut leakiness by the pathogenic and proinflammatory microbial product generation leading to disrupt liver metabolic pathways [171, 172]. Previous studies state that polyphenol consumption is connected to a rise in the bacteria, which are investigated to promote gut health; on the other hand, alcohol consumption solely could be lethal to healthy microbiota of the gut [173]. In patients with CD, smoking influences the GM by increasing the Bacteroides-Prevotella [174].

Physical Activity

Physical activity can be a possible regulator of GM integrity and composition, potentially contributing to musculoskeletal health and disease. The microbiota of the gut could indicate the extra-intestinal organs in setting up a system-level interconnection among the endocrine, metabolic, nervous, and immune framework of the host by producing a varied and large pool of bioavailable and bioactive substances [175]. Abundant and sterile microbiota diversity is essential for maintaining the homeostasis and normal physiology of the gut contributing toward a healthy brain-gut axis and overall health and well-being of a person. Physical activity, especially the low intensity exercises like yoga, is observed to enrich the GM diversity, enhancing the “Bacteroidetes-Firmicutes ratio” that could significantly add to weight reduction, controlling GI disorders and obesity-associated pathologies [144]. Increasing physical activity has been observed to prompt bacterial proliferation that can transform mucosal immunity toward improved barrier functions, eventuating in reduced incidence of obesity and other metabolic disorders [149].

Recent studies have shown that aerobic exercises have direct influence on the GM diversity, and an increase in the Firmicutes phylum has been reported. Increased abundance of Akkermansia genus has also been shown in athletes [176, 177]. Exercise could be used as a healthy option in maintaining the equilibrium of the GM or in restabilizing the eventual dysbiosis, thereby enhancing the brain health status [178]. Moreover, additional studies are required for further understanding of the processes and mechanisms that regulate the changes in the functions and compositions of the GM brought out through physical activity and its effects on brain health [178, 179]. Alteration in physical activity may provide a detailed relation to the associated advantages on the mood, brain health, and intestinal function [180].

Social Isolation

Social interaction plays a vital role in human health. Though this mechanism has not been proven in humans, several preclinical studies have shown a possible association of GM with social relationships. A 60-year-old Wisconsin longitudinal study discovered a correlation between variations in the human fecal microbiota and social interaction with family and friends [181]. Socially isolated individuals have limited possibilities to diversify their GM. Additionally, an isolated environment induces chronic stress, which may further alter microbiota equilibrium [135].

Moreover, social isolation also contributes to physical inactivity and has a psychological impact, which limits microbial diversity. Studies indicate that older people who interacted more frequently with others had resembling GM to younger people [182]. A reciprocal interaction between the GM and the social structure of the host occurs [183]. GM undergoes changes throughout the life of an individual. Advancing age has been associated with increased abundance of Bacteroides and lower population of Bifidobacteria [184]. A study done on rats showed social isolation is associated with microbial composition in a sex-dependent manner; i.e., social isolation caused short-term changes in the GM in females but not in males. Also, in these socially isolated rats, inflammatory response in the dorsal and ventral hippocampus was found to be correlated with the GM composition [185]. Studies indicate prolonged isolation is involved in altered neuronal activity and neurochemical expression in different brain regions [186]. A decrease in the concentration of Anaeroplasma species has also been reported post-isolation. Chen et al. [187], 2019, found Ruminococcaceae UCG-014 species reduced in socially isolated females, whereas socially isolated males showed reduced presence of Butyrivibrio species. Another study by Rincel et al. [188], 2019, found an increased presence of Lachnospiraceae UCG-001 and Desulfovibrio post-isolation. Other microbial taxa, like Oscillibacter species, have been found to be increased in isolated male rats, whereas the same has been found to be reduced in isolated females [186]. An enclosed and isolated environment significantly impacts the diversity and relative abundance of prominent taxa in the intestinal microbiota [189].

Mind-body techniques or practices are defined as the techniques that are used to enhance the brain’s positive impact on the body. The practices often include spiritual practices such as prayer, behavioral such as biofeedback, and psychological such as cognitive behavior therapy, guided imagery, yoga, and meditation [190]. Yoga and meditation can be considered both spiritual and behavioral depending upon the perception of the individual undergoing the mind-body technique [191]. However, the understanding and the positive impact of mind-body techniques on the human body still require research and evidence to be considered for being used in diseased populations as a treatment modality and in the general population for positive health outcomes [192].

It has already been established that GM relates to a healthy brain, and it has been shown that diverse and stable intestinal bacteria in human correlate with brain health by regulating the neuro-immune response in the CNS of the brain. Dysbiosis of the gut in humans causes a risk of neuro-degenerative diseases by causing adverse neuroinflammation [193]. The most common neurodegenerative diseases are AD and PD. A review article of 21 RCTs with 1,199 participants in which the impact of mind-body techniques on PD was analyzed [194]. The mind-body techniques that were included in the study included yoga, tai chi, and Health Qigong. The intervention that was given ranged between 4 and 24 weeks. It was observed that mind-body techniques administered to the patients have significant improvement in the quality of life, depression, and motor functions [194]. A similar systematic review and meta-analysis by Song et al. [195] (2017) on the impact of tai chi and Qigong with 21 studies including 735 patients have also shown a similar improvement in the PD patients. An RCT by Innes et al. [196] (2018) on the effects of meditation on the blood biomarkers of cellular aging and AD has been shown to improve and alter plasma amyloid beta levels, telomerase activity, and telomerase length. Apart from the blood biomarker levels, it is also shown to improve cognitive functions, sleep, mood, and quality of life as well.

As previously discussed, the relationship between the gut and the microbiota is unclear whether the mind-body techniques-related changes in the patients with neurodegenerative diseases bear a correlation to the GM or not. Although the research indicates that there is a relation between mental health and the GM [197] and positive outcomes are shown on GI disorders such as irritable bowel syndrome with mind-body techniques [198, 199]. Further research is warranted to understand the relationship between mind-body techniques, GM, and the onset of neurodegenerative diseases [200].

The microbiota plays a cardinal role in the functional interaction of GIT and CNS, producing a large number of biologically active substances that have various neurochemical effects mediated via immune, neuroendocrine, and metabolic pathways. A cumulative effort of research suggests the role of GM and its involvement in the evolution and advancement of various NDs, apart from its well-established role in the disease process of various GI disorders such as IBS and ulcerative colitis. The role of GM in regulating the physiological processes, for example, neurogenesis, microglial activation, myelination, and behavioral responses, has been widely studied [201‒203]. Several reports suggest the sensitivity of microbiota to lifestyle factors like food, sleep issues, sedentary behavior, and disturbances in circadian rhythm. These are also regarded as risk elements for NDs [203]. Moreover, the role of GM in maintaining a healthy state of microglia is critical in order to prevent NDs [204]. The GM is known to synthesize several metabolites and neuroactive compounds that modulate the progression and development of NDs. These micro-bacteria can regulate the immune system of the host and therefore may alter the communication between the immune system and CNS [44, 200].

The “microbiota-GBA is a bidirectional conveyance pathway between the microbiota, gut, and CNS” [205]. The microbiota of the gut communicates with the brain through the vagus nerve and the circulatory system; hence, the dysbiosis in the gut can increase the risk of developing ND by neuroinflammation and related pathophysiology [206]. GM manufactures and delivers products like neurotransmitters, neurotoxins, amyloids, and lipopolysaccharides that can unusually affect the neuro-chemistry of the CNS, provoking the incidence of synucleinopathies, amyloidosis, and tauopathies, hence promoting the evolution and progression of NDs [207]. The penetrability of the intestinal and blood-brain barrier varies based on the quality and quantity of human microbiota that can be altered depending on the symbionts-pathogens ratio [208]. The escalated BBR permeability of the translocated bacterial components and immune cells into the brain (CNS) influences and provokes neuroinflammation. The metabolites produced by the altered GM are capable of entering the bloodstream, possibly into the CNS, thereby disrupting its functioning. The resulting infections from the dysbiosis can play a remarkable role in the induction and progression of ND [102].

Alzheimer’s Disease

AD accounts for 60–80% of overall dementia cases in elderly population [209]. The GM composition is affected by the diet, and specific nutrients are found to influence the generation and aggregation of amyloid plaques and proteins, which is the characteristic feature of AD [210]. The scarcity of GM and dysbiosis producing abnormal bacterial products such as amyloids and lipopolysaccharides may contribute significantly to the development of AD, contributing to the pathological features of AD [211]. The microbiota of the gut is accountable for the production and absorption of substances such as vitamin B12 that reduces the risks of dementia and AD [212]. Abundance of Escherichia/Shigella and lower prevalence of Eubacterium rectale have been reported in the AD patients [213]. Studies suggest restoration of impaired memory after treatment with Lactobacillus rhamnosus and Lactobacillus helveticus [214]. Similarly, treatment with Bifidobacterium longum 1714 had improved effect on the learning memory [215, 216].

Parkinson’s Disease

The disease progression has been linked with the dysbiosis of the human GM. Several researches demonstrated the role of imbalanced GM in aggravating PD [193, 217]. In 2015, Scheperjans et al. [218] reported the lower prevalence of Prevotellaceae than Enterobacteriaceae in the stool sample of PD patients. Most of the patients with PD encounter functional gut symptom years before the appearance of motor symptoms, and a wide spectrum of studies have even illustrated the altered microbial composition in the gut samples of PD patients [219]. In a study by Sampson et al. [220], transposition of fecal microbiota from PD patients produced neuroinflammation and motor deficits in the mice, where the behavioral symptoms begin to revamp with the antibiotic treatment.

Multiple Sclerosis

MS is a neurological condition primarily affecting young adults, with demyelination and axonal damage caused by autoimmune-mediated inflammatory processes in the CNS’s CD4+ and CD25+ regulatory T cells [221]. Changes in the GM may result in a proinflammatory response that damages the CNS and causes MS to develop [222]. Lower abundance of Parabacteroides distasonis and Prevotella copri has been reported in RRMS patients [223]. However, increased abundance of Firmicutes has been found in the children with MS [224].

Amyotrophic Lateral Sclerosis

ALS is a deadly ND affecting the neurons of the brain and spinal cord, resulting in death. Most of the patients with ALS die within 3–5 years because of respiratory paralysis or distress [225]. From a large number of studies, it was found that the neurotoxins derived from the gut might include the botulinum and tetanus toxins that are produced by Clostridia species [226]. The gut dysbiosis that damages the structure of tight junctions in the gut causes leakiness (increased gut permeability) that is probably responsible for the precipitation of ALS, which was also revealed more recently by Wu’s mouse model of ALS [227]. Studies have reported lower levels of Oscillibacter, Anaerostipes, and Lachnospira in ALS patients, whereas there is an increased concentration of Dorea [214].

The microbiota of the gut is a crucial element in the integrity, maintenance and regulation of the intestinal flora, the brain physiology, endocrine system, immune system, and the bacterial metabolites. By regulating the vascular barriers and related neurotransmission, the GM can alter cognition, neuropsychological function, and cerebral vascular physiology of the host [228]. Functional disruption of the gastrointestinal system can pave the way for neurodegenerative processes to begin. The GM-targeted therapies could similarly have potential as future therapies for the neurodegenerative and neuropsychological diseases, improving the treatment outcomes [229].

The strategy for maintenance and regulation of the healthy GM can result in reducing the individual’s risk and preponderance of neurodegenerative diseases. Therefore, early detection and diagnosis, monitoring, and adequate treatment of pessimistic symptoms of GIT, including the GM normalization, can lead to a notable improvement in the patient’s quality of life with NDs [193].

Neurodegenerative diseases have always been poorly understood because of their complex mechanism of action and their involvement with environmental factors such as dietary and lifestyle factors. Environmental factors and gut dysbiosis also make them susceptible to these diseases. This has been strongly suggested in many neurodegenerative diseases such as PD, AD, and others [207, 230]. This has been proved by many studies showing the presence of Lewy bodies (aggregation of α-synuclein-containing [ASYN] insoluble fibrous molecules) in the vagus nerve, which acts as a transporter for the toxins from the gut to the brain, leading to PD. To further confirm, a complete truncal vagotomy has been shown to decrease the susceptibility of PD [231, 232].

NDs mainly occur due to protein misfolding and aggregation, which are the hallmarks of identification. Misfolding of proteins happens due to non-proteinogenic amino acids charged to tRNA, which are further incorporated into proteins, leading to neurodegeneration. One such piece of evidence is β-N-methylamino-l-alanine (BMAA), a non-proteogenic diamino acid in place of serine, which gets incorporated as a human protein [233]. The BMAA enters as a human protein, leading to the imbalance between the ASYN and serine phosphorylation and the ASYN, leading to PD [234]. BMAA can be incorporated into the body via a seafood diet and the production of BMAA from the Melainabacteria [235]. The mechanism gains prominence by the further presence of Lewy bodies in the human gut [235, 236]. The GM also influences the immune system, leading to inflammation, brain injury, and altered behavior via the developmental function of the microglia and astrocytes [237]. Although a direct correlation between the GM and immune response is not established, several researches indicated GM regulates the peripheral myeloid cells, T cells, and mast cells [237, 238]. In sporadic PD development, apart from chronic exposure to BMAA from human GM or from the diet, host genetic factors also play an important role in the development of the disease, especially with certain genetic polymorphisms that promote the incorporation of BMAA first in the enteric nervous system present in the gut followed to the CNS, which leads to PD [234]. The genetic association where mouse with c9orf72 mutation in ALS had shown shorter lifespan and movement problems compared to the mouse without the mutation [239, 240]. The differentiating aspect was that the mouse with cc9orf72 was bred at Harvard University, and the mouse without the mutation was bred at Broad, which has a diverse set of microbes compared to the facility at Harvard University [240]. These mechanisms, if combined with chronic BMAA exposure from diet and production by the microbiota, lead to the generation of Lewy bodies (shown in Fig. 2). Other possible mechanisms include the following.

Fig. 2.

GM-brain axis. The bidirectional communication is mediated by both the direct and indirect pathways in the brain-gut axis. The communication channels involve the autonomic nervous system (ANS), the HPA axis, the neuroendocrine system, the immunological system, and metabolic pathways. The secretions are passed into the circulation that interacts with the host system and affects metabolism.

Fig. 2.

GM-brain axis. The bidirectional communication is mediated by both the direct and indirect pathways in the brain-gut axis. The communication channels involve the autonomic nervous system (ANS), the HPA axis, the neuroendocrine system, the immunological system, and metabolic pathways. The secretions are passed into the circulation that interacts with the host system and affects metabolism.

Close modal

Production of Assorted Functional Metabolites

  • a.

    Through tryptophan-kynurenine and its metabolites (quinolinic acid [QA] and kynurenine uric acid). Directly regulated pathways include kynurenine and indole, whereas the serotonin pathway is indirectly controlled by the GM [241, 242]. Through NMDA-mediated excitotoxicity, QA can induce neurodegeneration. Kynurenine uric acid plays a neuroprotective role by regulating the neurotoxic effect of QA [200, 243].

  • b.

    Via SCFAs: It is among the end product of the GM. The composition of microbiota determines the types of SCFAs produced. These SCFAs are involved in the cellular signaling of the epithelium in the GIT through free fatty acid receptors 2 and 3 [78]. In vivo studies have demonstrated the role of SCFAs in the development of nervous system, where these small molecules affected the motor symptoms in PD mice model [244]. Acetate was able to penetrate the BBB and was involved in reduced appetite behavior [245].

  • c.

    Via neuro-metabolites: These molecules (neurotransmitters) are directly secreted by the GM that acts on the CNS. Now, these neuro-metabolites stimulate the local afferent vagal fibers and communicate with the CNS. Any variation in their level may result into the changing behavior; for example, increased level of norepinephrine and dopamine in the striatum may lead to the heightened response of spontaneous motor nerves [246].

Through MAMPs

These are conserved components of assorted microbials. By restoring the normal flora, GM influences the host’s organism exposure level and response to specific MAMPs, thereby inhibiting the neuroinflammation and regulating the overall health and behavioral responses [122].

The available research that has been published to date pertaining to microbiota is still inconsistent relative to the results obtained. Most of the existing RCT studies have smaller sample sizes and limited genome information. Therefore, bigger sample sizes with extensive genome information of the patients are required for a better understanding of the complex gut microbiome with reliable and concrete results. Indeed, extensive research is essential to explain the molecular mechanisms illuminating the composite gut microbiome, including the GBA [137], because of the vast complexity and compositeness of the gut microbiome, which advanced statistical methods can only address. Another issue limiting microbiota research could be the “logical flaws” in the terminology of “dysbiosis.” Most available observational studies on the gut microbiome are not strong enough, entailing further meta-analyses focused on the microbiota-disease associations with significant statistical interrelation and causal association [247].

Various studies have generated evidence of a positive association between GM and the brain. The communication network between the gut and brain is bidirectional. However, the mechanism of communication between them is yet to be discovered. GM plays a significant role (protective, metabolic, and trophic) throughout life, from when a baby is born, the type of milk received during the initial months, to the kind of food consumed. It defines the course of the various microbes constituting the GM, influencing the individual’s health outcomes. This impact also extends to the progression of ND, such as AD, PD, MS, and ALS.

Along with food, many factors, such as alcohol, tobacco use, nutrition, and physical activity, can also impact GM. Many studies have shown the association between medications/drug use and GM. This is either translocation (displacement of the bacteria) or bidirectional (either inhibiting or promoting the bacteria). However, additional experimental research needs to be done to understand the underlying complex mechanisms between the association of the gut and brain and the factors influencing them.

Most gastrointestinal diseases are related to the modified transmission mechanics under the influence of the GBA. As various drugs and therapies fail to treat NDs, besides the mechanism of the development of ND being poorly elucidated, it is essential to understand the complex association of gut and brain, which might open new avenues for developing targeted therapies centered on GM. The non-interfering strategies toward deregulating the GBA could be the key players in generating precise diagnostic mechanisms and individualized microbiota-based therapies. The lifestyle modification-based approaches, i.e., dietary changes, exercise, and yoga, may positively influence the GM and the associated host immune responses that halt the progression of neurodegenerative diseases. Hence, more global studies are needed to understand the GM.

We declare no competing interest.

No funding was received.

P.B. was involved in the conceptualization, overall drafting, and figure preparation. P.L. participated in writing of manuscript. M.S.S. was involved in the writing of the manuscript and table preparation. L.V.S.K. and A.C. participated in the manuscript writing. P.A. was involved in the editing of the manuscript. S.K. was involved in manuscript writing. A.A. was involved in the editing and conceptualization of the manuscript.

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