The Gut Microbiome and its Impact on Neurological Health: A Systematic Review

Table 2: Details the search process, including the keywords and engines used, as well as the total number of results shown.

Table 4: Summary of the outcomes of the articles that were chosen. ALS stands for Amyotrophic Lateral Sclerosis, and CNS is an abbreviation for the Central Nervous System.

Discussion

There is growing evidence from clinical trials, epidemiological studies, and immunological investigations indicating that the microbiota in the intestines affects the gut-brain axis, which includes cognitive function, emotional control, neuromuscular tone, and hypothalamus-pituitary-adrenal axis regulation [19]. The autonomic nervous system, hypothalamic-pituitary-adrenal axis, and vagus nerve connect the brain to the gut, enabling the former to affect the latter's functions, such as the activity of functional immunological effector cells [19]. However, scientists are still trying to figure out how gut microbiota works, but they know that it affects the brain’s emotion and cognition centres and that changes in these areas' communication circuits are associated with gut microbiota variations [19]. As an example, there are now well-established connections between changes in the gut microbiota and functional gastrointestinal disturbances in several mood disorders, including depression, anxiety, and autism spectrum disorders [19]. Disruption of the blood-brain barrier, activation of microglial cell populations and astrocytes, and neuroinflammation can occur when microbiota in unhealthy states produce more inflammatory cytokines, lipopolysaccharides, and T and B cells while decreasing the quantity of short-chain fatty acids [1]. Therefore, there is mounting evidence that changes in the makeup of gut bacteria may impact cerebral processes and vice versa, as a result of the two-way link [21].

Based on the connections between gut microbiota and neuronal function as well as cerebral processes, experimental and clinical data point to the intestinal microbiota as an essential component of the gut-brain axis. The cells of the intestinal tract and the enteric nervous system are local targets of its effects, but it also has direct communication with the central nervous system via endocrinology and metabolic pathways linked to memory, anxiety, and stress [7]. Crucially, the vagus nerve is the primary modulatory constitutive channel that links the brain to the microbiota, and it is involved in this communication [22]. The gut-brain axis is modulated by microbiota, which in turn, affects gut motility and pain perception by regulating afferent sensory nerves and increasing their excitability by blocking calcium-dependent potassium channels [23].

Expanding on the vast influence of bacteria on the enteric nervous system, their effect extends to the production of neurotransmitters, including acetylcholine, serotonin, melatonin, histamine, and gamma-aminobutyric acid [24]. An effective form of catecholamines is also generated in the gut lumen by these microbial populations [25]. Key bacterial metabolites, including butyric acid, propionic acid and acetic acid, impact memory and learning processes, stimulate the parasympathetic nervous system and influence the gut-brain axis via their metabolic byproducts and short-chain fatty acids (SCFAs) [26], [27]. The intestinal immune system’s impacts on the gut microbiota's ability to regulate the activity of the enteric nervous system is discussed in (Figure 3).

Figure 3: Intestinal immune system impacts the gut microbiota's ability to regulate the activity of the enteric nervous system, Illustrated by Asif S.

The discharge of physiologically active chemicals from enteroendocrine cells may modulate the effect of dietary changes on behaviour on microbiota composition [19]. Examples of peptides that can activate the hypothalamus-pituitary-adrenal axis include galanin [19]. This can lead to an increase in the secretion of glucocorticoids from the cortex of the adrenals, cortisol from norepinephrine from the adrenal medulla and adrenocortical cells. Similarly, ghrelin is known to release cortisol and adrenocorticotropin hormone, and it is believed that it plays a role in regulating the hypothalamus-pituitary-adrenal axis reaction to stress and changes in diet and metabolism [28]. Moreover, recent molecular research highlights that gut microbiota affects the central nervous system and enteric nervous system [7]. It further explains how gut microbiota impacts mucosal immune activation, as well as neurogenic inflammatory processes that arise from micro-element deficiencies secondary to functional and morphological changes in the digestive tract [31]. These processes can further link with the discharge of physiologically active chemicals from enteroendocrine cells, affecting behavior, and triggering the hypothalamus-pituitary-adrenal axis [29]. Additionally, in intestinal-immune mediated disorders it is highlighted that proteases are up-regulated and also serve as end-stage effectors of enteric nervous damage and mucosal [30]. Gut dysbiosis often leads to the loss of gut barrier integrity and increased intestinal permeability[6].  This state promotes the development of many neurological disorders by facilitating the increased translocation of metabolites produced by gut bacteria and microbe-associated molecular patterns into regional lymphoid tissues [1]. Glutamate, an important component in brain and gut physiological reactions [32], is found in both food sources and gut microorganisms, capable of producing glutamine. Glutaminase catalyzes the deamination of glutamine and its subsequent synthesis from α-ketoglutarate, both produced by neurons in the central nervous system [33]. Also, the astrocytic cytosol is rich in glutamine, which is then transported into the extracellular fluid and absorbed by neurons for glutamate synthesis. This leads to neuronal excitability that in turn alters in a pathogenic way [34]. Further, it seems that glutamate transmits signals from the epithelial layer to the enteric nervous system, functioning as a sensory transporter [35]. The main mechanism by which glutamatergic neurotoxicity is amplified is by selective activation of N-methyl-D-aspartate receptors within synapses rather than those outside of them [36]. Hydroxy tryptamine (5-HT) is another important neurotransmitter made by the gut microbiota from tyrosine with the help of tyrosine hydroxylase 1 [37]. Its significance in normal digestive systems is shown by the fact that 5-HT receptor antagonists affect enteric nervous system functioning [63]. Mutations in dopamine hydroxylase 2, have been associated with problems affecting enteric nervous system development and gastrointestinal functions [63]. A possible link between 5-HT and disorders like depression may lie in the fact that altered 5-HT levels in enteric neurons impact colon motility and gut transit rates [63].

Gut metabolites, such as short-chain fatty acids, produced by gut bacteria also affect 5-HT synthesis [37]. By interacting with orphan receptors coupled with G proteins (GPCRs), short-chain fatty acids, mainly function as signalling molecules. Furthermore, they inhibit histone deacetylases (HDACs) and interact with Sensory receptor 78 (Olfr78) [38], [39]. The immunological, vagal, endocrine and humoral pathways are the four primary means by which short-chain fatty acids impact central nervous system functioning. To influence brain processes, they directly activate immune cells associated with the enteric nervous system and vagal neurons to increase the production of regulated cytokines and peptides produced from the gut [1]. In addition to metabolites, components of the gut microbiota can influence the activities of the central nervous system and the endocannabinoid system by activating toll-like receptors, expressed in several brain cells, including enteric neurons, and cutaneous afferent cells [17].  Specifically, microglial cells, can increase inflammatory cytokine expression in the central nervous system and the gut as a result of LPS/TLR4 signaling [40], affecting the survival of the neurons in the enteric nervous system [41]. The presence of lipopolysaccharide at the blood-brain barrier raises the possibility that, under normal circumstances, it enters the brain via a lipoprotein mechanism for transport [42]. The abnormal levels of lipopolysaccharide make their way to the brain via the bloodstream, where they interact with toll-like receptor 4, triggering a cascade of harmful signalling events that lead to neural inflammation along with various neurological problems [1]. TLR4 is involved in neuroprotection from experimental brain injury, activating vascular endothelial cells and microglia, and other key processes [43], [42]. The transcription factor, Krüppel-like factors 4 (KLF4) is implicated in neuroinflammation and is involved in LPS-induced activation of microglia as well [44]. Microglia are like guardians of the brain, monitoring neuroinflammation, synaptic remodelling, and neurogenesis [11]. Many neurodevelopmental and neurodegenerative disorders, including schizophrenia, autism spectrum disorder, diseases such as multiple sclerosis, Alzheimer's illness, amyotrophic lateral sclerosis, Parkinson's condition, major depressive disorder, and multiple sclerosis are linked to microglial activity [20][13].  Microglial dysfunction and microbial dysbiosis in neurological diseases are discussed in (Figure 4).

Figure 4: Microglial dysfunction and microbial dysbiosis in neurological diseases.

Although microglia mostly respond to signals within the brain, new evidence suggests that they are not autonomous cells; but rather receive information from the periphery, specifically the gastrointestinal tract [20], as explained in the Gut Microbiota-Microglia Nexus. The intestinal microbiota may regulate several processes that impact microglia maturation and function [62]. Firstly, short-chain fatty acids generated by the gut microbiota can control the function or development of microglia by making their way through the host's circulatory system and eventually crossing the blood-brain barrier [62]. Secondly, short-chain fatty acid signals produced in the gut flora may cause immune cells with SCFA-recognition receptors to migrate across the blood-brain barrier and into the brain [62]. Furthermore, vagus nerves may allow the gut microbiota to communicate directly with microglia located in the brain [62]. Before the development of SCFA-recognizing receptors, microglia can be influenced by other metabolites or microbe-associated molecular patterns produced by the microbes in the gut [62]. Lastly, gut flora generates metabolites or microbe-associated molecular patterns that can be recognized by peripheral macrophages, which then travel to the brain across the blood-brain barrier in response to signals from these molecules [62].

Through the production of immune-related chemicals in the brain, such as cytokines, the major histocompatibility complicated (MHC), and Toll-like receptors, the host microbiome affects both responses to infection and brain development [1]. Additionally, the finding of meningeal lymphatic arteries in the brain suggests a possible connection between the central nervous system and the peripheral nervous system, which could impact autoimmune processes [45]. Moreover, available research points out the crucial functions of microglia and lymphocytes in controlling central nervous system immunological defence, neuronal circuitry, and cognition [46]. Furthermore, the gut microbiome continues to shape brain immunity throughout life by influencing microglial cell maturation, which begins during early development and continues throughout adulthood [47].

Recent research also highlights the importance of the gut microbiota's interaction with mitochondria for human health. Although this interaction is complex and context-dependent, the gut microbiota may regulate mitochondrial inflammatory responses through short-chain fatty acids and other pathways [48]. Mitochondrial production of ATP and NADH depends on short-chain fatty acids, particularly butyrate. The microbiota procures bile acids, which influence energy metabolism and regulate mitochondria. Nevertheless, mitochondrial energy production can be severely impacted by infections and high-protein diets [48]. Also, variables such as PGC-1α affect mitochondrial activity and energy production during endurance exercise. When you work out, your mitochondria release more reactive oxygen and nitrogen species through mitochondrial leaks. Although these compounds promote healthy blood vessel function and muscular development, they have the potential to damage DNA and mitochondria, hastening the ageing process [49]. The degree to which one exercises affects the onset of acute inflammation. Exercising causes mitochondrial stress, which in turn raises reactive oxygen and nitrogen production, activating inflammasomes [15]. A defence strategy against pathogens can include reactive oxygen species generation in mitochondria; however, pathogenic bacteria can adapt to control this process [15]. Disruption of the gut environment and immune system responses can be caused by dysregulated mitochondrial functions [50], [51]. Endurance exercise can cause mitochondria to multiply, which could lead to the accumulation of mutations, impacting mitochondrial functioning and the composition of the gut microbiota [15]. Diseases such as multiple sclerosis can be influenced by the oxidation and genetic/epigenetic alterations that can occur in mitochondrial DNA [15]. While reactive oxygen species in the gut can trigger protective mechanisms at lower levels, too much of them can damage mitochondria and lead to diseases like cancer (which is often caused by inefficient mitophagy) [59]. On the other hand, reactive oxygen species produced during respiration in the mitochondria can have beneficial effects on some cells in the gut. Additionally, the gut-brain axis connects the gut to mitochondria and brain health; hence, gut microbiota metabolites and dietary components can interfere with mitochondrial metabolism, leading to inflammation and oxidative stress discussed in (Figure 5).

Figure 5: Health benefits linked to regular exercise and a healthy digestive system.

There is mounting evidence that the gut microbiome plays a major role in determining the efficacy and safety of many drugs, including psychotropics. Antidepressants like selective serotonin reuptake inhibitors and other non-antibiotic medications have been investigated for their potential antimicrobial effects, and results have indicated that they inhibit a variety of bacterial strains [60]. According to research, certain microbial populations can be altered and reduced when using psychiatric medicines like desipramine and tricyclic antidepressants. There is evidence that atypical antipsychotics reduce microbial diversity, especially in females [61]. Furthermore, previous studies suggest that a decrease in the durability of the digestive barrier, caused by an aberrant intestinal microbiota, increases the number of lipopolysaccharides accessing the body, triggers systemic inflammation, and enhances the stress response [52]. However, there are several ways in which probiotics might lessen the physiological stress of the hypothalamus-pituitary–adrenal system and protect the intestinal barrier from harm [53], [54],[18]. The vagus nerve and the hippocampus secrete chemicals including oxytocin and brain-derived neurotrophic factor. Additionally, probiotics from the bacteria, Lactobacillus rhamnosus can lower the amount of corticosterone in the blood and alleviate depression [55,56]. The effects of probiotics may vary from patient to patient. In healthy people, daily intake of L. Caseiprobiotic supplement may help reduce stress symptoms and improve the composition of gut microbiota, according to a study [57]. Another study highlighted that stress conditions and negative mood management improved in healthy people who consumed the strain for 30 days, alongside a diet that included plants such as L. Helveticus and B. Longum [58]. In 2017, Bamling et al., tested a novel combination of antidepressants that included probiotics, magnesium, a mineral, and SSRIs, to impact therapy-resistant depression (TRD). Positive outcomes included a marked improvement in individuals' depressed symptoms [20].

Psychobiotics, also called psychomicrobiotics, are a new kind of probiotics that have just come to light as a non-toxic treatment for a range of mental health issues. Some probiotics have been tested in clinical trials for their potential to alleviate anxiety and depression [12]. However, this strategy for tackling anxiety and depression needs further validation in clinical trials with randomized controls due to the variation in probiotic dosage, strain selection, and treatment durations in existing investigations [12].

Limitations and Recommendations

Although there is a growing body of evidence linking gut microbiota to neurological health, establishing causality is difficult, as much research is predominantly observational or correlative. Future studies should focus on conducting more controlled experiments and clinical trials to better elucidate causal relationships. Another limitation is the fact that many drugs affect the gut bacteria. Future studies need to find out what kind of bacteria are involved and how metabolites affect neurological function, potentially leading to the discovery of beneficial microbial strains and interventions. It's still unknown how things like food choices and lifestyle can influence the gut-brain connection. Understanding these factors can help create possible preventive measures by learning how they affect the gut bacteria and, in turn, neurological health.

Conclusion

This systematic review highlights the important role of gut microbiota in affecting brain function, and its possible effects on neurological disorders. The gut-brain axis can either make brain problems worse or better. Hence, this paper concludes that an imbalance in the gut's microbiota can cause brain inflammation, chemical imbalances, and microglial and mitochondrial impairment— all of which are common features in various neurological disorders. This suggests that the gut-brain axis, through infections, metabolites, immune communication, and microglial and mitochondrial dysbiosis, impacts neurophysiological function and cognition. Understanding these complicated connections helps find new ways of treatment approaches aimed at improving neurological health outcomes for people suffering from neurological diseases.

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