The gut is a complex ecosystem that houses a dense and diverse microbial community called the gut microbiota, which co-evolves with the host and establishes a mutualistic relationship [1–3]. However, despite its significant influence on the state of human health and its relationship to the development or progression of diseases, it has only been studied in more detail in the recent years, coming to be highlighted by several researchers in the health field [1–3]. The most recent scientific advances have shown a close connection between the gastrointestinal tract (GIT), through the vagus nerve, with the central nervous system (CNS), contributing to the regulation of secretion, permeability, motility, and immunity of the digestive tract, exerting its effect on the enteric nervous system (ENS) [1, 4–6]. Due to this prominent role in the regulation and functionality of the CNS, the ENS has been considered a “second brain” since the structure of enteric neurons is a key factor in the control of the physiological response to the environment, muscle tissue, and the intestinal mucosa via the efferent autonomic nerve pathways [5, 7–9].

ENS influences brain functions through afferent signaling pathways and the secretion of biologically active substances in an intrinsic and bilateral relationship, providing a functional interaction and contributing to the coordination of the body’s metabolic and homeostatic functions [4, 6, 7, 10]. Thus, ENS has been suggested as an essential agent in the pathophysiology of chronic diseases, such as diabetes, metabolic syndromes, obesity, several autoimmune diseases, stress-induced psychosomatic disorders, schizophrenia, and some neurodegenerative diseases (NDs), as well as in the search for therapeutic targets and new drugs [7–9].

The human gut consists of approximately 1,000 species and 7,000 strains of bacteria, mainly belonging to the phyla Firmicutes (51%) and Bacteroidetes (48%). The remaining species (1%) belong to other divisions such as Proteobacteria, Actinobacteria, Fusobacteria, Spirochaetes, Verrucomicrobia, and Lentispherae [6]. The microorganisms consortia, which constitute the intestinal microbiota in healthy human beings, undergo important changes in quantity and quality among individuals and in pathological situations, as is the case of patients with NDs [11–13].

Dementias are some main causes of disability in the elderly, accompanied by physiological changes that include alteration in the intestinal microbiota, which seems to form a consensus regarding the relationship in the reduction of the number of species and their quantitative composition of Bifidobacterium and Lactobacillus in aging, with an increased incidence of chronic diseases [14–17]. One possible explanation is the reduction of symbionts that control mucus production. Once disturbances in mucus production occur, the possibility of damage to the intestinal epithelial barrier increases, leading to gut functionality restriction and increased susceptibility to gastrointestinal infections [10, 15, 18]. Thus, significant changes in the gut microbiome with aging constitute a significant risk factor for NDs [1, 10, 16, 18].

In this perspective, unhealthy diet, poor sleep quality, circadian rhythm disorders, sedentary behavior, drug abuse, and environmental factors may contribute to changes in the gut microbiota and, in turn, trigger NDs [1, 19–21]. Therefore, in this narrative review, the role of the gut microbiota, its relationship with CNS disorders, and the known mechanisms that drive dysbiosis, including its role in the pathophysiology of NDs and potential therapeutic aspects were discussed.

The gut microbiota plays a fundamental role in the biosynthesis of vitamins and cofactors, cleaving the structure of complex lipids and polysaccharides, and promoting detoxification by residual particles [2, 15, 21, 22]. The gut microbiota also contributes to the fermentation of non-digestible substrates, such as dietary fibers and endogenous intestinal mucus, supporting the growth of microorganisms specialized in the production of short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, and certain gases [2, 22–24]. Regarding SCFAs, another of their functions is to contribute to the improvement of intestinal health through a series of effects that include maintaining the integrity of the intestinal barrier, mucus production, and protection against inflammation [23–25]. Besides, evidence supports a potential key role of SCFAs in gut-brain axis signaling [23].

Preclinical and clinical studies have shown that SCFAs activate a series of receptors involved in the regulation of satiety and hunger by stimulating L cells, which are located in the intestine’s distal ileum of enteroendocrine cells (EECs) [23, 25]. They are responsible for the secretion of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), which induce satiety and behavioral changes [23, 26]. Alterations in this signaling process may favor CNS disorders that range from neurodevelopmental alterations to the NDs onset [23, 25]. Furthermore, the signaling role could be seen in intestinal microbial enzymes that contribute to the metabolism of bile acids, generating non-conjugated and secondary bile acid derivatives that act as signaling and regulatory molecules in different metabolic pathways [2].

The gut microbiota harbors a wide variety of microorganisms that have a central role in the fermentation of complex indigestible substances, contributing to the regulation of the immune system, and in the synthesis of vitamins. Taking into account, bacteria of the Bifidobacterium and Lactobacillus genera, have a prominent role for their active contribution in the production of γ-aminobutyric acid (GABA), one of the main inhibitory mediators of the CNS in humans and other mammals, involved in the modulation of neurotransmitters and metabolic processes in the brain [10, 14, 26–28]. Additionally, experimental evidence has revealed that GABA levels in the gut are related to its concentration in the CNS. However, a decreased population of Bifidobacterium and Lactobacillus could lead to brain dysfunction associated with synaptogenesis disorders, depression, and cognitive impairment [14, 26–28].

The imbalance in the gut microbiome triggers the overproduction of harmful molecules, which becomes a serious problem because these metabolites inform the ENS of the content of the gut lumen. Once the ENS translates the signal generated by the unbalanced microbiota, this information is transmitted to the CNS via the vagus nerve in milliseconds. In principle, the correlation between ENS and NDs can be established by the metabolism of essential amino acids, as they constitute one of the primary sources of neuromodulators, neurohormones, and neurotransmitters. Thus, changes in the production of these compounds impact the CNS with consequent effects on the stimulation of central receptors, peripheral neural stimulation, and endocrine and immunological mediators [6, 27–30].

Therefore, the gut microbiota contributes to the processes of fermentation of complex food [22, 31], including amino acids, such as L-tryptophan (compound 1, Figure 1), which is metabolized by the main serotonergic and kynurenic pathways. In turn, the products of its metabolism play an indispensable role in brain functioning and CNS physiology [3, 6, 32, 33].

Intestinal microbiota in a state of eubiosis/homeostasis has an important impact on several functions of the host’s ENS, including essential physiological processes like maintenance of metabolic and nutritional homeostasis, maturation and stimulation of the immune system, regulation of neurotransmitters, and activation of antioxidant enzymes [3, 5, 8, 9, 34]. The role of SCFAs (e.g., butyrate) can also be highlighted, whose concentrations are related to the production of mucin, which has anti-inflammatory effects and increases protein levels at the tight junction, promoting the maintenance of the intestinal barrier and reducing the permeability of the intestinal mucosa [35–38]. Changes resulting from dysbiosis in the elderly lead to increased intestinal permeability, which leads to systemic inflammatory processes, affecting a series of vital physiological cascades that favor depression, anxiety, and NDs [9, 18, 29, 35].

In sporadic forms of NDs, which are generally recorded in the elderly, the gut microbiome shows a reduction in diversity and quantity of essential microorganisms, such as Bifidobacteria, Lactobacillus, and Bacteroides, which guarantee the tolerance of the intestinal immune system [15, 18, 25, 39–41]. Changes in the gut microbiota composition in aging, seem to constitute an important risk factor for NDs, psychological disturbs, and other chronic pathologies due to cumulative systemic exposure to toxins [1, 18, 29, 42]. Thus, the maintenance and modulation of the homeostasis of the intestinal microbiota are currently seen as a beneficial path in the prevention of chronic diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) [18, 29, 42]. In this regard, under homeostatic conditions, epithelial cells produce antimicrobial peptides (AMPs) in response to interleukins (ILs, e.g., IL-22), and also express Toll-like receptor (TLR), a class of pattern recognition receptors. Besides regulation of mucosal secretion and AMPs production, intestinal microbiota also regulates/improves intestinal barrier integrity through the production of SCFAs. Goblet cells or caliciform cells produce mucus to restrict the invasion of pathobionts, and lymphoid cells [T helper 17, (TH17)] play a role in host defense by producing controlled arrays of IL-22. Moreover, dendritic cells (DCs) induce activation and differentiation of B cells to produce plasma cells that, in turn, produce commensal specific immunoglobulin A (IgA) in the lamina propria. IgA is transported into the intestinal lumen as secreted IgA (sIgA) via polymeric immunoglobulin receptors (pIgR), where sIgA then binds to commensal microbes soluble antigens, thereby restricting their adherence to the host epithelium and leakage across the intestinal barrier. However, under a dysbiosis condition, the altered microbiota composition can weaken the intestinal epithelium leading to increased permeability and the leakage of opportunistic pathobionts and their by-products across the intestinal barrier, which, in turn, instigates hyperinflammatory responses, and eventually increases host susceptibility to neurodegeneration [6, 8, 15].

L-tryptophan (compound 1, Figure 1), one of the 20 essential amino acids for humans, is metabolized in the intestine and used for protein synthesis, being the only biosynthesis precursor at the level of enterochromaffin cells (EC), which modulates neuronal signaling in the ENS [32, 43]. The potential role of L-tryptophan metabolism in the gut-brain axis serves as a sole precursor for the biosynthesis of the neurotransmitter serotonin (compound 3, Figure 1) and, subsequently, a pineal hormone called melatonin (compound 5, Figure 1) [32]. Notwithstanding, the manipulation of gut microbiota composition (e.g., antibiotics and probiotics) could contribute to changes in central L-tryptophan metabolism between serotonin synthesis and L-tryptophan degradation pathways, which thus influence individual functionality and behavior [32].

The signaling pathway occurs through the conversion of the biosynthetic precursor 5-hydroxy-L-tryptophan (compound 2, Figure 1) into the neurotransmitter serotonin, whose secretion in CNS plays a fundamental role in the modulation of emotional control, appetite, sleep, sex, temperature, and pain processing [3, 6, 43]. Therefore, L-tryptophan metabolism products, such as serotonin, melatonin, and tryptamine (compound 6, Figure 1) have profound effects on the interaction between gut microbiota and neuroendocrine system, and gut immune responses [3, 7, 32]. However, evidence supports those changes in gut microbiota composition may have implications for modulating L-tryptophan metabolism in the axis-gut-brain interaction [6, 32, 43]. Consequently, messages sent to the brain can propagate harmful signals, which are manifested as inflammatory processes, oxidative stress, imbalance of energy homeostasis, and a general increase in cellular degeneration [3, 32, 43].

It is worth mentioning that the L-tryptophan metabolism comprises two main pathways, both influenced by the intestinal microbiota, namely: (A) The serotonin production pathway in EC via L-tryptophan hydroxylase (Figure 1), and (B) The kynurenine and QUIN pathway (Figure 2), which plays a critical role in inflammatory mechanisms, neurobiological functions, and immune responses in epithelial cells via indoleamine 2,3-dioxygenase 1 [6, 32, 44, 45].

Abnormalities in the functional communication of the gut-brain axis can usually reflect a disruption of the integrated network of neurotransmitters in the endocrine, intestinal, and brain systems [8, 51, 57, 63, 64]. Three basic mechanisms mediate the communication between the gut and the CNS: i) direct neuronal communication, ii) endocrine signaling mediators, and iii) through the immune system. Therefore, the combination of these three systems establishes a highly integrated molecular communication network, that links systemic imbalances to the development of neurodegeneration, including insulin regulation, fat metabolism, oxidative markers, and immune signaling [7, 28]. Since gut-brain axis communication is efficient, disturbances in the gut microbial balance may be associated with AD and PD.

Understanding the greater influence of the intestinal microbiota on brain functions poses a great challenge to the research related to NDs, such as AD and PD, especially in the search for new therapeutic targets that could effectively prevent, or delay the NDs. It seems a consensus that the current strategies, which are focused only on the CNS and specific targets, such as AChE, and led to all available drugs worldwide, do not seem to reduce symptoms or modify the progress of the diseases [14, 18, 42]. Emerging evidence suggests that modulation of the gut microbiota by the use of probiotics, prebiotics, symbiotics, and antibiotics, or dietary change, could exert effective neurological and psychological changes [18, 86, 87]. For example, the supplementation with probiotics have shown to improve performance in cognitive tests and to increase the concentration of substances capable of delaying the neurodegenerative AD process in experimental models [14, 87–89]. In general, probiotics applications are considered a safe alternative treatment for several diseases and disorders because they can positively alter the host’s gut microbiome and improve the health status [87–90].

According to AD mice models studies, the supplementation with Lactobacillus and Bifidobacterium can restore GABA and glutamate levels in the frontal cortex and hippocampus, besides improving memory and learning functions [37, 38]. Bonfili and co-workers [87] used an AD model based on transgenic 3xTgDA mice, treated with the probiotic formulation SLAB51, which consists of a mixture of lactic acid and Bifidobacterium. As a result, significant inhibition of Aβ aggregation and reduction of oxidative stress were observed in the animal brains with the involvement of the sirtuin1 (SIRT1).

In another approach, this perspective was further enriched by Abdelhamid and co-workers [91], that evaluated the effects of oral supplementation with Bifidobacterium breve MCC1274 on cognitive function and AD-like pathologies in mice. Their results reinforced that the probiotic supplementation was effective in the prevention of memory impairment in mice App^NL−G−F, as well as led to decreased hippocampal Aꞵ levels by increasing levels of α-disintegrin and metalloproteinase 10 (ADAM10). Moreover, administration of the probiotic activated the extracellular signal-regulated kinase (ERK)/hypoxia-inducible factor-α (HIF-1α) signaling pathway responsible for increasing ADAM10 levels. Furthermore, Bifidobacterium breve MCC1274 supplementation led to attenuation of microglia activation, reducing pro-inflammatory cytokine, messenger ribonucleic acid (mRNA) expression levels in the brain, as well as increasing the levels of synaptic proteins in the hippocampus [91].

Based on the above-mentioned corroborative studies, the effect of Bifidobacterium and Lactobacillus probiotics was evidenced to be effective in improving memory, learning functions, inhibition of Aβ aggregation, and reduction of oxidative stress related to AD.

A new approach with AD patients was recently carried out by Leblhuber and co-workers [92]. A group of twenty AD outpatients (9 females, 11 males) aged 76.7 ± 9.6 years, were submitted to routine laboratory tests, as well as a mini-mental state examination with a score of 18.5 ± 7.7. The study was carried out for four weeks with 18 patients and was analyzed before and after supplementation using biomarkers of immune activation, serum neopterin, L-tryptophan breakdown, and markers of intestinal inflammation and microbiota composition in fecal samples. After treatment, a decline in fecal zonulin concentrations and an increase in Faecalibacterium prausnitzii compared to baseline were observed, with a concomitant increase in the concentrations of serum kynurenine. Experimental data showed that the multispecies probiotic supplementation in AD patients influenced the gut bacteria composition, as well as L-tryptophan metabolism in serum. In addition, it was evidenced that the correlation between kynurenine/L-tryptophan and neopterin concentrations points to the activation of macrophages and/or dendritic cells [92].

Some groups worldwide have been studying a therapeutic strategy of faecal microbiota transplantation from healthy individuals to patients with NDs. These studies have aimed to restore the intestinal microbiota to treat these diseases. However, so far, it’s still too early, and there is no evidence of its efficacy in the progression of AD and PD [21, 93, 94].

The benefits of probiotics supplementation can induce immune modulation, changes in the endocrine pathway, and increase neurotrophic factors, mainly by the production of high levels of SCFAs [21, 92–94]. As stated before, SCFAs regulate immune pathway, block pro-inflammatory mediators, while up-regulating anti-inflammatory mediators (Figure 6). Through the endocrine pathway, probiotics activate the HPA axis, stimulating the adrenal release of cortisol, which is the most potent anti-inflammatory hormone. In addition, probiotics stimulate the production of GLP-1 and PYY hormones by L cells in EECs via the endocrine pathway. By way of neuronal factors, probiotics stimulate the secretion of certain neurotransmitters, such as glutamate, or modulate the secretion of neurotransmitters through EC, such as serotonin. These neurotransmitters and neuroactive metabolites, released together, seem to exert neuroprotective effects, preventing neuronal apoptosis [95–97].

The intestinal microbiota plays a key role in the metabolism of essential amino acids as precursors of several neuromodulators. The resulting metabolic products have shown an important impact on the neuromodulation involving microbiota-ENS-CNS crosstalk, influencing brain functions through signaling pathways. However, disruption of the gut microbiota homeostasis by dysbiosis may be a determinant factor in the pathophysiology of NDs, such as AD. Therefore, treatments non-CNS-directed have been shown as promising alternatives aimed at restoring the microbiota by applying probiotics, prebiotics, and symbionts.

Nevertheless, to the best of our knowledge, and based on the sparse data in literature, despite the demonstrated relevance of the microbiota, ENS and its close relationship and influence on CNS physiology, research on natural products or the design of new bioactive molecules targeting the ENS-CNS is still very shy among medicinal chemists. Perhaps, in the coming years, the exploration of this alternative may indeed lead to the discovery of new prototype drug candidates with different mechanisms of action from those currently known, opening new ways for the development of more effective and safer disease-modifying medicines capable to modulate the progress and severity of CNS-related diseases.

The microbiota-targeted interventions, such as probiotics supplementation and fecal microbiota transplantation, might represent a potential therapeutic option for ND in the near future. However, before that, it is fundamental to understand the interactions between host and gut microbiota, and elucidate how these interactions are affecting CNS, to find new effective strategies in the treatment and prevention of NDs.