**2. Gut dysbiosis: a modality to understand neurodegenerative diseases: the disruption of blood-brain barrier (BBB) may explain the gut-oral-brain axis relationship**

The high and uncontrolled levels of pathogenic microorganism colonizing the gut contribute to a condition known as dysbiosis [14]. Since few years the dysbiosis has been associated with a variety of degenerative patterns that tend to subvert the metabolic/neuro/hormonal/immune axis contributing to a variety of disorders that round to different body systems ranging from skeleton, cardiovascular, to neuro system. There are several mechanisms proposed that are able to trigger this state of systemic disorders; one of the possibilities is linked to bacterial metabolites and immune-modulating mediators that contribute to the high permeability of intestinal mucosa allowing local pathogens to get through the mucosal barriers triggering a huge variety of immune responses. A second and though related mechanism is the sabotage of SCFAs' production; the consequences of this mechanism are the abrupt breakdown of energy balance mechanism, a reduction of cell-bacteria signaling pathway, and the worsening of epithelial cell layer integrity due to the decreased production of tight junction proteins which allows the translocation of LPS into the submucosa as well. The significant presence of pro-inflammatory cytokines and interleukins such as TNFα, IFN-γ, IL-1β, IL-2, IL-4, IL-5, and IL-6 is the peculiar trait of a dysbiotic gut (**Figure 1**) [14–16]. A third way of dysbiosis transmission is through the vagus nerve (VN), the main component of parasympathetic nervous system (PSN) which also constitutes an effective bridge of the gut/CNS axis. This hypothesis, today supported by a concrete line of evidences, proposes the existence of a reciprocal interference way between the CNS and gut through the VN. In this view the VN is able to perceive microbiota movement, grade of activity, and therefore degradation; on the other hand, pathogens once out from the gut mucosa barrier are able to communicate and move to the CNS through the VN pathway [14–18].

These essential structural alterations are at the base of neurodegenerative pathologies. Though it is a unique pathological aspect, we may see the presence of a common configuration indeed, which is a shared neurological chronic inflammatory pattern. In all these cases, the chronic neuro-inflammatory condition is characterized by an abnormal hyperactive behavior of neural immune cells, the microglia, known as macrophages of the brain [18, 19]. The chronic inflammatory state that from the gut opens up the pathway of pathogenic microbiota invasion all the way through oral and brain compartment, which is the hallmark of neurodegenerative disorders' dynamic pathogenesis. Patients with Parkinson's disease (PD), Alzheimer's (AD), multiple sclerosis (MS), or amyotrophic lateral sclerosis all present a variety of disturbances in intestinal microbial compared to healthy individuals. Neurodegenerative-affected patients' intestinal and fecal analysis showed a clear clinical picture of microbiota dysbiosis. The test outcomes showed high level of coliform and gram-negative bacteria from *Ralstonia* genus concomitantly with low critical level of anti-inflammatory strains related to *Blautia*, *Coprococcus*, and *Roseburia* genera. Another indicator was also noted; it was the low presence of *Prevotella* generally seen as beneficial bacteria, involved in the metabolism of plant polysaccharides and vitamins strictly associated with the production of neuroactive

*Prebiotics and Probiotics - Potential Benefits in Nutrition and Health*

The oral-gastro-intestinal-sex-skin can be classified as unique large and heterogeneous apparatus populated by a huge variety of microorganisms,

bacteria, virus, fungi, and other single-celled creatures, that compose the totality of human microbiota that contributes together with bone/skeleton system, to maintain the body energy homeostasis. The human body hosts something like 10–100 trillion microbial cells that coexist in a strict fruitful symbiotic relationship that persists as long as the body is kept in a balanced healthy state [1, 2]. The gut plays an important role in regulating metabolic immune activities. The gut's essential task is the absorption of nutrients and the synthesis of important micromolecules obtained from food that cannot be assimilated by the stomach and small intestine [1–3]. Xyloglucans and fructo-oligosaccharides from vegetables and fruits, protein, and lipids; the assimilation of essential vitamins like vitamins B-12, D, and K; and the synthesis of hormones like serotonin from tryptophan amino acid take place right in the gut, thanks to the constant activity of its entire microbiota. The microbiota are able to produce 50–100 mmol·L—1 per day of extremely important short-chain fatty acids (SCFAs), such as acetic, propionic, and butyric acids—and serve as an energy source to the host intestinal

The importance of SCFAs has been well described by several studies during the last decade; the activity of acetic acid, for instance, has been found to be essential against infections, in blood pressure regulation and against sclerotic plaque deposition in arterial walls. The presence of butyric acid is an essential anti-IBS agent due to its immune-modulator properties and anti-inflammatory action, while propionic acid has been found to be important in preventing obesity and

Although bacteria, viruses, and fungi might be very harmful and dangerous, they are indispensable for life as well. This symbiotic coexistence throughout the millennia made a deep crucial biological impact on human species, and it has become essential not only for survival but for evolution as well. Accumulating evidences have clearly demonstrated how part of these specific microorganisms can resume specific immunomodulatory roles and the way they affect either composition function or migration of various immune cell subpopulations from one site to a different location. For instance, oral macrophages may migrate under the influence of specific signal induction of local microbiota from oral either to the lungs or even the brain passing through the blood brain barrier

The outcomes from experiments performed on germ-free (GF) mice confirmed the great role of gut microbiota in the upsurge of immune system deficiencies. GF animals were shown to have compromised Paneth cells and low levels of natural killer (NK) cells, dendritic cells (DCs), and α/β + and γ/δ + T cell populations that play an important role in defense and pathogenesis during inflammation and infection, especially against certain types of malignancies. In addition, GF animals were highly susceptible to frequent infections due to a decline in angiogenin-4 (Ang4), a powerful antimicrobial part of the class of microbicide proteins in Paneth cells

The alteration of the gut microbiota may contribute to open up the invasion of exogenous pathogens that may destabilize the whole intestinal mucosa. The pathogen systematic overgrowth will trigger a cascade of strong inflammatory responses making intestinal mucosa highly susceptible and motile. The chronic inflammation will weaken the endothelial tide junction to the point that the walls become highly relaxed and permeable causing the phenomenon known as "leaky gut" that allows

**1. Introduction**

epithelium and skeleton [1–4].

diabetes 2 [1–4].

(BBB) [5–10].

**120**

[5–10].

#### **Figure 1.**

*The gut microbiota is a very dynamic ecosystem. The entire gut microbiota is composed of different subenvironments with unique features like niches with specific microbes and tissue interactions. The large intestine represents the more populated area and performs the highest variety of biotransformation under the guide of specific gene expression in charge of enzymes necessary for highly specific biotransformation necessary of the SCFAs. The local flora is crucial for the local microbiome homeostasis, and the whole chain of bio-reaction takes place in spaces with a specific mean pH of 6.5–7. The changes in local balance homeostasis and in pH negatively impact on the mucosa shield that repair the outside and inside permeability gradient. Once the stability and the equilibrium between all the components are broken, the gut walls become fragile under the constant attack of local immune cells that start to deteriorate the integrity of both endothelial wall and mucosa shield that induce on medium long term and accumulation of pro-inflammatory endotoxins, bacteria free passage into the system, and low antimicrobial peptide production with a consequent high gastrointestinal motility.*

SCFAs, such as GABA [20–31]. The *Prevotella* spp. is associated with mucin-type O-glycan production which is extremely important in the integrity of gut epithelial barrier; the absence of this mucin type (mucin-2 specifically) tends to compromise the correct homeostatic balance of the local microbiota, increasing intestinal permeability, a clinical feature associated with both microbial dysbiosis and neurodegenerative diseases [32–34].

Disruption of the BBB is a hallmark in individuals with neurodegenerative diseases that contributes to a steady and progressive death of dopaminergic neurons in the CNS. The BBB is a part of a systemic condition that eventually allows the invasion of pathogens and immune agents from a dysbiotic gut into the CNS. However, damages are also due to a series of changes that weaken the integrity of microvasculature and blood vessels; these modifications are mainly due to nutritional impairment as a consequence of gut microbiota disturbances that cause low-level intake of important nutrients. Deficiencies in vitamins like C, K, D, and folates responsible for low hydroxylation for the formation of chondro-sulfate necessary for healthy microvessel endothelial walls, the augmentation of free radicals, and depletion in oxygen contents and nitrogen, matrix metalloproteinases (MMPs), cyclooxygenases (COXs), and hypoxia-inducible factor-1*α* (HIF-1*α*) are all linked with BBB disruption as neuro-inflammatory responses tend to increase and evolve [35].

Thus the scenario existing in the great majority of neurodegenerative pathologies presents a combination of higher permeability of the intestinal barriers and the BBB, inducing a greater access between gut microbiota and the CNS compartment. Experiments conducted with the use of high dose of minocycline antibiotic are well known to have an impact on specific gut and oral invasive bacteria; the post-administration results showed significant protection on LPS-induced PD in mice data confirmed by a significant amelioration of neuro-inflammatory

**123**

*Probiotics in Health and Immunity: A First Step toward Understanding the Importance…*

**2.1 Crosslink between microbiota dysbiosis and osteo-decay**

markers such as TNF-α expression, IL-1α expression, and microglia activation and a substantial amelioration of astrocyte loss with an increased number of surviving dopaminergic neurons compared to control LPS only-injected mice [36, 37]. It follows that a correct use of antibiotics generally known to alter gut microbial diversity may disclose a positive immune protective side effect on inflammatory mechanism existent in PD patients [36–38]. Several other outcomes have shown the beneficial effects of oral antibiotic, minocycline, and tetracycline, in CNS degenerative condition like the experimental autoimmune encephalopathy (EAE) disease and MS. It was found a significant increase of IL-10 expression concomitant with a favorable increase of a subset of invariant NK T cells and in patients with MS, and there was a substantial reduction of CNS deteriorations

Aging brings generally substantial physiological alterations—hormonal, humoral, and physical—that involves the entire homeostatic organization of the human body. Of course the GI tract and its microbiota as well undergo through profound changes that under the variations of dietary influences bring to a general decline of cognitive and immune activities. With aging, the gut microbiota lost bacterial balanced diversity with an increase of "pathogenic Proteobacteria" vs. a continuing, steady, and progressive lower level of "friend bacteria" such as Firmicutes, *Faecalibacterium prausnitzii*, and Actinobacteria

Another important feature of gut microbiota is the ability to modulate genes that can be seen either on regulation or variation; this is one of the main factors that may explain the influences that gut microbiota eventually exert on bone development and on bone-related diseases such as osteoporosis, osteopenia, or the different types of arthritis. The delicate homeostatic balance that regulates bone formation and resorption is partly played by the activity of intestinal microorganisms. This activity is basically performed through the interaction with endocrine/nervous system axis; thereby the hormonal activity such as serotonin, cortisol, and sex hormones and several growth factors affect bone mass in mice and humans. In addition, bone marrow stem cells, circulatory stem cells, and stem cells from bone marrow niche are highly sensitive to gut microenvironment condition which eventually affects the differentiation process toward either osteoblasts or osteoclasts. In this case it has been proven that the metabolic pathway compartment which involves the ribosome activity, glycolysis, oxidative phosphorylation, carbon metabolism, and mitochondria ATP are fully responsible of regulating MSCs' functionality, growth, prolifera-

This important connection has also been confirmed by Xiao and colleagues; they were able to highlight through the single-cell RNA-sequencing analysis the existing connection between the gut microbiota, BM-MSCs, and bone metabolic functionality. The presence of several factors such as the HIF-1 together with the expression of infection/inflammatory signaling pathways could be the scattering patterns that influence MSC mobility and immunomodulation. These outcomes showed how HIF-1 signaling is involved in BM-MSC immunomodulation. In fact, the HIF-1 is notoriously known as a triggering factor of inflammatory transcription factor NFκB and an active regulator of specific cytokine and chemokine recruitment in inflammation and infection situations. The chronic presence of an inflammatory response under the triggering activity of pro-inflammatory cytokines such as the TNF superfamily IL-1β, IL-2, IL-4, IL-6, and IL-17 can deeply disturb the osteoclast and osteoblast balance, typically resulting in a net hyper-osteoclast activity and

*DOI: http://dx.doi.org/10.5772/intechopen.88601*

(mainly bifidobacteria) [42–45].

tion, and differentiation [45, 46].

[38–42].

*Probiotics in Health and Immunity: A First Step toward Understanding the Importance… DOI: http://dx.doi.org/10.5772/intechopen.88601*

markers such as TNF-α expression, IL-1α expression, and microglia activation and a substantial amelioration of astrocyte loss with an increased number of surviving dopaminergic neurons compared to control LPS only-injected mice [36, 37]. It follows that a correct use of antibiotics generally known to alter gut microbial diversity may disclose a positive immune protective side effect on inflammatory mechanism existent in PD patients [36–38]. Several other outcomes have shown the beneficial effects of oral antibiotic, minocycline, and tetracycline, in CNS degenerative condition like the experimental autoimmune encephalopathy (EAE) disease and MS. It was found a significant increase of IL-10 expression concomitant with a favorable increase of a subset of invariant NK T cells and in patients with MS, and there was a substantial reduction of CNS deteriorations [38–42].

#### **2.1 Crosslink between microbiota dysbiosis and osteo-decay**

Aging brings generally substantial physiological alterations—hormonal, humoral, and physical—that involves the entire homeostatic organization of the human body. Of course the GI tract and its microbiota as well undergo through profound changes that under the variations of dietary influences bring to a general decline of cognitive and immune activities. With aging, the gut microbiota lost bacterial balanced diversity with an increase of "pathogenic Proteobacteria" vs. a continuing, steady, and progressive lower level of "friend bacteria" such as Firmicutes, *Faecalibacterium prausnitzii*, and Actinobacteria (mainly bifidobacteria) [42–45].

Another important feature of gut microbiota is the ability to modulate genes that can be seen either on regulation or variation; this is one of the main factors that may explain the influences that gut microbiota eventually exert on bone development and on bone-related diseases such as osteoporosis, osteopenia, or the different types of arthritis. The delicate homeostatic balance that regulates bone formation and resorption is partly played by the activity of intestinal microorganisms. This activity is basically performed through the interaction with endocrine/nervous system axis; thereby the hormonal activity such as serotonin, cortisol, and sex hormones and several growth factors affect bone mass in mice and humans. In addition, bone marrow stem cells, circulatory stem cells, and stem cells from bone marrow niche are highly sensitive to gut microenvironment condition which eventually affects the differentiation process toward either osteoblasts or osteoclasts. In this case it has been proven that the metabolic pathway compartment which involves the ribosome activity, glycolysis, oxidative phosphorylation, carbon metabolism, and mitochondria ATP are fully responsible of regulating MSCs' functionality, growth, proliferation, and differentiation [45, 46].

This important connection has also been confirmed by Xiao and colleagues; they were able to highlight through the single-cell RNA-sequencing analysis the existing connection between the gut microbiota, BM-MSCs, and bone metabolic functionality. The presence of several factors such as the HIF-1 together with the expression of infection/inflammatory signaling pathways could be the scattering patterns that influence MSC mobility and immunomodulation. These outcomes showed how HIF-1 signaling is involved in BM-MSC immunomodulation. In fact, the HIF-1 is notoriously known as a triggering factor of inflammatory transcription factor NFκB and an active regulator of specific cytokine and chemokine recruitment in inflammation and infection situations. The chronic presence of an inflammatory response under the triggering activity of pro-inflammatory cytokines such as the TNF superfamily IL-1β, IL-2, IL-4, IL-6, and IL-17 can deeply disturb the osteoclast and osteoblast balance, typically resulting in a net hyper-osteoclast activity and

*Prebiotics and Probiotics - Potential Benefits in Nutrition and Health*

SCFAs, such as GABA [20–31]. The *Prevotella* spp. is associated with mucin-type O-glycan production which is extremely important in the integrity of gut epithelial barrier; the absence of this mucin type (mucin-2 specifically) tends to compromise the correct homeostatic balance of the local microbiota, increasing intestinal permeability, a clinical feature associated with both microbial dysbiosis and neuro-

*The gut microbiota is a very dynamic ecosystem. The entire gut microbiota is composed of different subenvironments with unique features like niches with specific microbes and tissue interactions. The large intestine represents the more populated area and performs the highest variety of biotransformation under the guide of specific gene expression in charge of enzymes necessary for highly specific biotransformation necessary of the SCFAs. The local flora is crucial for the local microbiome homeostasis, and the whole chain of bio-reaction takes place in spaces with a specific mean pH of 6.5–7. The changes in local balance homeostasis and in pH negatively impact on the mucosa shield that repair the outside and inside permeability gradient. Once the stability and the equilibrium between all the components are broken, the gut walls become fragile under the constant attack of local immune cells that start to deteriorate the integrity of both endothelial wall and mucosa shield that induce on medium long term and accumulation of pro-inflammatory endotoxins, bacteria free passage into the system, and low antimicrobial peptide production with a consequent high gastrointestinal* 

Disruption of the BBB is a hallmark in individuals with neurodegenerative diseases that contributes to a steady and progressive death of dopaminergic neurons in the CNS. The BBB is a part of a systemic condition that eventually allows the invasion of pathogens and immune agents from a dysbiotic gut into the CNS. However, damages are also due to a series of changes that weaken the integrity of microvasculature and blood vessels; these modifications are mainly due to nutritional impairment as a consequence of gut microbiota disturbances that cause low-level intake of important nutrients. Deficiencies in vitamins like C, K, D, and folates responsible for low hydroxylation for the formation of chondro-sulfate necessary for healthy microvessel endothelial walls, the augmentation of free radicals, and depletion in oxygen contents and nitrogen, matrix metalloproteinases (MMPs), cyclooxygenases (COXs), and hypoxia-inducible factor-1*α* (HIF-1*α*) are all linked with BBB disrup-

Thus the scenario existing in the great majority of neurodegenerative pathologies presents a combination of higher permeability of the intestinal barriers and the BBB, inducing a greater access between gut microbiota and the CNS compartment. Experiments conducted with the use of high dose of minocycline antibiotic are well known to have an impact on specific gut and oral invasive bacteria; the post-administration results showed significant protection on LPS-induced PD in mice data confirmed by a significant amelioration of neuro-inflammatory

tion as neuro-inflammatory responses tend to increase and evolve [35].

**122**

degenerative diseases [32–34].

**Figure 1.**

*motility.*

thus bone loss. While there is an evident mechanical effect on the bone where these cytokines stimulate osteoclast differentiation with a consequent upregulation of RANKL expression in progenitor osteoblasts together with a higher RANKL expression, a concomitant nonmechanical effect under the downregulation of specific deficit due to a metabolic inability of vitamin K and vitamin D synthesis in the intestinal lumen should be mentioned (**Figure 2**) [47–54].
