**2.2 Probiotic efficacy in therapy and clinically use**

The potential impact of the therapeutic effect of probiotic on a dysbiotic situation could not be seen without taking in consideration a change of lifestyle. Diet habits, stress, poor healthy conditions, and lack of exercise can significantly impact the gut microbiota stability [55–57]. There are many evidences that nutritional habits based on "Western diet" composed of huge additive and animal fats, processed glucose and excessive quantities of hypercaloric nutritional facts, low contents of fresh food, and low level of vitamins and minerals, essential for our body, all negatively affect the correct balance of gut microbiota, which eventually lead to the insurgence of metabolic dysfunctions. It is also well known that these bad behaviors are associated with an increased risk of developing several chronic diseases that may attack oral microbiota and vaginal microbiota that recent study findings have indicated as an independent risk factor for severe neurodegenerative conditions [9, 58–60].

#### **Figure 2.**

*The gut dysbiosis is one of the main contributors in osteo-degenerative conditions. The dysbiotic microenvironment increase the viability of systemic pro-inflammatory cytokines and interleukins generating three main anti-regenerative patterns, the increase of pH acidic level, decrease of the differentiating pathway from MSCs and SCs toward osteoblasts, and hyper-expression of osteoclast activity. The dysbiosis generates a defective absorption mechanism of important nutrients for bone homeostasis like vitamins, among them K and D, and hormones such as serotonin, testosterone, and estrogen. The prerogative of this condition is a cascade of events that will involve systemically and progressively the whole vital activity of cells, tissues, and systems of the organism.*

**125**

diet [67–70].

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

By definition, probiotic refers to large and diverse types of microbes both commensal that normally reside in the gut and exogenous that may migrate through the intestine following food or diet and supplement consumption. Probiotics might be composed of different microbial strains, the most common include species of *Lactobacillus*, *Bifidobacterium*, *Streptococcus*, and yeast *Saccharomyces* species [61]. As previously mentioned, currently there is a great interest on the use of specific probiotics as therapeutic tool to be associated as clinical approach toward immune system pathologies that may include autoimmune conditions that may attack nerves, bone, and bowel. Given the prevalence of probiotic use, the effects of

Significant positive clinical outcomes have been obtained in numerous studies conducted on CNS inflammatory condition that have therapeutically used different types of probiotic strains. The results showed a reduction of CNS inflammatory level and progression; these outcomes were eventually explained by the capacity of certain strains (*Lactobacillus* species including bacteria like the *Pediococcus acidilactici*, *Bifidobacterium bifidum*, *Bifidobacterium animalis*, *Streptococcus thermophiles*, and *Bifidobacterium infantis* 35,624) to modulate the expression of T-regs, B-regs,

In addition, an experiment with genetically engineered microbial strains such as *Lactococcus lactis* capable of expressing heat shock protein 65 obtained from another strain like the *Mycobacterium leprae* was seen highly efficient in reducing EAE symptoms and disease progression [63, 64]. The beneficial outcomes in this study were associated with a decrease in IL-17 pro-inflammatory interleukin with a parallel growth of IL-10 evaluated in the mesenteric lymph node and spleen cell cultures. Furthermore, mice showed a significant higher level of endogenous CD4 + Foxp3+ regulatory T-regs and CD4 + LAP+ (latency-associated peptide). These results might be also sustained by a higher production of SCFAs that, as stated by Opazo and colleagues, were seen to induce either a decrease in RORγt, a biomarker of IL-17, or IL-23 with a higher production of IL-10 and IL-12 with a similar beneficial

Therefore beneficial homeostatic-metabolic effect of specific probiotic strains can be seen on different systems such as the cardiovascular, immune, and CNS. For instance, few strains conserve a natural ability of inhibiting the insurgence of hypercholesteremia in both mice and human. In fact the use of *Lactobacillaceae* strains such as *L*. *acidophilus*, *Bifidobacterium bifidum*, and *L. plantarum* Lp9 strain showed a significant role in lowering the cholesterol level under in vivo conditions thanks to their ability of secreting functional bile salt hydrolase (BSH), an enzyme crucial in the protection against the insurgence of bad cholesterol in the host. Genomic analysis has indicated that *Lactobacillaceae* especially *L. plantarum* contain the highest presence of *BSH* genes. Intriguingly, milk fermented by *L. plantarum* NTU 102 revealed to have a high significant efficacy on total cholesterol and LDL cholesterol levels though in presence of individuals undergone a cholesterol-rich

Major depressive disorders have been seen even today as a consequence of decreased serotonin level; therefore, the therapeutic strategy has mainly concentrated on producing medication, which focused on serotonin only. The major treatments are based on a class of drugs known as selective serotonin reuptake inhibitors (SSRIs). These SSRIs stimulate the serotonin uptake between neurons, and, though it has been seen some improvements, the medium long-term use has produced serious side effects on gut homeostatic balance with severe metabolic disturbances. Nowadays, as above mentioned, following the fact that current researches have established associations between gut microbes, digestive function, and mental well-being especially under the fact that serotonin is synthesized in the gut by the

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

probiotics on bone health is of significant interest.

and IL-10 production such as [62–64].

effect on both EAE and IBS [61–66].

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

By definition, probiotic refers to large and diverse types of microbes both commensal that normally reside in the gut and exogenous that may migrate through the intestine following food or diet and supplement consumption. Probiotics might be composed of different microbial strains, the most common include species of *Lactobacillus*, *Bifidobacterium*, *Streptococcus*, and yeast *Saccharomyces* species [61].

As previously mentioned, currently there is a great interest on the use of specific probiotics as therapeutic tool to be associated as clinical approach toward immune system pathologies that may include autoimmune conditions that may attack nerves, bone, and bowel. Given the prevalence of probiotic use, the effects of probiotics on bone health is of significant interest.

Significant positive clinical outcomes have been obtained in numerous studies conducted on CNS inflammatory condition that have therapeutically used different types of probiotic strains. The results showed a reduction of CNS inflammatory level and progression; these outcomes were eventually explained by the capacity of certain strains (*Lactobacillus* species including bacteria like the *Pediococcus acidilactici*, *Bifidobacterium bifidum*, *Bifidobacterium animalis*, *Streptococcus thermophiles*, and *Bifidobacterium infantis* 35,624) to modulate the expression of T-regs, B-regs, and IL-10 production such as [62–64].

In addition, an experiment with genetically engineered microbial strains such as *Lactococcus lactis* capable of expressing heat shock protein 65 obtained from another strain like the *Mycobacterium leprae* was seen highly efficient in reducing EAE symptoms and disease progression [63, 64]. The beneficial outcomes in this study were associated with a decrease in IL-17 pro-inflammatory interleukin with a parallel growth of IL-10 evaluated in the mesenteric lymph node and spleen cell cultures. Furthermore, mice showed a significant higher level of endogenous CD4 + Foxp3+ regulatory T-regs and CD4 + LAP+ (latency-associated peptide). These results might be also sustained by a higher production of SCFAs that, as stated by Opazo and colleagues, were seen to induce either a decrease in RORγt, a biomarker of IL-17, or IL-23 with a higher production of IL-10 and IL-12 with a similar beneficial effect on both EAE and IBS [61–66].

Therefore beneficial homeostatic-metabolic effect of specific probiotic strains can be seen on different systems such as the cardiovascular, immune, and CNS. For instance, few strains conserve a natural ability of inhibiting the insurgence of hypercholesteremia in both mice and human. In fact the use of *Lactobacillaceae* strains such as *L*. *acidophilus*, *Bifidobacterium bifidum*, and *L. plantarum* Lp9 strain showed a significant role in lowering the cholesterol level under in vivo conditions thanks to their ability of secreting functional bile salt hydrolase (BSH), an enzyme crucial in the protection against the insurgence of bad cholesterol in the host. Genomic analysis has indicated that *Lactobacillaceae* especially *L. plantarum* contain the highest presence of *BSH* genes. Intriguingly, milk fermented by *L. plantarum* NTU 102 revealed to have a high significant efficacy on total cholesterol and LDL cholesterol levels though in presence of individuals undergone a cholesterol-rich diet [67–70].

Major depressive disorders have been seen even today as a consequence of decreased serotonin level; therefore, the therapeutic strategy has mainly concentrated on producing medication, which focused on serotonin only. The major treatments are based on a class of drugs known as selective serotonin reuptake inhibitors (SSRIs). These SSRIs stimulate the serotonin uptake between neurons, and, though it has been seen some improvements, the medium long-term use has produced serious side effects on gut homeostatic balance with severe metabolic disturbances. Nowadays, as above mentioned, following the fact that current researches have established associations between gut microbes, digestive function, and mental well-being especially under the fact that serotonin is synthesized in the gut by the

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

intestinal lumen should be mentioned (**Figure 2**) [47–54].

**2.2 Probiotic efficacy in therapy and clinically use**

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

The potential impact of the therapeutic effect of probiotic on a dysbiotic situation could not be seen without taking in consideration a change of lifestyle. Diet habits, stress, poor healthy conditions, and lack of exercise can significantly impact the gut microbiota stability [55–57]. There are many evidences that nutritional habits based on "Western diet" composed of huge additive and animal fats, processed glucose and excessive quantities of hypercaloric nutritional facts, low contents of fresh food, and low level of vitamins and minerals, essential for our body, all negatively affect the correct balance of gut microbiota, which eventually lead to the insurgence of metabolic dysfunctions. It is also well known that these bad behaviors are associated with an increased risk of developing several chronic diseases that may attack oral microbiota and vaginal microbiota that recent study findings have indicated as an independent risk factor for severe neurodegenerative conditions [9, 58–60].

*The gut dysbiosis is one of the main contributors in osteo-degenerative conditions. The dysbiotic* 

*microenvironment increase the viability of systemic pro-inflammatory cytokines and interleukins generating three main anti-regenerative patterns, the increase of pH acidic level, decrease of the differentiating pathway from MSCs and SCs toward osteoblasts, and hyper-expression of osteoclast activity. The dysbiosis generates a defective absorption mechanism of important nutrients for bone homeostasis like vitamins, among them K and D, and hormones such as serotonin, testosterone, and estrogen. The prerogative of this condition is a cascade of events that will involve systemically and progressively the whole vital activity of cells, tissues, and systems of the* 

**124**

**Figure 2.**

*organism.*

combined activity of different microbiota strain such as *Lactobacillus*. The connection was firstly seen in IBS patient who also manifests clear clinical signs of depressive disorders; the analysis of gut microbiota from these patients showed a very low level of *Lactobacillus* strains versus healthy subjects that might be explained by the increased expression of serotonin transporter (SERT) [71–74].

Overall the data on this specific topic all have evidenced the positive effects of probiotics in CNS health. These effects are explained by the ability of probiotics to directly interact with fundamental metabolic agents either within the gut or outside that eventually explain the Gut-CNS axis. The use of probiotics and in specific the *Lactobacillus* strains showed that mice fed with these probiotics revealed a better capacity of reabsorbing tryptophan amino acid the precursor or serotonin, the re-established normal level of those hormones strictly related to stress deviances and depression such as the adrenocorticotropic hormone (ACTH), corticosterone, adrenaline, noradrenaline and the re-increase expression of brain-derived neurotrophic factor (BDNF) a marker that indicate a neuronal health and memory functionality [74–79].

To conclude, the higher permeability of gut or "leaky gut" intensifies the fee passage of endotoxins such as the LPS and other forms of molecules and pathogens to leak into the bloodstream and thus in the entire system. The upsurge of these endotoxins, pathogens, and waste molecules eventually trigger the activation of a cascade of immune responses through switching on the Toll-like receptor 4 (TLR4) that mediates the recruitment of T and B lymphocytes together with a huge number of pro-inflammatory cytokines, interleukins, and IgA (**Figure 3**) [80, 81]. The current position therefore considers the use of probiotics as a therapeutic tool that

#### **Figure 3.**

*There is a strict connection between CNS and gut system. The connection takes place through the afferent and efferent pathways of vagus nerve that physically connects both CNS and gut. Both CNS and gut may undergo leaky phenomena; in both cases, the barriers of either CNS or gut become extremely permeable under the chronic attack of both pathogens and immune agents overexpressed on the site. This event may eventually explain degenerative condition of both systems including IBS, ulcerative colitis, depression, PD, AD, and MS.*

**127**

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

integrity of gut microbiota, decreasing systemic inflammation.

*2.2.1 Probiotics in the treatment of skin and oral mucosa dysbiosis*

may exert beneficial effects on the CNS by improving the stability homeostasis and

The skin represents another system where an immense variegation of microbiota environment can be found. Skin diseases caused by disturbances at the level of local microbiota that also showed to have strict connection with gut dysbiosis are quite exhaustive in explaining these malevolence patterns. Psoriatic lesions show a very specific histopathological conformation which present highly

showed to have a genetic family trait prevalent in twins; researchers have spotted 36 genetic loci associated with PS susceptibility 1 (*PSORS1*) locus on chromosome 6p21.3 [82, 83]. Data confirmed that most of them are directly involved in the overexpression of those genes that regulate part of pro-inflammatory innate immune responses such as the NFkB activation and interleukin (IL)-23 signaling pathway. Intriguingly a 2018 study performed on mice proved the use of two specific probiotic *Lactobacillus* strains, the *L*. *salivarius* L305 and *L. rhamnosus* L307, in alleviating the clinical symptoms of psoriasis through inhibiting the aggressive effect of pro-inflammatory cytokines and interleukins like TNF-α, IL-1β, IL-6, IL-17, and IL-22 and promoting the anti-inflammatory/modulatory activity of

In oral dysbiosis, we are facing a similar inflammatory arrangement; oral diseases manifest with high-grade inflammatory patterns that spread from the gums to the adjacent structures gradually destroying the supporting tissues of the teeth, both ligaments and alveolar bones, causing early loss. Similarly to psoriasis in periodontitis, we may encounter multifactorial condition due to a combination of genetic variants triggered by the initial subgingival dysbiosis and then become

The gram-negative bacteria such as *Porphyromonas gingivalis*, *Tannerella forsythia*, and *Aggregatibacter actinomycetemcomitans* are be able to migrate into the system either down to the heart, lungs, and sex apparatus or are capable to enter into the brain via the bloodstream or via infected periodontal sites. Histopathological analysis has confirmed these bacteria almost everywhere in atheromatous plaques, the vagina, amniotic fluid, rheumatoid arthritis bioptic samples, and brain plaques typical of neurodegenerative diseases AD, PD, and

As can be seen from published studies, different strains of probiotics have been used for the treatment of periodontitis. *Lactobacillus* strains are the commonest used in the majority of high-grade inflammatory disease. The use of *L. salivarius* in combination with *L. rhamnosus* and *B. subtilis* together with *L. reuteri* and *L. brevis* probiotics has shown the most promising results. High-positive results were also obtained by Laleman and colleagues in using *Streptococcus oralis* KJ3, *Streptococcus* 

Therefore an associated altered gut microbiota may lead to chronic gut dysbiosis

and propagation of systemic injuries that involve cells, tissues, system, and the

In summary, the present chapter reveals that gut microbiota and a correct use of probiotic may play important pleiotropic functions on several levels and

T cells and dendritic cells (DCs). Psoriasis

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

infiltrated immune cells like the CD3<sup>+</sup>

highly susceptible to wider disease progression [85].

*uberis* KJ2, and *Streptococcus ratti* JH145 [91, 92].

intrinsic dysfunction of the regenerative mechanism.

IL-4 and IL-10 [84].

MS [86–90].

**3. Conclusion**

may exert beneficial effects on the CNS by improving the stability homeostasis and integrity of gut microbiota, decreasing systemic inflammation.
