**5.2 Interaction of prebiotics in gut microbiota**

The non-digestible carbohydrates or prebiotics are selectively fermented by the microbiota that produces important metabolites for the health of the host, the SCFAs acetate, propionate, and butyrate mainly. Likewise, prebiotics have a direct impact on the gut-associated lymphoid tissue (GALT) with immunomodulatory functions [98]. The symbiotic association between the host and the microbiota is fundamental in its physiology. The increase of the beneficial populations in the intestinal lumen affects the establishment of opportunistic pathogens, contributing to the strengthening of the GALT.

### **5.3 Potential effects on microbiota-GALT-brain axis**

The stimulation of probiotic bacteria by prebiotics contributes to the increase of the production of beneficial metabolites for the host, such as the SCFAs. However, prebiotics not only have an impact on the intestinal microbiota. Oligofructose, an inulin type fructan, can bind to cellular receptors of pathogenic bacteria and block adhesion to the surface of enterocytes, helping to prevent colonization. In the same way, β (2→1)-fructans are ligands of TLR2, TLR4, TLR5, TLR7, TLR8, and NOD2. Moreover, levan (2→6)-fructans appears to be a recognized of TLR4 to reduce IgE serum levels and Th2 responses [98]. Bacterial metabolites travel through the vagus nerve to reach specific brain regions such as cerebellum and hippocampus and modify gene expression [99]. It has been described that alterations in intestinal microbiota due to exposure to chronic stress are reversed with the administration of prebiotics and/or probiotics [100].

According to the classification of microbiota obtained by statistical analysis of sequence data, an alpha diversity has been identified, which describes the diversity of bacteria within a single individual; while beta diversity describes the diversity of specimens between different individuals. It has been shown that different types of prebiotics have an effect on the microbiota-GALT-brain axis in mice and human models. Prebiotics treatments (isolated from acorn and sago) induced increased β-diversity in heart failure patient's fecal microbiome, while no significant change in β-diversity was seen in healthy fecal microbiome. Alpha diversity was significantly higher in both healthy and diseased fecal microbiome, which was accompanied with an increase of the beneficial bacteria and SCFAs. Moreover, prebiotics treatment ameliorated HFD-induced glucose intolerance and insulin resistance in diabetic mice. Feeding both prebiotics treatments and inulin increased SCFAs levels in the mouse gut, and decreased the gut hyperpermeability and mucosal inflammatory markers in HFD-fed mice. The expression of pro-opiomelanocortin was also modulated by prebiotics administration, suggesting an important role in the hypothalamic energy signaling in the mice [101]. In diabetic db/db mice, the administration of oligofructose increases the expression of tight junction proteins occludin and ZO-1, which improves the integrity of the BBB in the hypothalamus and normalizes

**205**

*Prebiotics and the Modulation on the Microbiota-GALT-Brain Axis*

the expression of mRNA of IL-6 in the hippocampus; however, it does not improve

Moreover, the administration of prebiotic chitosan oligosaccharides (COSs) in Male Sprague-Dawley rats increases cognitive function and reduces levels of TNF-α and IL-1β, both pro-inflammatory cytokines [103]. In a mouse model of amyotrophic lateral sclerosis, the oral administration of GOS reduced the motor neuron death and muscular atrophy and increased the levels of serum folate, vitamin B12, and homocysteine [104]. In the same way, in a mouse model with lipopolysaccharide-induced anxiety, the administration of bimuno-galacto-oligosaccharides (B-GOSs) reduced the pro-inflammatory cytokine IL-1β and expression of cortical 5-HT2A receptors [78]. In a mouse model of vascular dementia, the β-glucan from barley and arabinoxylan from the yeast *Triticum aestivum* demonstrated a protective

Interestingly, our research group previously demonstrated that the administration of oligofructose and *Agave* fructans decreased TBARS levels and carbonyls in learning and memory regions of the brain of overweight mice [106]. Also, in highfat diet-induced obese mice, prebiotics not only reduces the oxidative damage in the

On the other hand, the administration of synbiotics (probiotics and prebiotics in combination) shows interesting effects. In infants with cow's milk allergy, the treatment with based formula of amino-acid and symbiotics (a combination of fructo-oligosaccharides and *Bifdobacterium breve* M-16V) increased *Bifidobacterium* spp. and *Veillonella sp* bacteria substantially. Additionally, the lactate levels were increased, but the valerate and SCFAs levels were decreased [108]. Prolonged consumption of ADR-159 diet (fermentate generated from *Lactobacillus fermentum* and *Lactobacillus delbrueckii*) had no effect on anthropometrics or general health, but mice fed with ADR-159 presented increased sociability and lower baseline corticosterone levels (stress hormone). The diet also induced significant changes in

In patients with major depressive disorder (MDD), probiotics treatment

8 weeks improved depression symptoms, but the serum inflammatory cytokines marker (TNF-α, IL-1β, IL-6, and IL-10) levels were not improved, and the urinary cortisol levels decreased by 20% of baseline. However, the prebiotics treatment (galactooligosaccharides, GOS) had no effect on depression symptoms nor inflammatory marker levels [110]. In a like manner, oral GOS administration reduced the human stress hormone cortisol and increased attentional vigilance to positive

The effect of the probiotics on the intestinal microbiota is quite important not only for the functions on intestine, but also for the development and function of immune system, metabolism, and central nervous system. Moreover, these systems are closely related, so that any alteration will impact their functionality. Therefore, the balance on microbiota-gut-central nervous system axis is very important to

Intestinal dysbiosis leads to alterations in development and function of central nervous system, which is significantly improved upon intestinal colonization with normal microbiota and probiotics treatment. To date, the interaction of microbiotaintestine-brain axis is not completely clear. For this reason, it is interesting to redirect the investigation of CNS diseases whose pathological mechanism is unknown.

CFU of freeze-dried *Helveticus* R0052 and *B. longum* R0175 bacteria) for

same regions but also increases the levels of BDNF and GDNF [107].

*DOI: http://dx.doi.org/10.5772/intechopen.89690*

effect [105].

the microbiota [109].

versus negative stimuli [111].

maintain the adequate functions of these systems.

**6. Conclusions**

(≥10 × 109

alterations in behavior or in neurogenesis [102].

#### *Prebiotics and the Modulation on the Microbiota-GALT-Brain Axis DOI: http://dx.doi.org/10.5772/intechopen.89690*

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

**5.2 Interaction of prebiotics in gut microbiota**

**5.3 Potential effects on microbiota-GALT-brain axis**

to the strengthening of the GALT.

prebiotics and/or probiotics [100].

Different types of oligosaccharides considered as prebiotics have been reported, among them are: fructooligosaccharides (FOS), oligofructose (OF), the inulin type fructans (ITFs), galactooligosaccharides (GOS), transgalactooligosaccharides (TOS), and lactulose. However, there are others less known such as isomaltooligosaccharides (IMOS). Xylooligosaccharides (XOS) and mananooligosaccharides (MOS) also have a probiotic potential [90, 95]. It is well known that sucrose and starch are the main carbohydrates found in higher plants, followed by glucomannans and fructans are the main reserve sources in the vegetable kingdom

The non-digestible carbohydrates or prebiotics are selectively fermented by the microbiota that produces important metabolites for the health of the host, the SCFAs acetate, propionate, and butyrate mainly. Likewise, prebiotics have a direct impact on the gut-associated lymphoid tissue (GALT) with immunomodulatory functions [98]. The symbiotic association between the host and the microbiota is fundamental in its physiology. The increase of the beneficial populations in the intestinal lumen affects the establishment of opportunistic pathogens, contributing

The stimulation of probiotic bacteria by prebiotics contributes to the increase of the production of beneficial metabolites for the host, such as the SCFAs. However, prebiotics not only have an impact on the intestinal microbiota. Oligofructose, an inulin type fructan, can bind to cellular receptors of pathogenic bacteria and block adhesion to the surface of enterocytes, helping to prevent colonization. In the same way, β (2→1)-fructans are ligands of TLR2, TLR4, TLR5, TLR7, TLR8, and NOD2. Moreover, levan (2→6)-fructans appears to be a recognized of TLR4 to reduce IgE serum levels and Th2 responses [98]. Bacterial metabolites travel through the vagus nerve to reach specific brain regions such as cerebellum and hippocampus and modify gene expression [99]. It has been described that alterations in intestinal microbiota due to exposure to chronic stress are reversed with the administration of

According to the classification of microbiota obtained by statistical analysis of sequence data, an alpha diversity has been identified, which describes the diversity of bacteria within a single individual; while beta diversity describes the diversity of specimens between different individuals. It has been shown that different types of prebiotics have an effect on the microbiota-GALT-brain axis in mice and human models. Prebiotics treatments (isolated from acorn and sago) induced increased β-diversity in heart failure patient's fecal microbiome, while no significant change in β-diversity was seen in healthy fecal microbiome. Alpha diversity was significantly higher in both healthy and diseased fecal microbiome, which was accompanied with an increase of the beneficial bacteria and SCFAs. Moreover, prebiotics treatment ameliorated HFD-induced glucose intolerance and insulin resistance in diabetic mice. Feeding both prebiotics treatments and inulin increased SCFAs levels in the mouse gut, and decreased the gut hyperpermeability and mucosal inflammatory markers in HFD-fed mice. The expression of pro-opiomelanocortin was also modulated by prebiotics administration, suggesting an important role in the hypothalamic energy signaling in the mice [101]. In diabetic db/db mice, the administration of oligofructose increases the expression of tight junction proteins occludin and ZO-1, which improves the integrity of the BBB in the hypothalamus and normalizes

**204**

[96, 97].

the expression of mRNA of IL-6 in the hippocampus; however, it does not improve alterations in behavior or in neurogenesis [102].

Moreover, the administration of prebiotic chitosan oligosaccharides (COSs) in Male Sprague-Dawley rats increases cognitive function and reduces levels of TNF-α and IL-1β, both pro-inflammatory cytokines [103]. In a mouse model of amyotrophic lateral sclerosis, the oral administration of GOS reduced the motor neuron death and muscular atrophy and increased the levels of serum folate, vitamin B12, and homocysteine [104]. In the same way, in a mouse model with lipopolysaccharide-induced anxiety, the administration of bimuno-galacto-oligosaccharides (B-GOSs) reduced the pro-inflammatory cytokine IL-1β and expression of cortical 5-HT2A receptors [78]. In a mouse model of vascular dementia, the β-glucan from barley and arabinoxylan from the yeast *Triticum aestivum* demonstrated a protective effect [105].

Interestingly, our research group previously demonstrated that the administration of oligofructose and *Agave* fructans decreased TBARS levels and carbonyls in learning and memory regions of the brain of overweight mice [106]. Also, in highfat diet-induced obese mice, prebiotics not only reduces the oxidative damage in the same regions but also increases the levels of BDNF and GDNF [107].

On the other hand, the administration of synbiotics (probiotics and prebiotics in combination) shows interesting effects. In infants with cow's milk allergy, the treatment with based formula of amino-acid and symbiotics (a combination of fructo-oligosaccharides and *Bifdobacterium breve* M-16V) increased *Bifidobacterium* spp. and *Veillonella sp* bacteria substantially. Additionally, the lactate levels were increased, but the valerate and SCFAs levels were decreased [108]. Prolonged consumption of ADR-159 diet (fermentate generated from *Lactobacillus fermentum* and *Lactobacillus delbrueckii*) had no effect on anthropometrics or general health, but mice fed with ADR-159 presented increased sociability and lower baseline corticosterone levels (stress hormone). The diet also induced significant changes in the microbiota [109].

In patients with major depressive disorder (MDD), probiotics treatment (≥10 × 109 CFU of freeze-dried *Helveticus* R0052 and *B. longum* R0175 bacteria) for 8 weeks improved depression symptoms, but the serum inflammatory cytokines marker (TNF-α, IL-1β, IL-6, and IL-10) levels were not improved, and the urinary cortisol levels decreased by 20% of baseline. However, the prebiotics treatment (galactooligosaccharides, GOS) had no effect on depression symptoms nor inflammatory marker levels [110]. In a like manner, oral GOS administration reduced the human stress hormone cortisol and increased attentional vigilance to positive versus negative stimuli [111].
