**5. Probiotics and/or prebiotics as therapeutics to combat gastrointestinal diseases and bacterial infections**

Studies in using probiotics as a treatment for a diverse set of diseases ranging from colorectal cancer, traditional gastrointestinal diseases (i.e. IBS/IBD/RCDI), as well as non-gastrointestinal diseases such as arthritis, autism, multiple sclerosis, and Parkinson's among others [99] has been undertaken. In this chapter, we will focus mainly on the effect probiotic and/prebiotic treatments on gastrointestinal diseases.

The therapeutic potential of prebiotics has been investigated for some gastrointestinal disorders. Irritable bowel syndrome (IBS) is a gastrointestinal disease characterized by chronic pain and altered bowel movements with no clear cause. Crohn's disease, a chronic relapsing inflammatory bowel disease (IBD), can affect any part of the gastrointestinal tract. For both conditions, it has been speculated that a shift in the gut microbiota population lays at the foundation of these diseases. It has been shown that the *Bifidobacteria*, *Faecalibacterium prausnitzii*, *Bacteroides* to *Firmicutes* population ratio were decreased [100, 101].

Therefore, prebiotics were hypothesized as a potential therapeutic because of its known properties to stimulate the growth of beneficial bacteria. In regards to IBS, the results were unclear for 4 clinical trials. Two clinical trials had no improvement [102, 103] whereas two studies using FOS and GOS showed an improvement in IBS symptoms [104, 105]. In the case of Crohn's disease, one study showed improvement [106] while two did not [107, 108]. As reviewed in [109], their analysis of available studies indicated that generally, the conclusions were supportive of probiotic treatment for IBS, however, the exact beneficial strains to be used were unclear. The caveats from these studies were the variabilities in the type of prebiotic(s) used, the dosage, time of supplementation, and patient disease stage. As has been used in the treatment of recurrent *C. difficile* infection (RCDI), fecal microbiota transplantation (FMT) has also been used with success in the treatment of IBS and IBD (i.e. Crohn's disease) [99].

**105**

*Prebiotics, Probiotics, and Bacterial Infections DOI: http://dx.doi.org/10.5772/intechopen.89052*

ably very little effect on NEC.

unknown and not advised.

chickens [122].

≈92% of RCDI patients was found after FMT therapy.

The recurrent infection in humans with recurrent *Clostridium difficile* infection (RCDI) in hospitalized patients treated with antibiotics is a severe problem. Studies have successfully used the transfer of healthy gut microbiota to the infected individuals as a treatment [110, 111]. As reviewed in [99], an amazing success rate of

Another area of medical use that prebiotics may impact is on the health of preterm neonates. These babies are at significant risk of developing the severe gastrointestinal condition necrotizing enterocolitis (NEC), a life-threatening condition. Studies have shown that FOS and GOS prebiotics can help prime the growth of gut bacteria such as *Bifidobacteria* and reduce pathogenic organisms in preterm babies [112–114] thereby preventing NEC. Additionally, SCFAs from prebiotic fermentation enhances both gastric emptying and bowel motility [115, 116]. A systemic analysis of four randomized controlled trials showed elevated concentrations of fecal *Bifidobacteria* if babies were given FOS, GOS, or their mixture, but there was no significant risk reduction or progression to NEC [117]. In a review of several studies regarding probiotics and their effectiveness in preventing necrotizing enterocolitis (NEC) in preterm infants [13, 118], the authors concluded a beneficial effect of using probiotics but this benefit decreased over time. However, since the studies varied in age, doses, and duration of treatment, this observation has prob-

The successful use of probiotics in treating acute infectious diarrhea (AID) in children is well documented and accepted treatment therapy [119]. It has beneficial effects for children at risk (i.e. hospital acquired diarrhea) and should be used early after onset of symptoms. Its usage, however, in healthy populations as a preventive measure to prevent diarrhea in day care centers and communities is currently

It has been shown that *E. coli Nissle* 1917 can outcompete *Salmonella* for iron leading to reduced *Salmonella* colonization and inflammation [120]. *E. coli Nissle* 1917 also can prevent *L. monocytogenes* entry into cell lines [121]. Probiotic treatment against *Listeria* infections has best been shown in the poultry industry. Competitive exclusion (CE) cultures have been developed and used successfully. Pre-treatment with CE prevented the expansion of *Listeria monocytogenes* in young

The development of synthetic oligosaccharide-based mimics such as Synsorb (inert silica particles-linked to synthetic oligosaccharides) have been developed against a variety of toxins including: Stx1/2-Gb3, Stx2e-Gb4, Ctx-GM1, LT-GM1, epsilon toxin–GM2, TcdA-Lewis X and Lewis Y, botulinum neurotoxin- GD1a, GT1b, *E. coli* K88 ad fimbriae-nLc4, *E. coli* P pili- Gb3 and Gb4 [98]. However, the results for these synthetic oligosaccharide conjugates have been mixed. Synsorb-PK was designed as a mimic for Gb3, receptor for Stx1/2, to prevent intoxication with Shigella and STEC strains but failed to prevent the progression of children to hemolytic uremic syndrome (HUS) in a clinical trial [123]. However, there could be at least two reasons as to the failure of this compound, (1) treatment given late in the onset of disease and (2) potential steric hindrance of the size of the compound. Synsorb-90 was developed in the treatment of severe colitis due to *C. difficile* infection. This compound was able to bind TcdA *in vitro* as well as decrease toxinmediated fluid secretion in a rat-ileal loop model [124]. However, phase III clinical trials for Synsorb-90 was abandoned after promising results from both phase I and

STEC gastroenteritis has not been traditionally treated with probiotics/FMT as has been seen with acute gastroenteritis and RCDI. There has been a plethora of evidence suggesting the role of probiotic strains in having an antimicrobial effect

phase II trials so we still do not know its efficacy [125].

#### *Prebiotics, Probiotics, and Bacterial Infections DOI: http://dx.doi.org/10.5772/intechopen.89052*

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

significant degree in human infection is still unclear.

*Firmicutes* population ratio were decreased [100, 101].

**diseases and bacterial infections**

host receptors [96].

diseases.

In order to cause disease for foodborne botulism, BoNTs must first be able to survive in the intestinal lumen, bind to and translocate through the intestinal epithelium to reach the bloodstream [95]. Once in the bloodstream, BoNTs bind to peripheral cholinergic neurons to cleave SNAREs and block exocytosis of neurotransmitters hence leading to flaccid muscle paralysis. Similar to other classic A-B chain toxins, the heavy chain (B chain) of BoNTs bind to carbohydrate and protein receptors on their target cell while the light chain (A chain) has the enzymatic function. Therefore, there are two potential therapeutic pathways to block BoNT intoxication: (1) blocking binding/translocation at the intestinal epithelium/ target cells and (2) degradation or inactivation of the toxin It has been shown that pre-treatment with probiotics (*Saccharomyces cerevisiae* var. *boulardii*, *Lactobacillus acidophilus*, *Lactobacillus rhamnosus* LGG, and *Lactobacillus reuteri*) was able to block toxin binding to cells in an *in vitro* Caco-2 cell culture model and that the mechanism most likely used by the probiotics was steric hindrance of binding to

Another mechanism to inactivate bacterial toxins would to be to subject them to proteolysis thus rendering them inactive. *S. boulardii* has been shown to produce a 54-KDa protease that is able to cleave and inactivate the two main *C. difficile* toxins, TcdA and TcdB [97] in a HT-29 colonic cell model. Whether or not this occurs in any

**5. Probiotics and/or prebiotics as therapeutics to combat gastrointestinal** 

Studies in using probiotics as a treatment for a diverse set of diseases ranging from colorectal cancer, traditional gastrointestinal diseases (i.e. IBS/IBD/RCDI), as well as non-gastrointestinal diseases such as arthritis, autism, multiple sclerosis, and Parkinson's among others [99] has been undertaken. In this chapter, we will focus mainly on the effect probiotic and/prebiotic treatments on gastrointestinal

The therapeutic potential of prebiotics has been investigated for some gastrointestinal disorders. Irritable bowel syndrome (IBS) is a gastrointestinal disease characterized by chronic pain and altered bowel movements with no clear cause. Crohn's disease, a chronic relapsing inflammatory bowel disease (IBD), can affect any part of the gastrointestinal tract. For both conditions, it has been speculated that a shift in the gut microbiota population lays at the foundation of these diseases. It has been shown that the *Bifidobacteria*, *Faecalibacterium prausnitzii*, *Bacteroides* to

Therefore, prebiotics were hypothesized as a potential therapeutic because of its known properties to stimulate the growth of beneficial bacteria. In regards to IBS, the results were unclear for 4 clinical trials. Two clinical trials had no improvement [102, 103] whereas two studies using FOS and GOS showed an improvement in IBS symptoms [104, 105]. In the case of Crohn's disease, one study showed improvement [106] while two did not [107, 108]. As reviewed in [109], their analysis of available studies indicated that generally, the conclusions were supportive of probiotic treatment for IBS, however, the exact beneficial strains to be used were unclear. The caveats from these studies were the variabilities in the type of prebiotic(s) used, the dosage, time of supplementation, and patient disease stage. As has been used in the treatment of recurrent *C. difficile* infection (RCDI), fecal microbiota transplantation (FMT) has also been used with success in the treatment of IBS and

**104**

IBD (i.e. Crohn's disease) [99].

The recurrent infection in humans with recurrent *Clostridium difficile* infection (RCDI) in hospitalized patients treated with antibiotics is a severe problem. Studies have successfully used the transfer of healthy gut microbiota to the infected individuals as a treatment [110, 111]. As reviewed in [99], an amazing success rate of ≈92% of RCDI patients was found after FMT therapy.

Another area of medical use that prebiotics may impact is on the health of preterm neonates. These babies are at significant risk of developing the severe gastrointestinal condition necrotizing enterocolitis (NEC), a life-threatening condition. Studies have shown that FOS and GOS prebiotics can help prime the growth of gut bacteria such as *Bifidobacteria* and reduce pathogenic organisms in preterm babies [112–114] thereby preventing NEC. Additionally, SCFAs from prebiotic fermentation enhances both gastric emptying and bowel motility [115, 116]. A systemic analysis of four randomized controlled trials showed elevated concentrations of fecal *Bifidobacteria* if babies were given FOS, GOS, or their mixture, but there was no significant risk reduction or progression to NEC [117]. In a review of several studies regarding probiotics and their effectiveness in preventing necrotizing enterocolitis (NEC) in preterm infants [13, 118], the authors concluded a beneficial effect of using probiotics but this benefit decreased over time. However, since the studies varied in age, doses, and duration of treatment, this observation has probably very little effect on NEC.

The successful use of probiotics in treating acute infectious diarrhea (AID) in children is well documented and accepted treatment therapy [119]. It has beneficial effects for children at risk (i.e. hospital acquired diarrhea) and should be used early after onset of symptoms. Its usage, however, in healthy populations as a preventive measure to prevent diarrhea in day care centers and communities is currently unknown and not advised.

It has been shown that *E. coli Nissle* 1917 can outcompete *Salmonella* for iron leading to reduced *Salmonella* colonization and inflammation [120]. *E. coli Nissle* 1917 also can prevent *L. monocytogenes* entry into cell lines [121]. Probiotic treatment against *Listeria* infections has best been shown in the poultry industry. Competitive exclusion (CE) cultures have been developed and used successfully. Pre-treatment with CE prevented the expansion of *Listeria monocytogenes* in young chickens [122].

The development of synthetic oligosaccharide-based mimics such as Synsorb (inert silica particles-linked to synthetic oligosaccharides) have been developed against a variety of toxins including: Stx1/2-Gb3, Stx2e-Gb4, Ctx-GM1, LT-GM1, epsilon toxin–GM2, TcdA-Lewis X and Lewis Y, botulinum neurotoxin- GD1a, GT1b, *E. coli* K88 ad fimbriae-nLc4, *E. coli* P pili- Gb3 and Gb4 [98]. However, the results for these synthetic oligosaccharide conjugates have been mixed. Synsorb-PK was designed as a mimic for Gb3, receptor for Stx1/2, to prevent intoxication with Shigella and STEC strains but failed to prevent the progression of children to hemolytic uremic syndrome (HUS) in a clinical trial [123]. However, there could be at least two reasons as to the failure of this compound, (1) treatment given late in the onset of disease and (2) potential steric hindrance of the size of the compound. Synsorb-90 was developed in the treatment of severe colitis due to *C. difficile* infection. This compound was able to bind TcdA *in vitro* as well as decrease toxinmediated fluid secretion in a rat-ileal loop model [124]. However, phase III clinical trials for Synsorb-90 was abandoned after promising results from both phase I and phase II trials so we still do not know its efficacy [125].

STEC gastroenteritis has not been traditionally treated with probiotics/FMT as has been seen with acute gastroenteritis and RCDI. There has been a plethora of evidence suggesting the role of probiotic strains in having an antimicrobial effect

on STEC but the effects were dependent on the strain(s) used as reviewed in [126]. Additionally, recombinant receptor mimics have been targeted against STEC [98].

In the three studies that mimicked human digestive conditions, *S. cerevisiae* CNCM I-3856 was implicated in having antagonistic effects on STEC including downregulating Stx expression and how the resident microbiota regulates infectivity [126–129].

Though there have been many successful and safe uses of probiotics for treatment of multiple conditions, there have been reported side effects linked to their usage especially in vulnerable populations [130]. As reviewed in [131], there has been movement toward using extracellular vesicles (EVs) derived from probiotic strains (both Gram-negative and Gram-positive) to deliver the same beneficial effects as from using the probiotic strains themselves. There are many different pathways that EVs utilize including bacteria-bacteria communication, affecting host microbial interactions, host immune system, increasing tight junction function, and decreasing inflammatory responses from TLR signaling [131].
