E VIDENCE FOR THE E FFECT OF P RO -, P RE -, AND S YNBIOTICS IN H UMAN D ISEASES

15.7.5 E VIDENCE FOR THE E FFECT OF P RO -, P RE -, AND S YNBIOTICS IN H UMAN D ISEASES

15.7.5.1 Acute Disorders

15.7.5.1.1 Traveller’s Diarrhea Attempts to prevent or reduce the occurrence of traveller’s diarrhea have involved the intake of probiotic agents such as L. acidophilus, B. bifidum, L. bulgaricus, and

Probiotics, Prebiotics, and Synbiotics

L. GG . 109,110 In a placebo-controlled study of two cohorts travelling at two different holiday destinations L. GG was proven efficacious in reducing the incidence of diarrhea in one cohort, but no significant change was seen in the second cohort. Etiological agents involved in this study were not identified, but were likely to be different at both sites. This may explain the unsuccessful prophylactic action. A specific probiotic may not elicit antipathogenic activities toward a wide range of pathogens. Multibiotherapy or synbiotic products may increase the efficacy of the dietary strategy. More structure–function studies are required to identify oligosac- charides that could mimic receptor sites and, therefore, prevent adhesion of the pathogen to the intestinal mucosa.

15.7.5.1.2 Antibiotic-Associated Diarrhea Diarrhea often occurs as a side effect of antibiotherapy. The disruption of the intestinal microbial balance induces an attenuation of the natural defense barrier against pathogens. Opportunistic pathogens such as Clostridium difficile may then proliferate, and pseumembranous colitis may be seen as a complication. 111 L. GG and B. longum ingested solely have led to a significant decrease of diarrheal episodes in erythromycin-induced subjects. 112

A combination of L. acidophilus and L. bul- garicus has also reduced the incidence of diarrhea induced by ampicillin, neomycin, and amoxicillin-clavulanate. 113–115 An association of B. longum and L. acidophilus was also successfully used in the prevention of clyndamicin-induced diarrhea. 116

15.7.5.1.3 Rotaviral Diarrhea in Children Rotavirus is a common cause of gastroenteritis in infants. Probiotic strains L. GG and B. bifidum have been used effectively in clinical trials for prevention and shedding of rotavirus. 94,117 L. GG showed a drastic reduction of the duration of rotaviral diarrhea in several studies (Table 15.9), whereas the same probiotic seemed

less effective in diarrhea unrelated to rotavirus. 97 The putative mechanism of action is a stimulation of the immune response specific to rotavirus and reinforcement of

the mucosal integrity. A synbiotic combination of Lactobacillus rhamnosus and fructo-oligosaccharides has shown a significant reduction of duration of diarrhea in

infants with acute gastroenteritis. 96 15.7.5.1.4 Necrotizing Enterocolitis (NEC)

Enterocolitis is a gastrointestinal disorder of preterm neonates treated in intensive care units and receiving enteral feeds. The infectious agent is unclear, but bacteria from the commensal microflora, such as Clostridium difficile or Clostridium butyri-

cum , may be involved. 72 The bifidobacterial population in the intestinal lumen of neonates fed enterally is abnormally low. This may result in poor immunity and favorable conditions for translocation of bacteria to the systemic environment. 118 Preventive administration of L. acidophilus and Bifidobacterium infantis to newborns admitted in intensive care unit significantly reduced the occurrence of NEC in comparison to the historical cohort. 119 Animal models of NEC have also shown an effect of fructo-oligosaccharide in the reduction of necrosis and ulceration. Addi- tional clinical trials are needed to confirm observations in animals and underpin the mechanism of action.

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15.7.5.2 Chronic Disorders

15.7.5.2.1 Enzyme Deficiencies Probiotics have revealed a useful means of enzyme substitution therapy for digestive enzyme deficiency. Lactose intolerance is due to a deficiency in -galactosidase, an enzyme common to bacteria of Lactobacillus, Bifidobacterium, and Streptococcus groups often used as starter bacterial cultures in yogurts. Hydrolysis of lactose by bacterial -galactosidase justifies a better acceptance of fermented milk products than nonfermented milk by lactose-intolerant subjects. The ingestion of probiotic bacteria engineered to produce lipase or sucrase in vivo has been shown to improve lipid metabolism and sucrose digestion in enzyme-deficient subjects and animals. 120,121 To be efficient in vivo, the secretion of enzymes must take place in the upper intestinal tract, where the enzymatic digestion normally occurs. Appropriate combinations of synbiotics may be developed to ensure an optimal delivery of live probiotic bacteria capable of releasing the digestive enzymes in the intestinal chyme.

15.7.5.2.2 Autistic Children Gastroenteritis is commonly associated with autistic children spectrum disorders. Studies of fecal samples from autistic children have highlighted an alteration of the intestinal microflora. 122 Microbial metabolites released in the gut may play a psy- choactive role in autistic pathology. 123

A probiotic approach may contribute to the relief of gastrointestinal symptoms and help toward the normalization of the autistic intestinal flora. Clinical practices and carers of autistic individuals have circumstan- tially reported an improvement of autistic symptoms upon probiotic intake, but no appropriate epidemiological and feeding trials are currently available to confirm these observations. 123

15.7.5.2.3 Ulcerative Colitis (UC) Ulcerative colitis is characterized by an acute inflammation of the intestinal tract

with no relation to infection. Individuals affected by the disease experience periods of relapse and remission throughout their lives. The location of main symptoms in the large intestine suggests a link between the local microflora and the disease. Animal models suggest that the normal microflora is needed for the disease to occur, but no specific etiological agent has been identified. One hypothesis is that UC is due to a partial breakdown of tolerance to the normal commensal colonic flora. 124 Several pathogens have been suggested as causative agents of the disease: Escher- ichia coli , 125 sulfate-reducing bacteria, 126 mycobacteria, and Pseudomonas and Heli- cobacter species.

The control of the disease involves heavy anti-inflammatory medication or surgery. The use of antibiotics is often not conclusive. Manipulation of the diet of

colitis sufferers has shown an improvement at least in the maintenance of remission periods.

Randomized clinical trials have confirmed that pro- and prebiotic use may be effective in this pathology by prolonging the microbial composition of the remission

state. The mode of actions of probiotics and prebiotics in UC are thought to be manifold and complementary. Probiotic studies in UC animal models have demon- strated a probiotic interaction with colonocytes leading to a possible downregulation

Probiotics, Prebiotics, and Synbiotics

of the inflammatory response. 127 Prebiotics such as germinated barley are a conve- nient and efficacious way of stimulating the production of butyrate at the colitis site. Butyrate produced by fermentation of germinated barley promotes the proliferation of colonocytes and restores the integrity of the intestinal mucosa in animal models of colitis. 128

15.7.5.2.4 Colorectal Cancer (CRC) The human microflora has an important role in the development of CRC. Microbial

enzymes expressed by bacteria of the clostridium and bacteroides groups are able to convert dietary constituents to genotoxic or carcinogenic compounds. Probiotics are thought to act as a preventive agent of the carcinogenesis by inhibiting the activity of these enzymes. Most of the experimental evidence in vivo is based on animal

models. 40 Rodents fed a diet supplemented with several probiotic strains of Lacto- bacillus spp. and Bifidobacterium spp. developed less colonic DNA damage and fewer tumors than placebo-fed counterparts. 129 An epidemiological study reported a negative correlation between the consumption of dairy probiotics and colonic ade- nomas. 130 The probiotic effect is likely to take place over a long time frame. Results of prospective studies investigating the long-term preventive effect of probiotics against CRC are lacking. Prebiotics such as inulin, fructo-oligosaccharides, lactu- lose, and galacto-oligosaccharides have been shown to be effective protection in CRC animal models. However, results of human feeding trials are less consistent. In a parallel, placebo-controlled study of 20 volunteers, the administration of lactu- lose at half the pharmacological dose (10 g/day) did not influence significantly the

level of fecal genotoxicity. 2 The production of butyrate, a potent regulator of epi- thelial cells, is one of the mechanisms thought to underlie the preventive effect of prebiotics. Prebiotics may also maintain the metabolism of clostridia and bacteroides away from proteolysis toward carbohydrate hydrolysis, thereby releasing less harm- ful end products. A synbiotic combination containing L. rhamnosus, B. bifidum Bb12, and fructo-oligosaccharide has shown encouraging results in vitro and in animal models. 131 The synbiotic is currently being tested in a long-term prospective trial involving CRC patients and individuals at high risk of developing CRC (Syncan project).

15.7.5.2.5 Irritable Bowel Syndrome (IBS) Irritable bowel syndrome defines a range of symptoms, including abdominal pain,

flatulence, constipation, and diarrhea. 132 Unlike IBD, IBS is characterized by the absence of intestinal inflammation or pathology of the intestinal mucosa. The chronic stage occurs after gastroenteritis or a course of antibiotics. Women from Western countries are the major group of sufferers. The recurrence of yeast colonization by Candida albicans and a low prevalence of lactobacilli and bifidobacteria have been observed in IBS sufferers. 133 Probiotics may help the alleviation of the syndrome, but the effect is difficult to measure in vivo. L. plantarum 299v, L. GG, and VSL#3 were tested in separate randomized, placebo-controlled trials, and results showed only a limited effect on IBS symptoms. 134,135 Development of synbiotic products may be a more satisfactory strategy in IBS management, as it allows a dual action on the bowel motility and composition of intestinal microflora. 133

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