Advantages over Probiotics

Storage Stability

With the exception of some mechanisms of immunomodulation, the theoretical basis for many of the anticipated probiotic effects of bifidobacteria rely on the bacteria being viable in the intestinal tract. Currently, probiotics are limited by their stability largely to fresh food products such as fermented dairy products and juices, and nutraceutical products where they are formulated as dried powders. In contrast, prebiotics are stable, can be heat-processed, and can therefore be incorporated into a wider range of processed foods and beverages with longer shelf lives than probiotics.

Host-Microbiota Compatibility

It is clear that selected probiotic bifidobacteria do survive transit through the stomach and small intestine and can be recovered in feces. However, in most cases, ingested probiotic strains persist only transiently in the intestine (134,184-188). An introduced probiotic strain must compete with an already established microbiota. The application of molecular techniques to profile the complex microbial communities has revealed that each person has a unique intestinal microbiota at the community, genus, and species level (137-139). This has been demonstrated in the case of bifidobacteria using PCR-DGGE analysis of Bifidobacterium species in feces, where each individual has their own particular combination of species (121,125). This uniqueness appears to extend to the strain level too, with molecular fingerprinting techniques showing that each person generally harbors multiple and unique Bifidobacterium strains (138,189-191). This host-microbiota stability and individuality suggests that certain host-microbiota compatibilities exist, and using prebiotics that augment an individual's own bacteria may prove more successful than introducing an exogenous strain for some applications.

The importance of host species/probiotic species specificity remains a contentious question. It is often recommended that probiotics be selected from bacteria indigenous to the intestinal tract of the targeted host species (192). However, the predominant probiotic Bifidobacterium species currently used in human probiotics is Bif. animalis ( = Bif. lactis) (11), which is not an autochthonous member of the human intestinal microbiota. This species is taxonomically distant from human intestinal species (193), but is used because of its superior technological stability compared with human intestinal isolates. The prebiotic strategy overcomes any potential host/probiotic strain compatibility issues by targeting those strains already resident in the intestinal tract of an individual.

Inhibition of Pathogen Adhesion

One mechanism by which oligosaccharides may provide protection against infection by pathogenic micro-organisms has been hypothesized to be that of blocking adhesion to intestinal mucosa by acting as soluble receptor analogues (Fig. 3) (194-196). Microbial virulence factors, such as fimbriae and other membrane-based adhesins, control mucosal attachment and colonization of tissues. The recognition domains of fimbriae are similar to lectins that bind to carbohydrate epitopes on membrane glycocojugates of epithelial cells. Kunz and Rudloff (197) have listed the receptor specificities of glyco- and lactose-derived oligosaccharides and various pathogenic bacteria and viruses. Carbohydrate-mediated cell interactions affect cell-cell interactions, as well as bacterium, viral and toxin interactions with epithelial cells. The specificity of attachment provides potential for control of gastrointestinal infections through the use of specific oligosaccharide structures.

Stimulation of Fermentative Activity in the Gut

In addition to modifying population dynamics, prebiotics also modify the activity of the microbiota by providing a source of readily fermentable carbohydrate. Indeed, it may be this dietary fiber-like characteristic of modifying the fermentative activity of the existing microbiota that is the important factor in providing a number of health benefits to consumers (Figs. 2-4). Proposed health effects of prebiotics that are speculated to be largely contingent on modifications to metabolic activity of the microbiota include reductions in risk factors for colon cancer, increased mineral absorption, improved lipid metabolism, and increased resistance to intestinal pathogens.

Reduced Risk Factors for Colon Cancer. The intestinal microbiota has a number of biochemical activities relevant to colon cancer risk that relate to the composition and activity of different bacterial populations. Hence, prebiotics may have a role in reducing risk factors for colon cancer. Since they supply a source of fermentable carbohydrate to the colon, dietary fiber-like anti-carcinogenic effects have been proposed for prebiotics (Fig. 4). Proposed mechanisms include supplying the colonic epithelium with SCFA (particularly butyrate); suppression of microbial protein metabolism, bile acid conversion and other mutagenic and toxigenic bacterial reactions; and immunomodulation. Butyrate production in the distal colon is suspected to be beneficial in preventing the development of colorectal cancers (198-200). While Lactobacillus and Bifidobacterium probiotics do not produce butyrate as major fermentation end products, prebiotics can stimulate butyrate production by the colonic microbiota, which provides a potential advantage of this approach (37,201). To date, the capacity of prebiotics to significantly contribute to a reduced incidence of colorectal cancer remains unproven. However, the results of preliminary human and animal experiments have provided sufficient encouragement to maintain the impetus for continued research into the protective effects of prebiotics.

Numerous studies in humans and animals have shown that consumption of prebiotics can produce an improved colonic environment in terms of reducing the levels of mutagenic enzyme activities (e.g., ß-glucuronidase and azoreductase) and bacterial metabolites (e.g., secondary bile acids, phenols and indoles) that are purportedly associated with colon cancer risk. Examples include studies with lactulose (44,45,202), galacto-oligosaccharides (203), resistant starch (69,204-206) and lactosucrose (51). However, not all prebiotic feeding studies have shown improvements in these parameters (46,47,66,207), and in any case, the quantitative importance of these markers to eventual cancer development remains to be established.

A growing number of studies report protection by prebiotics against the development of pre-neoplastic lesions and/or tumors in rodent models of colon carcinogenesis. Again, these have used a variety of prebiotics including fructo-oligosaccharides and inulin (summarized by Pool-Zobel et al. (37)), lactulose (161,208) and resistant starch (209,210). Dose effects have been observed (37), but in general, very high doses of NDOs have been used in the animal studies. An important question that is beginning to be addressed is the significance of the sustainability of fermentation provided by different prebiotics during passage through the colon on their effectiveness in preventing colon cancer. The distal colon and rectum are the major sites of disease in humans, but SCFA produced by bacterial fermentation in the colon are rapidly absorbed by the colonic mucosa near the site of their production. Hence, prebiotics that can supply a persistent source of fermentable carbohydrate that sustains SCFA synthesis through to the distal colon may prove to be the most effective. Indeed, studies with different molecular sized fructan prebiotics have reported increased protection with the larger, more slowly fermented prebiotics (37).

Improving Mineral Absorption. As seen for dietary fibres, a number of prebiotics have been shown to increase mineral absorption in animal models (211-214). The precise mechanisms of prebiotic-mediated improvements in mineral uptake remain unclear, but fermentative activities of the microbiota including SCFA production and reductions in luminal pH are believed to be involved (Fig. 4) (213). Calcium and magnesium are the main minerals for which uptake is improved. Under normal circumstances dietary calcium is predominately absorbed in the small intestine with little calcium absorbed in the colon (215). However, prebiotic fermentation is believed to extend calcium uptake into the colon (34). In rats, increased calcium uptake has led to improved bone mineralization for animals fed galacto-oligosaccharides (216), lactulose (217) and fructo-oligosac-charides (218).

Although two human studies have shown little impact on mineral uptake (219,220), a number have reported beneficial effects on calcium (221-225) and magnesium absorption (226) using fructo-oligosaccharides, inulin and galacto-oligosaccharides. Differences in results have been attributed to differences in study designs and treatment populations (212,225). Griffin et al. (225) saw no effect with short chain fructo-oligosaccharides in a population of pubertal girls, but a significant increase in the calcium absorption and balance was observed when the girls consumed a mixture of fructo-oligosaccharides and inulin, perhaps reflecting a more sustained colonic fermentation. Overall, results so far are encouraging of a role for prebiotics in improving calcium uptake. Further research is warranted to investigate links between long-term prebiotic consumption and improved bone density in humans at risk of developing osteoporosis.

Effects on Serum Lipids and Cholesterol. A role for prebiotics in controlling hyperlipidemia has been proposed and a relatively large number of animal and human studies have focused on the effects of oligosaccharide and inulin intake on lipid metabolism. These include eight human trials summarized by van Loo et al. (34), and more recent trials (227-231). The mechanism by which lowering of serum lipids and cholesterol may occur has been speculated to be regulation of host de novo lipogenesis via SCFA absorbed from the gut (Fig. 4) (232). While convincing positive effects on lowering serum triglycerols and cholesterol have often been reported in animal studies (233) the results from human studies have tended to be contradictory, although no deleterious effects have been reported (232). The trials conducted to date indicate that while there is certainly potential for prebiotics to control serum lipids, more research is needed to identify the most appropriate target populations, the impact of background diet, and the mechanisms of action.

Improving Colonization Resistance in the Gut. The ability of prebiotics to improve colonization resistance and prevent bacterial infections from the gut has been only scantly explored, but results so far indicate a potential application for lactulose and NDOs in this capacity. Lactulose has the most accumulated evidence. Ozaslan et al. (234) observed lower caecal overgrowth and translocation of Escherichia coli in rats with obstructive jaundice when they were fed lactulose, while Bovee-Oudenhoven et al. (235) reported that consumption of lactulose increased colonization resistance against the invasive pathogen Salmonella enteritidis in rats. Indeed, lactulose consumption at high doses (up to 60 g per day) is effective in eliminating salmonella from the intestinal tract of chronic human carriers and is used as a pharmaceutical for this purpose in some countries (236). The mode of action is speculated to be acidification of the gut that prevents growth of this acid-sensitive pathogen.

The anti-infective effects of fructo-oligosaccharides and inulin have been examined in mice challenged with the enteric pathogen Candida albicans and with systemic infections of Salmonella and Listeria monocytogenes (237). Prebiotic feeding significantly reduced intestinal colonization by Candida and the mortality of the mice with the systemic infections, the latter effect hypothesized as being due to gut microbiota-induced immunomodulation. However, two randomized, blinded, and controlled trials in which Peruvian infants living in environments with a high burden of gastrointestinal and other infections were fed oligofructose failed to show any significant benefit in terms of preventing diarrhea or the use of health care resources (238), although a high level of breast feeding amongst these infants may have limited the opportunity for effect. Prebiotic intervention may prove effective in rapidly restoring colonization resistance and preventing infections in cases where the intestinal microbiota has been perturbed.

Other Physiological and Technological Benefits of Prebiotics

In addition to the effects elicited by prebiotics discussed thus far, prebiotics have a number of other functional properties that make them attractive pharmaceuticals and food ingredients. Through their action in fecal bulking and water retention in the bowel, prebiotics are effective in relieving constipation and maintaining normal stool frequency (34). Additionally, by stimulating bacterial protein synthesis and reducing production of ammonia by the microbiota, lactulose is effective in the treatment of hepatic encephalopathy (236). NDOs are sweet and can be used as low-cariogenic and low-calorific sugar substitutes, while polysaccharides such as inulin are used as fat replacers. Their indigestibility and subsequent impact on glucose and insulin responses also make them suitable for diabetics. In terms of food technology, NDOs supply a number of valuable physicochemical functionalities. They can be used to increase viscosity, reduce Malliard reactions, alter water retention, depress freezing points, and suppress crystal formation. Hence, they are used commercially in a wide variety of foods and beverages.

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