Prebiotic effects: metabolic and health benefits.

The different compartments of the gastrointestinal tract are inhabited by populations of micro-organisms. By far the most important predominant populations are in the colon where a true symbiosis with the host exists that is a key for well-being and health. For such a microbiota, 'normobiosis' characterises a composition of the gut 'ecosystem' in which micro-organisms with potential health benefits predominate in number over potentially harmful ones, in contrast to 'dysbiosis', in which one or a few potentially harmful micro-organisms are dominant, thus creating a disease-prone situation. The present document has been written by a group of both academic and industry experts (in the ILSI Europe Prebiotic Expert Group and Prebiotic Task Force, respectively). It does not aim to propose a new definition of a prebiotic nor to identify which food products are classified as prebiotic but rather to validate and expand the original idea of the prebiotic concept (that can be translated in 'prebiotic effects'), defined as: 'The selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host.' Thanks to the methodological and fundamental research of microbiologists, immense progress has very recently been made in our understanding of the gut microbiota. A large number of human intervention studies have been performed that have demonstrated that dietary consumption of certain food products can result in statistically significant changes in the composition of the gut microbiota in line with the prebiotic concept. Thus the prebiotic effect is now a well-established scientific fact. The more data are accumulating, the more it will be recognised that such changes in the microbiota's composition, especially increase in bifidobacteria, can be regarded as a marker of intestinal health. The review is divided in chapters that cover the major areas of nutrition research where a prebiotic effect has tentatively been investigated for potential health benefits. The prebiotic effect has been shown to associate with modulation of biomarkers and activity(ies) of the immune system. Confirming the studies in adults, it has been demonstrated that, in infant nutrition, the prebiotic effect includes a significant change of gut microbiota composition, especially an increase of faecal concentrations of bifidobacteria. This concomitantly improves stool quality (pH, SCFA, frequency and consistency), reduces the risk of gastroenteritis and infections, improves general well-being and reduces the incidence of allergic symptoms such as atopic eczema. Changes in the gut microbiota composition are classically considered as one of the many factors involved in the pathogenesis of either inflammatory bowel disease or irritable bowel syndrome. The use of particular food products with a prebiotic effect has thus been tested in clinical trials with the objective to improve the clinical activity and well-being of patients with such disorders. Promising beneficial effects have been demonstrated in some preliminary studies, including changes in gut microbiota composition (especially increase in bifidobacteria concentration). Often associated with toxic load and/or miscellaneous risk factors, colon cancer is another pathology for which a possible role of gut microbiota composition has been hypothesised. Numerous experimental studies have reported reduction in incidence of tumours and cancers after feeding specific food products with a prebiotic effect. Some of these studies (including one human trial) have also reported that, in such conditions, gut microbiota composition was modified (especially due to increased concentration of bifidobacteria). Dietary intake of particular food products with a prebiotic effect has been shown, especially in adolescents, but also tentatively in postmenopausal women, to increase Ca absorption as well as bone Ca accretion and bone mineral density. Recent data, both from experimental models and from human studies, support the beneficial effects of particular food products with prebiotic properties on energy homaeostasis, satiety regulation and body weight gain. Together, with data in obese animals and patients, these studies support the hypothesis that gut microbiota composition (especially the number of bifidobacteria) may contribute to modulate metabolic processes associated with syndrome X, especially obesity and diabetes type 2. It is plausible, even though not exclusive, that these effects are linked to the microbiota-induced changes and it is feasible to conclude that their mechanisms fit into the prebiotic effect. However, the role of such changes in these health benefits remains to be definitively proven. As a result of the research activity that followed the publication of the prebiotic concept 15 years ago, it has become clear that products that cause a selective modification in the gut microbiota's composition and/or activity(ies) and thus strengthens normobiosis could either induce beneficial physiological effects in the colon and also in extra-intestinal compartments or contribute towards reducing the risk of dysbiosis and associated intestinal and systemic pathologies.

Possible adjuvant cancer therapy by two prebiotics--inulin or oligofructose.

Dietary treatment with inulin or oligofructose incorporated in the basal diet for experimental animals: (I) reduced the incidence of mammary tumors induced in Sprague-Dawley rats by methylnitrosourea; (II) inhibited the growth of transplantable malignant tumors in mice; (III) decreased the incidence of lung metastases of a malignant tumor implanted intramuscularily in mice. (IV) Moroever, besides such cancer risk reduction effects, dietary treatment with inulin or oligofructose significantly potentiated the effects of subtherapeutic doses of six cytotoxic drugs commonly utilized in human cancer treatment. (V) The same prebiotics potentiated the effects of radiotherapy on solid form of TLT tumors to a statistically very high level. Such dietary treatment, with the inulin or oligofructose potentiating the effects of cancer therapy, might be introduced into classic protocols of human cancer treatment as a new, non-toxic and easily applicable adjuvant cancer therapy without any additional risk to patients.

Non-toxic potentiation of cancer radiotherapy by dietary oligofructose or inulin.

Non-toxic, dietary treatment with oligofructose or inulin clearly inhibited the growth of a transplantable mouse liver tumor (TLT) and potentiated its chemotherapy. Thus, it appeared interesting to investigate the possible radiotherapy-potentiating effects of the same dietary treatment. Dietary treatment with 15% oligofructose or inulin incorporated in the basal diet was started four weeks before intramuscular transplantation of TLT tumor cells into young adult male mice of the NMRI strain and was continued until the end of the experiment. When the tumors reached approximately 1000 mm3 they were irradiated with a single X-ray dose of 5 to 20 Gy. Tumor dimensions were measured twice weekly and their mean volume per group of mice was compared to the control groups fed the basal diet. This non-toxic dietary treatment with oligofructose or inulin potentiated the effects of radiotherapy at an optimal dose of 10 Gy to a statistically very highly significant (p < 0.0001) level. They were similar for oligofructose and inulin. The introduction of such non-toxic adjuvant treatment potentiating the effect of cancer radiotherapy in classical protocols of human cancer treatment appears to be possible and without any additional risk for the patients.

Dietary modulation of the human colonic microbiota: updating the concept of prebiotics.

Prebiotics are non-digestible (by the host) food ingredients that have a beneficial effect through their selective metabolism in the intestinal tract. Key to this is the specificity of microbial changes. The present paper reviews the concept in terms of three criteria: (a) resistance to gastric acidity, hydrolysis by mammalian enzymes and gastrointestinal absorption; (b) fermentation by intestinal microflora; (c) selective stimulation of the growth and/or activity of intestinal bacteria associated with health and wellbeing. The conclusion is that prebiotics that currently fulfil these three criteria are fructo-oligosaccharides, galacto-oligosaccharides and lactulose, although promise does exist with several other dietary carbohydrates. Given the range of food vehicles that may be fortified by prebiotics, their ability to confer positive microflora changes and the health aspects that may accrue, it is important that robust technologies to assay functionality are used. This would include a molecular-based approach to determine flora changes. The future use of prebiotics may allow species-level changes in the microbiota, an extrapolation into genera other than the bifidobacteria and lactobacilli, and allow preferential use in disease-prone areas of the body.

Prebiotics: the concept revisited.

A prebiotic is "a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well-being and health." Today, only 2 dietary nondigestible oligosaccharides fulfill all the criteria for prebiotic classification. The daily dose of the prebiotic is not a determinant of the prebiotic effect, which is mainly influenced by the number of bifidobacteria/g in feces before supplementation of the diet with the prebiotic begins. The ingested prebiotic stimulates the whole indigenous population of bifidobacteria to growth, and the larger that population, the larger is the number of new bacterial cells appearing in feces. The "dose argument" is thus not supported by the scientific data: it is misleading for consumers and should not be allowed. A prebiotic index is proposed, defined as "the increase in the absolute number of bifidobacteria expressed divided by the daily dose of prebiotic ingested."

Inulin-type fructans: functional food ingredients.

A food (ingredient) is regarded as functional if it is satisfactorily demonstrated to affect beneficially 1 or more target functions in the body beyond adequate nutritional effects. The term inulin-type fructans covers all beta(2<--1) linear fructans including native inulin (DP 2-60, DP(av) = 12), oligofructose (DP 2-8, DP(av) = 4), and inulin HP (DP 10-60, DP(av) = 25) as well as Synergy 1, a specific combination of oligofructose and inulin HP. Inulin-type fructans resist digestion and function as dietary fiber improving bowel habits. But, unlike most dietary fibers, their colonic fermentation is selective, thus causing significant changes in the composition of the gut microflora with increased and reduced numbers of potentially health-promoting bacteria and potentially harmful species, respectively. Both oligofructose and inulin act in this way and thus are prebiotic: they also induce changes in the colonic epithelium and in miscellaneous colonic functions. In particular, the claim "inulin-type fructans enhance calcium and magnesium absorption" is scientifically substantiated, and the most active product is oligofructose-enriched inulin (Synergy 1). A series of studies furthermore demonstrate that inulin-type fructans modulate the secretion of gastrointestinal peptides involved in appetite regulation as well as lipid metabolism. Moreover, a large number of animal studies and preliminary human data show that inulin-type fructans reduce the risk of colon carcinogenesis and improve the management of inflammatory bowel diseases. Inulin-type fructans are thus functional food ingredients that are eligible for enhanced function claims, but, as more human data become available, risk reduction claims will become scientifically substantiated.

Introducing inulin-type fructans.

Inulin is a generic term to cover all beta(2-->1) linear fructans. Chicory inulin is a linear beta(2-->1) fructan (degree of polymerisation (DP) 2 to 60; DPav=12), its partial enzymatic hydrolysis product is oligofructose (DP 2 to 8; DPav=4), and by applying specific separation technologies a long-chain inulin known as inulin HP (DP 10 to 60; DPav=25) can be produced. Finally, a specific product known as oligofructose-enriched inulin is obtained by combining chicory long-chain inulin and oligofructose. Because of the beta-configuration of the anomeric C2 in their fructose monomers, inulin-type fructans resist hydrolysis by intestinal digestive enzymes, they classify as 'non-digestible' carbohydrates, and they are dietary fibres. By increasing faecal biomass and water content of the stools, they improve bowel habits, but they have characteristic features different from other fibres. They affect gastrointestinal functions not because of their physico-chemical properties but rather because of their biochemical and physiological attributes. In the colon, they are rapidly fermented to produce SCFA that are good candidates to explain some of the systemic effects of inulin-type fructans. Fermentation of inulin-type fructans in the large bowel is a selective process; bifidobacteria (and possibly a few other genera) are preferentially stimulated to grow, thus causing significant changes in the composition of the gut microflora by increasing the number of potentially health-promoting bacteria and reducing the number of potentially harmful species. Both oligofructose and inulin are prebiotic. They also induce changes in colonic epithelium stimulating proliferation in the crypts, increasing the concentration of polyamines, changing the profile of mucins, and modulating endocrine as well as immune functions. From a nutrition labelling perspective, inulin-type fructans are not only prebiotic dietary fibres; they are also low-calorie carbohydrates [6.3 kJ/g (1.5 kcal/g)]. Supported by the results of a large number of animal studies and human nutrition intervention trials, the claim 'inulin-type fructans enhance calcium and magnesium absorption' is scientifically substantiated, but different inulin-type fructans have probably a different efficacy (in terms of effective daily dose), the most active product being the oligofructose-enriched inulin. A series of animal studies demonstrate that inulin-type fructans affect the metabolism of lipids primarily by decreasing triglyceridaemia because of a reduction in the number of plasma VLDL particles. The human data largely confirm the animal experiments. They demonstrate mainly a reduction in triglyceridaemia and only a relatively slight decrease in cholesterolaemia mostly in (slightly) hypertriglyceridaemic conditions. Inulin appears thus eligible for an enhanced function claim related to normalization of blood triacylglycerols. A large number of animal data convincingly show that inulin-type fructans reduce the risk of colon carcinogenesis and nutrition intervention trials are now performed to test that hypothesis in human subjects known to be at risk for polyps and cancer development in the large bowel.

Functional foods: concepts and application to inulin and oligofructose.

A food can be regarded as functional if it is satisfactorily demonstrated to affect beneficially one or more target functions in the body, beyond adequate nutritional effects, in a way which is relevant to either the state of well-being and health or the reduction of the risk of a disease. Health claims are expected to be authorized for functional foods based either on enhanced function (type A claim) or disease risk reduction (type B claim). Their development is a unique opportunity to contribute to the improvement of the quality of the food offered to consumer's choice for the benefit of his well-being and health. But only a rigorous scientific approach producing sound data will guarantee its success. The functional food components that are discussed in the proceedings of the 3rd ORAFTI Research Conference are the inulin-type fructans, natural food components found in miscellaneous edible plants. They are non-digestible oligosaccharides that are classified as dietary fiber. The targets for their functional effects are the colonic microflora that use them as selective 'fertilizers'; the gastrointestinal physiology; the immune functions; the bioavailability of minerals; and the metabolism of lipids. Potential health benefits may also concern reduction of the risk of some diseases like intestinal infections, constipation, non-insulin dependent diabetes, obesity, osteoporosis or colon cancer. The present proceedings review the scientific data available and, by reference to the concepts in functional food science, they assess the scientific evidence which will be used to substantiate health claims.

Dietary chicory inulin increases whole-body bone mineral density in growing male rats.

Chicory inulin is a natural linear fructan that is not digested in the upper part of the gastrointestinal tract but is fermented in the cecocolon. It enhances calcium absorption in rats and improves femur and tibia mineral contents in gastrectomized or ovariectomized rats. We studied the effect of inulin (0, 5 and 10 g/100 g diet) on whole-body bone mineral content (WBBMC), whole-body bone area (WBBA) and whole-body bone mineral density (WBBMD) in live, growing male rats fed diets containing 0.2, 0.5 or 1 g Ca/100 g. Three experiments, each corresponding to one of the different dietary Ca concentrations, were performed using male Wistar rats (n = 108; 4 wk old). WBBMC was measured by dual-energy X-ray absorptiometry every 4 wk up to wk 22. Inulin increased WBBMC (P < 0.05) and WBBMD (P < 0.001) significantly but not WBBA at all ages and all dietary calcium concentrations. This is the first report to demonstrate that chicory inulin not only increases calcium absorption but also increases mineral parameters in whole-body bones.

New scientific paradigms for probiotics and prebiotics.

The inaugural meeting of the International Scientific Association for Probiotics and Prebiotics (ISAPP) was held May 3 to May 5 2002 in London, Ontario, Canada. A group of 63 academic and industrial scientists from around the world convened to discuss current issues in the science of probiotics and prebiotics. ISAPP is a non-profit organization comprised of international scientists whose intent is to strongly support and improve the levels of scientific integrity and due diligence associated with the study, use, and application of probiotics and prebiotics. In addition, ISAPP values its role in facilitating communication with the public and healthcare providers and among scientists in related fields on all topics pertinent to probiotics and prebiotics. It is anticipated that such efforts will lead to development of approaches and products that are optimally designed for the improvement of human and animal health and well being. This article is a summary of the discussions, conclusions, and recommendations made by 8 working groups convened during the first ISAPP workshop focusing on the topics of: definitions, intestinal flora, extra-intestinal sites, immune function, intestinal disease, cancer, genetics and genomics, and second generation prebiotics.