Gluten, major histocompatibility complex, and the small intestine: A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’)

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.

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Prebiotic effects: metabolic and health benefits.

Food and Agricultural Organization of the United Nations PA N I S F I A T G u id e in e s o n fo o d fo r tific atio n w th m ic r o n u tr ie n ts Interest in micronutrient malnutrition has increased greatly over the last few years. One of the main reasons is the realization that micronutrient malnutrition contributes substantially to the global burden of disease. Furthermore, although micronutrient malnutrition is more frequent and severe in the developing world and among disadvantaged populations, it also represents a public health problem in some industrialized countries. Measures to correct micronutrient deficiencies aim at ensuring consumption of a balanced diet that is adequate in every nutrient. Unfortunately, this is far from being achieved everywhere since it requires universal access to adequate food and appropriate dietary habits. Food fortification has the dual advantage of being able to deliver nutrients to large segments of the population without requiring radical changes in food consumption patterns.

Guidelines on food fortification with micronutrients

Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms ‘intestinal barrier’ and ‘intestinal permeability’ are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by ‘intestinal permeability’. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and – more recently recognized – obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.

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Intestinal permeability – a new target for disease prevention and therapy

According to the German definition, probiotics are defined viable microorganisms, sufficient amounts of which reach the intestine in an active state and thus exert positive health effects. Numerous probiotic microorganisms (e.g. Lactobacillus rhamnosus GG, L. reuteri, bifidobacteria and certain strains of L. casei or the L. acidophilus-group) are used in probiotic food, particularly fermented milk products, or have been investigated—as well as Escherichia coli strain Nissle 1917, certain enterococci (Enterococcus faecium SF68) and the probiotic yeast Saccharomyces boulardii—with regard to their medicinal use. Among the numerous purported health benefits attributed to probiotic bacteria, the (transient) modulation of the intestinal microflora of the host and the capacity to interact with the immune system directly or mediated by the autochthonous microflora, are basic mechanisms. They are supported by an increasing number of in vitro and in vivo experiments using conventional and molecular biologic methods. In addition to these, a limited number of randomized, well-controlled human intervention trials have been reported.

Probiotics, Prebiotics, and Synbiotics

Helicobacter pylori is a highly prevalent pathogen considered as an aetiological factor for gastroduodenal ulcers, and a risk factor for gastric adenocarcinoma and lymphoma in humans. Most subjects colonized by this micro-organism are asymptomatic and remain untreated. In symptomatic patients, the antibiotic treatment has a high cost and is not 100% effective because of resistance to antibiotics and to moderate patient compliance. This review discusses the role of probiotics as alternative solutions to assist in the control of H. pylori colonization in at-risk populations. The evidence that some strains of Lactobacillus and Bifidobacterium are able to inhibit H. pylori growth through the release of bacteriocins or organic acids, and may also decrease its adhesion to epithelial cells, is reviewed. In addition, probiotics have a possible role in the stabilization of the gastric barrier function and the decrease of mucosal inflammation. Other aspects that are considered are the contribution of probiotics to the healing of the gastric mucosa linked to their antioxidant and anti-inflammatory properties. Clinical trials in colonized adults and children are reviewed, and suggest that probiotics do not eradicate H. pylori but maintain lower levels of this pathogen in the stomach; in combination with antibiotics, probiotics may increase eradication rate and/or decrease adverse effects. Papers suggesting similar effects on H. pylori by foodstuffs such as berry juice and some milk proteins are quoted. Regular intake of these and other dietary products might constitute a low-cost, large-scale alternative solution applicable for populations at-risk for H. pylori colonization.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2036.2006.02868.x

Systematic review: are probiotics useful in controlling gastric colonization by Helicobacter pylori?

Antibiotics exert deleterious effects on the intestinal microbiota, favoring the emergence of opportunistic bacteria and diarrhea. Prebiotics are nondigestible food components that stimulate the growth of bifidobacteria. Our aim was to evaluate the effects on the intestinal microbiota of a prebiotic-supplemented milk formula after an antibiotic treatment. A randomized, double-blind, controlled clinical trial was carried out in 140 infants 1-2 y of age distributed into two groups after a 1-wk amoxicillin treatment (50 mg/kg/d) for acute bronchitis. The children received for 3 wk >500 mL/d of a formula with prebiotics (4.5 g/L) or a control without prebiotics. Fecal samples were obtained on d -7 (at the beginning of the antibiotic treatment), on d 0 (end of the treatment and before formula administration), and on d 7 and 21 (during formula administration). Counts of Bifidobacterium, Lactobacillus-Enterococcus, Clostridium lituseburiense cluster, Clostridium histolyticum cluster, Escherichia coli, and Bacteroides-Prevotella were evaluated by fluorescent in situ hybridization (FISH) and flow cytometry. Tolerance and gastrointestinal symptoms were recorded daily. Amoxicillin decreased total fecal bacteria and increased E. coli. The prebiotic significantly increased bifidobacteria from 8.17 +/- 1.46 on d 0 to 8.54 +/- 1.20 on d 7 compared with the control 8.22 +/- 1.24 on d 0 versus 7.95 +/- 1.54 on d 7. The Lactobacillus population showed a similar tendency while the other bacteria were unaffected. No gastrointestinal symptoms were detected during the prebiotic administration. Prebiotics in a milk formula increase fecal bifidobacteria early after amoxicillin treatment without inducing gastrointestinal symptoms.

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Effect of a milk formula with prebiotics on the intestinal microbiota of infants after an antibiotic treatment.

The effects of a nucleotide-supplemented formula on diarrhoeal disease was studied in 141 infants (group 1) who belonged to the low socioeconomic stratum; 148 controls (group 2) received the same formula but unsupplemented. Group 1 experienced less episodes of diarrhoea (109 versus 140), including less first episodes (74 versus 102; chi-square = 8.19, p < 0.004; odds ratio 2.01) and for a lesser number of days (807 versus 996 days); 45.0% and 31.1% of infants in groups 1 and 2, respectively, never developed episodes of diarrhoea. There were no differences in the clinical characteristics of the episodes or in the enteropathogens isolated from symptomatic or asymptomatic infants. The mechanisms through which nucleotides decrease the incidence of diarrhoeal disease in infants remain unclear.

Effect of dietary nucleotide supplementation on diarrhoeal disease in infants

Aim To evaluate the effect of a probiotic, Lactobacillus acidophilus LB (LB), or a synbiotic, Saccharomyces boulardii plus inulin (SbI), on Helicobacter pylori (Hp) colonization in children. Subjects and methods A clinical trial was carried out in a school from a low socio-economic area of Santiago. Two hundred and fifty-four asymptomatic children (8.40+/-1.62 y) were screened for Hp by the (13)C-Urea Breath Test ((13)C-UBT). Hp-positive children were randomly distributed into three groups to receive either antibiotic treatment (lanzoprazole, clarythromycin and amoxicillin) for 8 d, or SbI or LB daily for 8 wk. A second (13)C-UBT was carried out at this time. Spontaneous clearance was evaluated in the same way in 81 infected, untreated children. The differences in the delta(13)CO(2) over baseline values before and after treatments (?DOB) were evaluated. Results 182 subjects (71.7%) were colonized by Hp, and 141 of them completed their treatment (22.5% dropout). Hp was eradicated in 66%, 12% and 6.5% of the children from the Ab, SbI and LB groups, respectively, while no spontaneous clearance was observed in the children without treatment. A moderate but significant difference in ?DOB was detected in children receiving living SbI (-6.31; 95% CI: -11.84 to -0.79), but not in those receiving LB (+0.70; 95% CI: -5.84 to +7.24). Conclusion S. boulardii seems promising as an agent that interferes with Hp in colonized individuals. More studies are needed to confirm these results and to elucidate the mechanisms by which Sb inhibits Hp.

Oscar Brunser

Papers

Systematic review: are probiotics useful in controlling gastric colonization by Helicobacter pylori?

Effect of a milk formula with prebiotics on the intestinal microbiota of infants after an antibiotic treatment.

Effect of dietary nucleotide supplementation on diarrhoeal disease in infants

Effect of regular ingestion of Saccharomyces boulardii plus inulin or Lactobacillus acidophilus LB in children colonized by Helicobacter pylori

Jejunal Mucosa in Infant Malnutrition