Regulation of mucosal immune responses in effector sites

In human disease and rodent models, immune responses in the intestinal mucosa can be damaging. Damage is characterised by villus atrophy, crypt hyperplasia and reduced ability to digest and absorb nutrients. In normal individuals active responses to harmless environmental antigens associated with food and commensal bacteria are controlled by the development of immunological tolerance. Similar pathological changes occur in piglets weaned early from their mothers. Active immune responses to food antigens are observed in these piglets, and we and others have hypothesised that the changes occur as a result of transient allergic immune responses to novel food or bacteria antigens. The normal mechanism for producing tolerance to food antigens may operate at induction (Peyer's patches and mesenteric lymph nodes) or at the effector stage (intestinal lamina propria). In our piglet studies immunological tolerance occurs despite the initial active response. Together with evidence from rodents, this observation suggests that active responses are likely to be controlled at the effector stage, within the intestinal lamina propria. Support for this mechanism comes from the observation that human and pig intestinal T-cells are susceptible to apoptosis, and that this process is accelerated by antigen. We suggest that the role of the normal mature intestinal lamina propria is a balance between immunological effector and regulatory function. In neonatal animals this balance develops slowly and is dependant on contact with antigen. Immunological insults such as weaning may tip the balance of the developing mucosal immune system into excessive effector or regulatory function resulting in transient or chronic allergy or disease susceptibility.     

Dietary microparticles and their impact on tolerance and immune responsiveness of the gastrointestinal tract

Dietary microparticles are non-biological bacterial-sized particles of the gastrointestinal lumen that occur due to endogenous formation (calcium phosphate) or following oral exposure (exogenous microparticle). In the UK, about 40 mg (10(12)) of exogenous microparticles are ingested per person per day, through exposure to food additives, pharmaceutical/supplement excipients or toothpaste constituents. Once ingested, exogenous microparticles are unlikely to pass through the gastrointestinal tract without adsorbing to their surfaces some ions and molecules of the intestinal lumen. Both entropy and ionic attraction drive such interactions. Calcium ions are especially well adsorbed by dietary microparticles which then provide a positively charged surface for the attraction (adsorption) of other organic molecules such as lipopolysaccharides, peptidoglycans or protein antigen from the diet or commensal flora. The major (but not only) sites of microparticle entry into intestinal tissue are the M-cell rich lymphoid aggregates (termed Peyer's patches in the small bowel). Indeed, it is well established that this is an efficient transport route for non-biological microparticles although it is unclear why. We hypothesise that this pathway exists for "endogenous microparticles" of calcium phosphate, with immunological and physiological benefit, and that "exogenous dietary microparticles", such as titanium dioxide and the silicates, hijack this route. This overview focuses on what is known of these microparticles and outlines their potential role in immune tolerance of the gut (endogenous microparticles) or immune activation (exogenous microparticles) and inflammation of the gut.     

The development of the mucosal immune system pre- and post-weaning: balancing regulatory and effector function

The mucosal immune system fulfils the primary function of defence against potential pathogens that may enter across vulnerable surface epithelia. However, a secondary function of the intestinal immune system is to discriminate between pathogen-associated and 'harmless' antigens, expressing active responses against the former and tolerance to the latter. Control of immune responses appears to be an active process, involving local generation of IgA and of regulatory and/or regulated T lymphocytes. Two important periods of maximum exposure to novel antigens occur in the young animal, immediately after birth and at weaning. In both cases the antigenic composition of the intestinal contents can shift suddenly, as a result of a novel diet and of colonisation by novel strains and species of bacteria. Changes in lifestyles of man, and husbandry of animals, have resulted in weaning becoming much more abrupt than previously in evolution, increasing the number of antigens that must be simultaneously evaluated by neonates. Thus, birth and weaning are likely to represent hazard and critical control points in the development of appropriate responses to pathogens and harmless dietary and commensal antigens. Neonates are born with relatively undeveloped mucosal immune systems. At birth this factor may prevent both expression of active immune responses and development of tolerance. However, colonisation by intestinal flora expands the mucosal immune system in antigen-specific and non-specific ways. At weaning antibody to fed proteins can be detected, indicating active immune responses to fed proteins. It is proposed that under normal conditions the ability of the mucosal immune system to mount active responses to foreign antigens develops simultaneously with the ability to control and regulate such responses. Problems arise when one or other arm of the immune system develops inappropriately, resulting in inappropriate effector responses to harmless food proteins (allergy) or inadequate responses to pathogens (disease susceptibility).     

Early nutrition and immunity - progress and perspectives

The immune system exists to protect the host against pathogenic organisms and highly complex pathways of recognition, response, elimination and memory have evolved in order to fulfil this role. The immune system also acts to ensure tolerance to 'self', to food and other environmental components, and to commensal bacteria. A breakdown in the tolerogenic pathways can also lead to inflammatory diseases. The prevalence of inflammatory diseases, including atopic disorders, has increased over the last 60 years. The development of tolerance is the result of active immune mechanisms and both development and maintenance of tolerance are lifelong processes which start very early in life, even prenatally. Profound immunologic changes occur during pregnancy, involving a polarization of T helper (Th) cells towards a dominance of Th2 and regulatory T cell effector responses in both mother and fetus. This situation is important to maintain pregnancy through avoidance of the rejection of the immunologically incompatible fetus. During the third trimester of human pregnancy, fetal T cells are able to mount antigen-specific responses to environmental and food-derived antigens and antigen-specific T cells are detectable in cord blood in virtually all newborns indicating in utero sensitization. If the neonatal immune system is not able to down-regulate the pre-existing Th2 dominance effectively then an allergic phenotype may develop. Changes occur at, and soon after, birth in order that the immune system of the neonate becomes competent and functional and that the gut becomes colonized with bacteria. Exposure to bacteria during birth and from the mother's skin and the provision of immunologic factors in breast milk are amongst the key events that promote maturation of the infant's gut and gut-associated and systemic immune systems. The introduction of formula and of solid foods exposes the infant to novel food antigens and also affects the gut flora. Nutrition may be the source of antigens to which the immune system must become tolerant, provide factors, including nutrients, that themselves might modulate immune maturation and responses, and provide factors that influence intestinal flora, which in turn will affect antigen exposure, immune maturation and immune responses. Through these mechanisms it is possible that nutrition early in life might affect later immune competence, the ability to mount an appropriate immune response upon infection, the ability to develop a tolerogenic response to 'self' and to benign environmental antigens, and the development of immunologic disorders. A Workshop held in February 2006 considered recent findings in the areas of oral tolerance, routes of sensitization to allergens and factors affecting the development of atopic disease; factors influencing the maturation of dendritic cells and the development of regulatory T cells; the influence of gut microflora on immunity, allergic sensitization and infectious disease; the role of nutrition in preventing necrotizing enterocolitis in an animal model of preterm birth; and the role of PUFA of different classes in influencing immune responses and in shaping the development of atopic disease. This report summarizes the content of the lectures and the subsequent discussions.     

Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Disease

The gastrointestinal (GI) microbiota is the collection of microbes which reside in the GI tract and represents the largest source of non-self antigens in the human body. The GI tract functions as a major immunological organ as it must maintain tolerance to commensal and dietary antigens while remaining responsive to pathogenic stimuli. If this balance is disrupted, inappropriate inflammatory processes can result, leading to host cell damage and/or autoimmunity. Evidence suggests that the composition of the intestinal microbiota can influence susceptibility to chronic disease of the intestinal tract including ulcerative colitis, Crohn’s disease, celiac disease and irritable bowel syndrome, as well as more systemic diseases such as obesity, type 1 diabetes and type 2 diabetes. Interestingly, a considerable shift in diet has coincided with increased incidence of many of these inflammatory diseases. It was originally believed that the composition of the intestinal microbiota was relatively stable from early childhood; however, recent evidence suggests that diet can cause dysbiosis, an alteration in the composition of the microbiota, which could lead to aberrant immune responses. The role of the microbiota and the potential for diet-induced dysbiosis in inflammatory conditions of the GI tract and systemic diseases will be discussed.     

Dendritic cells and immune responses to orally administered antigens

The intestinal immune system discriminates between invasive pathogens and antigens that are harmless, such as food proteins and commensal bacteria. The latter groups of antigens normally induce tolerance and the nature of the intestinal immune response depends on how antigen is presented to CD4+ T cells by dendritic cells (DC). Expanding the numbers of DC in vivo using the cytokine flt3 ligand (flt3L) enhances the susceptibility of mice to the induction of oral tolerance. The relevant DC may be in Peyer's patches (PP), mesenteric lymph node (MLN) or the lamina propria (LP)of the villus mucosa. All these tissues contain a number of distinctive DC subsets, including some that can preferentially induce the differentiation of regulatory T cells. However, we find that the largest proportion of orally administered protein is taken up by DC in the lamina propria. Intestinal DC are not inherently tolerogenic. Under physiological conditions they are "quiescent", capable of presenting antigen and inducing tolerance, but being sufficiently responsive to inflammatory stimuli to allow T cell priming and protective immunity when necessary. Targeting local DC may be a useful means of inducing either tolerance or active immunity. We have achieved this using immune stimulating complexes (ISCOMS) containing Quil A, which are highly immunogenic by the oral route and appear to act by targeting DC preferentially. ISCOMS or saponins such as Quil A may prove useful adjuvants to incorporate in plant derived, mucosally active vaccines.     

Phenotypic localization of distinct DC subsets in mouse Peyer Patch

Peyer's patch have been extensively studied as a major inductive site for mucosal immunity within the small intestine. The intestinal mucosa contains numerous dendritic cells, which induce either protective immunity to infectious agents or tolerance to innocuous antigens, including food and commensal bacteria. Although during the past few years, several subsets of human mucosal dendritic cells have been described, a precise characterization of the different mouse mucosal dendritic cells subpopulations remains to be achieved with regard to their phenotype and localization in Peyer's patch. In this report, we have investigated by immunofluorescence on cryosection and by flow cytometry, the phenotype and the localization of dendritic cells into Peyer's patch of C57Bl/6 mouse intestine using dendritic cells markers. Positive and double staining for CD11c and BDCA-2, pDC/IPC, DC-LAMP, DC-SIGN, TLR8 and Langerin have been observed revealing new mouse intestinal DC subsets. This study provides new insight in the understanding of mucosal immune responses induced by natural processes as infections but also new perspectives for the evaluation of oral vaccines.     

The Mediterranean food pattern: a good recipe for patients with the metabolic syndrome

The metabolic syndrome is a complex condition characterized by dyslipidaemia, high blood pressure, impaired glucose tolerance and abdominal fat accumulation. Subjects with the metabolic syndrome are at high risk of atherosclerosis and coronary heart disease. A comprehensive approach is required for patients suffering this cluster of clinical manifestations. Indeed, subjects with the metabolic syndrome could benefit from life-style modifications, particularly through exercise and diet. In this article, the evidence regarding the role of diet, in particular the role of food patterns based on the Mediterranean-style diet, in preventing and treating the metabolic syndrome are reviewed.     

Dietary Modification of the Intestinal Microbiota

Humans harbor a consortium of commensal bacteria in their gut that are thought to be crucial for normal health. However, the extent of microbial diversity in the gut and the physiologic functions of the microflora have not yet been fully characterized. Molecular tools are now available to characterize the associations between diet, microflora composition, and health in greater depth. New molecular studies have confirmed earlier culture-based observations that diet has a role in the regulation of microflora composition. In the near future, new insight into these associations should allow for the design of specific diets aimed at improving health by modulating microflora .     

Comparison between Sardinia and Malta: the Mediterranean diet revisited

The Mediterranean diet is often characterized in terms of food items only. In this paper, the comparison of meals, in-between meals snack consumption and total daily food intake is presented between Sardinia and Malta in terms of structure, social environment and hours, together with their changes. Data were collected in 2001 in Sardinia and 2002 in Malta. A structured qualitative questionnaire, articulated around four main themes: food supply, transformation, preparation and consumption habits, was administered by face-to-face interviews with the help of a local person. Inquiries were carried out over two generations with 30 'mother-daughter' couples in each island. We highlighted some Mediterranean characteristics in Sardinia by showing striking contrasts between Sardinian and Maltese food habits such as meal preparation times, both breakfast and main meal structures, total daily food intake profiles, mealtimes and commensality in the mothers' generation. Some of these characteristics were also maintained in the daughters' generation. This investigation has presented evidence that beyond foods, meal pattern, structure and commensal rituals appeared as fundamental aspects of Sardo-Mediterranean food habits, which are important to consider when trying to maintain or implement the Mediterranean dietary model.     

Position of the American Dietetic Association: Functional foods

It is the position of the American Dietetic Association that functional foods, including whole foods and fortified, enriched, or enhanced foods, have a potentially beneficial effect on health when consumed as part of a varied diet on a regular basis, at effective levels. The Association supports research to define further the health benefits and risks of individual functional foods and their physiologically active components. Dietetics professionals will continue to work with the food industry, the government, the scientific community, and the media to ensure that the public has accurate information regarding this emerging area of food and nutrition science. Knowledge of the role of physiologically active food components, from both phytochemicals and zoochemicals, has changed the role of diet in health. Functional foods have evolved as food and nutrition science has advanced beyond the treatment of deficiency syndromes to reduction of disease risk. This position reviews the definition of functional foods, their regulation, and the scientific evidence supporting this emerging area of food and nutrition. Foods can no longer be evaluated only in terms of macronutrient and micronutrient content alone. Analyzing the content of other physiologically active components and evaluating their role in health promotion will be necessary. The availability of health-promoting functional foods in the US diet has the potential to help ensure a healthier population. However, each functional food should be evaluated on the basis of scientific evidence to ensure appropriate integration into a varied diet.     

Artificial food dyes and attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most common behavioral disorders in children. Symptoms of ADHD include hyperactivity, low frustration tolerance, impulsivity, and inattention. While the biological pathways leading to ADHD are not clearly delineated, a number of genetic and environmental risk factors for the disorder are recognized. In the early 1970s, research conducted by Dr. Benjamin Feingold found that when hyperactive children were given a diet free of artificial food additives and dyes, symptoms of hyperactivity were reduced. While some clinical studies supported these findings, more rigorous empirical studies conducted over the next 20 years were less positive. As a result, research on the role of food additives in contributing to ADHD waned. In recent years, however, interest in this area has revived. In response to more recent research and public petitions, in December 2009 the British government requested that food manufacturers remove most artificial food dyes from their products. While these strictures could have positive effects on behavior, the removal of food dyes is not a panacea for ADHD, which is a multifaceted disorder with both biological and environmental underpinnings.     

Utilization of gut environment-mediated control system of host immunity in the development of vaccine adjuvants

Vaccination is one of the most powerful strategies for the preventive and therapeutic control of infectious diseases and other diseases such as cancer. To maximize the effectiveness of vaccines, it is necessary to modify the immune responses by means of adjuvants. The gut environment, including commensal bacteria and dietary components, has been proven to be able to mediate host immunity. An understanding of gut microbiota–related regulation of immune responses has revealed the potential adjuvanticity of particular microbiota-derived compounds, driving exploration into their development as vaccine adjuvants. In this review, we discuss how commensal bacteria and compounds derived from them regulate host immune responses, and we propose the potential application of these compounds as vaccine adjuvants.     

Alteration of glucose tolerance by dietary L-tryptophan in rats.

L-Tryptophan is known to have pharmacological effects on carbohydrate metabolism. In a scrutiny for possible physiological relationships, intravenous glucose tolerance was measured in rats fed various diets of defined L-tryptophan-content. Within 14 days, animals which had been fed a tryptophan-deficient diet diet removed excess glucose from their blood at a reduced rate. This decreased tolerance to glucose was dose dependent to dietary L-tryptophan and the intolerance was reversed by feeding a complete diet. The intolerance was not dependent on dietary protein source, not reversed by added niacin or vitamin B-6, not a necessary consequence of decreased food consumption and growth, and not duplicated by a lack of dietary lysine. The results suggest that dietary L-tryptophan is active in physiological regulation of carbohydrate metabolism.     

高糖高脂饲料对Wistar大鼠生长和糖脂代谢的影响

目的观察高糖高脂饲料对Wistar大鼠生长及糖脂代谢的影响。方法雄性Wistar大鼠20只,按体重和空腹血糖随机分为2组(n=10):对照组和实验组,分别以普通饲料和高糖高脂饲料喂养6周,观察大鼠的生长曲线、食物利用率,测定大鼠的糖脂代谢指标。结果喂养6周后,实验组大鼠的体重、食物利用率、内脏脂肪占体重百分比、血清总胆固醇和低密度脂蛋白胆固醇均显著高于对照组(P<0.05),血清高密度脂蛋白胆固醇显著低于对照组(P<0.01)。两组的空腹血糖(FPG)无显著差异。实验组大鼠的糖耐量降低,葡萄糖曲线下面积显著高于对照组。结论正常血糖状态下,高糖高脂饲料可引起Wistar大鼠中心型积聚的体脂增加,血清总胆固醇增加,导致葡萄糖耐量能力减退,为2型糖尿病进程中的重要危险因素。     

The IGD report ‘Energy density and its role in helping consumers make healthy choices’: a resource for food businesses

Energy density is the energy (calorie) content per unit weight of a food, meal or diet. It is important in terms of its impact on an individual's energy intake and overall energy balance. With obesity as a major public health issue in the UK and many other countries, encouraging intake of foods that are lower in energy density could help consumers to reduce their energy intake and eat a healthy, balanced diet. The food industry has a role in helping consumers achieve a healthy, balanced diet. Incorporating energy density as an element of the design or development of their products is one way through which food businesses might support this aim. The Institute of Grocery Distribution's (IGD) Industry Nutrition Strategy Group has produced a report for food businesses to help them to consider energy density as part of new product development or product reformulation. ‘The role of energy density in helping consumers make healthy choices’ provides information on energy density and its role in energy balance, techniques to adjust the energy density of foods, with guidance on using this concept in consumer communications.     

Ameliorating effects of water-soluble polysaccharides from woody ear (Auricularia auricula-judae Quel.) in genetically diabetic KK-Ay mice

We investigated the ameliorating effects of the three groups of water-soluble polysaccharides, a mixture of crude polysaccharides (FA), acidic polysaccharide fractions (FA-A), and neutral polysaccharide fractions (FA-N), obtained from the hot water extracts of the fruit bodies of Auricularia auricula-judae Quel. In genetically diabetic KK-Ay mice from 6 to 11 weeks of age. Male mice were divided into five dietary groups: 1) control group, given a basal diet; 2) FA group, given an FA diet (15 g FA/kg diet); 3) FA-A group, given an FA-A diet (8 g FA-A/kg diet); 4) low FA-N group, given a low FA-N diet (2 g FA-N/kg diet); and 5) high FA-N group, given a high FA-N diet (8 g FA-N/kg diet). Compared with the control diet, FA supplementation had significant effects in lowering fasting and nonfasting blood glucose, HbA1c, urinary glucose, food intake, and water intake. FA administration also improved glucose tolerance to intraperitoneal glucose loading, but it did not affect the nonfasting insulin level. FA-N supplementation had dose-dependent effects in lowering fasting and nonfasting food glucose, insulin, HbA1c, urinary glucose, food intake, and water intake. However, the glucose tolerance was not ameliorated by either the low or the high FA-N diet. FA-A administration showed no beneficial effects in KK-Ay mice.     

Consumption of rice bran increases mucosal immunoglobulin A concentrations and numbers of intestinal Lactobacillus spp

Gut-associated lymphoid tissue maintains mucosal homeostasis by combating pathogens and inducing a state of hyporesponsiveness to food antigens and commensal bacteria. Dietary modulation of the intestinal immune environment represents a novel approach for enhancing protective responses against pathogens and inflammatory diseases. Dietary rice bran consists of bioactive components with disease-fighting properties. Therefore, we conducted a study to determine the effects of whole dietary rice bran intake on mucosal immune responses and beneficial gut microbes. Mice were fed a 10% rice bran diet for 28 days. Serum and fecal samples were collected throughout the study to assess total immunoglobulin A (IgA) concentrations. Tissue samples were collected for cellular immune phenotype analysis, and concentrations of native gut Lactobacillus spp. were enumerated in the fecal samples. We found that dietary rice bran induced an increase in total IgA locally and systemically. In addition, B lymphocytes in the Peyer's patches of mice fed rice bran displayed increased surface IgA expression compared with lymphocytes from control mice. Antigen-presenting cells were also influenced by rice bran, with a significant increase in myeloid dendritic cells residing in the lamina propria and mesenteric lymph nodes. Increased colonization of native Lactobacillus was observed in rice bran-fed mice compared with control mice. These findings suggest that rice bran-induced microbial changes may contribute to enhanced mucosal IgA responses, and we conclude that increased rice bran consumption represents a promising dietary intervention to modulate mucosal immunity for protection against enteric infections and induction of beneficial gut bacteria.     

Effects of prostaglandin modifiers and zinc deficiency on possibly related functions in rats

Experiments were conducted to investigate the role of prostaglandins (PG) in zinc absorption and biological functions (food intake and weight gain, alkaline phosphatase activity, T-cell-mediated immune response). PG levels were modified by administering an inhibitor of their synthesis, aspirin or indomethacin in the diet. Zinc level was modified by controlling the dietary concentration. Weanling rats were fed the assigned diets for 1 month after which they were anesthetized with ether. Samples of blood, gut contents and mucosa, liver, lung and tibia were collected for zinc, PG, lymphocyte stimulation with T-cell mitogen, and alkaline phosphatase assays. There was more than 50% inhibition of PG synthesis by indomethacin and aspirin. This inhibition of PG synthesis, however, did not affect the zinc status of the rats as measured by general appearance, food intake, weight gain, organ weight, zinc concentration in different organs, serum alkaline phosphatase activity, and cell-mediated immune response to T-cell mitogens. It is concluded that under physiological conditions inhibitors of PG synthesis do not alter these zinc metabolic functions.     

Effects of kiwifruit extracts on colonic gene and protein expression levels in IL-10 gene-deficient mice

Inflammatory bowel disease (IBD) is a collective term for conditions characterised by chronic inflammation of the gastrointestinal tract involving an inappropriate immune response to commensal micro-organisms in a genetically susceptible host. Previously, aqueous and ethyl acetate extracts of gold kiwifruit (Actinidia chinensis) or green kiwifruit (A. deliciosa) have demonstrated anti-inflammatory activity using in vitro models of IBD. The present study examined whether these kiwifruit extracts (KFE) had immune-modulating effects in vivo against inflammatory processes that are known to be increased in patients with IBD. KFE were used as a dietary intervention in IL-10-gene-deficient (Il10(-/-)) mice (an in vivo model of IBD) and the C57BL/6J background strain in a 3 × 2 factorial design. While all Il10(-/-) mice developed significant colonic inflammation compared with C57BL/6J mice, this was not affected by the inclusion of KFE in the diet. These findings are in direct contrast to our previous study where KFE reduced inflammatory signalling in primary cells isolated from Il10(-/-) and C57BL/6J mice. Whole-genome gene and protein expression level profiling indicated that KFE influenced immune signalling pathways and metabolic processes within the colonic tissue; however, the effects were subtle. In particular, expression levels across gene sets related to adaptive immune pathways were significantly reduced using three of the four KFE in C57BL/6J mice. The present study highlights the importance of investigating food components identified by cell-based assays with appropriate in vivo models before making dietary recommendations, as a food that looks promising in vitro may not be effective in vivo.