Nutrition Publication

NNIW64 -Microbial–Host Interaction: Tolerance versus Allergy

Editor(s): P. Brandtzaeg, E. Isolauri, S.L. Prescott. vol. 64

The past 20 years research has evolved enormously on the topic of allergy, tolerance and immunology and one specific topic that has currently moved to the centre of allergy research is the role that microbes and their interaction with the host play in the process of immune programming. This workshop brought outstanding scientists to discuss changing environmental factors, including nutritional changes impacting on early microbe-host interaction and thus immune programming. New approaches to allergy prevention and ways to favour oral tolerance development along with the role of dietary compounds and allergens to treat food allergies have been largely discussed.

Related Articles

A Paradigm for Commensalism: The Role of a Specific Microbial Polysaccharide in Health and Disease

Author(s): D.L. Kasper

The human gastrointestinal tract is colonized by 100 trillion microorganisms, including both beneficial and potentially pathogenic species. A zwitterionic polysaccharide (PSA) from the gastrointestinal microorganism Bacteroides fragilis has been shown to be the archetypal molecule of commensal bacteria that mediates development of the host immune system. PSA stimulates the normal balance of Th1 and Th2 CD4+ T cells and can correct histologic defects in the spleen and thymus of germ-free mice. PSA stimulates the innate immune system as a ligand for Toll-like receptor 2 and thereby promotes interactions with the adaptive immune system that are required for T-cell activation. PSA protects animals from colitis induced by Helicobacter hepaticus, a commensal with pathogenic potential. In animals harboring a B. fragilis mutant that does not express PSA, H. hepaticus colonization leads to disease and proinflammatory cytokine production in colonic tissues. Purified PSA administered to animals suppresses the production of the proinflammatory cytokine interleukin-17 by intestinal immune cells. PSA protects animals from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. Thus polysaccharides of the bacterial microbiota can mediate the critical balance between health and disease in the host. As evidence accumulates, this concept is being accepted as an important feature of the immune repertoire.

The Hygiene Hypothesis: Do We Still Believe in It?

Author(s): B. Björkstén

Numerous epidemiological studies suggest that there is an inverse relationship between allergic diseases and infections in early childhood, but there are also several well-conducted epidemiological studies that seemingly contradict this relationship. The maturation of the immature immune regulation after birth is largely driven by exposure to microbes. Germ-free animals manifest excessive immune responses when immunized and they do not develop normal immune regulation. The controversy regarding the role of infections for subsequently developing allergy is partly due to varying clinical definitions of ‘allergy’. Thus, wheezing and asthma have often been included as outcomes. The hypothesis that commensal microbes are the normal stimulants for the maturation towards a balanced immune response is relevant for IgE-mediated disease manifestations, rather than recurrent bronchial obstruction per se. Epidemiological, clinical and animal studies taken together suggest that broad exposure to a wealth of commensal, non-pathogenic microorganisms early in life are associated with protection, not only against IgE-mediated allergies, but also conceivably against type-1 diabetes and inflammatory bowel disease. This has little relationship with ‘hygiene’ in the usual meaning of the word. The term ‘hygiene hypothesis’ is unfortunate, as it is misleading. A better term would be ‘microbial deprivation hypothesis’.

‘ABC’ of Mucosal Immunology

Author(s): P. Brandtzaeg

Two adaptive homeostatic mechanisms normally preserve mucosal integrity: (i) immune exclusion mediated by secretory antibodies to inhibit penetration of potentially dangerous microorganisms and proteins, and (ii) immunosuppression to counteract hypersensitivity against innocuous antigens. The latter mechanism is called ‘oral tolerance’ when induced via the gut. Similar mechanisms are suppressive against commensal bacteria. Such two-layered anti-inflammatory defense explains why persistent allergy to dietary proteins is not more common, with the exception of gluten intolerance (celiac disease) where abrogation of mucosal homeostasis is overt. Thus, mucosally induced tolerance is generally a robust adaptive mechanism in view of the fact that a ton of food may pass annually through the gut of an adult – regularly giving rise to uptake of intact dietary antigens in the nanogram range after a meal. However, the immunoregulatory network and the epithelial barrier are poorly developed in the neonatal period, which therefore is critical with regard to priming for allergy. Notably, the postnatal development of mucosal immune homeostasis depends on appropriate microbial colonization. In this process, antigen-presenting cells are ‘decision makers’, linking innate and adaptive immunity. Their microbe-sensing function is influenced by both microbial products and dietary constituents, including vitamin A and lipids such as polyunsaturated n-3 fatty acids.

Innate and Adaptive Immune Pathways to Tolerance

Author(s): C.A. Thornton, G. Morgan

There is a vast scientific literature on the innate and adaptive immune responses that contribute to the development of tolerance with growing appreciation that innate and adaptive immunity do not function independently of each other. Innate immune pathways of current interest are those involving pattern recognition receptors, such as Toll-like receptors, particularly their expression by epithelial cells and dendritic cells at mucosal surfaces. The study of adaptive immune pathways has traditionally focused on specific IgA and the development of effector T-cell populations: the Th1/Th2 paradigm has evolved to encompass Th17 cells. Recent years have seen a dramatic resurgence in the investigation of regulatory T-cell populations that can modify a broad range of immunological activities. Dendritic cells play a key role in linking innate and adaptive immunity. The microenvironment of the dendritic cell at the time of antigen encounter modulates co-stimulatory molecule expression and cytokine production which orchestrate antigen-specific activity by T cells, especially the development of different effector T-cell populations (Th1/Th2/Th17) or regulatory T cells. Cascades of cytokines/chemokines play central roles in many types of immune responses. These include: (i) TGF-; (ii) IL-10, and (iii) thymic stromal lymphopoietin (TSLP). Current paradigms of immunity and tolerance in relation to the development of allergy relate to the interplay between innate and immunoregulatory mechanisms.

Hitting the Mucosal Road in Tolerance Induction

Author(s): U. Wiedermann

Within the last decades a dramatic increase in allergic diseases has been recognized in the Westernized societies, leading to the fact that meanwhile 25–30% of the population is afflicted by allergic disorders. Besides a hereditary disposition, other factors, including a reduced microbial contact early in life or changes in nutrition, might also have influenced this epidemiological development. So far the only causative treatment against type-I allergies is specific immunotherapy. In young and monosensitized patients this treatment is highly efficacious, while there are clear limitations in older or multisensitized patients. Allergy research therefore aims at establishing new and more efficacious treatment strategies in prophylactic as well as therapeutic settings. Our research programs focus on the development of novel allergy vaccines based on the induction of mucosal tolerance. In different mouse models of respiratory allergy mucosal treatment with genetically engineered allergen constructs proved to prevent the development of allergic mono- and multisensitivities. The additional use of mucosal adjuvants seems particularly important to improve therapeutic treatment approaches. Recent studies on the inverse relation of certain parasite infections and the development of allergy prompted us to search for selected parasitic molecules with immunosuppressive properties as potential adjuvant systems for novel allergy vaccines. An overview of our recent studies will be given.

Obesity – Extending the Hygiene Hypothesis

Author(s): E. Isolauri, M. Kalliomäki, S. Rautava, S. Salminen, K. Laitinen

The hygiene hypothesis proposes that the growing epidemic of atopic eczema, allergic rhinoconjunctivitis and asthma is related to reduced exposure to microbes at an early age as a result of environmental changes in the industrialized world. These include improved sanitation and living conditions, vaccinations and antimicrobial therapy, together with declining family size and changes in dietary intake. Recent scientific advances demonstrate that the hygiene hypothesis needs to be extended in three respects. Firstly, rigorous research in the field of probiotics points to the importance of the collective composition and the compositional development of the gut microbiota in consolidation of healthy immune responsiveness. Secondly, immunomodulatory and suppressive immune responses have been shown to complement the original immunological basis of the hygiene hypothesis, the so-called T helper 1/T helper 2 paradigm. Thirdly, host–microbe interaction appears to affect the risk of developing not only atopic disease but also other inflammatory Western lifestyle diseases, including obesity. The results of experimental studies suggest that deviations in gut microbiota composition predispose to excessive energy storage and obesity, and, more recently in humans, aberrant compositional development of the gut microbiota has been shown to precede overweight, inviting enormous possibilities to reach preventive and therapeutic applications in weight management.

Autoimmunity and Diet

Author(s): N. Cerf-Bensussan

Whether diet may influence autoimmunity has been the subject of many unsolved debates. Interestingly, growing evidence indicates a large overlap between the mechanisms controlling tolerance to dietary antigens and autoimmunity. To discuss these links, we will focus on two model human diseases. The first one is IPEX syndrome due to mutations in the X-linked foxp3 gene. Studies of this disease underscore the role of regulatory FOXP3+ T cells in controlling the reactivity against self antigens and the response to dietary proteins in humans. The second is celiac disease, a complex polygenic disease where exposure to dietary wheat proteins can trigger an autoimmunelike attack of the intestine frequently associated with the onset of extra-digestive autoimmune disorders. In the later disease, recent work shed light on the mechanisms that drive the intestinal inflammatory response to gluten and suggests impairment of immunoregulatory mechanisms that control intestinal tolerance and autoimmunity. Yet the exact role of gluten in the pathogenesis of extra-intestinal autoimmunity has not been elucidated. Interestingly, recent work indicates that dietary factors, including vitamin A and breast milk feeding, can protect against the development of harmful responses to dietary proteins. It is unclear whether this protection can apply to the prevention of autoimmunity.

Eosinophilic Esophagitis: Example of an Emerging Allergic Manifestation?

Author(s): R.G. Heine

Over the past decade, there has been a significant increase in the number of children and adults with eosinophilic esophagitis (EE). This recently recognized form of chronic pan-esophagitis is characterized by dense eosinophilic infiltration of the esophageal mucosa. EE is closely associated with male gender and allergic disorders, such as food allergy, eczema and asthma. The diagnosis relies on demonstration of increased numbers of eosinophils (≥15 per high power field) in esophageal biopsies. There is clinical overlap between EE and gastroesophageal reflux disease (GERD). Patients with EE typically present with reflux symptoms but are unresponsive to proton pump inhibitor therapy. While dysphagia, regurgitation and retrosternal pain are the clinical hallmarks of EE, many patients are asymptomatic. Treatment aims to prevent long-term complications, such as acute food bolus impaction or esophageal strictures. In childhood, treatment relies on elemental or elimination diets. Skin prick and atopy patch testing have proved useful in guiding specific dietary elimination. In adolescents and adults, broad-based elimination diets are commonly not tolerated or may be ineffective. These patients may respond to swallowed corticosteroid aerosols or other immune-modulating drugs. Further prospective clinical trials are needed to outline the most effective long-term treatment of EE.

Microbial–Host Interactions in Inflammatory Bowel Diseases and Experimental Colitis

Author(s): R.B. Sartor

The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are immunologically mediated with genetic and environmental influences. Genetic factors include defective immunoregulation, mucosal integrity/repair and bacterial killing. Commensal bacteria activate pathogenic bacterial antigen-specific effector T cells that cause chronic inflammation in genetically susceptible hosts but induce protective immune responses in normal subjects. Both host and microbial specificities are important. Some bacterial species are aggressive, some are neutral and others protective, but each species has different effects in various hosts. Molecular techniques demonstrate contraction of certain bacterial populations in IBD, especially clostridial subsets, and expansion of others, including Enterobacteriaceae. The balance of beneficial and detrimental bacterial species determines homeostasis vs. inflammation; this balance can be manipulated by antibiotics, probiotics and prebiotics to treat and prevent relapses of IBD. Adherent/invasive Escherichia coli that adhere to and invade epithelial cells and resist killing by macrophages are increased in ileal CD. Hypothesis: Invasive, translocating, intracellular commensal bacteria induce Th1 and Th17 responses that cause CD in susceptible individuals with genetically determined innate immune defects. UC is caused by bacterial metabolic products that induce epithelial injury by blocking epithelial metabolism or overwhelming the genetically susceptible host’s ability to degrade reactive oxygen species.

Development and Regulation of Immune Responses to Food Antigens in Pre- and Postnatal Life

Author(s): H. Renz, P.I. Pfefferle, R. Teich, H. Garn

Food antigens are harmless environmental components. The physiological response is the development of clinical and immunological tolerance. It is now well appreciated that tolerance development is the result of active immunoregulation and depends on a close interaction between the innate and adaptive immune system resulting in the development of tolerance-mediating T-cell responses. Programming of the immune system, particularly with regard to tolerance development, already starts before birth and stays under close control of the maternal immune system. Therefore, the preand postnatal period represents an important ‘window of opportunity’ for immunoprogramming. Underlying mechanisms include maternal cell transmission, antibody transfer, transfer of mediates/cytokines, and transmission of antigens and allergens. Immunoprogramming is fostered and augmented in the context of microbial components. Recently, several microbes have been identified which possess the capacity of immunoprogramming early in life. Epigenetic regulation represents an important novel mechanism in this regard. This concept opens new avenues for the development of preventive strategies to avoid inappropriate immune responses against food antigens.

Novel Approaches in Treating Food Allergy Using Allergens

Author(s): F. Rancé

Food allergy may be life-threatening and its management continues to consist of avoiding relevant allergens and, in the case of accidental ingestion, initiation of appropriate emergency therapy. The purpose of this review is to highlight the most promising novel approaches for treating food allergy using allergens. The use of specific immunotherapy for food allergy treatment is described. Clinical trials of immunotherapy have been published in the past. However, randomized, placebo-controlled studies are needed, including the evaluation of immune mechanisms. Immunotherapy is mainly indicated for persistent food allergy after the usual age of recovery. Reactive dose and symptoms of food allergy are less defined to indicate immunotherapy. Several procedures have been described: subcutaneous with constant adverse effects; oral tolerance induction with efficacy in a third of the cases, and sublingual which seems promising. The significance of the immunotherapy effect, persistent or transitory, or increasing the tolerated dose need to be defined.

Allergen Avoidance Approaches in Food Allergy Management

Author(s): S. Koletzko, B. Koletzko

Dietary elimination of causative food ingredients, usually food proteins, is the basis of treating food hypersensitivity. Proper diagnostic assessment is essential to avoid burdening children with unnecessary dietary restrictions with potential adverse effects. Diagnosis requires a detailed history, allergen elimination, and re-challenge with suspected foods. Complete elimination of causative food components depends on professional counseling and training of the patient and family, and transparent labeling of food products. Elimination diets carry the risk of inducing insufficient supplies of critical nutrients with adverse effects on health and wellbeing, particularly in children with exclusion of foods that provide a major part of dietary supply and patients with multiple food allergies. Infants and young children with cow’s milk allergy, who have not been fully breastfed, require milk substitutes based on extensively hydrolyzed protein or amino acids. Elimination diets must be supervised and monitored to a similar degree as drug treatments, and the need for continued dietary elimination should be reviewed on a regular basis and re-challenges considered.

Role of Dietary Immunomodulatory Factors in the Development of Immune Tolerance

Author(s): S.L. Prescott

The development of oral tolerance occurs during critical early stages of immune development. Rising rates of food allergy and other immune-mediated food reactions are an indication that oral tolerance is highly susceptible to environmental change. There is growing evidence that this many not be due food allergens per se, but rather to changing exposure to other key immunomodulatory exposures in this critical period. Successful tolerance appears to depend on many concurrent environmental influences during the period of first allergen encounter, including favorable gut colonization, and the presence of key immunomodulatory factors in breast milk and the infant diet. This review explores the potential effects of early dietary and nutritional factors in tolerogenic immune processes that are normally initiated during initial food allergen encounter.

Microbial–Host Interactions: Selecting the Right Probiotics and Prebiotics for Infants

Author(s): S. Salminen,M.C. Collado, ME. Isolauri, M. Gueimonde

Probiotics were originally used to influence human health through intestinal microbiota alterations. At present, probiotics and their effects on human health have been demonstrated both within different food matrices and as single or mixed culture preparations. The health-promoting properties are known to be strain-dependent. Thus, strain identification and characterization are important: only well-characterized strains identified with modern techniques are acceptable, especially if health claims are desired. Linking the strain to a specific health effect as well as to enable accurate surveillance and epidemiological studies are important targets. Currently there are specific strains which have demonstrated beneficial in vitro properties and clinically proven health benefits. Such specific probiotics have been included in recommendations on pediatric nutrition. The model is the microbiota of the healthy breastfed infant. Molecular methods in microbiota assessment enable more specific probiotics and prebiotics to be identified for infants with aberrancies in intestinal microbiota. Probiotic products require information on the concentration and viability of the strain(s) in the product as well as data on required dosages. Continuous control of probiotic strains or strain combinations is a must as small changes in production process or growth media may significantly affect the properties of a strain or strain combination.

Probiotics and Prebiotics: Immunological and Clinical Effects in Allergic Disease

Author(s): M.L.K. Tang

The intestinal microbiota plays an important role in immune development and may play a role in the development of allergic disorders. Manipulation of the intestinal microbiota may therefore offer an approach to the prevention or treatment of allergic diseases. Probiotics and prebiotics, used alone or together (synbiotics), can influence the intestinal microbiota and modulate immune responses in vitro and in vivo. Clinical studies suggest a potential role for selected probiotics (alone or in combination with prebiotics) in the prevention of atopic eczema. A prenatal component of treatment appears important for beneficial effects. Effects are dependent upon the specific bacteria and characteristics of the study population. One study reported beneficial effects for prebiotics in the prevention of eczema in high-risk infants, however, further studies are required to confirm this. The use of probiotics in the treatment of allergic disease is less promising. A Cochrane meta-analysis concluded that probiotics are not effective for the treatment of atopic dermatitis. Probiotic effects in the treatment of asthma and allergic rhinitis are conflicting. Probiotics, prebiotics and synbiotics offer potential treatments for the prevention of atopic eczema; however, there is currently insufficient evidence to recommend their use in clinical practice. Studies to clarify the optimal dose, bacterial species/strains, whether there is added benefit with synbiotics, the optimal timing for intervention, and the patient populations who would benefit most from such therapies are warranted.

Modified Proteins in Allergy Prevention

Author(s): A. Von Berg

Around 2.5% of neonates experience hypersensitivity reactions to cow’s milk protein during the first year of life, which is highly associated with early exposure to cow’s milk. To prevent early allergy development, cow’s milk proteins in infant formulas were modified by hydrolyzation processes for use in children at high atopic risk who need milk supplementation in the first months of life. Dependent on the degree of modification, hydrolyzed cow’s milk formulas are differentiated into extensively and partially hydrolyzed whey or casein hydrolysates (pHF, eHF). However, their allergy-preventive potential seems not only to dependent on the degree but also on the process of hydrolysis. pHF and eHF can be used for primary prevention of allergy in infants at high atopic risk, while only eHFs are indicated for secondary prevention in patients with manifest cow’s milk allergy. In clinical trials a consistent trend to a reduction in atopy, mainly atopic eczema and food allergy, by certain pHFs and eHFs could be demonstrated in children with a familial risk of atopy until the age of 6 years. Because more than 50% of allergic children do not have a family history of atopy, it would be worthwhile to consider primary allergy prevention with hydrolysates for all children who need supplementation to breastfeeding.


Author(s): P. Brandtzaeg, E. Isolauri, S.L. Prescott

The fundamental aim of this conference was to add new dimensions to our understanding of how complex gene–environmental interactions influence immune programming and disease predisposition. This theme was selected based on the concerning global rise in many diseases associated with immune dysfunction, including allergic diseases and many autoimmune conditions. While these disorders have been most prevalent in industrialized countries, the same concerning trends are now being observed in many developing countries as they also undergo complex environmental change. All of these conditions arise as a result of inappropriate responses to otherwise innocuous environmental or self antigens. The very fact that these immune disorders are susceptible to environmental change highlights that environmental modification may also be useful for disease prevention, and this is the ultimate goal of research in this field. Thus, understanding candidate environmental factors that influence immune programming and how these interact with genetic predisposition, is fundamental for determining more effective strategies for preventing immune disease. As one of the leading candidates in the allergy epidemic, microbial exposure was of central interest to our discussions, particularly how early colonization interacts with antigen exposure and other immunomodulatory exposures to influence immune development...

Concluding Remarks

Author(s): P. Brandtzaeg, E. Isolauri, S.L. Prescott

So we are now coming to an end; the summary and concluding session. As the senior partner in this team of chairpersons, I would like to start by expressing my sincere thanks to the Nestlé Nutrition Institute, Ferdinand Haschke and Petra Klassen for taking the initiative for this conference. It’s more than a year since we met in Helsinki and started planning, and it has been a great pleasure all the way....