Microbial exposures that establish immunoregulation are compatible with targeted hygiene.

It is often suggested that hygiene is not compatible with the microbial exposures that are necessary for establishment of the immune system in early life. However, when we analyze the microbial exposures of modern humans in the context of human evolution and history, it becomes evident that whereas children need exposure to the microbiotas of their mothers, other family members, and the natural environment, exposure to the unnatural microbiota of the modern home is less relevant. In addition, any benefits of exposure to the infections of childhood within their household setting are at least partly replaced by the recently revealed nonspecific effects of vaccines. This article shows how targeting hygiene practices at key risk moments and sites can maximize protection against infection while minimizing any impact on essential microbial exposures. Moreover, this targeting must aim to reduce direct exposure of children to cleaning agents because those agents probably exert TH2-adjuvant effects that trigger allergic responses to normally innocuous antigens. Finally, we need to halt the flow of publications in the scientific literature and the media that blame hygiene for the increases in immunoregulatory disorders. Appropriately targeted hygiene behavior is compatible with a healthy lifestyle that promotes exposure to essential microorganisms.

Immune responses to tuberculosis in developing countries: implications for new vaccines.

Tuberculosis is out of control in developing countries, where it is killing millions of people every year. In these areas, the present vaccine - Mycobacterium bovis bacillus Calmette-Guérin (BCG) - is failing. Progressive tuberculosis occurs because the potentially protective T helper 1 (T(H)1)-cell response is converted to an immunopathological response that fails to eliminate the bacteria. Here, we discuss the data indicating that the problem in developing countries is not a lack of adequate T(H)1-cell responses but, instead, an exaggerated tendency to switch to immunopathological responses. We propose that a successful vaccine needs to block this immunopathology, because it is not the quantity of T(H)1-cell activity that matters but, rather, its context.

Infection, immunoregulation, and cancer.

As man has moved rapidly from the hunter-gatherer environment to the living conditions of the industrialized countries, the incidences of some cancers have increased alarmingly. Recent increases are usually attributed to dietary changes or to altered exposures to putative carcinogens associated with the modern lifestyle. However, the changes in cancer incidence parallel similar increases in non-neoplastic chronic inflammatory disorders (inflammatory bowel disease, allergies, and autoimmunity), and the epidemiology is often strikingly similar. This parallel is worth exploring, because the increases in chronic inflammatory disorders are at least partly explained by immunoregulatory defects resulting from diminished exposure to microorganisms that co-evolved with mammals and developed a role in driving immunoregulatory circuits (the hygiene hypothesis). Dysregulated chronic inflammation can drive oncogenesis and also provides growth and angiogenic factors that enhance the subsequent proliferation and spread of tumor cells. Thus, a modern failure to downregulate inappropriate inflammation could underlie increases in some cancers in parallel with the increases in chronic inflammatory disorders. This possibility is supported by recent work showing that in some circumstances regulatory T cells protect against cancer, rather than aggravating it, as previously assumed. A greater understanding of these interactions might pave the way to improved microbe-based immunotherapies.

Microbiota, immunoregulatory old friends and psychiatric disorders.

Regulation of the immune system is an important function of the gut microbiota. Increasing evidence suggests that modern living conditions cause the gut microbiota to deviate from the form it took during human evolution. Contributing factors include loss of helminth infections, encountering less microbial biodiversity, and modulation of the microbiota composition by diet and antibiotic use. Thus the gut microbiota is a major mediator of the hygiene hypothesis (or as we prefer, "Old Friends" mechanism), which describes the role of organisms with which we co-evolved, and that needed to be tolerated, as crucial inducers of immunoregulation. At least partly as a consequence of reduced exposure to immunoregulatory Old Friends, many but not all of which resided in the gut, high-income countries are undergoing large increases in a wide range of chronic inflammatory disorders including allergies, autoimmunity and inflammatory bowel diseases. Depression, anxiety and reduced stress resilience are comorbid with these conditions, or can occur in individuals with persistently raised circulating levels of biomarkers of inflammation in the absence of clinically apparent peripheral inflammatory disease. Moreover poorly regulated inflammation during pregnancy might contribute to brain developmental abnormalities that underlie some cases of autism spectrum disorders and schizophrenia. In this chapter we explain how the gut microbiota drives immunoregulation, how faulty immunoregulation and inflammation predispose to psychiatric disease, and how psychological stress drives further inflammation via pathways that involve the gut and microbiota. We also outline how this two-way relationship between the brain and inflammation implicates the microbiota, Old Friends and immunoregulation in the control of stress resilience.

Evolution and the critical role of the microbiota in the reduced mental and physical health associated with low socioeconomic status (SES).

The evolution of the gut-microbiota-brain axis in animals reveals that microbial inputs influence metabolism, the regulation of inflammation and the development of organs, including the brain. Inflammatory, neurodegenerative and psychiatric disorders are more prevalent in people of low socioeconomic status (SES). Many aspects of low SES reduce exposure to the microbial inputs on which we are in a state of evolved dependence, whereas the lifestyle of wealthy citizens maintains these exposures. This partially explains the health deficit of low SES, so focussing on our evolutionary history and on environmental and lifestyle factors that distort microbial exposures might help to mitigate that deficit. But the human microbiota is complex and we have poor understanding of its functions at the microbial and mechanistic levels, and in the brain. Perhaps its composition is more flexible than the microbiota of animals that have restricted habitats and less diverse diets? These uncertainties are discussed in relation to the encouraging but frustrating results of attempts to treat psychiatric disorders by modulating the microbiota.

The old friends hypothesis: evolution, immunoregulation and essential microbial inputs.

In wealthy urbanised societies there have been striking increases in chronic inflammatory disorders such as allergies, autoimmunity and inflammatory bowel diseases. There has also been an increase in the prevalence of individuals with systemically raised levels of inflammatory biomarkers correlating with increased risk of metabolic, cardiovascular and psychiatric problems. These changing disease patterns indicate a broad failure of the mechanisms that should stop the immune system from attacking harmless allergens, components of self or gut contents, and that should terminate inappropriate inflammation. The Old Friends Hypothesis postulates that this broad failure of immunoregulation is due to inadequate exposures to the microorganisms that drive development of the immune system, and drive the expansion of components such as regulatory T cells (Treg) that mediate immunoregulatory mechanisms. An evolutionary approach helps us to identify the organisms on which we are in a state of evolved dependence for this function (Old Friends). The bottom line is that most of the organisms that drive the regulatory arm of the immune system come from our mothers and family and from the natural environment (including animals) and many of these organisms are symbiotic components of a healthy microbiota. Lifestyle changes that are interrupting our exposure to these organisms can now be identified, and many are closely associated with low socioeconomic status (SES) in wealthy countries. These insights will facilitate the development of education, diets and urban planning that can correct the immunoregulatory deficit, while simultaneously reducing other contributory factors such as epithelial damage.

Evolution, the Immune System, and the Health Consequences of Socioeconomic Inequality.

Healthy development and function of essentially all physiological systems and organs, including the brain, require exposure to the microbiota of our mothers and of the natural environment, especially in early life. We also know that some infections, if we survive them, modulate the immune system in relevant ways. If we study the evolution of the immune and metabolic systems, we can understand how these requirements developed and the nature of the organisms that we need to encounter. We can then begin to identify the mechanisms of the beneficial effects of these exposures. Against this evolutionary background, we can analyze the ways in which the modern urban lifestyle, particularly for individuals experiencing low socioeconomic status (SES), results in deficient or distorted microbial exposures and microbiomes. Thus, an evolutionary approach facilitates the identification of practical solutions to the growing scandal of health disparities linked to inequality.

Lymphocytes in neuroprotection, cognition and emotion: is intolerance really the answer?

Clinical, epidemiological and therapeutic studies indicate that some human depression is associated with proinflammatory cytokines, chronic inflammatory disorders, and inflammation-inducing lifestyle factors. Moreover depression can be induced by administration of proinflammatory cytokines, including IL-2 or IFN-α. However, recent studies in specific pathogen-free (SPF) rodents suggest a different--and potentially contradictory--relationship between immune processes and mental health. These studies suggest that effector T cells specific for central nervous system (CNS) antigens can assist recovery from an array of environmental insults ranging from nerve injury to psychological stress, while in contrast, regulatory T cells (Treg) oppose such recovery. Indeed, some reported effects of this so-called "protective autoimmunity" seem of direct relevance to depressive disorders. These findings pose a dilemma for those intending to manipulate inflammatory pathways as a treatment for depression. Should we administer anti-inflammatory treatments, or should we induce self-reactive T cells? We re-examine the rodent findings and outline immunological peculiarities of SPF rodents, the abnormal properties of their regulatory T cells, and the impact of gut microbiota. We find that "protective autoimmunity" is likely to be relevant only to very clean SPF animals that lack normal levels of activated T cells, CNS T cell traffic and mature Treg. The data indicate that even in SPF models the effectors of beneficial effects are not the proinflammatory autoimmune cells themselves, but rather unidentified regulatory cells. This reinterpretation of findings relevant to "protective autoimmunity" suggests that ongoing, and planned, clinical trials of anti-inflammatory strategies to treat depressive disorders are justified.

Hygiene and other early childhood influences on the subsequent function of the immune system.

The current 'Darwinian' synthesis of the hygiene (or 'Old Friends') hypothesis suggests that the increase in chronic inflammatory disorders that started in Europe in the mid-19th century and progressed until the late 20th century is at least partly attributable to immunodysregulation resulting from lack of exposure to microorganisms that were tasked by co-evolutionary processes with establishing the 'normal' background levels of immunoregulation, a role that they perform in concert with the normal microbiota. This is an example of 'evolved dependence'. The relevant organisms co-evolved with mammals, already accompanied early hominids in the Paleolithic era and are associated with animals, mud and faeces. These organisms often establish stable carrier states, or are encountered continuously in primitive environments as 'pseudocommensals' from mud and water. These organisms were not lost during the first epidemiological transition, which might even have resulted in increased exposure to them. However, the crucial organisms are lost progressively as populations undergo the second epidemiological transition (modern urban environment). Recently evolved sporadic 'childhood infections' are not likely to have evolved immunoregulatory roles, and epidemiology supports this contention. The consequences of the loss of the Old Friends and distortion of the microbiota are aggravated by other modern environmental changes that also lead to enhanced inflammatory responses (obesity, vitamin D deficiency, pollution (dioxins), etc.). The range of chronic inflammatory disorders affected may be larger than had been assumed (allergies, autoimmunity, inflammatory bowel disease, but also coeliac disease, food allergy, vascular disease, some cancers, and depression/anxiety when accompanied by raised inflammatory cytokines).

Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis.

Man has moved rapidly from the hunter-gatherer environment to the living conditions of the rich industrialized countries. The hygiene hypothesis suggests that the resulting changed and reduced pattern of exposure to microorganisms has led to disordered regulation of the immune system, and hence to increases in certain inflammatory disorders. The concept began with the allergic disorders, but there are now good reasons for extending it to autoimmunity, inflammatory bowel disease, neuroinflammatory disorders, atherosclerosis, depression associated with raised inflammatory cytokines, and some cancers. This review discusses these possibilities in the context of Darwinian medicine, which uses knowledge of evolution to cast light on human diseases. The Darwinian approach enables one to correctly identify some of the organisms that are important for the 'Hygiene' or 'Old Friends' hypothesis, and to point to the potential exploitation of these organisms or their components in novel types of prophylaxis with applications in several branches of medicine.

Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties.

RATIONALE: Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation in a murine model of allergic asthma. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory effects of M. vaccae are not known. OBJECTIVES: Our objective was to identify and characterize novel anti-inflammatory molecules from M. vaccae NCTC 11659. METHODS: We have purified and identified a unique anti-inflammatory triglyceride, 1,2,3-tri [Z-10-hexadecenoyl] glycerol, from M. vaccae and evaluated its effects in freshly isolated murine peritoneal macrophages. RESULTS: The free fatty acid form of 1,2,3-tri [Z-10-hexadecenoyl] glycerol, 10(Z)-hexadecenoic acid, decreased lipopolysaccharide-stimulated secretion of the proinflammatory cytokine IL-6 ex vivo. Meanwhile, next-generation RNA sequencing revealed that pretreatment with 10(Z)-hexadecenoic acid upregulated genes associated with peroxisome proliferator-activated receptor alpha (PPARα) signaling in lipopolysaccharide-stimulated macrophages, in association with a broad transcriptional repression of inflammatory markers. We confirmed using luciferase-based transfection assays that 10(Z)-hexadecenoic acid activated PPARα signaling, but not PPARγ, PPARδ, or retinoic acid receptor (RAR) α signaling. The effects of 10(Z)-hexadecenoic acid on lipopolysaccharide-stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice. CONCLUSION: Future studies should evaluate the effects of 10(Z)-hexadecenoic acid on stress-induced exaggeration of peripheral inflammatory signaling, central neuroinflammatory signaling, and anxiety- and fear-related defensive behavioral responses.

Th2 cytokines in susceptibility to tuberculosis.

We need to understand what is different about susceptibility to tuberculosis (TB) in developing countries where most TB occurs, and where the current vaccine, Bacillus Calmette et Guérin (BCG) usually fails to protect. The presence of a background mixed IFN-gamma and Th2 response to mycobacterial antigens before infection with M. tuberculosis (Mtb), and the development of a large IL-4 response during progressive TB, are characteristics of individuals in the locations where BCG fails, which are also seen in animal models in the same countries. Recent data suggest that the background Th1 component in developing countries protects from low dose challenge with Mtb in mouse and man, but that following high dose challenge the pre-existing IL-4 component increases and blocks immunity unless the individual's immune system releases IL-4delta2, an antagonist of IL-4, which is raised in the blood of donors with stable latent TB. We outline how IL-4 (and IL-13) can undermine Th1-mediated immunity and drive inappropriate alternative activation of macrophages. The mechanisms of the effects of IL-4 include impaired antimicrobial activity due to reduced TNF-alpha-mediated apoptosis of infected cells, reduced activity of iNOS, increased availability of iron to intracellular Mtb, and increased proliferation of antigen-specific FOXP-3+ regulatory T cells. IL-4 also increases the toxicity of TNF-alpha and drives pulmonary fibrosis, thus enhancing immunopathology. The conclusion is that a vaccine that will work in developing countries might need to do more than enhance the existing Th1 response. In these environments it might be more important to block the Th2 component.

The stability of mRNA encoding IL-4 is increased in pulmonary tuberculosis, while stability of mRNA encoding the antagonistic splice variant, IL-4delta2, is not.

The prototype Th2 cytokine IL-4, and its competitive antagonist IL-4delta2, may be important determinants of outcome in human tuberculosis (TB). However, there are no data on how gene expression of these cytokines is regulated. To evaluate this the stability of IL-4 and IL-4delta2 mRNA after the addition of actinomycin-D, was evaluated in whole blood from subjects with pulmonary TB and uninfected healthy volunteers. The Th2/Th1 (IL-4/IFN-gamma) mRNA ratio in unstimulated cells in whole blood was significantly greater in TB subjects than in controls (p<0.05). The mRNA half-life of the agonist (IL-4), but not the antagonist (IL-4delta2), was significantly prolonged in subjects with TB compared to healthy volunteers ( approximately 5-fold, p=0.0016), and the IL-4/IL-4delta2 ratio was higher in TB patients compared to controls (p<0.05). The differential stability of the Th2 agonist, IL-4, compared to the antagonist IL-4delta2, represents a hitherto undescribed post-transcriptional regulatory mechanism that may modulate the polarisation of Th1/Th2 responses in human TB.

Mycobacteria and allergies.

Exposure to mycobacteria was inevitable throughout mammalian evolution. Most mycobacteria are saprophytic environmental organisms that are enormously abundant in soil and untreated water and evoke immune responses in the residents of developing countries. A few species are pathogens. For example Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects approximately 1/3 of the world's population. Many individuals also receive vaccination with the Bacille Calmette Guérin (BCG), which is an attenuated form of the organism causing bovine TB. In order to understand the possible role that mycobacteria might have in the increases in allergic disorders over the last decades, it is necessary to dissect out these different mycobacterial influences. Above all it is essential, when analysing tuberculin test results, to distinguish between individuals who have latent TB and those who do not. Only then can probable effects of diverse types of exposure emerge. There is no doubt that in animal models mycobacteria can both prevent and treat allergic responses either by boosting Th1 or by driving allergen-specific regulatory T cells (RegT). Clinical trials in man remain inconclusive.

The hygiene hypothesis and the increasing prevalence of chronic inflammatory disorders.

The 'Hygiene' or 'Old Friends' hypothesis suggests that increases in chronic inflammatory disorders (allergies, inflammatory bowel disease and autoimmunity) in developed countries are partly attributable to diminishing exposure to organisms that were part of mammalian evolutionary history. Crucial organisms, including helminths and saprophytic mycobacteria, are recognised by the innate immune system as harmless or, in the case of helminths, as organisms that once established must be tolerated. This recognition then triggers development of regulatory dendritic cells that drive regulatory T-cell responses to the 'Old Friends' themselves and to simultaneously processed 'forbidden' target antigens of the chronic inflammatory disorders.

The pathogen recognition sensor, NOD2, is variably expressed in patients with pulmonary tuberculosis.

BACKGROUND: NOD2, an intracellular pathogen recognition sensor, modulates innate defences to muropeptides derived from various bacterial species, including Mycobacterium tuberculosis (MTB). Experimentally, NOD2 attenuates two key putative mycobactericidal mechanisms. TNF-alpha synthesis is markedly reduced in MTB-antigen stimulated-mononuclear cells expressing mutant NOD2 proteins. NOD2 agonists also induce resistance to apoptosis, and may thus facilitate the survival of MTB in infected macrophages. To further define a role for NOD2 in disease pathogenesis, we analysed NOD2 transcriptional responses in pulmonary leucocytes and mononuclear cells harvested from patients with pulmonary tuberculosis (PTB). METHODS: We analysed NOD2 mRNA expression by real-time polymerase chain-reaction in alveolar lavage cells obtained from 15 patients with pulmonary tuberculosis and their matched controls. We compared NOD2 transcriptional responses, in peripheral leucocytes, before and after anti-tuberculous treatment in 10 patients. In vitro, we measured NOD2 mRNA levels in MTB-antigen stimulated-mononuclear cells. RESULTS: No significant differences in NOD2 transcriptional responses were detected in patients and controls. In some patients, however, NOD2 expression was markedly increased and correlated with toll-like-receptor 2 and 4 expression. In whole blood, NOD2 mRNA levels increased significantly after completion of anti-tuberculosis treatment. NOD2 expression levels did not change significantly in mononuclear cells stimulated with mycobacterial antigens in vitro. CONCLUSION: There are no characteristic NOD2 transcriptional responses in PTB. Nonetheless, the increased levels of NOD2 expression in some patients with severe tuberculosis, and the increases in expression levels within peripheral leucocytes following treatment merit further studies in selected patient and control populations.

Tryptophan metabolism in the central nervous system: medical implications.

The metabolism of the amino acid L-tryptophan is a highly regulated physiological process leading to the generation of several neuroactive compounds within the central nervous system. These include the aminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), products of the kynurenine pathway of tryptophan metabolism (including 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic acid and kynurenic acid), the neurohormone melatonin, several neuroactive kynuramine metabolites of melatonin, and the trace amine tryptamine. The integral role of central serotonergic systems in the modulation of physiology and behaviour has been well documented since the first description of serotonergic neurons in the brain some 40 years ago. However, while the significance of the peripheral kynurenine pathway of tryptophan metabolism has also been recognised for several decades, it has only recently been appreciated that the synthesis of kynurenines within the central nervous system has important consequences for physiology and behaviour. Altered kynurenine metabolism has been implicated in the pathophysiology of conditions such as acquired immunodeficiency syndrome (AIDS)-related dementia, Huntington's disease and Alzheimer's disease. In this review we discuss the molecular mechanisms involved in regulating the metabolism of tryptophan and consider the medical implications associated with dysregulation of both serotonergic and kynurenine pathways of tryptophan metabolism.

Immune systems in developed and developing countries; implications for the design of vaccines that will work where BCG does not.

New vaccine candidates for tuberculosis are beginning to enter clinical trials. In this review we discuss issues surrounding the design of these candidates, and the way they were screened in animal models. First, screening vaccines for their ability to attenuate inevitably fatal tuberculosis in immunologically naïve mice might be leading to the selection of inappropriate candidates. We need to screen vaccines for their ability to stop the development of progressive disease, since this is what they must achieve in man. A solution to this problem is proposed. Secondly, we point out that some mouse models of tuberculosis in laboratories in developing countries, where exposure to environmental mycobacteria is large, mimic neglected aspects of human disease more closely than do low-dose infections in hyper-susceptible immunologically naïve mice in the USA or Europe. We need to think more about geographical differences in immunological experience, and these mouse models can help us. Thirdly, we conclude that in developing countries where BCG fails this is not because there is too little Th1 response, but rather because the Th1 response is rendered ineffective and immunopathological by other subversive mechanisms, including IL-4 responses and inappropriate regulatory T cell function. Therefore, we suggest that vaccines that will work in those countries might need to have immunoregulatory properties that can switch off pre-existing subversive mechanisms, and block their development in the future. The development of such vaccines, that might work where BCG does not, will require a greater understanding of the roles of the many types of regulatory T cell in tuberculosis.

Expression of IL-4 mRNA in peripheral blood mononuclear cells from normal donors in relation to expression of TLR2.

When IL-4 mRNA was distinguished from mRNA encoding its antagonist, the splice variant IL-4delta2, it was found to correlate directly with expression of TLR2 in fresh peripheral blood mononuclear cells (PBMCs) from normal donors (p=0.0013). Similarly IL-4 mRNA was high when TLR2 mRNA was abundant compared to levels of mRNA encoding its heterodimerisation partners TLR1 (p=0.0007) or TLR6 (p=0.0007). IL-4delta2 tended to show the reverse effect; IL-4delta2 mRNA was high when TLR2 was low relative to TLR1 (p=0.001). When subpopulations of the PBMCs were examined these relationships were found to be restricted to the CD3+ cells. The CD3+ cell population from 5 of 10 donors had detectable TLR2 mRNA. When levels of TLR1, IL-4 and IFN-gamma mRNA were assayed in the TLR2(low) and TLR2(high) CD3+ cells, it was found that IL-4 mRNA was restricted to the TLR2(high) T cells (p=0.007) while TLR1 was higher in the TLR2(low) T cells (p=0.015). IFN-gamma was also somewhat increased in the TLR2(low) (ns). None of these correlations with TLR mRNA expression levels were found in similar samples from tuberculosis patients, or when similar analyses were performed with data for IL-10 mRNA in cells from the same donors. We conclude that in T cell populations from normal donors, expression of IL-4 (but not of its antagonist, IL-4delta2, or of IL-10) is associated with high TLR2 and low TLR1.

Mechanisms of disease: the hygiene hypothesis revisited.

In industrialized countries the incidence of diseases caused by immune dysregulation has risen. Epidemiologic studies initially suggested this was connected to a reduction in the incidence of infectious diseases; however, an association with defects in immunoregulation is now being recognized. Effector T(H)1 and T(H)2 cells are controlled by specialized subsets of regulatory T cells. Some pathogens can induce regulatory cells to evade immune elimination, but regulatory pathways are homeostatic and mainly triggered by harmless microorganisms. Helminths, saprophytic mycobacteria, bifidobacteria and lactobacilli, which induce immunoregulatory mechanisms in the host, ameliorate aberrant immune responses in the setting of allergy and inflammatory bowel disease. These organisms cause little, if any, harm, and have been part of human microecology for millennia; however, they are now less frequent or even absent in the human environment of westernized societies. Deficient exposure to these 'old friends' might explain the increase in immunodysregulatory disorders. The use of probiotics, prebiotics, helminths or microbe-derived immunoregulatory vaccines might, therefore, become a valuable approach to disease prevention.