Association of the Salivary Microbiome With Animal Contact During Early Life and Stress-Induced Immune Activation in Healthy Participants.

The prevalence of stress-associated somatic and psychiatric disorders is increased in environments offering a narrow relative to a wide range of microbial exposure. Moreover, different animal and human studies suggest that an overreactive immune system not only accompanies stress-associated disorders, but might even be causally involved in their pathogenesis. In support of this hypothesis, we recently showed that urban upbringing in the absence of daily contact with pets, compared to rural upbringing in the presence of daily contact with farm animals, is associated with a more pronounced immune activation following acute psychosocial stressor exposure induced by the Trier Social Stress Test (TSST).

Less immune activation following social stress in rural vs. urban participants raised with regular or no animal contact, respectively.

Urbanization is on the rise, and environments offering a narrow range of microbial exposures are linked to an increased prevalence of both physical and mental disorders. Human and animal studies suggest that an overreactive immune system not only accompanies stress-associated disorders but might even be causally involved in their pathogenesis. Here, we show in young [mean age, years (SD): rural, 25.

The Microbiota, Immunoregulation, and Mental Health: Implications for Public Health.

The hygiene or "Old Friends" hypothesis proposes that the epidemic of inflammatory disease in modern urban societies stems at least in part from reduced exposure to microbes that normally prime mammalian immunoregulatory circuits and suppress inappropriate inflammation. Such diseases include but are not limited to allergies and asthma; we and others have proposed that the markedly reduced exposure to these Old Friends in modern urban societies may also increase vulnerability to neurodevelopmental disorders and stress-related psychiatric disorders, such as anxiety and affective disorders, where data are emerging in support of inflammation as a risk factor. Here, we review recent advances in our understanding of the potential for Old Friends, including environmental microbial inputs, to modify risk for inflammatory disease, with a focus on neurodevelopmental and psychiatric conditions.

Time to abandon the hygiene hypothesis: new perspectives on allergic disease, the human microbiome, infectious disease prevention and the role of targeted hygiene.

Aims: To review the burden of allergic and infectious diseases and the evidence for a link to microbial exposure, the human microbiome and immune system, and to assess whether we could develop lifestyles which reconnect us with exposures which could reduce the risk of allergic disease while also protecting against infectious disease.

Methods: Using methodology based on the Delphi technique, six experts in infectious and allergic disease were surveyed to allow for elicitation of group judgement and consensus view on issues pertinent to the aim.

Results: Key themes emerged where evidence shows that interaction with microbes that inhabit the natural environment and human microbiome plays an essential role in immune regulation.

Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice.

The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation.

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.

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

The immune system influences brain development and function. Hygiene and other early childhood influences impact the subsequent function of the immune system during adulthood, with consequences for vulnerability to neurodevelopmental and psychiatric disorders. Inflammatory events during pregnancy can act directly to cause developmental problems in the central nervous system (CNS) that have been implicated in schizophrenia and autism.

Microbial 'Old Friends', immunoregulation and stress resilience.

Chronic inflammatory diseases (autoimmunity, allergy and inflammatory bowel diseases) are increasing in prevalence in urban communities in high-income countries. One important factor is reduced exposure to immunoregulation-inducing macro- and microorganisms and microbiota that accompanied mammalian evolution (the hygiene hypothesis or 'Old Friends' mechanism). Reduced exposure to these organisms predisposes to poor regulation of inflammation.

Regulation of the immune system by biodiversity from the natural environment: an ecosystem service essential to health.

Epidemiological studies suggest that living close to the natural environment is associated with long-term health benefits including reduced death rates, reduced cardiovascular disease, and reduced psychiatric problems. This is often attributed to psychological mechanisms, boosted by exercise, social interactions, and sunlight. Compared with urban environments, exposure to green spaces does indeed trigger rapid psychological, physiological, and endocrinological effects.

Regulation of inflammation by interleukin-4: a review of "alternatives".

Studies of IL-4 have revealed a wealth of information on the diverse roles of this cytokine in homeostatic regulation and disease pathogenesis. Recent data suggest that instead of simple linear regulatory pathways, IL-4 drives regulation that is full of alternatives. In addition to the well-known dichotomous regulation of Th cell differentiation by IL-4, this cytokine is engaged in several other alternative pathways.

Pathways underlying afferent signaling of bronchopulmonary immune activation to the central nervous system.

Bronchopulmonary inflammation, such as that associated with asthma, activates afferent neural pathways. We recently demonstrated that localized inflammation in the lungs, induced by intratracheal administration of ovalbumin in ovalbumin-preimmunized mice (an animal model of asthma) results in activation of the dorsolateral part of the nucleus of the solitary tract, a major target of vagal afferent fibers innervating the lungs and airways. Activation of the nucleus of the solitary tract was evident in the absence of activation of the area postrema, a circumventricular organ, consistent with the hypothesis that localized inflammation in the bronchopulmonary system can signal to the central nervous system via specific neural pathways, in the absence of circulating proinflammatory mediators.

Can we vaccinate against depression?

Major depression is common in the context of autoimmune and inflammatory diseases and is frequently associated with persistently raised levels of proinflammatory cytokines and other markers of inflammation, even in the absence of another diagnosable immune pathology to account for these findings. Therefore immunoregulation-inducing vaccines or manipulations of the gut microbiota might prevent or treat depression. These strategies are already undergoing clinical trials for chronic inflammatory disorders, such as allergies, autoimmunity and inflammatory bowel disease.

Hygiene hypothesis and autoimmune diseases.

Throughout the twentieth century, there were striking increases in the incidences of many chronic inflammatory disorders in the rich developed countries. These included autoimmune disorders such as Type 1 diabetes and multiple sclerosis. Although genetics and specific triggering mechanisms such as molecular mimicry and viruses are likely to be involved, the increases have been so rapid that any explanation that omits environmental change is incomplete.

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.

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.

CCL2, CCL18 and sIL-4R in renal, meningeal and pulmonary TB; a 2 year study of patients and contacts.

The role of Th2 cytokines and Th2-associated chemokines in tuberculosis (TB) remains controversial, though in Mexico a polymorphism causing increased production of CCL2 is a risk factor. We studied levels of the Th2-associated chemokines CCL2 and CCL18, circulating soluble IL-4 receptors (sIL-4R), IL-4 and the inhibitory splice variant of IL-4 (IL-4δ2) in a cohort of patients with pulmonary TB and their healthy contacts. These were followed for 2 years during which time 10 contacts developed pulmonary TB.

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.

Inflammation, sanitation, and consternation: loss of contact with coevolved, tolerogenic microorganisms and the pathophysiology and treatment of major depression.

Context: Inflammation is increasingly recognized as contributing to the pathogenesis of major depressive disorder (MDD), even in individuals who are otherwise medically healthy. Most studies in search of sources for this increased inflammation have focused on factors such as psychosocial stress and obesity that are known to activate inflammatory processes and increase the risk for depression. However, MDD may be so prevalent in the modern world not just because proinflammatory factors are widespread, but also because we have lost contact with previously available sources of anti-inflammatory, immunoregulatory signaling.

An assessment of air as a source of DNA contamination encountered when performing PCR.

Sensitive molecular methods, such as the PCR, can detect low-level contamination, and careful technique is required to reduce the impact of contaminants. Yet, some assays that are designed to detect high copy-number target sequences appear to be impossible to perform without contamination, and frequently, personnel or laboratory environment are held responsible as the source. This complicates diagnostic and research analysis when using molecular methods.

Advances in immunotherapy for tuberculosis treatment.

Immunotherapies have the potential to improve the outcome in all patients with tuberculosis (TB) including those with multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB. Immunotherapy for TB may shorten duration of treatment and reduce pathology in individuals cured by chemotherapy, potentially preventing recurrence. Currently none of the available candidate agents have proof of efficacy for use in MDR-TB or XDR-TB.

Tuberculosis due to high-dose challenge in partially immune individuals: a problem for vaccination?

The currently available vaccine for tuberculosis (TB) is ineffective in developing countries. We need to understand the pathogenesis of TB in those countries and how it differs from the pathogenesis of TB in wealthy countries, to facilitate the design and interpretation of clinical trials of new vaccine candidates that are now available. We show here that these geographical differences parallel the strikingly different immunology and bacterial growth curves seen in animal models after high-dose and low-dose challenge with M.

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.

Orally administered Mycobacterium vaccae modulates expression of immunoregulatory molecules in BALB/c mice with pulmonary tuberculosis.

The environmental saprophyte Mycobacterium vaccae induces a Th1 response and cytotoxic T cells that recognize M. tuberculosis, and by subcutaneous injection, it is therapeutic for pulmonary tuberculosis (TB) induced by high-dose challenge in BALB/c mice. However, M.

The changing microbial environment and chronic inflammatory disorders.

: There is much to be gained from examining human diseases within the expanding framework of Darwinian medicine. This is particularly true of those conditions that change in frequency as populations develop from the human "environment of evolutionary adaptedness" to the living conditions of the rich industrialized countries. This development entails major changes in lifestyle, leading to reductions in contact with environmental microorganisms and helminths that have evolved a physiologic role as drivers of immunoregulatory circuits.