Early-life interactions between the microbiota and immune system: impact on immune system development and atopic disease.

Prenatal and early postnatal life represent key periods of immune system development. In addition to genetics and host biology, environment has a large and irreversible role in the immune maturation and health of an infant. One key player in this process is the gut microbiota, a diverse community of microorganisms that colonizes the human intestine. The diet, environment and medical interventions experienced by an infant determine the establishment and progression of the intestinal microbiota, which interacts with and trains the developing immune system. Several chronic immune-mediated diseases have been linked to an altered gut microbiota during early infancy. The recent rise in allergic disease incidence has been explained by the 'hygiene hypothesis', which states that societal changes in developed countries have led to reduced early-life microbial exposures, negatively impacting immunity. Although human cohort studies across the globe have established a correlation between early-life microbiota composition and atopy, mechanistic links and specific host-microorganism interactions are still being uncovered. Here, we detail the progression of immune system and microbiota maturation in early life, highlight the mechanistic links between microbes and the immune system, and summarize the role of early-life host-microorganism interactions in allergic disease development.

Evaluation of selected aspects of the hygiene hypothesis and their effect on the incidence of allergy.

OBJECTIVES: The development of allergic conditions is largely dependent on the interactions between genetic (individual genetic predisposition) and environmental factors (exposure to risk factors). The aim of this study was an attempt to assess the influence of selected elements of the hygiene theory in the development of allergic diseases such as allergic rhinitis and asthma. MATERIAL AND METHODS: The study group consisted of 5518 women and 3868 men. The method that was used was the European Community Respiratory Health Survey II and International Study of Asthma and Allergies in Childhood questionnaire validated and adapted to Central and Eastern European conditions. The project was conducted in 8 urban areas (Gdansk, Wroclaw, Poznan, Katowice, Kraków, Lublin, Bialystok, Warsaw) and 1 rural area (Krasnystaw county). This study had 2 stages; the first stage involved grouping the 22 500 respondents based on their questionnaire responses with the use of a Personal Digital Assistant (PDA); the second stage involved 7000 subjects, who underwent additional assessments: skin prick tests (birch, grasses/cereals, Dermatophagoides pteronyssinus and Dermatophagoides farinae, molds [set I: Botrytis cinerea, Cladosporium herbarum, Alternaria tenuis, Curvularia lunata, Fusarium moniliforme, Helminthosporium], molds [set II: Aspergillus fumigatus, Mucor mucedo, Penicillium notatum, Pullularia pullulans, Rhizopus nigricans, Serpula lacrymans], cat, dog, molds Cladosporium herbarum, Alternaria tenuis) and spirometry tests. RESULTS: The age at which children attend the nursery school is critical to the development of allergic diseases; in allergic rhinitis, the risk of an IgE-dependent reaction is 2 times higher in the second than in the first year of life (p = 0.00147, p < 0.05), while in asthma, having a large number of siblings increases the risk of developing obstructive disease by almost 6 times (p = 0.00316, p < 0.05).The age at which children attend the nursery school is critical to the development of allergic diseases; in allergic rhinitis, the risk of an IgE-dependent reaction is 2 times higher in the second than in the first year of life (p = 0.00147, p < 0.05), while in asthma, having a large number of siblings increases the risk of developing obstructive disease by almost 6 times (p = 0.00316, p < 0.05). CONCLUSIONS: The hygiene theory is particularly applicable and can explain the relationship of selected habits in the development of allergic diseases. Int J Occup Med Environ Health. 2023;36(1):69-83.

[Toll-like receptors link atopic march and hygiene hypothesis].

The atopic march reveals that infants with atopic dermatitis are prone to food allergy, allergic rhinitis and asthma later in life. The hygiene hypothesis holds that the cleaner the personal hygiene and environment, the higher the incidence rate of asthma and allergy. It is believed that Toll like receptors (TLRs) are the bridge between innate immunity and adaptive immunity, playing an important role in inflammatory and immune diseases. More and more evidence shows that TLRs, involved in the pathophysiology of atopic march, connect atopic march with hygiene hypothesis as a potential therapeutic target for asthma and allergy.

Microbial (co)infections: Powerful immune influencers.

It is well established that by modulating various immune functions, host infection may alter the course of concomitant inflammatory diseases, of both infectious and autoimmune etiologies. Beyond the major impact of commensal microbiota on the immune status, host exposure to viral, bacterial, and/or parasitic microorganisms also dramatically influences inflammatory diseases in the host, in a beneficial or harmful manner. Moreover, by modifying pathogen control and host tolerance to tissue damage, a coinfection can profoundly affect the development of a concomitant infectious disease. Here, we review the diverse mechanisms that underlie the impact of (co)infections on inflammatory disorders. We discuss epidemiological studies in the context of the hygiene hypothesis and shed light on the sometimes dual impact of germ exposure on human susceptibility to inflammatory disease. We then summarize the immunomodulatory mechanisms at play, which can involve pleiotropic effects of immune players and discuss the possibility to harness pathogen-derived compounds to the host benefit.

Hygiene Hypothesis Indicators and Prevalence of Antinuclear Antibodies in US Adolescents.

Autoimmunity prevalence, as measured by antinuclear antibodies (ANA), is increasing in U.S. adolescents. Improved hygiene and cleaner environments in childhood may reduce exposure to infections and other immune challenges, resulting in improper immune responses to later-life exposures. We examined associations of hygiene hypothesis indicators, including asthma, allergies, and antibodies to infectious agents, with ANA prevalence, measured by HEp-2 immunofluorescence, in adolescents (aged 12-19 years) over a 25-year time span in the National Health and Nutrition Examination Survey (NHANES) (N=2,709), adjusting for age, sex, race/ethnicity, body mass index, education and survey cycle, overall and within individual time periods, using logistic regression. Prevalence of ANA in adolescents increased from 5.0% in 1988-1991 to 12.8% in 2011-2012. ANA were positively associated with diagnosis of asthma in early childhood (OR: 2.07, CI: 1.09-3.99) and the effect estimate for current hay fever was elevated but not statistically significant (OR: 1.55, CI: 0.85-2.84). Fewer than 2% of those with ANA in 1988-1991 had been diagnosed with asthma, compared with 18% in 1999-2000, and 27% in 2003-2004 and 2011-2012. ANA trended negatively with Helicobacter pylori antibodies (OR: 0.49, CI: 0.24-0.99). ANA may be useful as an additional indicator of inadequate immune education in adolescence, a critical period of growth and development.

Florence Nightingale: higienista y estadística de referencia para Pedro Felipe Monlau / Florence Nightingale was a reference hygienist and statistician for Pedro Felipe Monlau

Pedro Felipe Monlau fue un destacado higie-nista español y defensor de la Teoría Miasmáticade las enfermedades. La España del siglo XIX te-nía escasa infraestructura sanitaria, por lo que suspublicaciones se convirtieron en una poderosafuente de transmisión de las ideas científicas do-minantes del higienismo europeo. Levy, Londe,Villermé, Chadwick, Farr y Smith fueron perso-najes que influenciaron en el pensamiento del hi-gienista español. El objetivo del presente trabajoes evidenciar si la doctrina higienista de FlorenceNightingale influyó en España a través de la obrade Monlau. Se realizó una revisión de fuentes do-cumentales primarias y se analizaron los resulta-dos desde la perspectiva hermenéutica. Se utilizócomo recurso principal la Hemeroteca Digital de laBiblioteca Nacional de España. Monlau referencióa Nightingale en once ocasiones. Nueve fragmentosrespondían a los Aforismos Higiénicos de Monlau.Recomendaba las ideas de Nightingale en relacióncon la ventilación, iluminación y limpieza domésti-ca, entre otros. Además, Monlau sugería la necesi-dad de elaborar estadísticas hospitalarias siguiendola propuesta de Nightingale. En este sentido, el ci-rujano Rubio y Galí fue un claro ejemplo de su apli-cabilidad en el Instituto de Terapéutica Operatoria.Monlau también reconoció la labor de Nightingaleen la Guerra de Crimea. Los resultados muestran lanecesidad de visibilizar a la mujer científica en lahistoria contemporánea, revisitando las biografíasescritas hasta el momento.(AU)

Pedro Felipe Monlau was a prominent Spanishhygienist and defender of the Miasmatic Theoryof Diseases. By the nineteenth-century, Spain hadnot enough health infrastructure. Monlau’s publi-cations became a powerful source of transmissionof the dominant scientific ideas of European hygie-nism. Levy, Londe, Villermé, Chadwick, Farr andSmith were personalities who influenced the thin-king of the Spanish hygienist. The aim of this pa-per is to show whether the Florence Nightingale’shygienist doctrine influenced Spain through thework of Monlau. A review of primary documentarysources was carried out and the results were analy-sed from the hermeneutic perspective. The DigitalNewspaper Library of the National Library of Spainwas used as the main resource. Monlau referred toNightingale eleven times. Nine fragments respon-ded to Monlau’s Hygienic Aphorisms. He recom-mended Nightingale’s ideas regarding ventilation,lighting and housekeeping, among others. In addi-tion, Monlau suggested the need for hospital statis-tics following Nightingale’s proposal. In this sense,the surgeon Rubio y Galí was a clear example of itsapplicability in the Institute of Therapeutic Surgery.Monlau also recognized the work of Nightingalein the Crimean War. The results show the need tomake women scientists visible in contemporaryhistory, revisiting the biographies written so far.(AU)

Effect of inactivated nature-derived microbial composition on mouse immune system.

INTRODUCTION: The hygiene hypothesis suggests that decrease in early life infections due to increased societal-level hygiene standards subjects one to allergic and autoimmune diseases. In this report, we have studied the effect of sterilized forest soil and plant-based material on mouse immune system and gut microbiome. METHODS: Inbred C57Bl/6 mice maintained in normal sterile environment were subjected to autoclaved forest soil-derived powder in their bedding for 1 h a day for 3 weeks. Immune response was measured by immune cell flow cytometry, serum cytokine enzyme-linked immunoassay (ELISA) and quantitative polymerase chain reaction (qPCR) analysis. Furthermore, the mouse gut microbiome was analyzed by sequencing. RESULTS: When compared to control mice, mice treated with soil-derived powder had decreased level of pro-inflammatory cytokines namely interleukin (IL)-17F and IL-21 in the serum. Furthermore, splenocytes from mice treated with soil-derived powder expressed less IL-1b, IL-5, IL-6, IL-13, and tumor necrosis factor (TNF) upon cell activation. Gut microbiome appeared to be stabilized by the treatment. CONCLUSIONS: These results provide insights on the effect of biodiversity on murine immune system in sterile environment. Subjecting mice to soil-based plant and microbe structures appears to elicit immune response that could be beneficial, for example, in type 2 inflammation-related diseases, that is, allergic diseases.

Hygiene Hypothesis as the Etiology of Kawasaki Disease: Dysregulation of Early B Cell Development.

Kawasaki disease (KD) is an acute systemic vasculitis that occurs predominantly in children under 5 years of age. Despite much study, the etiology of KD remains unknown. However, epidemiological and immunological data support the hygiene hypothesis as a possible etiology. It is thought that more sterile or clean modern living environments due to increased use of sanitizing agents, antibiotics, and formula feeding result in a lack of immunological challenges, leading to defective or dysregulated B cell development, accompanied by low IgG and high IgE levels. A lack of B cell immunity may increase sensitivity to unknown environmental triggers that are nonpathogenic in healthy individuals. Genetic studies of KD show that all of the KD susceptibility genes identified by genome-wide association studies are involved in B cell development and function, particularly in early B cell development (from the pro-B to pre-B cell stage). The fact that intravenous immunoglobulin is an effective therapy for KD supports this hypothesis. In this review, I discuss clinical, epidemiological, immunological, and genetic studies showing that the etiopathogenesis of KD in infants and toddlers can be explained by the hygiene hypothesis, and particularly by defects or dysregulation during early B cell development.

Helminth infections and cardiovascular diseases: A role for the microbiota and Mϕs?

Cardiovascular diseases are rising in developing countries with increasing urbanization and lifestyle changes and remains a major cause of death in the developed world. In this mini review, we discuss the possibility that the effect of helminth infections on the immune system and the microbiota may affect risk factors in cardiovascular diseases such as atherosclerosis, as part of the hygiene hypothesis. The effects of Type 2 immune responses induced by helminths and helminth derived molecules on regulating metabolism and Mϕ function could be a mechanistic link for further investigation. We emphasize the complexity and difficulties in determining indirect or direct and causal relationships between helminth infection status and cardiovascular diseases. New experimental models, such as rewilding laboratory mice, whereby different aspects of the environment and host genetics can be carefully dissected may provide further mechanistic insights and therapeutic strategies for treating cardiovascular diseases.

Mycobacterium-Induced Th1, Helminths-Induced Th2 Cells and the Potential Vaccine Candidates for Allergic Asthma: Imitation of Natural Infection.

Bronchial asthma is one of the most chronic pulmonary diseases and major public health problems. In general, asthma prevails in developed countries than developing countries, and its prevalence is increasing in the latter. For instance, the hygiene hypothesis demonstrated that this phenomenon resulted from higher household hygienic standards that decreased the chances of infections, which would subsequently increase the occurrence of allergy. In this review, we attempted to integrate our knowledge with the hygiene hypothesis into beneficial preventive approaches for allergic asthma. Therefore, we highlighted the studies that investigated the correlation between allergic asthma and the two different types of infections that induce the two major antagonizing arms of T cells. This elucidation reflects the association between various types of natural infections and the immune system, which is predicted to support the main objective of the current research on investigating of the benefits of natural infections, regardless their immune pathways for the prevention of allergic asthma. We demonstrated that natural infection with Mycobacterium tuberculosis (Mtb) prevents the development of allergic asthma, thus Bacille Calmette-Guérin (BCG) vaccine is suggested at early age to mediate the same prevention particularly with increasing its efficiency through genetic engineering-based modifications. Likewise, natural helminth infections might inhabit the allergic asthma development. Therefore, helminth-derived proteins at early age are good candidates for designing vaccines for allergic asthma and it requires further investigation. Finally, we recommend imitation of natural infections as a general strategy for preventing allergic asthma that increased dramatically over the past decades.

Hygiene hypothesis and autoimmune diseases: A narrative review of clinical evidences and mechanisms.

Since the start of the "modern era", characterized by the increase in urbanization, a progressive attention to hygiene and autoimmune conditions has considerably grown. Although these diseases are often multifactorial, it was demonstrated that environment factors such as pollution, diet and lifestyles may play a crucial role together with genetic signature. Our research, based on the newest and most significant literature of this topic, highlights that the progressive depletion of microbes and parasites due to increased socioeconomic improvement, may lead to a derangement of immunoregulatory mechanisms. Moreover, special attention was given to the complex interplay between microbial agents, as gut microbiome, diet and vitamin D supplementation with the aim of identifying promising future therapeutic options. In conclusion, autoimmunity cannot be limited to hygiene-hypothesis, but from the point of view of precision medicine, this theory represents a fundamental element together with the study of genomics, the microbiome and proteomics, in order to understand the complex functioning of the immune system.

The Hygiene Hypothesis - Learning From but Not Living in the Past.

Postulated by Strachan more than 30 years ago, the Hygiene Hypothesis has undergone many revisions and adaptations. This review journeys back to the beginnings of the Hygiene Hypothesis and describes the most important landmarks in its development considering the many aspects that have refined and generalized the Hygiene Hypothesis over time. From an epidemiological perspective, the Hygiene Hypothesis advanced to a comprehensive concept expanding beyond the initial focus on allergies. The Hygiene Hypothesis comprise immunological, microbiological and evolutionary aspects. Thus, the original postulate developed into a holistic model that explains the impact of post-modern life-style on humans, who initially evolved in close proximity to a more natural environment. Focusing on diet and the microbiome as the most prominent exogenous influences we describe these discrepancies and the resulting health outcomes and point to potential solutions to reestablish the immunological homeostasis that frequently have been lost in people living in developed societies.

The Interplay between Immune System and Microbiota in Inflammatory Bowel Disease: A Narrative Review.

The importance of the gut microbiota in human health is currently well established. It contributes to many vital functions such as development of the host immune system, digestion and metabolism, barrier against pathogens or brain-gut communication. Microbial colonization occurs during infancy in parallel with maturation of the host immune system; therefore, an adequate cross-talk between these processes is essential to generating tolerance to gut microbiota early in life, which is crucial to prevent allergic and immune-mediated diseases. Inflammatory bowel disease (IBD) is characterized by an exacerbated immune reaction against intestinal microbiota. Changes in abundance in the gut of certain microorganisms such as bacteria, fungi, viruses, and archaea have been associated with IBD. Microbes that are commonly found in high abundance in healthy gut microbiomes, such as F. prausnitzii or R. hominis, are reduced in IBD patients. E. coli, which is usually present in a healthy gut in very low concentrations, is increased in the gut of IBD patients. Microbial taxa influence the immune system, hence affecting the inflammatory status of the host. This review examines the IBD microbiome profile and presents IBD as a model of dysbiosis.

The Hygiene Hypothesis and New Perspectives-Current Challenges Meeting an Old Postulate.

During its 30 years history, the Hygiene Hypothesis has shown itself to be adaptable whenever it has been challenged by new scientific developments and this is a still a continuously ongoing process. In this regard, the mini review aims to discuss some selected new developments in relation to their impact on further fine-tuning and expansion of the Hygiene Hypothesis. This will include the role of recently discovered classes of innate and adaptive immune cells that challenges the old Th1/Th2 paradigm, the applicability of the Hygiene Hypothesis to newly identified allergy/asthma phenotypes with diverse underlying pathomechanistic endotypes, and the increasing knowledge derived from epigenetic studies that leads to better understanding of mechanisms involved in the translation of environmental impacts on biological systems. Further, we discuss in brief the expansion of the Hygiene Hypothesis to other disease areas like psychiatric disorders and cancer and conclude that the continuously developing Hygiene Hypothesis may provide a more generalized explanation for health burden in highly industrialized countries also relation to global changes.