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Kramer, A., Bekeschus, S., Bröker, B. M., Schleibinger, H., Razavi, B., & Assadian, O. (2013). Maintaining health by balancing microbial exposure and prevention of infection: the hygiene hypothesis versus the hypothesis of early immune challenge. Journal of Hospital Infection, 83, S29–S34.
Abstract: The human immune system is inseparably bonded to an individual's personal micro-biome from birth to death. Since the beginning of life, commensal relationships have ensured the survival of micro- and macro-organisms within complex relationships. However, technological advances and altered lifestyle imposed new rules for this interaction during recent decades. It has been observed that reduced exposure to micro-organisms and parasites results in decreased morbidity and mortality, but is also associated with a rising prevalence of atopic disorders and autoimmune diseases, mostly in industrialized countries. This inverse relationship is described by the “hygiene hypothesis”, put forward in 1989, yet this term only imperfectly describes these observations, as excessive hygiene or hygienic measures may not directly be the central cause. The lack of appropriate immune stimulation during early childhood with the consequence of disturbed alignment in the sequence of encountering self- or non-self-antigens might account in the rise of atopy and autoimmune disease. For this reason we propose the term “early immune challenge hypothesis”. This concept highlights the importance of immune priming in early life in the context of genetic, social, geographic, cultural, and economic background. Moreover, it emphasizes the central role of “training” of regulatory T-cells through sufficient microbial exposure, leading to a robust, healthy balance between inflammation and anti-inflammation or immune tolerance. Insufficient exposure might result in abnormal immune regulatory development. Finally, it incorporates the idea of encountering “old friends”--organisms that shaped our immune system during human phylogeny. This article gives a comprehensive overview of the relationship between microbial exposure, and the incidence of asthma and hay fever is outlined. Although the outcomes of these studies originally were interpreted in the framework of the hygiene hypothesis, they may suit the concept of the hypothesis of early immune challenge even better. Moreover, recent studies have revealed that TH or TReg imbalances in disease may be partially corrected by the administration of helminthic or bacterial extracts.
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Kuntz, T. M., & Gilbert, J. A. (2017). Introducing the Microbiome into Precision Medicine. Trends Pharmacol Sci, 38(1), 81–91.
Abstract: Understanding how individual people respond to medical therapy is a key facet of improving the odds ratio that interventions will have a positive impact. Reducing the non-responder rate for an intervention or reducing complications associated with a particular treatment or surgery is the next stage of medical advance. The Precision Medicine Initiative, launched in January 2015, set the stage for enhanced collaboration between researchers and medical professionals to develop next-generation techniques to aid patient treatment and recovery, and increased the opportunities for impactful pre-emptive care. The microbiome plays a crucial role in health and disease, as it influences endocrinology, physiology, and even neurology, altering the outcome of many different disease states, and it augments drug responses and tolerance. We review the implications of the microbiome on precision health initiatives and highlight excellent examples, whereby precision microbiome health has been implemented.
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Lal, D., Keim, P., Delisle, J., Barker, B., Rank, M. A., Chia, N., et al. (2017). Mapping and comparing bacterial microbiota in the sinonasal cavity of healthy, allergic rhinitis, and chronic rhinosinusitis subjects. Int Forum Allergy Rhinol, 7(6), 561–569.
Abstract: BACKGROUND: The role of microbiota in sinonasal inflammation can be further understood by targeted sampling of healthy and diseased subjects. We compared the microbiota of the middle meatus (MM) and inferior meatus (IM) in healthy, allergic rhinitis (AR), and chronic rhinosinusitis (CRS) subjects to characterize intrasubject, intersubject, and intergroup differences. METHODS: Subjects were recruited in the office, and characterized into healthy, AR, and CRS groups. Endoscopically-guided swab samples were obtained from the MM and IM bilaterally. Bacterial microbiota were characterized by sequencing the V3-V4 region of the 16S ribosomal RNA (rRNA) gene. RESULTS: Intersubject microbiome analyses were conducted in 65 subjects: 8 healthy, 11 AR, and 46 CRS (25 CRS with nasal polyps [CRSwNP]; 21 CRS without nasal polyps [CRSsNP]). Intrasubject analyses were conducted for 48 individuals (4 controls, 11 AR, 8 CRSwNP, and 15 CRSwNP). There was considerable intersubject microbiota variability, but intrasubject profiles were similar (p = 0.001, nonparametric t test). Intrasubject bacterial diversity was significantly reduced in MM of CRSsNP subjects compared to IM samples (p = 0.022, nonparametric t test). CRSsNP MM samples were enriched in Streptococcus, Haemophilus, and Fusobacterium spp. but exhibited loss of diversity compared to healthy, CRSwNP, and AR subject-samples (p < 0.05; nonparametric t test). CRSwNP patients were enriched in Staphylococcus, Alloiococcus, and Corynebacterium spp. CONCLUSION: This study presents the sinonasal microbiome profile in one of the larger populations of non-CRS and CRS subjects, and is the first office-based cohort in the literature. In contrast to healthy, AR, and CRSwNP subjects, CRSsNP MM samples exhibited decreased microbiome diversity and anaerobic enrichment. CRSsNP MM samples had reduced diversity compared to same-subject IM samples, a novel finding.
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Plunkett, C. H., & Nagler, C. R. (2017). The Influence of the Microbiome on Allergic Sensitization to Food. J Immunol, 198(2), 581–589.
Abstract: The alarming increase in the incidence and severity of food allergies has coincided with lifestyle changes in Western societies, such as dietary modifications and increased antibiotic use. These demographic shifts have profoundly altered the coevolved relationship between host and microbiota, depleting bacterial populations critical for the maintenance of mucosal homeostasis. There is increasing evidence that the dysbiosis associated with sensitization to food fails to stimulate protective tolerogenic pathways, leading to the development of the type 2 immune responses that characterize allergic disease. Defining the role of beneficial allergy-protective members of the microbiota in the regulation of tolerance to food has exciting potential for new interventions to treat dietary allergies by modulation of the microbiota.
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Rehman, A., Rausch, P., Wang, J., Skieceviciene, J., Kiudelis, G., Bhagalia, K., et al. (2016). Geographical patterns of the standing and active human gut microbiome in health and IBD. Gut, 65(2), 238–248.
Abstract: OBJECTIVE: A global increase of IBD has been reported, especially in countries that previously had low incidence rates. Also, the knowledge of the human gut microbiome is steadily increasing, however, limited information regarding its variation on a global scale is available. In the light of the microbial involvement in IBDs, we aimed to (1) identify shared and distinct IBD-associated mucosal microbiota patterns from different geographical regions including Europe (Germany, Lithuania) and South Asia (India) and (2) determine whether profiling based on 16S rRNA transcripts provides additional resolution, both of which may hold important clinical relevance. DESIGN: In this study, we analyse a set of 89 mucosal biopsies sampled from individuals of German, Lithuanian and Indian origins, using bacterial community profiling of a roughly equal number of healthy controls, patients with Crohn's disease and UC from each location, and analyse 16S rDNA and rRNA as proxies for standing and active microbial community structure, respectively. RESULTS: We find pronounced population-specific as well as general disease patterns in the major phyla and patterns of diversity, which differ between the standing and active communities. The geographical origin of samples dominates the patterns of beta diversity with locally restricted disease clusters and more pronounced effects in the active microbial communities. However, two genera belonging to the Clostridium leptum subgroup, Faecalibacteria and Papillibacter, display consistent patterns with respect to disease status and may thus serve as reliable 'microbiomarkers'. CONCLUSIONS: These analyses reveal important interactions of patients' geographical origin and disease in the interpretation of disease-associated changes in microbial communities and highlight the added value of analysing communities on both the 16S rRNA gene (DNA) and transcript (RNA) level.
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Romano-Keeler, J., & Weitkamp, J. - H. (2015). Maternal influences on fetal microbial colonization and immune development. Pediatr Res, 77(1-2), 189–195.
Abstract: While critical for normal development, the exact timing of establishment of the intestinal microbiome is unknown. For example, although preterm labor and birth have been associated with bacterial colonization of the amniotic cavity and fetal membranes for many years, the prevailing dogma of a sterile intrauterine environment during normal term pregnancies has been challenged more recently. While found to be a key contributor of evolution in the animal kingdom, maternal transmission of commensal bacteria may also constitute a critical process during healthy pregnancies in humans with yet unclear developmental importance. Metagenomic sequencing has elucidated a rich placental microbiome in normal term pregnancies likely providing important metabolic and immune contributions to the growing fetus. Conversely, an altered microbial composition during pregnancy may produce aberrant metabolites impairing fetal brain development and life-long neurological outcomes. Here we review the current understanding of microbial colonization at the feto-maternal interface and explain how normal gut colonization drives a balanced neonatal mucosal immune system, while dysbiosis contributes to aberrant immune function early in life and beyond. We discuss how maternal genetics, diet, medications, and probiotics inform the fetal microbiome in preparation for perinatal and postnatal bacterial colonization.
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Ruokolainen, L., von Hertzen, L., Fyhrquist, N., Laatikainen, T., Lehtomaki, J., Auvinen, P., et al. (2015). Green areas around homes reduce atopic sensitization in children. Allergy, 70(2), 195–202.
Abstract: BACKGROUND: Western lifestyle is associated with high prevalence of allergy, asthma and other chronic inflammatory disorders. To explain this association, we tested the 'biodiversity hypothesis', which posits that reduced contact of children with environmental biodiversity, including environmental microbiota in natural habitats, has adverse consequences on the assembly of human commensal microbiota and its contribution to immune tolerance. METHODS: We analysed four study cohorts from Finland and Estonia (n = 1044) comprising children and adolescents aged 0.5-20 years. The prevalence of atopic sensitization was assessed by measuring serum IgE specific to inhalant allergens. We calculated the proportion of five land-use types--forest, agricultural land, built areas, wetlands and water bodies--in the landscape around the homes using the CORINE2006 classification. RESULTS: The cover of forest and agricultural land within 2-5 km from the home was inversely and significantly associated with atopic sensitization. This relationship was observed for children 6 years of age and older. Land-use pattern explained 20% of the variation in the relative abundance of Proteobacteria on the skin of healthy individuals, supporting the hypothesis of a strong environmental effect on the commensal microbiota. CONCLUSIONS: The amount of green environment (forest and agricultural land) around homes was inversely associated with the risk of atopic sensitization in children. The results indicate that early-life exposure to green environments is especially important. The environmental effect may be mediated via the effect of environmental microbiota on the commensal microbiota influencing immunotolerance.
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Solt, I. (2015). The human microbiome and the great obstetrical syndromes: a new frontier in maternal-fetal medicine. Best Pract Res Clin Obstet Gynaecol, 29(2), 165–175.
Abstract: The emergence of the concept of the microbiome, together with the development of molecular-based techniques, particularly polymerase chain reaction (PCR) amplification using the 16S ribosomal RNA (rRNA) gene, has dramatically increased the detection of microorganisms, the number of known species, and the understanding of bacterial communities that are relevant to maternal-fetal medicine in health and disease. Culture-independent methods enable characterization of the microbiomes of the reproductive tract of pregnant and nonpregnant women, and have increased our understanding of the role of the uterine microbiome in adverse obstetric outcomes. While bacterial ascent from the vaginal tract is recognized as the primary cause of intrauterine infection, the microbiomes of the gastrointestinal, oral, and respiratory tracts are shown to be involved by means of hematogenous spread. The transmission of maternal microbiomes to the neonate, by vaginal delivery or cesarean section, is shown to affect health from birth to adulthood.
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Stiemsma, L. T., Arrieta, M. - C., Dimitriu, P. A., Cheng, J., Thorson, L., Lefebvre, D. L., et al. (2016). Shifts in Lachnospira and Clostridium sp. in the 3-month stool microbiome are associated with preschool age asthma. Clin Sci (Lond), 130(23), 2199–2207.
Abstract: Asthma is a chronic disease of the airways affecting one in ten children in Westernized countries. Recently, our group showed that specific bacterial genera in early life are associated with atopy and wheezing in 1-year-old children. However, little is known about the link between the early life gut microbiome and the diagnosis of asthma in preschool age children. To determine the role of the gut microbiota in preschool age asthma, children up to 4 years of age enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) study were classified as asthmatic (n=39) or matched healthy controls (n=37). 16S rRNA sequencing and quantitative PCR (qPCR) were used to analyse the composition of the 3-month and 1-year gut microbiome of these children. At 3 months the abundance of the genus, Lachnospira (L), was decreased (P=0.008), whereas the abundance of the species, Clostridium neonatale (C), was increased (P=0.07) in asthmatics. Quartile analysis of stool composition at 3-months revealed a negative association between the ratio of these two bacteria (L/C) and asthma risk by 4 years of age [quartile 1: odds ratio (OR)=15, P=0.02, CI (confidence interval)= 1.8-124.7; quartile 2: OR=1.0, ns; quartile 3: OR=0.37, ns]. We conclude that opposing shifts in the relative abundances of Lachnospira and C. neonatale in the first 3 months of life are associated with preschool age asthma, and that the L/C ratio may serve as a potential early life biomarker to predict asthma development.
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Turnbaugh, P. J. (2017). Microbes and Diet-Induced Obesity: Fast, Cheap, and Out of Control. Cell Host Microbe, 21(3), 278–281.
Abstract: Here I revisit our early experiments published in Cell Host & Microbe (Turnbaugh et al., 2008) showing that a diet rich in fat and simple sugars alters the gut microbiome in a manner that contributes to host adiposity, and reflect upon the remarkable advances and remaining challenges in this field.
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