Asthma is a chronic disease affecting millions of children worldwide, and in severe cases requires hospitalization. The etiology of asthma is multifactorial, caused by both genetic and environmental factors. In recent years, the role of the early-life gut microbiome in relation to asthma has become apparent, supported by an increasing number of population studies, in vivo research, and intervention trials. Numerous early-life factors, which for decades have been associated with the risk of developing childhood asthma, are now being linked to the disease through alterations of the gut microbiome. These factors include cesarean birth, antibiotic use, breastfeeding, and having siblings or pets, among others. Association studies have highlighted several specific microbes that are altered in children developing asthma, but these can vary between studies and disease phenotype. This demonstrates the importance of the gut microbial ecosystem in asthma, and the necessity of well-designed studies to validate the underlying mechanisms and guide future clinical applications. In this review, we examine the current literature on the role of the gut microbiome in childhood asthma and identify research gaps to allow for future microbial-focused therapeutic applications in asthma.

Parasites generally survive in their hosts by employing various immunomodulation and immune evasion mechanisms. "helminth therapy" is one strategy that harnesses these parasite-specific beneficial properties for the therapeutic treatment of autoimmune and allergic diseases. Although numerous experimental reports have documented the anti-autoimmune activities of parasitic infections and parasite-derived products, the underlying mechanisms remain insufficiently elucidated due to the significant diversity among parasite species and autoimmune conditions. Rheumatoid arthritis (RA) is one of the most prevalent autoimmune disorders, presenting a substantial opportunity for the therapeutic use of parasites as novel disease-modifying antirheumatic drugs (DMARDs). In this paper, we summarize the immunomodulatory properties of parasites, focusing on their anti-arthritic mechanisms, and discuss the potential of parasite-derived products for the treatment of RA.

Immune health and metabolic functions are intimately connected via diet and the microbiota. Immune cells are continuously exposed to a wide range of microbes and microbial-derived compounds, with important mucosal and systemic ramifications. Microbial fermentation of dietary components in vivo generates thousands of molecules, some of which are integral components of the molecular circuitry that regulates immune and metabolic functions. These in turn protect against aberrant inflammatory or hyper-reactive processes and promote effector immune responses that quickly eliminate pathogens, such as SARS-CoV-2. Potent tolerance mechanisms should ensure that these immune cells do not over-react to non-pathogenic factors (e.g. food proteins), while maintaining the ability to respond to infectious challenges in a robust, effective and well controlled manner. In this review we examine the factors and mechanisms that shape microbiota composition and interactions with the host immune system, their associations with immune mediated disorders and strategies for intervention.

The increasing global incidence of atopic dermatitis (AD) in children, especially in Western industrialized nations, has attracted considerable attention. The hygiene hypothesis, which posits that early pathogen exposure is crucial for immune system development, is central to understanding this trend. Furthermore, advanced machine learning algorithms have provided fresh insights into the interactions among various risk factors. This study investigates the relationship between early childhood antibiotic use, the duration of exclusive breastfeeding, indoor environmental factors, and child AD. By integrating machine learning techniques with the hygiene hypothesis, we aim to assess and interpret the significance of these risk factors. In this community-based case-control study with a 1:4 matching design, we evaluated the prevalence of AD in preschool-aged children. Data were collected via questionnaires completed by the parents of 771 children diagnosed with AD, matched with controls based on gender, age, and ethnicity. Univariate analyses identified relevant characteristics, which were further examined using multivariable logistic regression to calculate odds ratios (ORs). Stratified analyses assessed confounders and interactions, while the significance of variables was determined using a machine learning model. Renovating the dwelling during the mother's pregnancy (OR = 1.50; 95% CI 1.15-1.96) was identified as a risk factor for childhood AD. Additionally, antibiotic use three or more times during the child's first year (OR = 1.92; 95% CI 1.29-2.85) increased the risk of AD, independent of the parents' history of atopic disease and the child's mode of birth. Moreover, exclusive breastfeeding for four months or more (OR = 1.59; 95% CI 1.17-2.17) was identified as a risk factor for AD, particularly in the group without a maternal history of atopic disease. In contrast, having older siblings in the family (OR = 0.76; 95% CI 0.63-0.92) and low birth weight (OR = 0.62; 95% CI 0.47-0.81) were identified as protective factors against AD. Machine learning modeling indicated that the duration of exclusive breastfeeding, having older siblings, low birth weight, and parental history of AD or allergic rhinitis are key predictors of childhood AD. Our findings support the broader interpretation of the hygiene hypothesis. Machine learning analysis highlights the key role of the hygiene hypothesis and underscores the need for future AD prevention and healthcare initiatives focusing on children with a parental history of AD or allergic rhinitis. Moreover, minimizing antibiotic overuse may be essential for preventing AD in children. Further research is necessary to elucidate the impact and mechanisms of exclusive breastfeeding on AD to instruct maternal and child healthcare practices.

Neonates primarily rely on innate immune defense, yet their inflammatory responses are usually restricted compared to adults. This is controversially interpreted as a sign of immaturity or essential programming, increasing or decreasing the risk of sepsis, respectively. Here, combined transcriptomic, metabolic, and immunological studies in monocytes of healthy individuals reveal an inverse ontogenetic shift in metabolic pathway activities with increasing age. Neonatal monocytes are characterized by enhanced oxidative phosphorylation supporting ongoing myeloid differentiation. This phenotype is gradually replaced during early childhood by increasing glycolytic activity fueling the inflammatory responsiveness. Microbial stimulation shifts neonatal monocytes to an adult-like metabolism, whereas ketogenic diet in adults mimicking neonatal ketosis cannot revive a neonate-like metabolism. Our findings disclose hallmarks of innate immunometabolism during healthy postnatal immune adaptation and suggest that premature activation of glycolysis in neonates might increase their risk of sepsis by impairing myeloid differentiation and promoting hyperinflammation.

It has long been appreciated that farm exposure early in life protects individuals from allergic asthma. Understanding what component(s) of this exposure is responsible for this protection is crucial to understanding allergic asthma pathogenesis and developing strategies to prevent or treat allergic asthma. In this review, we introduce the concept of Farm-Friends, or specific microbes associated with both a farm environment and protection from allergic asthma. We review the mechanism(s) by which these Farm-Friends suppress allergic inflammation, with a focus on the molecule(s) produced by these Farm-Friends. Finally, we discuss the relevance of Farm-Friend administration (oral vs. inhaled) for preventing the development and severity of allergic asthma throughout childhood and adulthood. By developing a fuller understanding of which Farm-Friends modulate host immunity, a greater wealth of prophylactic and therapeutic options becomes available to counter the current allergy epidemic.

The prevalence of noncommunicable inflammatory disease is increasing in modern urban societies, posing significant challenges to public health. Novel prevention and therapeutic strategies are needed to effectively deal with this issue. One promising approach is leveraging microorganisms such as Mycobacterium vaccae ATCC 15483, known for its anti-inflammatory, immunoregulatory, and stress-resilience properties. This study aimed to assess whether weekly subcutaneous administrations of a whole-cell, heat-killed preparation of M. vaccae ATCC 15483 (eleven injections initiated one week before the onset of the diet intervention), relative to vehicle injections, in adolescent male C57BL/6N mice can mitigate inflammation associated with Western-style diet-induced obesity, which is considered a risk factor for a number of metabolic and inflammatory diseases. Our results show that treatment with M. vaccae ATCC 15483 prevented Western-style diet-induced excessive weight gain, visceral adipose tissue accumulation, and elevated plasma leptin concentrations. The Western-style diet, relative to a control diet condition, decreased alpha diversity and altered the community composition of the gut microbiome, increasing the Bacillota to Bacteroidota ratio (formerly referred to as the Firmicutes to Bacteroidetes ratio). Despite the finding that M. vaccae ATCC 15483 prevented Western-style diet-induced excessive weight gain, visceral adipose tissue accumulation, and elevated plasma leptin concentrations, it had no effect on the diversity or community composition of the gut microbiome, suggesting that it acts downstream of the gut microbiome to alter immunometabolic signaling. M. vaccae ATCC 15483 reduced baseline levels of biomarkers of hippocampal neuroinflammation and microglial priming, such as Nfkbia and Nlrp3, and notably decreased anxiety-like defensive behavioral responses. The current findings provide compelling evidence supporting the potential for M. vaccae ATCC 15483 as a promising intervention for prevention or treatment of adverse immunometabolic outcomes linked to the consumption of a Western-style diet and the associated dysbiosis of the gut microbiome.

Previous studies found that children with siblings, farm residence, and other proxies of greater microbial contacts had lower rates of hyper-responsive immune disorders. Yet, scientific debate persists regarding whether the human immune system is educated in early life primarily as a function of pathogenic or benign microbial exposures, or both. Furthermore, pregnancy relies on women's intrinsic immunosuppressive function, yet it remained unknown how immunoregulation in pregnant women relates to early-life microbial exposures. Here, we conduct a preliminary examination of whether childhood microbial exposures prime women's pregnancy-related immunoregulatory capacity.

We administered retrospective questionnaires to estimate 55 pregnant women's early-life exposure to pathogenic (e.g., illness) and benign (e.g., pets; rural residence) microbes. Tolerogenic regulatory T-cells (Tregs) and Treg subtypes were measured by flow cytometry from peripheral blood.

Results show that proxies for both pathogenic and benign exposures were positively associated with Treg concentrations.

These findings offer insights that may help elucidate the relative contributions of early-life pathogenic ("hygiene hypothesis") and benign ("old friends hypothesis") microbial exposures toward the expansion of the Treg compartment. Human evolutionary history is characterized by changing microbial exposures as human residency patterns, living environments, and subsistence strategies changed. In this context, our findings suggest the possibility of less gestational pathology in human evolutionary past conditions typified by richer diversity of microbial exposure.

Type 2 immunity represents a unique immune module that provides host protection against macro-parasites and noxious agents such as venoms and toxins. In contrast, maladaptive type 2 immune responses cause allergic diseases. While multiple cell types play important roles in type 2 immunity, recent studies in humans and murine models of chronic allergic diseases have shown that a distinct population of tissue-resident, CD4+ T helper type 2 (Th2) cells play a critical role in chronic allergic inflammation. The rules regulating Th2 cell differentiation have remained less well defined than other T cell subsets, but recent studies have shed new light into the specific mechanisms controlling Th2 cell biology in vivo. Here, we review our current understanding of the checkpoints regulating the development and function of tissue-resident Th2 cells with a focus on chronic allergic diseases. We discuss evidence for a barrier tissue checkpoint in initial Th2 cell priming, including the role of neuropeptides, damage-associated molecular patterns, and dendritic cell macro-clusters. Furthermore, we review the evidence for a second barrier tissue checkpoint that instructs the development of multi-cytokine producing, tissue-resident Th2 cells that orchestrate allergic inflammation. Lastly, we discuss potential approaches to therapeutically target tissue-resident Th2 cells in chronic allergic diseases.

Eukaryotic organisms are associated with complex microbial communities. Changes within these communities have been implicated in disease development. Nonetheless, it remains unclear whether these changes are a cause or a consequence of disease. Here, we report a causal link between environment-induced shifts in the microbiota and disease development. Using the model organism Hydra, we observed changes in microbial composition when transferring laboratory-grown Hydra to natural lake environments. These shifts were caused not only by new colonizers, through the process of community coalescence (merging of previously separate microbial communities), but also by lake water nutrients. Moreover, selective manipulation of the nutrient environment induced compound-specific shifts in the microbiota followed by disease development. Finally, L-arginine supplementation alone caused a transition in Pseudomonas from symbiotic to pathogenic, leading to an upregulation of immune response genes, tissue degradation, and host death. These findings challenge the notion that the host-associated microbiota is exclusively controlled by the host, highlighting the dynamic interplay between host epithelial environment, microbial colonizer pool, and nutrient conditions of the surrounding water. Furthermore, our results show that overfeeding of the microbiota allows for uncontrolled microbial growth and versatile interactions with the host. Environmental conditions may thus render symbionts a potential hazard to their hosts, blurring the divide between pathogenic and non-pathogenic microbes.IMPORTANCEThis study highlights the critical need to understand the dynamic interplay between host-associated microbiota and environmental factors to obtain a holistic view on organismal health. Our results demonstrate that ecosystem-wide microbial trafficking (community coalescence) and environmental nutrient conditions reshape microbial communities with profound implications for host health. By exploring nutrient-driven changes in microbial composition, our research finds experimental support for the "overfeeding hypothesis," which states that overfeeding alters the functionality of the host microbiota such that an overabundance in nutrients can facilitate disease development, transforming non-pathogenic microbes into pathogens. These findings emphasize the critical role of metabolic interactions driving microbial pathogenicity. Furthermore, our research provides empirical evidence for the "pathogenic potential" concept, challenging traditional distinctions between pathogenic and non-pathogenic microbes and supporting the idea that any microbe can become pathogenic under certain conditions.

Epidemiological studies indicate a rising prevalence of allergic diseases, now recognized as a major global public health concern. In children, the progression of these diseases often follows the "atopic march," beginning with eczema, followed by food allergies, allergic rhinitis, and asthma. Recent research has linked gut microbiota dysbiosis to the development of allergic diseases in children. The gut microbiota, a crucial component of human health, plays a vital role in maintaining overall well-being, highlighting its potential in preventing and modifying the course of allergic diseases. This review examines the relationship between childhood allergic diseases and gut microbiota, drawing on the latest evidence. We first elaborated the concepts of allergic diseases and gut microbiota, followed by a discussion of the developmental trajectory of the gut microbiota in healthy children. This review further explored the richness, diversity, and composition of the gut microbiota, as well as specific microbial taxa associated with allergic disease. Lastly, we discussed the current status and future potential of probiotic interventions in managing pediatric allergic diseases.

Toll-like receptors (TLR), the key players of the innate immune system, contribute to the pathogenesis of atopic dermatitis (AD) through multiple pathways. TLRs play a crucial role in delaying barrier repair, promoting Th2-mediated dermatitis, shifting the response toward Th1 in the chronic phase, and contributing to the establishment of the itch-scratch cycle, as well as mediating the effects of UV radiation. The dysregulation of proinflammatory and immunomodulatory effects of TLRs can be attributed to their ligand structures, receptor heterodimerization, the relative frequency of each TLR, interactions with other receptors/signalling pathways, cytokine milieu, and genetic polymorphisms. Current AD treatments like vitamin-D analogs, tacrolimus, and cyclosporine partially work through TLR modulation. Direct TLR stimulation using different compounds has shown therapeutic benefits in preclinical studies. However, significant challenges exist, including off-target effects due to ubiquitous TLR expression and complex roles in immune responses. Future directions include CRISPR-based gene editing to understand TLR functions, development of specific TLR modulators for targeted therapy, and machine learning applications to predict drug responses and identify novel ligands. Patient heterogeneity, including the presence or absence of polymorphisms, variations in TLR expression levels, and differences in immune responses, underscores the need for personalized therapeutic approaches.

Allergic and autoimmune disorders are characterised by dysregulation of the immune responses to otherwise inert environmental substances and autoantigens, leading to inflammation and tissue damage. Their incidence has constantly increased in the last decades, and their co-occurrence defies current standards in patient care. For years, allergy and autoimmunity have been considered opposite conditions, with IgE and Th2 lymphocytes cascade driving canonical allergic manifestations and Th1/Th17-related pathways accounting for autoimmunity. Conversely, growing evidence suggests that these conditions not only share some common inciting triggers but also are subtended by overlapping pathogenic pathways. Permissive genetic backgrounds, along with epithelial barrier damage and changes in the microbiome, are now appreciated as common risk factors for both allergy and autoimmunity. Eosinophils and mast cells, along with autoreactive IgE, are emerging players in triggering and sustaining autoimmunity, while pharmacological modulation of B cells and Th17 responses has provided novel clues to the pathophysiology of allergy. By combining clinical and therapeutic evidence with data from mechanistic studies, this review provides a state-of-the-art update on the complex interplay between allergy and autoimmunity, deconstructing old dichotomic paradigms and offering potential clues for future research.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex relationship to allergens. While AD itself is not an allergic reaction and does not necessarily involve allergen sensitization, AD patients show higher rates of sensitization to food and inhalant allergens compared to the general population. Recent evidence refining the "dual allergen exposure hypothesis" demonstrates that early oral exposure to allergens through an intact gastrointestinal barrier typically promotes tolerance, while exposure through compromised skin or respiratory barriers often leads to sensitization. Therefore, the impaired skin barrier function in AD patients increases the risk of transcutaneous sensitization and may interfere with oral tolerance development. Interestingly, AD patients' sensitivity to contact allergens (such as metals and fragrances) is not necessarily higher than that of the general population, which may be related to the inherent properties of these allergens. Personalized allergen testing can help guide appropriate allergen avoidance and reintroduction strategies in AD management. The insights into optimal allergen exposure conditions have also expanded the potential applications of allergen-specific immunotherapy in preventing AD onset in high-risk populations and halting the atopic march.

Asthma is a multifaceted and multicausal disease. Childhood asthma is strongly influenced by genetic traits and is characterized by hyperreactivity of the airways so that also unspecific triggers including moulds can trigger an asthma attack. Therefore, it is undisputed that moulds in the home can cause asthma attacks in asthmatic children. It is, however, unclear if mould in homes also induce the development of asthma. Because more and more severe attacks in asthmatic children living in mouldy homes might speed up the diagnosis of asthma, cross-sectional studies are not well-suited to differentiate between mould as a causative or only as a precipitating factor. Cross-sectional studies show an increased asthma risk and poorer lung function in children living in mouldy homes. To better understand the causal role of mould in homes, a systematic review was performed with random effects meta-analysis focusing on cohort and case-control studies only.We found 21 case-control and 11 cohort studies examining the association between mould at home and later advent of childhood asthma. According to the case-control studies, mouldy homes increase the risk of asthma by 53% (95 confidence interval [CI]: 42-65%) with no evidence of heterogeneity or publication bias. Risk estimates based on cohort studies were smaller with 15% (1-31%). The cohort studies also showed no publication bias but substantial heterogeneity (I2 = 60.5, p = 0.005). Heterogeneity could be partly explained by percentage of male children, age of participants, and publication year, but was not affected by study quality.In conclusion, living in mouldy homes during childhood seems to increase the risk of later developing bronchial asthma.

This study aimed to explore the characteristics, overall anxiety and depression status, and influencing factors of only-child and non-only-child students by examining a medical student population in the post-COVID-19 era.

This study was a cross-sectional design.

An online questionnaire survey was administered among medical students. The psychological problems related to depression and anxiety were measured using Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale (GAD-7), respectively, which were scored via a Likert-4 scale. Statistical analysis was employed to explore the characteristics and overall differences between only-child and non-only-child students, along with the factors affecting their anxiety and depression.

A total of 1688 participants were enrolled. No significant differences were observed in the prevalence of anxiety (χ2 = 1.154, P = 0.283) and depression (χ2 = 0.313, P = 0.576) between only-child and non-only-child students. School level, single status, and desire for only child status are associated with anxiety and depression in the two groups. Region and loneliness are merely related to anxiety and depression among only-child students, while gender, willingness to apply for medical school, and equal treatment are associated with anxiety and depression among non-only-child students.

Our study found the factors that are associated with depression or anxiety inthe only-child and non-only-child medical students jointly and separately, which could provide a new theoretical basis for the psychological intervention of medical students, that is, to identify the high risk factors of depression and anxiety from the perspective of only child and non-only child.

Despite advances in our understanding of their diagnosis and treatment, pediatric allergies impose substantial burdens on affected children, families, and healthcare systems. Further, the prevalence of allergic diseases has dramatically increased over the past half-century, leading to additional concerns and concerted efforts to identify the origins, potential predictors and preventions, and therapies of allergic diseases. Together with the increase in allergic diseases, changes in lifestyle and early-life environmental influences have corresponded with changes in colonization patterns of the infant gut microbiome. The gut microbiome plays a key role in developing the immune system, thus greatly influencing the development of allergic disease. In this review, we specifically highlight the importance of the proper maturation and composition of the gut microbiome as an essential step in healthy child development or disease progression. By exploring the intertwined development of the immune system and microbiome across pediatric allergic diseases, we provide insights into potential novel strategies for their prevention and management.

Relationships between parasites, host physiology, and behaviours are complex. Parasites can influence host hormonal microenvironment and behaviour through "sickness behaviours" that generally conserve energy. Using a parasite removal experiment, we examined the effects of gastrointestinal parasites on fecal glucocorticoid metabolites (fGC) and behaviours of vervet monkeys (Chlorocebus pygerythrus) at Lake Nabugabo, Uganda. We collected parasitological, hormonal, and behavioural data from adult and subadult male and female vervets (N = 19) in 2014 across four study phases: pre-deworming, post-deworming, early reinfection, and late reinfection as well as in 2015. Overall, there was no decrease in fGC after deworming, but there was an increase following natural reinfection. There was no change in feeding across study phases; however, moving, grooming, and resting changed between the post-deworming and late reinfection phases, but not always in the predicted direction. Comparing behaviour across the same months in the following year as in the 2014 experimental study period, we found no differences in moving, feeding, grooming, and resting events. Despite behavioural variation between study phases, we cannot conclude that behavioural changes are due to parasitism rather than other seasonal variation. However, fGC increased following reinfection, which is consistent with parasitism being costly for hosts.

The immune response is an intricate system that involves the complex connection of cellular and molecular components, each with distinct functional specialisations. It has a distinct capacity to adjust and mould the immune response in accordance with specific stimuli, influenced by both genetic and environmental factors. The presence of genetic diversity, particularly across different ethnic and racial groups, significantly contributes to the impact of incidence of diseases, disease susceptibility, autoimmune disorders, and cancer risks in specific regions and certain populations. Environmental factors, including geography and socioeconomic status, further modulate the variety of the immune system responses. These, in turn, affect the susceptibility to infectious diseases and development of autoimmune disorders. Despite the complexity of the relationship, there remains a gap in understanding the specificity of immune indices across races, immune reference ranges among populations, highlighting the need for deeper understanding of immune diversity for personalized approaches in diagnostics and therapeutics. This review systematically organizes these findings, with the goal of emphasizing the potential of targeted interventions to address health disparities and advance translational research, enabling a more comprehensive strategy. This approach promises significant advancements in identifying specific immunological conditions, focusing on personalized interventions, through both genetic and environmental factors.

Currently, whether exposure to pets is a protective factor for atopic dermatitis (AD) is controversial.

To investigate the association of pet exposure in early life with the incident AD.

This study was based on PRISMA. The authors independently searched PubMed, Cochrane Library, and EMBASE. We gathered cohort studies reporting on the ratio of pet exposure and incident AD and meta-analyzed them by relative risks (RRs) and 95% confidence interval (CI). Newcastle-Ottawa Scale (NOS) and funnel plot were performed to evaluate the quality of the study and publication bias, respectively. P < 0.05 was considered statistically significant.

We included 23 studies comprising 3174-25,527 participants with exposure age 0-12. The quality of included studies was generally gorgeous, with NOS 5-8. Dog exposure was negatively associated with the incident AD, with RRs of 0.82 (P = 0.002), but this trend was insignificant in cats (RR = 1.08; P = 0.490) and other pets (RR = 0.94; P = 0.550). Subgroup analysis showed participants exposed to dogs had a further lower AD risk in the North American populations (RR = 0.60; P < 0.001). Publication bias was not supported by the funnel plot.

This study finds exposure to dog pets in early life is negatively associated with newly developed AD, especially in North American populations.

Currently, whether exposure to pets is a protective factor for atopic dermatitis (AD) is controversial. This study finds exposure to dog pets in early life is negatively associated with newly developed atopic dermatitis, and this trend is more remarkable in North American populations. Associations of exposure to cats and other pets with atopic dermatitis are not found. These results discover a novel insights to prevention AD and related diseases.

Mental health disorders and neurodegenerative diseases place a heavy burden on patients and societies, and, although great strides have been made to understand the pathophysiology of these conditions, advancement in drug development is lagging. The importance of gastrointestinal health in maintaining overall health and preventing disease is not a new concept. Hundreds of years ago, healers from various cultures and civilizations recognized the crucial role of the gut in sustaining health. More than a century ago, scientists began exploring the restorative effects of probiotics, marking the early recognition of the importance of gut microbes. The omics era brought more enlightenment and enabled researchers to identify the complexity of the microbial ecosystems we harbour, encompassing bacteria, eukaryotes (including fungi), archaea, viruses, and other microorganisms. The extensive genetic capacity of the microbiota is dynamic and influenced by the environment. The microbiota therefore serves as a significant entity within us, with evolutionarily preserved functions in host metabolism, immunity, development, and behavior. The significant role of the bacterial gut microbiome in mental health and neurodegenerative disorders has been realized and described within the framework of the microbiota-gut-brain axis. However, the bacterial members do not function unaccompanied, but rather in concert, and there is a substantial knowledge gap regarding the involvement of non-bacterial microbiome members in these disorders. In this review, we will explore the current literature that implicates a role for the entire metagenomic ensemble, and how their complex interkingdom relationships could influence CNS functioning in mental health disorders and neurodegenerative diseases.

Respiratory syncytial virus (RSV) infection in the first year of life has been linked with an increased risk for asthma. Some propose that RSV-induced inflammation leads to lasting airway changes, while others contend that RSV bronchiolitis is a marker for underlying predisposition. Social distancing adopted during the COVID-19 pandemic has led to a dramatic reduction in RSV activity, providing an unexpected opportunity to investigate this debate.

To compare the incidence of asthma-related healthcare-utilization (HCU) in 1-3 years of age between children born in March-June 2020 (l-RSV) and children born during the same months in the years 2014-2017 (H-RSV).

This retrospective study utilized nationwide healthcare database records from Clalit-Healthcare-Services, the largest healthcare organization in Israel. The study analyzed asthma-related HCU, using multivariate logistic regression and Bayesian analyses.

172,463 children were included in the study: 32,927 in the l-RSV group versus 139,536 in the H-RSV group. The l-RSV cohort showed insignificant changes and increased rates of asthma-related HCU between 1 and 3 years of age in some asthma surrogates, compared to the H-RSV group.

Reduction in RSV exposure during the first year of life did not correlate with a decrease in asthma-related HCU. This may imply that RSV infection in infancy functions as an indicator of underlying predisposition rather than a direct cause of asthma.

Significant debate exists on the association between Helicobacter pylori infection and childhood asthma. We aimed to explore this association in a cohort of children in Palestine while estimating the prevalence of H. pylori in this population.

We conducted a prospective case-control study among children aged 6-15 years in Palestine, including 44 asthma cases diagnosed by pediatric pulmonologists and 99 age-matched healthy controls recruited through cluster sampling from schools. H. pylori status was determined using a stool antigen test. Asthma severity was assessed using the International Study of Asthma and Allergies in Childhood questionnaire. Data on recent antibiotic use, which could affect H. pylori status, were collected for both groups. Multiple logistic regression analyzed the association between H. pylori and asthma, adjusting for age and sex. The chi-square test assessed the impact of antibiotic use on H. pylori status.

The prevalence of H. pylori infection in the study population was 45%. Children with asthma had a lower prevalence of H. pylori infection compared to healthy controls (32% vs. 51%, adjusted odds ratios, 0.46; 95% confidence interval, 0.22-0.99; p=0.04). Antibiotic use in the past month or year did not significantly impact H. pylori status. Among children with asthma, H. pylori infection rates did not vary by asthma severity (p=0.05).

H. pylori infection is associated with a reduced risk of asthma in children, suggesting a potential protective role. Further prospective cohort studies are warranted to clarify the mechanisms underlying this association.

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a nonspecific chronic inflammation of the gastrointestinal tract. Despite recent advances in therapeutics and newer management strategies, IBD largely remains untreatable. Helminth therapy is a promising alternative therapeutic for IBD that has gained some attention in the last two decades. Helminths have immunomodulatory effects and can alter the gut microbiota. The immunomodulatory effects include a strong Th2 immune response, T-regulatory cell response, and the production of regulatory cytokines. Although concrete evidence regarding the efficacy of helminth therapy in IBD is lacking, clinical studies and studies done in animal models have shown some promise. Most clinical studies have shown that helminth therapy is safe and easily tolerable. Extensive work has been done on the whipworm Trichuris, but other helminths, including Schistosoma, Trichinella, Heligmosomoides, and Ancylostoma, have also been explored for pre-clinical and animal studies. This review article summarizes the potential of helminth therapy as an alternative therapeutic or an adjuvant to the existing therapeutic procedures for IBD treatment.

Since we published the "IV Brazilian Consensus on Rhinitis", in2017, several advances have been achieved and have enabled a further understanding of the different aspects of "Rhinitis". This new guideline, developed jointly by ASBAI, SBP and SBORL, represents a relevant milestone in the updated and integrated management of the different forms of the disease, and it aims to unify evidence-based approaches to improve the diagnosis and treatment of this common and often underestimated condition. The document covers a wide range of topics, including clear definitions of the different phenotypes and endotypes of rhinitis, risk factors, updated diagnostic criteria, and recommended methods for clinical and laboratory investigation. We stress the importance of detailed clinical history and objective assessment, as well as tools for control and assessing severity tools an accurate diagnostic approach to the disease. Regarding treatment, it emphasizes the treatment customization, considering the severity of symptoms, the presence of comorbidities and the impact on the patient's quality of life. We discuss different drug treatment, in addition to non-pharmacological measures, such as environmental control and specific immunotherapy; and the possible role of immunobiological agents. Furthermore, the consensus addresses issues related to patient education, prevention and management of special situations, such as rhinitis in children, in pregnant women and in the elderly. In short, the "V Brazilian Consensus on Rhinitis" represents a comprehensive and updated guide for healthcare professionals involved in the diagnosis and management of rhinitis, aiming to improve patients' quality of life through an integrated and evidence-based approach.

Sepsis is a disorder of immune regulation caused by pathogenic microorganisms. A large number of inflammatory factors and inflammatory mediators are released, resulting in systemic inflammatory response disorder and acute lung injury (ALI). Helminths infection activate Th2 cytokines and immunomodulatory pathways, which have the function of anti-infection effector molecules. The early infection of Trichinella spiralis (T. spiralis) was mainly intestinal phase. In this study, we explored the effect of intestinal phase infection of T. spiralis on LPS-induced ALI. Compared with control mice, the serum and lung tissues of T. spiralis infected mice had a significant decrease of Th1 inflammatory cytokines, a significant increase of Th2 anti-inflammatory cytokines, and a significant decrease of inflammatory cell infiltration in lung tissue. These results suggest that T. spiralis during the intestinal phase can act on distal organs (lung) and reduce LPS-induced lung inflammation, providing evidence for a potential new pathway for immune-mediated disease in helminths and a possible role for intestinal worms in the gut-lung axis.

Allergic rhinitis (AR) within the pediatric population affects more patients than any other chronic disease. Inferior turbinate hypertrophy (ITH) is a common cause of nasal obstruction in children and is strongly associated with AR. Inferior turbinate reduction (ITR) surgery is used in patients with ITH who have failed medical management. While surgery is curative for most, there remains a subset of patients who continue to have symptoms of nasal obstruction despite ITR, which can cause discomfort and significant impacts on quality of life. Additionally, some patients with persistent disease go on to require revision surgery. The objectives in this study were to assess the impact of allergy testing results in patients undergoing ITR and evaluate if they predict long-term durability of surgical outcome.

A retrospective chart review of patients undergoing ITR between January and December of 2015 was performed. Data pertaining to demographics, allergy testing results, surgical technique, and medical management was collected. Patients who underwent concomitant procedures at the time of ITR were excluded. Data analysis included descriptive statistics, chi-squared tests, and t-test analyses.

297 patients who underwent ITR were included for data analysis. Overall, 20.9 % of patients had recurrent nasal obstruction after ITR and 5.4 % required revision surgery. Among all included patients, 37.7 % underwent allergy testing of which 53 (47.3 %) tested positive and 54 (48.2 %) tested negative; results were unknown for 5 (4.5 %) patients. In patients with positive allergy tests, 36 % had recurrent nasal obstruction and 11 % required revision surgery. In patients with negative allergy tests, 41 % had recurrent nasal obstruction and 13 % required revision surgery. There were no significant associations among those with positive and negative allergy tests and recurrence of nasal obstruction or need for revision surgery. Patients with a documented clinical diagnosis of AR were more likely to have recurrence of nasal obstruction after surgery than those without (28 % vs 12 %, p = 0.001) and were more likely to require revision surgery (9 % vs 1 %, p = 0.001).

ITR is a reasonable choice for the treatment of nasal obstruction in children. However, there remains a subset of patients who have recurrent nasal obstruction following initial surgery. Allergy testing results do not appear to impact the rate of recurrent nasal obstruction or the need for revision surgery. Therefore, the utility of allergy testing may have a limited benefit in the management of nasal obstruction in children. However, a clinical diagnosis of allergic rhinitis does appear to be a prognostic factor for experiencing post-operative recurrent nasal obstruction and requiring revision surgery.

Antinuclear antibodies (ANAs) are critical immunological markers commonly associated with various connective tissue diseases (CTDs). However, these autoantibodies are also detectable in healthy individuals, patients with non-rheumatic autoimmune diseases, those with viral infections, and subjects using specific medications (such as procainamide, hydralazine, and minocycline) that can lead to drug-induced ANA elevation. The standard method for ANA detection is indirect immunofluorescence, a process that requires precision and thoroughness as it assesses both titer and fluorescence patterns. Additionally, immunoblotting and enzyme-linked immunosorbent assay (ELISA) are recommended to identify specific ANAs precisely, highlighting the importance of precision in ANA detection. This review explores the advantages and limitations of current ANA detection methods. It also describes the clinical implications of ANA presence in non-rheumatic diseases, including autoimmune disorders, infectious conditions, non-autoimmune and non-infectious diseases, and autoimmune cutaneous diseases. The presence of elevated ANA titers in these contexts can complicate clinical decision-making, as the diagnostic value of ANA testing alone is limited in non-rheumatic conditions. However, despite these limitations, ANA remains a key component in diagnosing and prognosis systemic CTDs, as it can indicate disease activity, severity, and response to treatment, which is of utmost importance in rheumatology and internal medicine. This paper provides a comprehensive review of the role of ANA in non-rheumatic diseases. It focuses on ANA diagnostic and prognostic significance and offers valuable insights for clinical practice.

Asthma, allergic rhinitis, atopic dermatitis, and food allergy are type 2 inflammation diseases. Since the 1960s, the prevalence of those diseases has steadily increased, presumably due to the "Hygiene hypothesis" which suggests that early exposure of infants to pathogens, siblings, and environmental dust, has a protective effect against the development of allergic diseases. The COVID-19 pandemic increased environmental hygiene due to lockdowns, masks, and social distancing.

To compare the prevalence of allergic diseases among children born before and during the pandemic.

The Cow's Milk Early Exposure Trial prospectively followed newborns until 12-months of age using monthly survey and examined milk allergy development. Some were born before the first COVID-19 lockdown in Israel (April 2018-March 2020), and some were born during the pandemic (March 2020-May 2021). The monthly surveys included questions regarding atopic comorbidities.

A total of 1,989 infants completed 12-months of follow-up. Among them, 1,086(54.5%) were diagnosed with at least one atopic disease. Among 235 infants born after the last lockdown, 162 were diagnosed with airway hyperresponsiveness (AHR)(68.9%), significantly more than in any other group. No other significant differences were found between the study groups.

There was no significant difference in the development of atopic comorbidities between infants born before and during the pandemic. Significantly more infants who were born after restrictions were eased were diagnosed AHR. A longer follow-up period is needed to obtain a better understanding of the influence of the COVID-19 restrictions on the development of atopic comorbidities.

NIH Clinical Trials Registry: NCT02785679.

Laboratory mice are instrumental for preclinical research but there are serious concerns that the use of a clean standardized environment for specific-pathogen-free (SPF) mice results in poor bench-to-bedside translation due to their immature immune system. The aim of the present study was to test the importance of the gut microbiota in wild vs. SPF mice for evaluating host immune responses in a house-dust-mite-induced allergic airway inflammation model without the influence of pathogens. The wild mouse microbiome reduced histopathological changes and TNF-α in the lungs and serum when transplanted to microbiota-depleted mice compared to mice transplanted with the microbiome from SPF mice. Moreover, the colonic gene expression of Gata3 was significantly lower in the wild microbiome-associated mice, whereas Muc1 was more highly expressed in both the ileum and colon. Intestinal microbiome and metabolomic analyses revealed distinct profiles associated with the wild-derived microbiome. The wild-mouse microbiome thus partly reduced sensitivity to house-dust-mite-induced allergic airway inflammation compared to the SPF mouse microbiome, and preclinical studies using this model should consider using both 'dirty' rewilded and SPF mice for testing new therapeutic compounds due to the significant effects of their respective microbiomes and derived metabolites on host immune responses.

The growing global incidence of immune-mediated and inflammatory diseases (IMIDs) is worrisome, with evidence suggesting that environmental factors, notably urbanization and the reduction of green spaces, may act as potential instigators. However, conflicting findings in studies necessitate a closer examination of recent research (January 2020 - February 2024) to elucidate the factors contributing to these inconsistencies. This review explores study protocols to avoid erroneously endorsing the null hypothesis of no association between green space coverage and IMID risks. A literature search adhering to PRISMA-ScR guidelines yielded 46 relevant papers from Google Scolar and Pub Meb. The studies varied in design, with 17 being longitudinal, 24 cross-sectional, and five focusing on longitudinal parent-offspring connections. Geographic scope differed, with 21 multi-location and 25 single-location studies. Participant numbers ranged from 144 to 982,131 across diverse demographics. Additionally, some studies examined disease frequencies in large groups (several million people) residing in specific regions. Green space metrics encompassed NDVI, land cover data, plant biodiversity, and novel indexes, measured within 7.5-5000 m diameter buffers around residences or schools. The review advises against making definitive statements regarding the relationship between urban green spaces and the prevalence of IMIDs. It suggests that inconsistencies in study results may stem from variations in study designs and methodologies, as well as the complex, interacting mechanisms through which green spaces affect immune health. Future research recommendations include larger cohorts, early-life exposure data, and testing specific hypotheses related to vegetation types and participants' genetic predispositions.

Indoor environments serve as habitat for humans and are replete with various reservoirs and niches for microorganisms. Microorganisms enter indoor spaces with their human and non-human hosts, as well as via exchange with outdoor sources, such as ventilation and plumbing. Once inside, many microorganisms do not survive, especially on dry, barren surfaces. Even reduced, this microbial biomass has critical implications for the health of human occupants. As urbanization escalates, exploring the intersection of the indoor environment with the human microbiome and health is increasingly vital. The indoor microbiome, a complex ecosystem of microorganisms influenced by human activities and environmental factors, plays a pivotal role in modulating infectious diseases and fostering healthy immune development. Recent advancements in microbiome research shed light on this unique ecological system, highlighting the need for innovative approaches in creating health-promoting living spaces. In this Review, we explore the microbial ecology of built environments - places where humans spend most of their lives - and its implications for immune, endocrine and neurological health. We further propose strategies to harness the indoor microbiome for better health outcomes.

In the past decades, food allergies became increasingly dominant since early childhood, leading to a lower quality of life and to increasing costs addressed by the health care system. Beside standard avoidance of specific allergens and drug treatments following allergen exposure, a great deal of research has lately focused on Food Allergy Allergen Immunotherapy (FA-AIT). SCIT and EPIT (Subcutaneous and Epicutaneous Immunotherapy), OIT (Oral Immunotherapy), and SLIT (Sublingual Immunotherapy) consist in gradual exposure to allergens to desensitize and achieve tolerance once therapy has ended. Although promising, FA-AIT may bring acute local and systemic adverse reactions. To enhance efficacy, safety and convenience of AIT, the quest of potential adjuvants to mitigate the adverse reactions becomes crucial. Immunomodulatory activities, such as that of increasing the regulatory T cells and decreasing the IgE, have been observed in specific probiotics' strains and multiple studies elucidated the role of gut microbiota as a major interplayer among the host and its immune system. In this review, the microbiome modulation is shown as potential AIT adjuvant, nevertheless the need of more clinical studies in the near future is pivotal to assess the efficacy of targeted bacterial therapies and faecal microbiota transplantation.

Inflammatory bowel disease (IBD) is a chronic and recurrent disease of the gastrointestinal tract that enhances the chance of developing colorectal cancer. Since standard treatments such as Mesalazine have limited effectiveness and are often accompanied by numerous side effects, the use of immune modulators derived from worms has been proposed as a new immunotherapy method for inflammatory diseases such as ulcerative colitis. The aim of this study is to investigate the protective effects of D. dendriticum egg antigen on DSS-induced colitis in C57BL/6 mice.

D. dendriticum egg antigen was extracted and DSS (3.5%) was used to induce colitis in mice. Treatment and prophylaxis included intraperitoneal injections of D. dendriticum egg antigen. Histopathological indicators and the disease activity index (DAI), including weight loss, rectal bleeding, stool consistency, and rectal prolapse, were used to assess the severity of colitis. Real-time PCR measured the expression of transforming growth factor-β (TGF-β) and interleukin-17 (IL-17), while ELISA determined the concentration of these cytokines.

Treatment with D. dendriticum egg antigen significantly improved the clinical symptoms and decreased the severity of DSS-induced colitis. Furthermore, D. dendriticum egg antigen increased the expression of TGF-β mRNA and reduced the expression of IL-17 mRNA, leading to a positive adjustment in the regulation of proteins and reduction of inflammatory proteins. As a result, the macroscopic, microscopic inflammation and activity index (DAI) of DSS-induced decreased.

D. dendriticum egg antigen provides a promising new way to modulate the immune system and improve ulcerative colitis.

The Anthropocene is a proposed geological epoch reflecting the large-scale impact of human activity on the Earth's natural systems. This era is also characterized by other significant threats to ecologic well-being that are less evident in the sedimentary records. Extensive environmental changes with industrialization and urbanization have also contributed to declining biodiversity and microbial dysbiosis in essential ecosystems-the original and foundational lifeforms that continue to sustain virtually all ecosystems today, including our own. These changes, along with numerous other social and ecologic disruptions at all scales are implicated in the rising rates of physical and mental ill-health, particularly the immune dysregulation and noncommunicable diseases that characterize the Anthropocene. This narrative review considers how urgent structural changes in how we live are essential to the future of human health and the flourishing of all life on Earth. It explores planetary health as a solutions-oriented, transdisciplinary field and social movement aimed at addressing these interconnected global challenges through integrated ecologic approaches. Planetary health considers not only the vital biophysical "planetary boundaries" required to support human flourishing, but also the upstream social, political, and economic ecosystems that support (or undermine) well-being at all scales. The value systems and the worldviews that have contributed to our global challenges are a central consideration in the planetary health agenda-emphasizing the imperative to address structural inequalities, injustices, and the social, emotional, and spiritual dimensions of unrealized human potential. Promoting these inner assets is essential to human flourishing and fostering the cultural capacities necessary to ensure sustainable planetary health.

Human gut microbiota plays a crucial role in health and disease. Infancy is a critical period for gut microbiota maturation and immune system development and has the potential to affect long-term health. Understanding the development of gut microbiota in Japanese children is essential because of regional differences and the long-term health effects of the early gut microbiota. However, while several longitudinal studies in Japan have explored the development of the gut microbiota after birth, more extended follow-up periods are still needed. In this study, we aimed to analyze the gut microbiota of 106 Japanese mother-child pairs from the Chiba Study of Mother and Child Health, Japan, over 3.5 years. The results showed that the alpha diversity of the gut microbiota in children increased with age, and its composition began to resemble that of adults. We identified four distinct clusters of gut microbiota that reflected different maturation stages. The similarity between the maternal and child gut microbiota appeared to follow a bimodal-like distribution, suggesting that the presence of older siblings may enhance this similarity. This study highlights the dynamic nature of gut microbiota development in Japanese children and deepens our understanding of the similarities between maternal and child gut microbiota.

From the start of life on Earth, several immune defense mechanisms have evolved to guarantee cellular integrity, homeostasis, and host survival. All these sophisticated balances as shaped by and towards the environmental needs have occurred over hundreds of millions of years. Human spaceflight involves various health hazards, such as higher levels of radiation, altered gravity, isolation and confinement, living in tight quarters, and stress associated with being away from home. A growing body of evidence points towards immunological changes in astronauts, including heightened pro-inflammatory responses, reactivation of latent viruses, and cell-mediated alterations, reflecting a dysbalanced state in astronauts. Simultaneously, enhanced pathogenicity, virulence, and drug resistance properties of microorganisms tip the scale out of favor for prolonged stay in space. As we have learned from the past, we see potential for the human immune system, forged and maintained throughout evolutionary history, to adapt to the space exposome. It is unlikely that this will happen in the short time frames set for current space exploration missions. Instead, major risks to astronaut health need to be addressed first, before humans can safely evolve into the space environment.

Alterations in intestinal permeability and microbiota dysregulation have been linked to the development of multiple sclerosis (MS). Short-chain fatty acids (SCFA) and medium-chain fatty acids (MCFA) are products of gut bacteria fermentation which are involved in immune regulation processes. In MS, SCFA have important immunomodulatory properties both in the periphery and the central compartment. Interferon β (IFNβ) was the first disease-modifying therapy approved for the treatment of MS and its effects on the gut microbiota are not fully elucidated.

We performed a prospective observational study aimed to assess peripheral levels of SCFA and MCFA in 23 newly diagnosed, treatment-naïve MS patients (nMS) before and after one year of IFNβ treatment and 23 healthy controls (HC). We investigated their associations with inflammation, interleukin-10 (IL-10), and blood-brain barrier permeability, matrix metalloproteinase 9 (MMP9).

No significant differences in SCFA/MCFA levels were observed between baseline and after IFNβ treatment. Caproic acid levels were significantly higher in nMS compared to HC (1.64 vs 1.27 µM, p=0.005). The butyric acid/caproic acid ratio was higher in HC compared to nMS (5.47 vs 2.55, p=0.005). Correlation analysis revealed associations between SCFA/MCFA levels and inflammatory biomarkers.

nMS have a higher gut-inflammatory activity as seen by the caproic acid ratio as opposed to HC. In this cohort, IFNβ does not appear to modify the peripheral SCFA/MCFA levels after one year of treatment. The quantifications of peripheral SCFA/MCFA may prove to be a useful biomarker for gut-brain axis disruption in MS patients.

In this manuscript, we explore the potential therapeutic use of helminths. After analyzing helminths' role in connection with human health from the perspective of their symbiotic and evolutionary relationship, we critically examine some studies on their therapeutic applications. In doing so, we focus on some prominent mechanisms of action and potential benefits, but also on the exaggerations and theoretical and methodological difficulties of such proposals. We conclude that further studies are needed to fully explore the potential benefits of this perspective, and we encourage the scientific community in doing so.

Autoimmune diseases are prevalent among people of African ancestry living outside Africa. However, the burden of autoimmune diseases in Africa is not well understood. This article provides a global overview of the current burden of autoimmune diseases in individuals of African descent. It also discusses the major factors contributing to autoimmune diseases in this population group, as well as the challenges involved in diagnosing and managing autoimmune diseases in Africa.