The epithelial barrier: The gateway to allergic, autoimmune, and metabolic diseases and chronic neuropsychiatric conditions.

Since the 1960 s, our health has been compromised by exposure to over 350,000 newly introduced toxic substances, contributing to the current pandemic in allergic, autoimmune and metabolic diseases. The "Epithelial Barrier Theory" postulates that these diseases are exacerbated by persistent periepithelial inflammation (epithelitis) triggered by exposure to a wide range of epithelial barrier-damaging substances as well as genetic susceptibility. The epithelial barrier serves as the body's primary physical, chemical, and immunological barrier against external stimuli. A leaky epithelial barrier facilitates the translocation of the microbiome from the surface of the afflicted tissues to interepithelial and even deeper subepithelial locations. In turn, opportunistic bacterial colonization, microbiota dysbiosis, local inflammation and impaired tissue regeneration and remodelling follow. Migration of inflammatory cells to susceptible tissues contributes to damage and inflammation, initiating and aggravating many chronic inflammatory diseases. The objective of this review is to highlight and evaluate recent studies on epithelial physiology and its role in the pathogenesis of chronic diseases in light of the epithelial barrier theory.

Recent advances in the epithelial barrier theory.

The epithelial barrier theory links the recent rise in chronic non-communicable diseases, notably autoimmune and allergic disorders, to environmental agents disrupting the epithelial barrier. Global pollution and environmental toxic agent exposure have worsened over six decades because of uncontrolled growth, modernization, and industrialization, affecting human health. Introducing new chemicals without any reasonable control of their health effects through these years has led to documented adverse effects, especially on the skin and mucosal epithelial barriers. These substances, such as particulate matter, detergents, surfactants, food emulsifiers, micro- and nano-plastics, diesel exhaust, cigarette smoke, and ozone, have been shown to compromise the epithelial barrier integrity. This disruption is linked to the opening of the tight-junction barriers, inflammation, cell death, oxidative stress, and metabolic regulation. Consideration must be given to the interplay of toxic substances, underlying inflammatory diseases, and medications, especially in affected tissues. This review article discusses the detrimental effect of environmental barrier-damaging compounds on human health and involves cellular and molecular mechanisms.

Epithelial barrier theory in the context of nutrition and environmental exposure in athletes.

Exposure to toxic substances, introduced into our daily lives during industrialization and modernization, can disrupt the epithelial barriers in the skin, respiratory, and gastrointestinal systems, leading to microbial dysbiosis and inflammation. Athletes and physically active individuals are at increased risk of exposure to agents that damage the epithelial barriers and microbiome, and their extreme physical exercise exerts stress on many organs, resulting in tissue damage and inflammation. Epithelial barrier-damaging substances include surfactants and enzymes in cleaning products, laundry and dishwasher detergents, chlorine in swimming pools, microplastics, air pollutants such as ozone, particulate matter, and diesel exhaust. Athletes' high-calorie diet often relies on processed foods that may contain food emulsifiers and other additives that may cause epithelial barrier dysfunction and microbial dysbiosis. The type of the material used in the sport equipment and clothing and their extensive exposure may increase the inflammatory effects. Excessive travel-related stress, sleep disturbances and different food and microbe exposure may represent additional factors. Here, we review the detrimental impact of toxic agents on epithelial barriers and microbiome; bring a new perspective on the factors affecting the health and performance of athletes and physically active individuals.

Epithelial barrier dysfunction and associated diseases in companion animals: Differences and similarities between humans and animals and research needs.

Since the 1960s, more than 350,000 new chemicals have been introduced into the lives of humans and domestic animals. Many of them have become part of modern life and some are affecting nature as pollutants. Yet, our comprehension of their potential health risks for both humans and animals remains partial. The "epithelial barrier theory" suggests that genetic predisposition and exposure to diverse factors damaging the epithelial barriers contribute to the emergence of allergic and autoimmune conditions. Impaired epithelial barriers, microbial dysbiosis, and tissue inflammation have been observed in a high number of mucosal inflammatory, autoimmune and neuropsychiatric diseases, many of which showed increased prevalence in the last decades. Pets, especially cats and dogs, share living spaces with humans and are exposed to household cleaners, personal care products, air pollutants, and microplastics. The utilisation of cosmetic products and food additives for pets is on the rise, unfortunately, accompanied by less rigorous safety regulations than those governing human products. In this review, we explore the implications of disruptions in epithelial barriers on the well-being of companion animals, drawing comparisons with humans, and endeavour to elucidate the spectrum of diseases that afflict them. In addition, future research areas with the interconnectedness of human, animal, and environmental well-being are highlighted in line with the "One Health" concept.

The epithelial barrier theory and its associated diseases.

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide. It attributes their onset to a functionally impaired epithelial barrier triggered by the toxicity of the exposed substances, associated with microbial dysbiosis, immune system activation, and inflammation. Diseases encompassed by the epithelial barrier theory share common features such as an increased prevalence after the 1960s or 2000s that cannot (solely) be accounted for by the emergence of improved diagnostic methods. Other common traits include epithelial barrier defects, microbial dysbiosis with loss of commensals and colonization of opportunistic pathogens, and circulating inflammatory cells and cytokines. In addition, practically unrelated diseases that fulfill these criteria have started to emerge as multimorbidities during the last decades. Here, we provide a comprehensive overview of diseases encompassed by the epithelial barrier theory and discuss evidence and similarities for their epidemiology, genetic susceptibility, epithelial barrier dysfunction, microbial dysbiosis, and tissue inflammation.

Lifestyle Changes and Industrialization in the Development of Allergic Diseases.

PURPOSE OF REVIEW: Modernization and Westernization in industrialized and developing nations is associated with a substantial increase in chronic noncommunicable diseases. This transformation has far-reaching effects on lifestyles, impacting areas such as economics, politics, social life, and culture, all of which, in turn, have diverse influences on public health. Loss of contact with nature, alternations in the microbiota, processed food consumption, exposure to environmental pollutants including chemicals, increased stress and decreased physical activity jointly result in increases in the frequency of inflammatory disorders including allergies and many autoimmune and neuropsychiatric diseases. This review aims to investigate the relationship between Western lifestyle and inflammatory disorders. RECENT FINDINGS: Several hypotheses have been put forth trying to explain the observed increases in these diseases, such as 'Hygiene Hypothesis', 'Old Friends', and 'Biodiversity and Dysbiosis'. The recently introduced 'Epithelial Barrier Theory' incorporates these former hypotheses and suggests that toxic substances in cleaning agents, laundry and dishwasher detergents, shampoos, toothpastes, as well as microplastic, packaged food and air pollution damage the epithelium of our skin, lungs and gastrointestinal system. Epithelial barrier disruption leads to decreased biodiversity of the microbiome and the development of opportunistic pathogen colonization, which upon interaction with the immune system, initiates local and systemic inflammation. Gaining a deeper comprehension of the interplay between the environment, microbiome and the immune system provides the data to assist with legally regulating the usage of toxic substances, to enable nontoxic alternatives and to mitigate these environmental challenges essential for fostering a harmonious and healthy global environment.

The impact of genetic variants related to the fatty acid metabolic process pathway on milk production traits in Jersey cows.

The synthesis of fatty acids plays a critical role in shaping milk production characteristics in dairy cattle. Thus, identifying effective haplotypes within the fatty acid metabolism pathway will provide novel and robust insights into the genetics of dairy cattle. This study aimed to comprehensively examine the individual and combined impacts of fundamental genes within the fatty acid metabolic process pathway in Jersey cows. A comprehensive phenotypic dataset was compiled, considering milk production traits, to summarize a cow's productivity across three lactations. Genotyping was conducted through PCR-RFLP and Sanger sequencing, while the association between genotype and phenotype was quantified using linear mixed models. Moderate biodiversity and abundant variation suitable for haplotype analysis were observed across all examined markers. The individual effects of the FABP3, LTF and ANXA9 genes significantly influenced both milk yield and milk fat production. Additionally, this study reveals novel two-way interactions between genes in the fatty acid metabolism pathway that directly affect milk fat properties. Notably, we identified that the GGAAGG haplotype in FABP3×LTF×ANXA9 interaction may be a robust genetic marker concerning both milk fat yield and percentage. Consequently, the genotype combinations highlighted in this study serve as novel and efficient markers for assessing the fat content in cow's milk.

Mechanisms of gut epithelial barrier impairment caused by food emulsifiers polysorbate 20 and polysorbate 80.

BACKGROUND: The rising prevalence of many chronic diseases related to gut barrier dysfunction coincides with the increased global usage of dietary emulsifiers in recent decades. We therefore investigated the effect of the frequently used food emulsifiers on cytotoxicity, barrier function, transcriptome alterations, and protein expression in gastrointestinal epithelial cells. METHODS: Human intestinal organoids originating from induced pluripotent stem cells, colon organoid organ-on-a-chip, and liquid-liquid interface cells were cultured in the presence of two common emulsifiers: polysorbate 20 (P20) and polysorbate 80 (P80). The cytotoxicity, transepithelial electrical resistance (TEER), and paracellular-flux were measured. Immunofluorescence staining of epithelial tight-junctions (TJ), RNA-seq transcriptome, and targeted proteomics were performed. RESULTS: Cells showed lysis in response to P20 and P80 exposure starting at a 0.1% (v/v) concentration across all models. Epithelial barrier disruption correlated with decreased TEER, increased paracellular-flux and irregular TJ immunostaining. RNA-seq and targeted proteomics analyses demonstrated upregulation of cell development, signaling, proliferation, apoptosis, inflammatory response, and response to stress at 0.05%, a concentration lower than direct cell toxicity. A proinflammatory response was characterized by the secretion of several cytokines and chemokines, interaction with their receptors, and PI3K-Akt and MAPK signaling pathways. CXCL5, CXCL10, and VEGFA were upregulated in response to P20 and CXCL1, CXCL8 (IL-8), CXCL10, LIF in response to P80. CONCLUSIONS: The present study provides direct evidence on the detrimental effects of food emulsifiers P20 and P80 on intestinal epithelial integrity. The underlying mechanism of epithelial barrier disruption was cell death at concentrations between 1% and 0.1%. Even at concentrations lower than 0.1%, these polysorbates induced a proinflammatory response suggesting a detrimental effect on gastrointestinal health.

The variation in the beta-casein genotypes and its effect on milk yield and genomic values in Holstein-Friesian cows.

The A2 milk marker is gaining popularity worldwide; thus, many farms plan to convert their dairy cattle herds to the A2A2 genotype. Variation in beta-casein genotypes needs to be monitored in large dairy cattle populations. Therefore we aimed to evaluate the genotypic distributions, population genetics, and diversity parameters in Holstein-Friesian cows. A total of 1200 cattle were genotyped using the Affymetrix® Axiom® array system. We performed an association analysis regarding the CSN2 genotypes and phenotypic traits, including lactation and test-day milk yield. We next evaluated the effects of the genotypes considering the genetic merit of the animals. Animals were grouped based on their PTAs for milk production, fat, protein, and daughter pregnancy rate. Thus, we tested the genotype × genetic merit interaction for significance. The A2 allele frequency is remarkably high (0.68), and the heterozygous genotype is predominant (46.25%). The marker showed intermediate variability and diversity levels, indicating a considerable frequency of the A1A1 genotype (9.33%) remains in the population. ANOVA results showed no significant association between the CSN2 genotypes and milk yield traits. A similar finding is valid for the genotype × genetic merit regarding the genomic test results. The data presented here may be helpful for further investigations and applications on A2 milk production.

Association of polymorphisms in lipid and energy metabolism-related genes with fattening performance in Simmental cattle.

Lipid and energy metabolism are major constituents of mammal growth and thus fattening performance of cattle. This study was designed to evaluate the effects of polymorphisms in lipid and energy metabolism-related genes including oxidized low-density lipoprotein receptor 1 (OLR1), lactoferrin (LTF), stearoyl-CoA desaturase (SCD), beta-lactoglobulin (LGB), thyroglobulin (TG), annexin A9 (ANXA9), myogenic factor 5 (MYF5), protein kinase AMP-activated non-catalytic subunit gamma 3 (PRKAG3), and pituitary-specific transcriptional factor 1 (PIT1), on fattening performance in Simmental cattle. A total of 72 purebred Simmental bulls with a similar initial age and weight were fattened on the same farm for 10 months. Association analysis was performed using linear mixed models. The OLR1 marker was significantly associated with the final weight (FW), hot carcass weight (HCW), chilled carcass weight (CCW), dressing percentage (DP), and total weight gain (TWG). SCD affected the FW, TWG, and average daily live weight gain (ADWG). The present results clearly demonstrated the significant impact of the TG marker on fattening performance. It was highly significantly associated with the FW, HCW, CCW, and TWG. The SCD × TG and the OLR1 × TG interactions had remarkable effects on the traits analyzed. The GACC and CCCC haplotypes of the SCD × TG and OLR1 × TG, respectively, were found to be powerful markers for fattening performance in Simmentals. Novel associations in this study may be useful for further genetic evaluations to improve beef cattle breeding.

Paclitaxel resistance and the role of miRNAs in prostate cancer cell lines.

PURPOSE: To investigate the expression profiles of 86 miRNAs in paclitaxel-resistant prostate cancer cell lines and to identify the genes that have a role in the development of drug resistance. METHODS: Three prostate cancer cell lines, androgen-dependent VCaP, androgen-independent PC-3 and DU-145, were used to obtain paclitaxel-resistant cells by progressively increasing the concentration of paclitaxel in the culture medium. Viability assays with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium and sulforhodamine B were used to assess the cell resistance level and cytotoxic effects of paclitaxel treatment. Total RNA was isolated from both prostate cancer cell lines and their resistant versions, and cDNA samples were reverse transcribed from total RNA. Selected target genes of miRNAs that showed differences in expression and were estimated to be effective on drug resistance mechanism were analyzed with western blot analysis. RESULTS: Expression study of 86 miRNAs by RT-PCR demonstrated that several of the miRNAs were expressed at different levels in paclitaxel-resistant cells compared to wild-type cells. Moreover, the expression profiles of these miRNAs varied among different prostate cancer cell line types, with 13 miRNAs being up-regulated in the resistant cells. Among these, miR-200b-3p, miR-34b-3p and miR-375 exhibited a marked up-regulation. Further, miR-100-5p showed a prominent increase in paclitaxel-resistant VCaP-R and DU145-R cells. Western blot and RT-PCR studies showed that only the LARP1 and CCND1 genes were over-expressed up to 2-5 times in all paclitaxel-resistant cell lines compared to the other investigated genes. CONCLUSIONS: In this study, the three paclitaxel-resistant prostate cancer cell lines examined showed remarkably different miRNA expression profiles.

Unraveling the Complexities of Beef Marination: Effect of Marinating Time, Marination Treatments, and Breed.

The present study focused on evaluating the effects of beef marination on quality traits and consumer acceptability. In this context, m. longissimus thoracis et lumborum and m. semimembranosus samples (n = 192) were obtained from Aberdeen Angus, Hereford, Charolais, and Limousine bulls and were marinated with milk (pasteurized, 100%), garlic and olive oil (2.35 g/500 mL), and lemon (citrus) juice (31% orange juice, 31% lemon juice, 38% distilled water) for 12, 24, and 72 h. Marinade components were selected based on traditional culinary practices and their scientifically proven effects on meat quality. Beef samples on day 0 and non-marinated samples were used as control groups. Beef color, water holding capacity, pH, cooking loss, and Warner-Bratzler shear force were measured three times for each sample. A taste panel assessment was performed to determine the sensory characteristics. Statistical analysis was performed using general linear model (GLM) procedures followed by Tukey's post-hoc comparison. Results revealed that marination time, as well as its two- and three-way interactions, significantly influenced beef quality parameters. These results indicate that the cattle breed is an important factor in evaluating the effectiveness of beef marination applications. The olive oil-garlic marinade was the most preferred by the panel across both types of muscle, as indicated by sensory evaluation results. The findings will not only enrich the scientific literature but also have practical implications for the beef industry.

Epithelial barrier dysfunction, type 2 immune response, and the development of chronic inflammatory diseases.

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, humans have been increasingly exposed to substances toxic for epithelial cells, including air pollutants, laundry and dishwashers, household chemicals, toothpaste, food additives, microplastics, and nanoparticles, introduced into our daily lives as part of industrialization, urbanization, and modernization. These substances disrupt the epithelial barriers and lead to microbial dysbiosis and cause immune response to allergens, opportunistic pathogens, bacterial toxins, and autoantigens followed by chronic inflammation due to epigenetic mechanisms. Recent evidence from studies on the mechanisms of epithelial barrier damage has demonstrated that even trace amounts of toxic substances can damage epithelial barriers and induce tissue inflammation. Further research in this field is essential for our understanding of the causal substances and molecular mechanisms involved in the initiation of leaky epithelial barriers that cascade into chronic inflammatory diseases.

The markers of the predictive DNA test for canine hip dysplasia may have a stronger relationship with elbow dysplasia.

Canine hip and elbow dysplasias, which are prevalent orthopedic conditions rooted in developmental and hereditary factors are yet to be comprehensively assessed. This study aimed to address this gap by exploring the prognostic significance of five markers linked to canine hip dysplasia using available genome-wide association studies (GWAS) data. The influence of these markers on both hip and elbow dysplasia was examined in dogs exposed to standardized environmental conditions. We made a groundbreaking discovery using custom primers, qPCR assays, and evaluation of fluorescent resonance energy transfer (FRET) probes. Three specific SNPs previously associated with the risk of canine hip dysplasia demonstrated a potentially stronger correlation with elbow dysplasia. Notably, the SNP at nucleotide position 22691322, located near the canine CHST3 gene, displayed significance as a marker in multivariable logistic regression analysis. Surprisingly, none of the initially targeted SNPs showed a direct association with hip dysplasia. The genomic positions of these SNPs reside within a region conserved across mammals. In silico analyses suggested that the relevant variant might be positioned in a region linked to bone and muscle structures. Our findings revealed a remarkable relationship between SNP2 genotypes and methylation patterns, shedding light on the underlying mechanism that partially explains the genotype-phenotype correlation in canine CHST3. These groundbreaking findings offer essential insights for future, more extensive investigations into canine orthopedic health. This research significantly contributes to our understanding of the molecular foundations of hip and elbow dysplasia in dogs by charting a course for advancements in veterinary medicine and the overall well-being of canine companions.

Epithelial Barrier Theory: The Role of Exposome, Microbiome, and Barrier Function in Allergic Diseases.

Allergic diseases are a major public health problem with increasing prevalence. These immune-mediated diseases are characterized by defective epithelial barriers, which are explained by the epithelial barrier theory and continuously emerging evidence. Environmental exposures (exposome) including global warming, changes and loss of biodiversity, pollution, pathogens, allergens and mites, laundry and dishwasher detergents, surfactants, shampoos, body cleaners and household cleaners, microplastics, nanoparticles, toothpaste, enzymes and emulsifiers in processed foods, and dietary habits are responsible for the mucosal and skin barrier disruption. Exposure to barrier-damaging agents causes epithelial cell injury and barrier damage, colonization of opportunistic pathogens, loss of commensal bacteria, decreased microbiota diversity, bacterial translocation, allergic sensitization, and inflammation in the periepithelial area. Here, we review scientific evidence on the environmental components that impact epithelial barriers and microbiome composition and their influence on asthma and allergic diseases. We also discuss the historical overview of allergic diseases and the evolution of the hygiene hypothesis with theoretical evidence.

Dietary intake of Spirulina platensis alters HSP70 gene expression profiles in the brain of rats in an experimental model of mixed stress.

Spirulina platensis has gradually gained more attention for its therapeutic, antioxidant, and anti-inflammatory potential worldwide. However, the current molecular knowledge about the effects of spirulina on stress-related genes is rather limited. The effects of dietary intake of spirulina on the HSP70 gene expression were assessed in a controlled in vivo experimental design. Moreover, alterations in serum corticosterone levels, IL-2, IL-4, IFN-Υ, triglyceride, ALT, AST, relative gene expression values, and the correlations between them were evaluated. A total of 36 rats were divided into four groups: control group, stress-only group, spirulina group, and spirulina+stress group. To control the dose administration, S. platensis was applied by a gastric gavage in stress groups. Crowded environment stress and hosting alone stress were applied to the stress-only group and spirulina + stress group. RNA was extracted from brain samples using TRIpure and the relative gene expression assessment was performed using Roche-LightCycler-480-II real-time PCR-System. Gene expression values were remarkably different among the four experimental groups. The differences between stress-only and the spirulina groups were statistically significant (P<0.05). The correlation between the HSP70 gene expression and the IFN-Υ was found to be statistically significant (P<0.05; r=0.50). Results indicate a novel effect of spirulina on the HSP70 expression related to the stress-response. Data presented in this study may be useful for further studies to define not only the molecular genetic aspects through dietary S. platensis but also the effects of spirulina on stress-response and animal welfare.

Physical quality characteristics of breast and leg meat of slow- and fast-growing broilers raised in different housing systems.

This study was made to determine the effects of genotype and housing system on physical quality characteristics of breast and leg meat of broilers under experimental conditions. The 150 slow-growing and 150 fast-growing 1 d old chicks were divided into three sub-groups with indoor raised slatted plastic floor, indoor concrete floor with rice hull litter, and free-range housing systems (2 genotype groups  × â€¯3 housing systems). All birds were offered the same diet and were housed in similar conditions until they were 56 d old. At slaughter, 10 birds from each main group were selected randomly to determine the quality characteristics of the meat. In total, 60 breast meat pieces (pectoralis major muscle) and 60 legs of the chickens were used for meat quality analysis including pH, shear force, and colour characteristics such as lightness ( L ∗ ), redness ( a ∗ ), yellowness ( b ∗ ), saturation ( C ∗ ), and hue angle ( h ∗ ). The pH of breast meat was significantly affected by genotype and housing system ( P < 0.001 and P < 0.001 ). There were significant genotype  × â€¯housing system interactions for pH ( P < 0.015 and P < 0.001 ) and shear force values ( P < 0.007 and P < 0.012 ) of leg and breast meat. There were no significant effects of genotype and housing system on leg and breast meat colour properties except for effects of genotype on redness ( a ∗ ) of breast meat ( p < 0.005 ) and effects of housing on redness of leg meat colour ( p < 0.031 ). Slow-growing chickens and chickens housed in deep litter had a higher redness (darker) value of breast and leg meat colour compared to fast-growing birds and free range and slatted floor. In conclusion, it can be said that fast-growing broilers may be more appropriate for slatted plastic floor housing and slow-growing broilers may be more suitable for a free-range housing system, but further research on factors affecting meat quality would be very beneficial, especially in slow-growing broilers.

Comprehensive assessment of candidate genes associated with fattening performance in Holstein-Friesian bulls.

The objective of this study was to determine the association of single nucleotide polymorphisms (SNPs) in selected candidate genes with fattening performance traits in a commercial cattle herd. Fifteen SNPs in 12 candidate genes (LEP, FABP4, DGAT1, TG, IGF1, IGF1R, MYF5, LGB, CAPN1, CAST, GHR, and OLR1) were evaluated in 296 purebred Holstein-Friesian bulls using PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism). Associations between each segregating SNP and genetic merit for fattening performance were quantified using linear mixed models. Traits included in the study were fattening period, final weight, dry matter intake, feed conversion rate, and average daily weight gain. Apart from the general determination of the above-mentioned traits, each trait was evaluated based on the fattening periods between five selected target body weights (W1  =  100 kg, W2  =  200 kg, W3  =  300 kg, W4  =  400 kg, W5  =  450 kg). All markers with the exception of CAPN1 530, IGF1R, TG, and DGAT1 were associated with at least one of the traits. Furthermore, novel associations were observed for LEP  × â€¯GHR, IGF1  × â€¯LEP, FABP4 3691  × â€¯FABP4 2834, and FAP4 3533  × â€¯LEP interactions. The results of this study confirm some previously reported associations. Moreover, novel associations have been identified, which may be incorporated into breeding programs to improve fattening performance.