Biomarkers of the epithelial barrier
Environmental factors, microbiome, epithelial cells and immune cells show a dynamic crosstalk at the skin and mucosal barriers in the development of AD, AR, CRS, eosinophilic esophagitis and asthma.162,289-294 Studies on the pathogenesis of these diseases have clearly demonstrated a barrier defect in the skin and involved mucosas and a systemic inflammation.293-296 Defects in the epithelial barriers, caused by both environmental risk factors and a genetic predisposition, may represent the starting point of a chronic inflammation and allergen sensitization.293-296 A significant number of studies have reported that environmental factors directly affect the barrier function of epithelium.150,297,298 In addition, T helper 2 cells, ILC2s and their cytokine IL-13 damage skin and lung barriers.293 299 In addition mast cells and their enzyme chymase damage the epithelial barrier.300 290 The effects of environmental factors may, at least in part, be mediated by epigenetic mechanisms. Histone deacetylase activation by type 2 immune response has a major effect on leaky barriers and blocking of histone deacetylase activity corrects the defective barrier in human air-liquid interface cultures and mouse models of allergic asthma with rhinitis.95,293,301 The assessment of the barrier function of the skin and mucosas in vivo has an extremely high value in the clinics to identify barrier leakiness for an individual patient and requires the discovery of biomarkers.
To date, there were a few noninvasive methods to assess the skin epidermal barrier function in vivo . The quantification of transepidermal water loss (TEWL) in the skin across the stratum corneum had received some interest for early prediction of atopy prone children and detection of skin barrier.302 Although TEWL increases in proportion to the level of damage, it is also affected by environmental factors such as humidity, temperature, season and moisture content of the skin.303 The noninvasive and rapid measurement of natural moisturizing factor by Raman Spectroscopy provides a method suitable for use in children. The association of natural moisturizing factor, filaggrin null mutations and AD suggest Raman Spectroscopy as a promising approach for stratification of endotypes in AD in the clinics. Other noninvasive methods currently used include assessment of the stratum corneum hydration, colorimetry, skin surface pH and sebometry, but they only provide information on different characteristics and/or the condition of the skin and do not directly measure the barrier function.304
Recently, electrical impedance spectroscopy (EIS) has been identified as an effective and stable tool for the detection of epidermal barrier.163 This method works by transmitting a harmless electrical signal through the skin at several depths and frequencies and measuring the electrical resistance and impedance response of the tissue. EIS reflects particularly the tissue barrier status by collecting the electric impedance information from extracellular and intracellular tissue.305 Recently, our group has studied the impairment of the epidermal barrier in mice by the epicutaneous administration of barrier damaging proteases, such as papain, trypsin, Vibrio cholera toxin or by tape stripping. We were able to show the barrier damaging effects of these substances which correlates with the electric conductivity of the skin, causing a decrease of electrical impedance. According to these results, EIS shows a broad range of possible clinical applications in AD and atopic march, including early prediction of atopy prone children, early diagnosis of the disease, stratification and endotyping of patients, evaluation of the overall therapy response as well as single lesions and assessment of disease severity.
A critical feature of the gastrointestinal epithelium is intestinal barrier permeability as it must allow an efficient passage of nutrients while restricting the entry of larger molecules to avoid food allergy development. Multiple autoimmune diseases have been identified to arise or be exacerbated by a leaky gut, such as in inflammatory bowel disease, celiac disease, type 1 diabetes, systemic lupus erythematosus, multiple sclerosis.306-309 Recent studies point to a leaky gut as the initiator of type 1 diabetes because a subclinical intestinal barrier dysfunction was already detected before clinical onset of type 1 diabetes.310 Zonulin is a prehaptoglobulin protein and a biomarker for gut barrier leakiness that downregulates TJ function and it has been proposed to play a role in several autoimmune diseases.311
Translocation of bacterial endotoxin (lipopolysaccharide, LPS) from the gut microbiota to blood circulation stimulates systemic inflammatory responses.312 Measurement of intestinal permeability is often used in the examination of inflammatory gastrointestinal disorders. It can be assessed by measurement of urinary recovery of ingested non-metabolizable lactulose and mannitol. Urine L/M ratio measured by 1H NMR spectroscopy showed high correlation with the standard measurement of the urinary recoveries by enzymatic assays. In conclusion, NMR metabolomics enables simultaneous intestinal permeability testing and discovery of biomarkers associated with an impaired intestinal permeability.313 In conclusion, identification of clinically reliable biomarkers for skin, respiratory and intestinal barrier measurements represent an important future research area.