Allergies come clean: The role of detergents in epithelial barrier dysfunction

Abstract

Purpose of Review:

The prevalence and incidence of allergic disease have been rising in Westernized countries since the 20th century. Increasingly, evidence suggests that damage to the epithelium initiates and shapes innate and adaptive immune responses to external antigens. The objective of this review is to examine the role of detergents as a potential risk factor for developing allergic disease.

Recent Findings:

Herein, we identify key sources of human detergent exposure. We summarize the evidence suggesting a possible role for detergents and related chemicals in initiating epithelial barrier dysfunction and allergic inflammation. We primarily focus on experimental models of atopic dermatitis, asthma, and eosinophilic esophagitis, which show compelling associations between allergic disease and detergent exposure. Mechanistic studies suggest that detergents disrupt epithelial barrier integrity through their effects on tight junction or adhesion molecules and promote inflammation through epithelial alarmin release.

Summary:

Environmental exposures that disrupt or damage the epithelium may account for the increasing rates of allergic disease in genetically susceptible individuals. Detergents and related chemical compounds represent possible modifiable risk factors for the development or exacerbation of atopy.

Introduction

Allergies are among the most common chronic diseases in industrialized nations and incorporate manifestations at nearly every skin and mucosal surface of the human body. In the United States (US), approximately 30% of the population reports at least one form of atopy. Allergic rhinitis is the most common allergic disease affecting 18.9% of children and 25.7% of adults [1]. Thirteen percent of the US population has asthma [2] and up to 8% of children have food allergy [3]. Alarmingly, rates of allergic disease are increasing, particularly among children. For example, food allergy prevalence increased 50% among children 0-17 years old from 1997-2011 in the US. This increase is paralleled by an almost 70% increase in skin allergies over the same timeframe [4]. Recent decades have also seen the emergence of new allergic diseases such as eosinophilic esophagitis (EoE). First described in the 1990’s [5, 6], this disease now has an estimated prevalence of 0.5-1:1000 and is the leading cause of food impaction in adults [7–9].

The etiology of atopic disease is multifactorial; however, the environment likely plays a significant role. Increases in allergic disease have been attributed to changes in the microbiome linked with the transition from an agrarian lifestyle to living in industrialized urban settings (i.e., hygiene or old friends hypothesis) [10, 11]. As an extension, several alterations in microbial exposure may lead to dysbiosis and have been linked with increased risk of atopy, including the following: antibiotic use, Cesarean delivery, lack of breastfeeding, and changes in food processing [12–14]. Climate change (e.g., increased pollen season duration due to warming temperatures) and environmental pollutants (e.g. microplastics) are additional factors of interest. Mechanistic investigations have identified the epithelium at the center of the immune alterations associated with allergic disease [15, 16]. Indeed, many of the same pathways and disease processes implicated in atopic dermatitis also play a role in asthma. Moreover, a disrupted epithelium provides a logical starting point for understanding the immune dysregulation characteristic of atopy that likely begins as an immuno-protective response. Consequently, it is critical to evaluate the environmental exposures, which may initiate epithelial barrier dysfunction.

Since the 1940’s, detergents have been incorporated into household products such as laundry detergents, industrial cleaners, shampoos, and toothpaste [17]. These products were historically evaluated for their acute toxicity, but their chronic effects on the epithelial barrier are increasingly appreciated. Pothoven and Schleimer proposed the barrier hypothesis, which postulates that allergic sensitization and type 2 inflammation result from epithelial barrier dysfunction and inappropriate exposure to the environment [18]. Akdis et al, extended the barrier theory to suggest that detergents and other compounds provoke epithelial barrier dysfunction and promote dysbiosis and translocation of microbiota through the epithelium [16].

Herein, we provide background information on common household detergents and review epidemiologic and mechanistic studies examining detergents and related compounds as risk factors for allergic disease.

Detergents

History and Definition

Detergents belong to a class of surfactants characterized by an amphiphilic structure with polar and nonpolar moieties. The polar moiety is hydrophilic and nonpolar moiety is hydrophobic, facilitating the mixture of hydrophobic compounds (e.g., oil) with water [17]. Detergents form micelles in water above specific concentrations (i.e. critical micelle concentration, CMC), which can remove grease. Most surfactants employed in everyday household use are anionic, but surfactants may also be cationic, nonionic, or amphoteric.

Detergents are synthetic soap substitutes that were developed for cleaning applications due to critical shortages of the natural fats required to make soap during World War I. German chemists alkylated naphthalene and polynuclear aromatics from coal tar with short-chain and fatty alcohols to produce alkylaromatics which were then sulfonated to produce surfactants. Alkylene sulfates presented unique advantages to traditional soap because they are soluble in hard water and do not leave scum. Further advancements by the chemicals industry led to the production of the first alcohol sulfates in the 1930’s from coconut and palm kernel oil derivatives. Refinements in the petrochemicals industry led to the production of branched chain alkyl benzenes, which were incorporated into laundry detergents in the 1940’s-1950’s. However, branched chain alkyl benzenes were found to be poorly biodegradable, leading to the development of linear alkyl sulfates, including sodium lauryl sulfate (SLS also known as sodium dodecyl sulfate or SDS) and sodium dodecyl benzenesulfonate (SDBS) [19]. These are the most common detergents used in commercial household products and are the focus of recent investigations into the potential link between detergents and atopic disease.

Linear alkyl sulfates have been assessed for safety, and SDS and SDBS are generally considered safe at exposure levels commonly found in the household. Indeed, SDS is even approved as a food additive at low concentrations [20]. Previous assessments have identified these detergents as irritants. Unfortunately, these studies generally focus on toxicity and mutagenicity and do not assess effects on mucosal barrier function or alterations to microbiota or the potential effects of early-life exposure [21].

Sources and Routes of Exposure

Surfactants have been incorporated into most of the cleaning and personal care products used daily. According to a database of 97,370 active personal and home care products, unmodified SDS is contained in 3,990 products. Modified sulfate surfactants are present in a total of 10,564 products [22]. This ubiquitous exposure begins at birth during neonatal resuscitation with laundered cloths or blankets, followed by swaddling and clothing, and then with an infant’s first bath. Table 1 lists common routes and sources of human exposure to detergents.

Table 1.

Routes and sources of human detergent exposure

Route of Exposure	Surfactant Source or Product
Skin	Laundry detergent
	Dishwashing detergent
	Hard surface cleaning agents
	Detergent residue in clothing
	Bubble bath
	Cosmetics
	Shampoo
	Bar and hand soap
	Shaving cream
Inhalation	Laundry detergent dust
	Surface cleaning sprays
Oral	Toothpaste
	Medications
	Residue on fruits and vegetables
	Processed foods (e.g., dairy and baked goods)
	Residue on utensils and dishware
	Drinking water

Effects on Barrier Function

SDS can penetrate the skin [23], enhances intestinal permeability [23], and has been used to facilitate uptake of pharmacological agents [24]. Detergents are capable of solubilizing plasma membranes [25, 26] through saturation of the plasma membrane with detergent monomers followed by fragmentation and release of mixed micelles comprised of detergent monomers and membrane lipids [27]. Notably, SDS can also alter protein structure and function [28, 29].

Association with antigen sensitization

Some detergents can elicit an allergic response; however, SDS and SDBS are largely considered irritants that do not provoke direct sensitization. On the other hand, SDS may serve as a vehicle (skin penetrating/irritant agent) or adjuvant, facilitating sensitization to nickel and chrome when painted on the skin only when mixed with 1% SDS [30]. Indeed, SDS has since been used in multiple skin tests for allergens or irritants in humans, specifically to enhance skin permeability and aid in assessment of sensitization [31]. Recent studies suggest SDS can lower the sensitization threshold by up to a factor of 10 for a weak sensitizer [32]. Studies in mice indicate that SDS can enhance local lymph node responses to sensitizers, possibly by increasing dendritic cell migration [33, 34]. Another noteworthy study showed that mice injected subcutaneously with 1-10 mg/L SDS with ovalbumin (OVA) promoted anti-OVA IgE production [35]. Interestingly, rat peritoneal mast cells release up to 85% of stored histamine at SDS concentrations as low as 0.03 mM [36].

Other cofactors may play an important role. Notably, sensitivity to isothiazolinone, which is often found in liquid laundry detergents as a preservative, is extremely common [37, 38]. It is unclear if this may be linked with co-exposure to surfactants such as SDBS.

Organ-specific Effects

Skin

The irritant properties of SDS on the skin are well appreciated. In fact, SDS serves as a prototypical irritant for pharmacologic investigations of anti-inflammatory topicals and is utilized in routine patch testing to assess skin irritability [39]. SDS causes lipid extraction and swelling in exposed skin [40, 41] and increases absorption of hydrophilic compounds, in particular [42]. Investigations with confocal Raman and infrared microspectroscopy have revealed penetration of SDS to the stratum corneum and, with longer incubation, to the dermal region, suggesting SDS may directly interact with keratinocytes [43]. Penetration of the stratum corneum has also been shown by radiolabeled probe assays [44, 45]. SDS activates the NLRP3 inflammasome and induces caspase-dependent IL-1β secretion by human keratinocytes [46]. Additionally, SDS increases intracellular reactive oxygen species (ROS) and IL-1α secretion by human keratinocytes by increasing intracellular calpain activity and intracellular Ca²⁺ concentration, promoting prostaglandin E3 (PGE3) release [47, 48]. Notably, SDS also alters protease expression and S100 proteins, including filaggrin, in keratinocytes [49].

Atopic dermatitis

The role of detergents such as SDS and SDBS in promoting atopic dermatitis is unclear; however, clinical studies have shown that atopic dermatitis patients are more susceptible to SDS-induced irritant dermatitis [50] and show increased transepidermal water loss in response to SDS. Moreover, detergent use can trigger flares of atopic dermatitis [51]. In vitro studies identified both SDS and SDBS as having cytotoxic effects on human keratinocytes [52]. Notably, in air-liquid interface (ALI) cultures, both SDS and SDBS affected barrier function at nontoxic doses, reducing transepithelial electrical resistance (TEER) and increasing FITC-dextran permeability. These results were also observed using commercial detergents at a 10⁶ dilution. Moreover, alterations in tight junction proteins claudin-1 and occludin were variously observed with SDS, SDBS, and commercial detergents. Together, these results suggest anionic surfactants can influence skin barrier function, opening the possibility of increased penetration of toxicants and allergens, which may contribute to atopic dermatitis.

Contact Dermatitis

Contact dermatitis encompasses irritant contact dermatitis (ICD: ~80% cases) and allergic contact dermatitis (ACD: ~20%) along with photocontact dermatitis and contact urticaria. ICD irritants can cause damage on the first exposure (i.e. an adaptive immune response is not required), whereas ACD is a type IV delayed hypersensitivity reaction requiring sensitization. SDS is considered an irritant; however, it is commonly used in testing for ACD to facilitate penetration of the skin by potential allergens. For example, a 1955 study found that 1% SDS painted on guinea pig skin could provoke a response to nickel and chrome. Specifically, fur-clipped guinea pig skin was painted with nickel or chrome in the presence or absence of 1% SDS for 8 days and then challenged at day 12. The authors found that, in the absence of SDS, nickel and chrome produced mild to no reactions. However, in the presence of SDS, they observed scaling, erythema, and inflammation. The authors concluded that the eczematogenic properties of the metals were “brought about by the permeability of the skin increasing under the influence of lauryl sulphate” [30].

SDS has also be used to enhance sensitization in humans. Specifically, various methods of altering inflammation were tested to maximize contact sensitization, including tape stripping, UV exposure, cantharidin blistering, freezing, dimethylsulfoxide (DMSO), and SDS. Of all methods tested, SDS was the most effective at inducing contact sensitization [53]. Many early studies are now considered unethical as experiments were performed on a prison population without appropriate respect or protections for the subjects. SDS appears to have a synergistic effect with nickel likely due to increased penetration and proinflammatory effects that lower the threshold for elicitation of an allergic response [54].

Other detergents are more clearly linked with ACD. Namely, cocamidopropyl betaine, the ingredient in no-tears formulations of shampoo, was named Allergen of the Year in 2004 by the American Contact Dermatitis society due to its propensity to induce type IV contact hypersensitivity reactions in up to 7.2% of exposed individuals [55, 56].

Lung

Asthma

Defective epithelial barrier function is associated with asthma [57–59]. Several studies show an increased incidence of allergic respiratory symptoms and risk of asthma development due to occupational exposure to detergents and cleaning products (e.g., detergent factory workers and domestic housekeepers) [60–66]. Most of these reports are related to sensitization to enzymes as components of commercial detergents.

Recently, Wang et al. [67] investigated the effects of SDBS on the human respiratory epithelium using ALI cultures. The goal of this study was to test the effects of laundry detergents on human bronchial epithelial cell barrier function and identify changes in the transcriptomic and epigenomic signatures following detergent exposure. The authors found that the SDBS concentration in rinse residue was approximately a 1:2,500 dilution of the laundry detergent. Using this concentration, they demonstrated cytotoxic and barrier-disruptive effects on human bronchial epithelial cells in vitro. This was evidenced by decreased tight junction protein expression (occludin and zonulin-1), decreased TEER, and increased FITC-dextran flux in ALI cultures. No significant epigenetic changes were identified, and RNAseq revealed downregulation of genes related to cell adhesion and upregulation of genes related to lipid metabolism and apoptosis. Using monolayer cultures, they showed dose-dependent cytotoxicity with two different commercial detergents at dilutions less than 1:20,000-1:40,000. Even at nontoxic detergent concentrations, the authors noted decreased staining intensity of junctional proteins by immunofluorescence. Interestingly, these findings were reproducible with a 1:10 dilution of residual liquid from laundered clothing. These observations suggest that SDBS at low concentrations compromises the barrier function of airway epithelial cells and alters their gene expression.

Gastrointestinal Tract

Oral Ulcers and Oral Allergy Syndrome

SDS is a common component of toothpaste at concentrations up to 3% w/v and can be found in mouthwash as well. As toothbrushing is typically performed multiple times daily for several minutes, the oral mucosa is one of the most highly exposed tissues to SDS. SDS increases oral mucosa permeability in rabbits [68] and has been linked with oral ulceration [69]. Oral desquamation from toothpaste was noted in 1972 [70]. Later studies found that SDS could mediate this activity [71, 72]. A double-blind, cross-over clinical study of 28 females found that toothpaste containing as little as 0.5% SDS significantly increased oral desquamation relative to detergent-free toothpaste or toothpaste containing a less hydrophilic detergent, cocoamidopropyl-betaine [71]. Interestingly, one study found that 1% SDS in mouthwash reduced salivary bacterial counts, which remained significant at 7 hours post rinse. This antimicrobial activity was greater than 0.2% triclosan [73]. In addition, SDS is reported to have direct antimicrobial properties [74, 75]. Specifically, SDS may form pores in the lipid membranes of gram-positive organisms. Gram-negative organisms appear to be resistant to this bacteriostatic property [76, 77]. The significance of the sensitivity to SDS in the oral cavity and whether there could be any link to allergic sensitization and/or oral allergy syndrome requires investigation.

Eosinophilic Esophagitis

Recent investigations in our laboratory revealed that ALI cultures of human esophageal epithelium (i.e., EPC2 cells) exposed to 5,000 ng/mL SDS (~1:600 dilution of the SDS concentration in toothpaste) decreased TEER and increased passage of 4 kDa FITC-dextran, indicating induction of barrier dysfunction. Moreover, expression of DSG-1, an epithelial junction protein dysregulated in active EoE subjects, was markedly decreased while expression of the epithelial alarmin IL-33 was increased. IL-33 can potentiate type 2 immune responses and is upregulated in active EoE [78]. Further, mice exposed to 0.5% SDS in drinking water (~1/6^th the concentration in toothpaste) for two weeks exhibited striking EoE-like pathology including eosinophilia, eosinophilic abscesses, dilated intracellular spaces, and basal zone hyperplasia. Interestingly, infiltration of CD4⁺ cells was increased in the esophagus, and RNAseq pathway analysis on whole esophagus homogenates indicated increased innate and adaptive immune responses along with responses to external biotic stimuli [79]. In unpublished studies, we have found marked alterations of the esophageal microbiome of mice in response to oral SDS exposure. Future studies are needed to understand the extent and contribution of dysbiosis to the observed pathology and to explore the potential for sensitization to food components. Concerningly, we were not the first to note the potential hazards of oral exposure to detergents. In 1939, Epstein et al. noted gastrointestinal irritation of the esophagus and forestomach in rats exposed to low concentrations of SDS over the course of 7 weeks, including edema, loss of keratin, and leukocytic infiltration, warning of the potential injurious effects of replacing traditional soap with SDS in toothpastes [80].

Household cleaning products often contain detergents mixed with other types of cleaning agents. Thus, it may be critically important to evaluate the sensitization potential in combination with proteases. Notably, Tanzer et al [81] found that laundry detergent containing microbial proteases damaged the skin barrier in mice, and, when combined with OVA, epicutaneous exposure (~10% concentrated laundry detergent), induced sensitization to OVA. Markedly increased IL-33 expression was noted in the skin, and sensitized mice challenged intranasally with OVA alone showed eosinophilic inflammation in the esophagus.

Intestinal permeability and food allergy

Ethoxylated alcohols are nonionic surfactants and are a component of rinse aids commonly used in commercial washers to leave dishes with a clean appearance. A recent study by Ogulur et al [82] found that human gut epithelial cell lines exposed to diluted rinse aid showed evidence of toxicity at levels similar to those present on cleaned dishes (e.g., 1:10,000). Moreover, evidence of barrier disruption was observed at a 1:40,000 dilution. Specifically, monolayer cultures of Caco-2 or HT-29 cells exposed to dilutions of rinse aid revealed cellular lysis at dilutions as low as 1:20,000. Liquid-liquid interface cultures of differentiated Caco-2 cells and organoid cultures responded similarly. Rinse aid was also found to induce barrier disruption with decreased TEER following five days of exposure to a 1:10,000 dilution. Increased FITC-dextran permeability and altered immunofluorescent staining of claudin-1 and occludin were observed at three days at a 1:20,000 dilution. Similar results showing barrier disruption were observed using Caco-2 cells in a gut-on-a-chip model. Finally, transcriptome analysis of Caco-2 monolayer cultures exposed to rinse aid showed altered expression of epithelial junction proteins. In addition, pathway analysis showed upregulation of proinflammatory, pattern recognition, and cytokine pathways. Similar results were observed by proteomic analysis. Strikingly, rinse aid residues extracted from cups washed in a professional dishwasher induced toxicity to Caco-2 cells even at a 1:10 dilution, while a 1:5 dilution impaired barrier function.

Notably, the authors also found that 1:20,000 dilutions of multiple common household dishwasher detergents also induced toxicity to Caco-2 cells though this is a higher concentration than the 1:80,000 dilution commonly used in dishwashers. These dishwasher detergents may contain SDS, which was also found to affect barrier function in Caco-2 cell cultures.

Together, these results suggest the gut epithelial barrier is susceptible to commonly used detergents, indicating the potential for barrier dysfunction, increased allergen exposure, and effects on chronic inflammation of the gut.

Conclusions

Allergic disease has increased markedly since the mid-20th century. Although the etiology of allergic disease is unknown, the environment plays a prominent role in disease pathogenesis. Coincident to increases in atopic disease, is the widespread use of detergents in household and personal care products in industrialized nations. The epithelium is central to the pathogenesis of allergic diseases. Common household detergents induce epithelial barrier dysfunction in the skin, lung, and gastrointestinal tract. While detergents are widely considered irritants, they appear to lower the threshold for sensitization, possibly by enhancing epithelial permeability and inducing inflammatory responses. In addition to these direct effects on the epithelium, detergents induce dysbiosis, which is associated with allergic disease. Pervasive and perpetual exposures position detergents prominently among environmental pollutants that may provoke barrier dysfunction. Figure 1 summarizes the potential role of detergents in allergic disease pathogenesis.

Figure 1. Detergent exposure model.

Exposure to detergents and other environmental toxicants, particularly in genetically susceptible individuals, results in epithelial barrier dysfunction, microbial dysbiosis, and alarmin release. This milieu promotes allergic sensitization, epithelial remodeling, and allergic disease.

Additional research is needed to better understand the immunologic and molecular mechanisms involved in detergent-induced barrier dysfunction and inflammation. Studies examining each epithelial surface is needed to understand how timing, route, and co-exposure with potential allergens promote allergic disease. This knowledge must be combined with research on gene-environment interactions as detergent exposure is common, but not all those exposed develop atopy. Further work investigating the effects of other chemical compounds with surfactant properties (i.e., emulsifiers) is needed. It will also be important to examine whether detergent-induced dysregulated barrier function, immunity, and the microbiome possibly contribute to other forms of immune mediated disease, such as autoimmunity.

Abbreviations used:

ALI

Air-liquid interface

ACD

allergic contact dermatitis

CMC

critical micelle concentration

DMSO

dimethylsulfoxide

EoE

eosinophilic esophagitis

FITC

fluorescein isothiocyanate

ICD

irritant contact dermatitis

IgE

immunoglobulin E

OVA

ovalbumin

PGE3

prostaglandin E3

ROS

reactive oxygen species

SDBS

sodium dodecyl benzene sulfonate

SDS

sodium dodecyl sulfate

SLS

sodium lauryl sulfate

TEER

transepithelilal electrical resistance

US

United States