Exposure to isocyanates predicts atopic dermatitis prevalence and disrupts therapeutic pathways in commensal bacteria

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin condition increasing in industrial nations at a pace that suggests environmental drivers. We hypothesize that the dysbiosis associated with AD may signal microbial adaptations to modern pollutants. Having previously modeled the benefits of health-associated Roseomonas mucosa , we now show that R. mucosa fixes nitrogen in the production of protective glycerolipids and their ceramide by-products. Screening EPA databases against the clinical visit rates identified diisocyanates as the strongest predictor of AD. Diisocyanates disrupted the production of beneficial lipids and therapeutic modeling for isolates of R. mucosa as well as commensal Staphylococcus . Last, while topical R. mucosa failed to meet commercial end points in a placebo-controlled trial, the subgroup who completed the full protocol demonstrated sustained, clinically modest, but statistically significant clinical improvements that differed by study site diisocyanate levels. Therefore, diisocyanates show temporospatial and epidemiological association with AD while also inducing eczematous dysbiosis.

Diisocyanates influence models of atopic dermatitis through direct activation of TRPA1

“…Our findings beget a working hypothesis in which (di)isocyanate exposure induces dysbiosis [9] through carbamoylation of the amine-groups on the ceramide-sphingolipid family of lipids [37] needed for proper skin barrier function [38]. While altering commensal metabolism, (di)isocyanates may also directly activate TRPA1 to induce itch, rash, Th2 cytokines, and…”

“…The interaction between TDI and TRPA1 presents an intriguing pathology suggesting a role in allergic disease. TDI is a TRPA1 agonist [15] and component of numerous exposures that are known to increase the incidence and severity of AD ranging from fabrics like nylon and polyester to home remodeling chemicals like paint, polyurethane, and memory foam furniture [9]. TDI is a TRPA1-dependent inducer of other atopic models such as contact dermatitis [3], asthma [10,12], allergic rhinitis [25,26], and chronic itch [27].…”

“…We recently reported that an untargeted comparison of Environmental Protection Agency (EPA) pollution databases versus AD rates by US zip codes revealed that isocyanates, such as toluene diisocyanate (TDI), is the pollutant class with the strongest spatiotemporal association with AD [9]. We further demonstrated exposure of health-associated commensal bacteria to TDI shifts the microbial metabolism towards an AD-like phenotype; both TDI and hydrogen isocyanate disrupted lipid homeostasis in and negated the modeled benefit of commensal isolates of Roseomonas mucosa through disrupting nitrogen fixation [9]. However, beyond the impacts on commensal bacteria, the discovery that TRPA1 is directly activated by TDI [10][11][12][13][14][15] suggested that this pollutant may also contribute to AD through directly impact the host.…”

Antimony Compounds Associate with Atopic Dermatitis and Influence Models of Itch and Dysbiosis

“…Our prior work established the importance of bacterial-sourced, ceramide-family lipids in the modeled benefits of R. mucosa treatment . We determined that TDI inhibited ceramide production in healthy isolates of R. mucosa through disruption of nitrogen fixation .…”

“…■ METHODS Spatial Mapping and Environmental Survey. As detailed previously, 5 data on pollution derived from the EPA's Risk-Screening Environmental Indicators (RSEI) system from 2015 to 2019 were contrasted against the Definitive Health database, which contains 1.2 billion diagnostic billing codes per year from 2019 across 20,000 postal codes in the United States, including Hawaii, Alaska, and U.S. territories for ICD-10 code L40.9. Elemental compounds, including antimony, can be reported in TRI as pure elemental release or a metal-containing compounding (that may also be mixed with pure element).…”