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Principal Investigator: Debajyoti Ghosh
Organization: UNIVERSITY OF CINCINNATI
Fiscal Year: 2024
Award: $216,766
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
The prevalence of atopic diseases such as atopic dermatitis (AD) and asthma are increasing at high rates that
can't be explained by purely genetic etiology, indicating the roles of environmental exposures in increasing
disease risk. Environmental exposures that alter the risk of allergic diseases (farm exposure, C-section, breast
feeding, antibiotic exposure) also influence microbial colonization. Altered microbial composition (aka dysbiosis)
at mucosal surfaces, specifically within the perinatal period (<1 year of life) has been linked to increased risk for
developing several atopic diseases. Interestingly, atopic diseases are also associated with epithelial barrier
dysfunction. Our preliminary data suggest that perinatal dysbiosis is associated with 1) increase in allergen-
induced pulmonary responses; 2) a period of increased skin permeability (barrier dysfunction) extending even
after resolution of immediate dysbiosis; 3) significant alterations in gene expression in the skin of dysbiotic
animals, including dampened TNFα signaling, and predominantly Th2 biased transcriptomic profiles.
Interestingly, an isolate of gram negative commensal Roseomonas mucosa identified from healthy volunteers
(RMhv) was associated with increased skin barrier function and clinical benefits demonstrated by mouse studies
and clinical trials. RMhv-induced improvement in skin barrier function were linked to elevated TNF-related
epithelial repair mechanism. Therefore, we hypothesize that by impairing skin barrier function, perinatal dysbiosis
can exacerbate sensitivity to the development of skin-associated allergic diseases, and that treatment with a
clinically relevant Roseomonas mucosa bacterial isolate is sufficient to protect mice from perinatal dysbiosis-
associated defects in skin barrier function. This hypothesis will be tested in two Aims: (1) To determine if perinatal
dysbiosis alters susceptibility to the development of skin-associated allergic diseases; (2) To determine if a
clinically relevant Roseomonas mucosa isolate identified from healthy volunteers can protect mice against
perinatal dysbiosis associated skin barrier dysfunction and house dust mite allergen -induced allergic diseases.
Collectively, these studies will elucidate the mechanisms by which perinatal dysbiosis influences skin barrier
function and associated allergic diseases.
Terms: <(TNF)-α><0-11 years old><Abdominal Delivery><Affect><Age><Airway Disease><Allergens><Allergic Disease><Allergic asthma><Allergic rhinitis><Allergic rhinitis due to allergen><Allergic rhinosinusitis><Allergic to food><Allergy to food><Animals><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Asthma><Atopic Dermatitis><Atopic Eczema><Atopic Neurodermatitis><Atopic rhinitis><Automobile Driving><Birth><Blood Serum><Breast Feeding><Breast fed><Breastfed><Breastfeeding><Bronchial Asthma><C section><CD 120b Antigen><CD120b Antigens><Cachectin><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cesarean><Cesarean section><Child><Child Youth><Childhood><Children (0-21)><Clinical><Clinical Trials><Cohort Studies><Concurrent Studies><Cutaneous><Data><Defect><Dermatophagoides Allergens><Developed Countries><Development><Disease><Disorder><Disseminated Neurodermatitis><Drug Prescribing><Drug Prescriptions><Dysfunction><Economic Burden><Environmental Exposure><Epithelium><Exposure to><Expression Signature><Extrinsic asthma><Farm><Food Allergy><Food Hypersensitivity><Functional disorder><Gene Expression><Gene Expression Profile><Gene Transcription><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic Transcription><Genetic propensity><Gram-Negative Bacteria><House Dust Mite Allergens><Hydrogen Oxide><IgE><Immunoglobulin E><Impairment><Industrialized Countries><Industrialized Nations><Infant><Inherited Predisposition><Inherited Susceptibility><Intracellular Communication and Signaling><Life><Link><Lung><Lung Diseases><Lung Respiratory System><Macrophage-Derived TNF><Measurement><Measures><Mice><Mice Mammals><Miscellaneous Antibiotic><Monocyte-Derived TNF><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Outcome><Parturition><Pattern><Perinatal><Peripartum><Permeability><Physiopathology><Population><Predisposition><Prevalence><Protocol><Protocols documentation><Public Health><Pulmonary Diseases><Pulmonary Disorder><RNA Expression><Receptors, Tumor Necrosis Factor, Type II><Resolution><Rhinitis allergic atopic><Risk><Risk Factors><Role><Roseomonas><Saline><Saline Solution><Sampling><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Skin development><Skin repair><Societies><Surface><Susceptibility><TNF><TNF A><TNF Alpha><TNF gene><TNF-R2><TNF-RII><TNF-α><TNFA><TNFBR><TNFR p75><TNFR2><TNFR80><TNFRSF1B><TNFRSF1B Receptor><TNFRSF1B gene><TNFα><Testing><Topical Drug Administration><Topical application><Transcription><Tumor Necrosis Factor><Tumor Necrosis Factor Beta Receptor><Tumor Necrosis Factor Receptor 2><Tumor Necrosis Factor Receptor 75><Tumor Necrosis Factor Receptor Type 2><Tumor Necrosis Factor-alpha><Water><Writing><administer topically><ages><allergic dermatitis><allergic eczema><apply topically><atopic asthma><biological signal transduction><cell type><chronic rhinosinusitis><clinical relevance><clinically relevant><commensal bacteria><commensal bacterial species><commensal community><commensal microbiome><commensal species><cutaneous barrier><cutaneous repair><deliver topically><dermal barrier><dermal repair><developed country><developed nation><developed nations><developmental><disease of the lung><disease risk><disorder of the lung><disorder risk><driving><dust mite allergens><dysbacteriosis><dysbiosis><dysbiotic><early life exposure><epidermal barrier><epithelial repair><extrinsic allergic asthma><gene expression pattern><gene expression signature><gene function><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><global gene expression><global transcription profile><healthy volunteer><improved><insight><kids><lung disorder><medication prescription><microbial><microbial colonization><microbial composition><microbial imbalance><mouse model><murine model><novel><offspring><pathophysiology><pediatric><perinatal period><perinatal phase><prescribed medication><prevent><preventing><pulmonary><resident commensals><resolutions><response><restoration><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skin barrier><skin organogenesis><social role><topical administration><topical delivery><topical drug application><topical treatment><topically administered><topically applied><topically delivered><topically treated><transcriptional profile><transcriptional signature><transcriptome><transcriptomics><treat topically><tumor necrosis factor receptor superfamily, member 1B><youngster>