The gut–skin axis in chronic urticaria: Role of gut dysbiosis in understanding of urticaria and its management

Clinical definition and classification of urticaria

Urticaria is a common cutaneous disorder characterized by the appearance of transient, pruritic wheals with or without angioedema. Based on duration, urticaria is classified into acute urticaria (duration <6 weeks) and chronic urticaria (CU) (duration ≥6 weeks). Acute urticaria is typically triggered by identifiable external factors, including allergen exposure, infections, or medications, and generally resolves spontaneously. In contrast, CU is subdivided into two major phenotypes: Chronic spontaneous urticaria (CSU), which occurs without identifiable specific triggers, and chronic inducible urticaria, which is provoked by defined physical or chemical stimuli such as pressure, heat, or cold exposure.

Epidemiology and clinical impact

CSU represents the most prevalent form of CU, affecting 0.5-1% of the general population, with lifetime prevalence reaching 15-20%. Geographic variation exists, with a higher incidence in developed nations, potentially reflecting improved diagnostic awareness and environmental factors. The disease imposes substantial morbidity, with patients experiencing chronic pruritus, sleep disruption, anxiety, and depression, collectively reducing quality of life as measured by the dermatology life quality index (DLQI).^[1,2] Economic burden encompasses frequent healthcare visits, medication costs, and workplace absenteeism, imposing significant healthcare costs on both individuals and healthcare systems.^[1,2]

Current treatment limitations

Current first-line therapy consists of second-generation, non-sedating H1-antihistamines, which provide symptom control in ~60% of patients. However, ~40% of patients with CSU demonstrate inadequate response to standard-dose antihistamine therapy, necessitating dose escalation or transition to second-line treatments. These alternatives, including biologic agents such as omalizumab (antiimmunoglobulin E [IgE]) and dupilumab (anti-interleukin 4 [IL-4] receptor) as well as immunosuppressive agents such as cyclosporine, provide variable efficacy, carry significant costs, and are associated with potential adverse effects.^[1,2] These limitations underscore the urgent need for novel, mechanistically targeted therapeutic approaches.

The gut microbiota: Structure and function

The human gut microbiota is a complex microbial ecosystem comprising bacteria, viruses, fungi, archaea, and protozoa, with bacterial populations reaching approximately 10¹⁴ cells. The colon harbors the highest microbial density, with the core microbiota dominated by four major bacterial phyla accounting for approximately 90% of the bacterial population: Firmicutes (including Clostridium, Lactobacillus, and Faecalibacterium), Bacteroidetes (including Bacteroides and Prevotella), Actinobacteria (including Bifidobacterium), and Proteobacteria (including Escherichia and Klebsiella).^[3,4] In healthy individuals, Firmicutes and Bacteroidetes comprise 70-80% of total bacteria.

Beyond structural composition, the microbiota functions as a metabolic organ, producing bioactive molecules that influence both local gastrointestinal and systemic physiology. Short-chain fatty acids (SCFAs), particularly acetate, propionate, and butyrate, are generated through bacterial fermentation of dietary fiber, primarily by butyrate-producing taxa including Roseburia hominis and Faecalibacterium prausnitzii. SCFAs serve as signaling molecules via G protein-coupled receptors (GPR43, GPR109A) and as histone deacetylase inhibitors, orchestrating immune tolerance through expansion of regulatory T cells (Tregs) and suppression of pro-inflammatory cytokines, including IL-6 and tumor necrosis factor alpha (TNF-a).^[4,5]

The gut-skin axis: Conceptual framework

The gut-skin axis represents a bidirectional communication network linking the intestinal microbiota to cutaneous immunity and barrier function through interconnected immune, metabolic, hormonal, and microbial pathways.^[2,6] Dysbiosis, defined as a disruption in microbial composition, diversity, or functionality, compromises multiple components of this axis. Dysbiotic microbiota produce altered metabolite profiles and elevated levels of pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), which translocate across a compromised intestinal epithelial barrier and activate pattern recognition receptors, including toll-like receptor 4 (TLR4), on innate immune cells.^[3,5] This triggers systemic inflammation characterized by elevated T-helper cell (Th)2 and Th17 responses, ultimately amplifying mast cell activation and cutaneous inflammation.^[2,3] Evidence increasingly supports dysbiosis as a pathogenic contributor to CSU rather than merely an epiphenomenon.^[6,7]

Immune mechanisms in urticaria

CSU is driven by multifactorial immune dysregulation centered on mast cell activation.^[1,2] Mast cells, residing in dermal and mucosal tissues, undergo degranulation in response to cross-linking of high-affinity IgE receptors (FceRI) or activation of complement (C3a, C5a) and other pattern recognition receptors. Degranulation releases preformed mediators (histamine, tryptase, heparin) and newly synthesized molecules (leukotrienes, prostaglandins, cytokines), resulting in vasopermeability, plasma leakage, and pruritus.

Approximately 30–50% of Patients with CSU possess circulating autoantibodies against either IgE itself or the a-subunit of FceRI. These autoantibodies activate mast cells in an IgG-mediated, cross-linking manner, establishing an autoimmune phenotype. Even in seronegative patients, mast cell activation appears to be amplified by dysregulated Th2 and Th17 responses.^[2,6] Th2-derived cytokines (IL-4, IL-5, IL-13) promote IgE production and mast cell survival, while Th17-secreted IL-17 and IL-23 enhance mast cell tissue infiltration and activation.^[2,6] Notably, elevated IL-17 correlates with antihistamine-resistant disease, implicating Th17 responses in severe phenotypes.

Dysbiosis-mediated mechanisms

The pathogenic contribution of dysbiosis to CSU involves three principal mechanisms:

Microbial compositional changes

High-throughput sequencing studies have revealed consistent dysbiotic patterns in CSU.^[6,7] Compared to healthy controls, patients with CSU exhibit significantly reduced microbial a-diversity (Shannon index, P < 0.05) and alterations in b-diversity (community composition).^[6,7] SCFA-producing bacteria, particularly Roseburia spp. and F. prausnitzii, are substantially depleted (20-40% reduction). Conversely, potentially pathogenic Proteobacteria, including K. pneumoniae, E. coli, Lactobacillus spp., and Turicibacter, are enriched.

These microbial shifts are not random; multiple studies demonstrate consistency across independent cohorts, suggesting dysbiosis is a disease-associated signature rather than individual variation.^[6,7] Metagenomic analysis reveals dysbiosis-associated alterations in metabolic pathways, including reduced butanoate and SCFA biosynthesis, coupled with increased LPS synthesis pathways.^[6,7]

Functional dysbiosis

Beyond compositional changes, CSU-associated dysbiosis exhibits functional impairment. Fecal metabolomics reveal decreased concentrations of acetate, propionate, and butyrate (20-40% reduction compared to controls) and altered tryptophan metabolites.^[6,7] Bioaccumulation of dysbiosis-associated compounds, including a-mangostin and glycyrrhizic acid, correlates with disease severity as measured by urticaria activity score 7 (UAS7).

Barrier integrity and intestinal permeability

Dysbiosis-associated reductions in tight junction proteins result in elevated zonulin, a marker of intestinal permeability.^[3,4] Increased paracellular transport allows bacterial translocation and elevation of lipopolysaccharide-binding protein (LBP) and soluble CD14 (sCD14), serological markers of microbial translocation and monocyte activation. These alterations directly correlate with circulating LPS levels and disease activity.^[3,4]

Inflammatory bowel disease (IBD)

IBD (encompassing Crohn’s disease and ulcerative colitis) and CSU share similar dysbiotic signatures and immune dysregulation.^[7,9] Both conditions feature reduced Firmicutes/Bacteroidetes ratios and enriched Proteobacteria. Both exhibit elevated systemic LPS, reduced fecal SCFA concentrations, and Th17-skewed immune responses. Epidemiological studies demonstrate that urticaria prevalence is 2–3-fold higher in patients with IBD compared to the general population, and patients with concurrent IBD and urticaria exhibit more severe disease phenotypes.

FMT in patients with IBD results in microbial diversity restoration and reduction in IL-17, providing a mechanistic template for CSU therapy development.

Irritable bowel syndrome (IBS)

IBS, characterized by altered bowel motility and visceral hypersensitivity, shares dysbiotic patterns with CSU, including increased Proteobacteria and decreased Bacteroidetes. Both conditions are frequently preceded by gastrointestinal infections and manifest elevated intestinal permeability. The gut-brain axis, mediated through the vagus nerve and hypothalamic-pituitary-adrenal axis, may contribute bidirectionally to symptom amplification in patients with concurrent IBS and urticaria.

Microbial and metabolic biomarkers

Multiple candidate biomarkers reflect dysbiotic imbalance and correlate with disease activity:

Immunological biomarkers

Circulating IL-17 (associated with Th17 responses) and IL-4/IL-5 (associated with Th2 responses) are elevated in CSU. IL-10 (produced by Tregs) is reduced. The IL-17/IL-10 ratio may serve as a biomarker predicting antihistamine response and disease severity. Elevated mast cell tryptase and heightened basophil activation tests reflect mast cell burden and reactivity.

Barrier function markers

Serum zonulin, claudin-2, and soluble occludin reflect epithelial tight junction disruption.^[6,7] These markers correlate with microbial translocation and disease activity. Zonulin, quantifiable through enzyme-linked immunosorbent assay, is increasingly explored as a functional biomarker of barrier integrity.

Probiotics and prebiotics

Fecal microbiota transplantation (FMT)

FMT involves the transfer of intact fecal microbiota from healthy donors to dysbiotic recipients, aiming to restore microbial diversity and function. FMT addresses the underlying dysbiosis more comprehensively than individual probiotic strains, restoring complex microbial communities and their collective metabolic output.

An open-label trial (n = 30) of colonoscopic FMT in antihistamine-resistant CSU demonstrated 58% UAS7 reduction at 12 weeks, with 75% of patients achieving partial or complete symptom remission at 6-month follow-up. FMT increased fecal Firmicutes and Bacteroidetes combined abundance by 35% and reduced serum LPS by 48% (P < 0.001). Mechanistically, FMT enhances SCFA production, strengthens tight junctions, and restores Treg-promoting bacteria.^[5,11]

Mouse studies corroborate clinical observations: FMT from healthy donors reduces dermal hives by 70%, decreases serum IgE by 50%, and normalizes Th17/Treg balance within 6 weeks.

Targeted antibiotic therapy

Antibiotics targeting specific pathogenic bacteria represent a mechanistically focused approach.^[12,13] In patients with documented H. pylori infection, eradication using standard triple or quadruple therapy resolves urticaria in 50-80% within 4-8 weeks.

Targeted therapy for other pathogenic taxa is emerging. An RCT (n = 40) of rifaximin, a poorly-absorbed antibiotic effective against Gram-negative bacteria, in patients with CSU with elevated Klebsiella abundance demonstrated a 40% reduction in Proteobacteria abundance, 35% decrease in serum LPS, and 45% UAS7 improvement (P < 0.01). Combination therapy with probiotics (rifaximin plus Lactobacillus) achieved 55% UAS7 improvement compared to 40% with rifaximin monotherapy (P < 0.01), suggesting synergistic effects.

Biologics and immunomodulators combined with microbiome therapy

Biologic agents (omalizumab, dupilumab) achieve 70-85% efficacy in antihistamine-resistant CSU but address immune dysregulation without correcting underlying dysbiosis.^[1,2] Combination approaches may yield superior outcomes.

An RCT (n = 60) combining omalizumab with multi-strain probiotics (L. rhamnosus and B. longum) for 12 weeks achieved 70% UAS7 reduction compared to 50% with omalizumab monotherapy. Probiotics increased fecal Bifidobacterium by 40% and reduced serum IL-17 by 35% (P < 0.001), suggesting probiotics enhance biologic efficacy by restoring immune tolerance and reducing dysbiosis-associated inflammation.

Immunomodulators (cyclosporine, methotrexate) used in severe CSU suppress overactive T-cell responses but do not directly address dysbiosis.^[1,2] A case series (n = 15) combining cyclosporine with synbiotics (probiotics plus prebiotics) achieved 60% UAS7 reduction and 25% increase in Roseburia abundance compared to cyclosporine alone (p < 0.05), indicating synergistic benefit.

Postbiotics and microbial metabolites

Postbiotics, non-living microbial products or fermentation metabolites, offer advantages of safety and stability relative to live probiotics.^[7,11]

Phage therapy and microbial engineering

Bacteriophage therapy employs viruses targeting specific pathogenic bacteria (e.g., Klebsiella-specific phages) while preserving beneficial microbiota.^[14] A murine study of a Klebsiella-specific phage cocktail reduced Proteobacteria by 50%, decreased skin inflammation by 40%, and lowered serum IgE in CSU models. A Phase I human trial (n = 10) reported reduced Klebsiella abundance without adverse effects, though sample size remains small.

Microbial engineering through CRISPR-based editing of probiotic strains to overproduce SCFAs or IPA is in preclinical development.^[15] A study showed engineered Lactobacillus strains increased butyrate production by 30%, reducing Th17 activity and improving barrier function in CSU models. These approaches require extensive safety and efficacy validation before clinical translation.

Mediterranean diet

High fiber, polyphenol, and omega-3 fatty acid content promotes Bacteroidetes and SCFA-producing bacteria while reducing Proteobacteria and serum LPS. A 12-week trial in Patients with CSU documented 25% UAS7 reduction.

Low-histamine diet

Restriction of histamine-rich foods (fermented products, aged cheese, alcohol) may benefit 20-30% of patients, though evidence remains inconsistent.^[1,7] Individual food challenge testing identifies patient-specific triggers.

Prebiotic food sources

Inulin-rich foods (garlic, onions, bananas) and resistant starches (oats, green bananas) promote Bifidobacterium and Roseburia, enhancing SCFA production.

Probiotic foods

Fermented products (yogurt, kefir, kimchi) containing Lactobacillus and Bifidobacterium may reduce inflammation and improve barrier function.

Elimination protocols

Systematic elimination and reintroduction of suspected triggers (gluten, dairy) identifies food sensitivities in 10-20% of patients.^[1,7]

Outstanding questions and challenges

Emerging research directions