Altered intestinal permeability and inflammatory activation, particularly elevated LPS levels, are closely associated with gastrointestinal manifestations and disease activity in HAE, suggesting a gut-angioedema axis contributes to phenotype-specific disease expression.
Key Findings
Results
Patients with recent gastrointestinal edema had significantly higher serum LPS levels compared to those without recent gastrointestinal edema.
Study included 169 patients with hereditary angioedema in a cross-sectional design
LPS difference between groups was statistically significant (P = 0.030)
Multivariable logistic regression confirmed LPS was independently associated with recent gastrointestinal edema (odds ratio = 3.90, 95% CI: 1.58–10.35, P = 0.004)
LPS was also independently associated with HAE activity score (β = 1.499, P = 0.046) in linear regression
Results
IL-6 levels were significantly higher in patients with recent gastrointestinal edema and were independently associated with this manifestation.
IL-6 difference between groups with and without recent gastrointestinal edema was statistically significant (P = 0.031)
Multivariable logistic regression showed IL-6 was independently associated with recent gastrointestinal edema (odds ratio = 1.15, 95% CI: 1.01–1.31, P = 0.038)
IL-6 was interpreted as potentially reflecting concurrent inflammatory activation rather than a mediator of LPS effects
No significant mediation or interaction between LPS and IL-6 was observed in exploratory analyses
Results
FABP2 levels did not significantly differ between patients with and without recent gastrointestinal edema.
FABP2 (fatty acid-binding protein 2) is a marker of intestinal epithelial injury and permeability
The absence of elevated FABP2 suggests that gastrointestinal edema in HAE can occur without overt epithelial injury
LPS but not FABP2 was elevated, indicating altered intestinal permeability may not be uniformly accompanied by epithelial cell damage
The finding distinguishes the mechanism of HAE gastrointestinal involvement from conditions characterized by frank mucosal injury
Results
LPS was independently associated with overall HAE disease activity as measured by the HAE activity score (HAE-AS).
Linear regression analysis was used to assess the association between LPS and HAE-AS
LPS was independently associated with HAE-AS (β = 1.499, P = 0.046) after multivariable adjustment
This association extended beyond gastrointestinal edema to overall disease activity
The HAE-AS is a validated instrument for measuring disease burden in hereditary angioedema
Results
No significant mediation or interaction between LPS and IL-6 was found in exploratory analyses.
Exploratory mediation and interaction analyses were performed to assess potential relationships among LPS, IL-6, and gastrointestinal edema
Neither mediation (LPS acting through IL-6) nor statistical interaction between LPS and IL-6 reached significance
This suggests LPS and IL-6 may contribute independently to gastrointestinal manifestations rather than through a sequential pathway
Authors note that IL-6 may reflect concurrent inflammatory activation rather than being causally downstream of LPS in this context
Discussion
The authors propose a 'gut-angioedema axis' as a contributor to phenotype-specific disease expression in HAE.
The concept emerges from the combined findings of elevated LPS (a marker of gut-derived bacterial translocation) and IL-6 specifically in patients with gastrointestinal involvement
The authors suggest the gut environment may shape disease heterogeneity in HAE
The findings are described as providing a basis for further mechanistic studies
The cross-sectional design limits causal inference, and the authors describe analyses as exploratory
What This Means
This research suggests that the gut barrier and immune system play a role in how hereditary angioedema (HAE) — a condition causing recurrent episodes of swelling under the skin and in internal organs — affects different patients differently. In a study of 169 HAE patients, researchers measured blood markers related to intestinal 'leakiness' (how well the gut wall keeps bacteria and their products from entering the bloodstream) and inflammation. They found that patients who had recently experienced swelling episodes in their gastrointestinal tract had notably higher levels of a bacterial product called LPS (lipopolysaccharide) and the inflammatory signal IL-6 in their blood compared to patients without recent gut involvement. LPS levels were also linked to overall disease activity scores.
Interestingly, another marker of intestinal damage called FABP2 was not elevated in patients with gastrointestinal swelling, which suggests that the gut swelling in HAE may occur without the gut lining cells themselves being directly damaged. This is a meaningful distinction because it implies the mechanism may involve changes in how the intestinal barrier functions rather than outright destruction of the gut lining. The authors propose the idea of a 'gut-angioedema axis,' meaning the gut environment may influence how severely and in what way HAE manifests in individual patients.
This research suggests that gut permeability and related inflammation could be important factors in understanding why some HAE patients experience more gastrointestinal symptoms than others. These findings open the door for future studies to explore whether targeting gut health or inflammation could influence HAE outcomes, though the cross-sectional design of this study means it cannot establish whether gut changes cause the attacks or result from them.
Wang X, Zhou N, Zhi Y. (2026). Associations of hereditary angioedema attacks with intestinal permeability and inflammatory cytokines.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1873666