Altered Gut Microbiota in H1-Antihistamine-Resistant Chronic Spontaneous Urticaria Associates With Systemic Inflammation

Abstract

Background and objective: Chronic spontaneous urticaria (CSU) is a histamine-mediated inflammatory skin disease, and second-generation non-sedating H1-antihistamines (nsAH) at licensed doses have long been the first-line therapy in CSU. However, about 50% of patients are resistant to nsAH, and the precise pathogenesis remains largely unknown but seems to be associated with low-level systemic or intestinal inflammation. We aim to determine the fecal microbial composition and clarify its correlation with the clinical profiles og CSU with nsAH resistance.

Methods: A total of 25 CSU patients with or 19 CSU patients without nsAH resistance and 19 healthy controls (HC) were enrolled in this study. The intestinal microbiome was detected by 16S rRNA sequencing. The data were analyzed using R language software.

Results: Significantly higher urticarial activity score for 7 days, stool calprotectin, erythrocyte sedimentation rate, serum C-reactive protein, and interleukin-6, but much lower alpha-diversity and evenness of fecal bacterial community were observed in CSU patients with nsAH resistance than in those without (P <0.05 for all variables). Compared to patients with nsAH-responsiveness, the abundance of fecal genera Prevotella, Megamonas, and Escherichia were significantly increased, while that of Blautia, Alistipes, Anaerostipes, and Lachnospira were remarkably reduced in nsAH-resistant patients (uncorrected P <0.05 for all variables). Finally, systemic not intestinal inflammation degree was positively correlated with genera Escherichia, while negatively with genera Blautia, Dorea, Lactobacillus, Eubacterium_hallii_group, and Roseburia. CSU without nsAH resistance and HC individuals showed almost unchanged genera bacterium.

Conclusions: Among CSU patients, pro-inflammation phenotype relating to enteric dysbacteriosis features nsAH resistance in CSU patients. The results provide clues for future microbial-based or anti-inflammatory therapies on nsAH resistant CSU.

Keywords: 16S rRNA sequencing; antihistamine resistance; chronic spontaneous urticaria (CSU); gut microbiota; inflammation.

Figure 1

Analysis of 16s rRNA sequencing depth. Refraction curve analysis with Shannon (A) or Sobs index (B) on OTU level.

Figure 2

β Diversity analysis of gut microbial structure. (A) Comparison of distance rank on OTU level among three groups was shown by partial least squares-discriminant analysis (PLS-DA). (B) Similarities in the microbial composition on OTU level among three groups were presented by non-metric multidimensional scaling (NMDS). R, RCSU; N, CSU; C, HC.

Figure 3

The composition and relative proportion of gut bacteria in the three groups on Phylum level (A) and Genus level (B).

Figure 4

Differently abundant taxa identified using LEfSe analysis among groups. Distribution of differently abundant taxa from phylum to genera levels between the RCSU and the CSU groups (A) and between the CSU and the HC groups (C). LDA showing the impact of different species on the difference between the RCSU and the CSU groups (B), and between the CSU and the HC groups (D), and visualization of only taxa meeting an LDA ≥2.

Figure 5

Correlation analysis of gut bacteria and related clinical indicators.