Xianjun Xiao,1,* Peiwen Xue,1,* Xiangyun Yan,2,* Yanqiu Li,2,* Yunzhou Shi,2 Haiyan Qin,2 Di Qin,2 Wei Cao,2 Zihao Zou,2 Lu Wang,2 Rongjiang Jin,1 Ying Li,2 Junpeng Yao,2 Juan Li1,3 

1School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, People’s Republic of China; 2Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, People’s Republic of China; 3Affiliated Sichuan Provincial Rehabilitation Hospital of Chengdu University of TCM, Chengdu, Sichuan, 611135, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Junpeng Yao; Juan Li, Email yjp@cdutcm.edu.cn; 785939016@qq.com

Background: Emerging evidence links gut microbiota and their by-products, notably short-chain fatty acids (SCFAs), to urticaria. This study employs multiple Mendelian Randomization (MR) analyses to unravel the complex interactions among gut microbiota, SCFAs, and different subtypes of urticaria, aiming to elucidate the underlying mechanisms and enhance future clinical research.
Methods: We analyzed published genome-wide association study (GWAS) summary statistics to identify associations between gut microbiota and three common subtypes of urticaria: spontaneous, dermatographic, and temperature-triggered. Initial two-sample and reverse MR analyses explored the causality in these relationships. Subsequent multivariate MR analyses investigated the role of SCFAs in modulating these interactions, with multiple sensitivity analyses to ensure robustness.
Findings: Specific taxa were differently associated with various urticaria subtypes. From microbiota to urticaria: one taxon was negatively associated with dermatographic urticaria; seven taxa were negatively associated and four positively associated with temperature-triggered urticaria; four taxa were negatively associated and six positively associated with spontaneous urticaria. Conversely, from urticaria to microbiota: five taxa were negatively associated with dermatographic urticaria; four were negatively and two positively associated with temperature-triggered urticaria; and two were negatively associated with spontaneous urticaria. These associations were observed at a nominal significance level (P < 0.05). After applying Bonferroni correction for multiple testing, these associations did not reach statistical significance. The observed trends, however, provide insights into potential microbiota-urticaria interactions. Multivariate MR analyses elucidated the role of SCFAs, particularly acetate, which plays a crucial role in modulating immune response. Adjusting for acetate revealed direct effects of Actinobacteria, Bifidobacteriales, and Bifidobacteriaceae on spontaneous urticaria, with corresponding mediation effects of − 22%, − 24.9%, and − 24.9% respectively. Similarly, adjustments for Alcaligenaceae and Betaproteobacteria indicated significant negative effects of acetate on dermatographic and spontaneous urticaria, with mediation effects of − 21.7% and − 23.7%, respectively.
Conclusion: This study confirms the interconnected roles of gut microbiota, SCFAs, and urticaria. It highlights SCFAs’ potential mediating role in influencing urticaria through microbiota, providing insights for future therapeutic strategies.

Keywords: urticaria, short-chain fatty acids, gut microbiota, gut-skin axis, Mendelian randomization