Integrative multi-omics investigation of gut carboxylic metabolites in the gut-skin axis of IBD and AD comorbidity

Butyrate and lactate are microbial-derived gut carboxylic metabolites (GCMs) generated by intestinal fermentation. Their potential involvement in inflammatory bowel disease (IBD) and atopic dermatitis (AD) comorbidity through the gut-skin axis remains unclear. In this study, we investigated the associations between genetically predicted gut microbial taxa and IBD/AD using Mendelian randomization (MR) and integrated network pharmacology, molecular docking, single-cell RNA sequencing, and in silico knockout analyses to characterize GCM-associated molecular features. The effects of butyrate and lactate were further evaluated in LPS-treated intestinal fibroblasts and skin keratinocytes. MR revealed that higher genetically predicted abundance of Faecalicoccus pleomorphu s and CAG-884 was associated with reduced susceptibility to both IBD and AD. Network pharmacology identified 14 shared GCM-associated candidate genes. Single-cell RNA sequencing demonstrated their cell-type-specific expression patterns, while in silico knockout analysis prioritized TLR4 , HDAC9 , and LDHA as potentially influential nodes in disease-associated regulatory networks. In LPS-treated cells, butyrate and lactate reduced the expression of these genes, decreased HDAC9 protein levels, and restored the Ac-H3/H3 ratio. These findings suggest that GCMs are associated with shared inflammatory and epigenetic features in IBD and AD comorbidity, potentially involving HDAC-related regulation. Dietary tracing further identified potential fermentation substrates and food sources associated with butyrate and lactate production, providing insights for future dietary investigations.