Berberine suppresses colon inflammation via integrated modulation of host metabolism, microbial ecology, and innate immune signaling

<b>Background:</b> Berberine, a natural compound with unique bioactivity, has been widely used in the treatment of gastrointestinal inflammatory diseases. Despite its well-documented anti-inflammatory properties, the system-level regulatory network underlying its multifaceted mechanisms remains poorly understood. <b>Methods:</b> In this study, we employed a multi-level analytical approach, integrating single-cell RNA sequencing, targeted metabolomics, 16S rRNA gene sequencing, and drug-target analysis, to elucidate the integrative effects of berberine on gut microbiota-metabolism-immune interactions. <b>Results:</b> Single-cell RNA sequencing revealed that berberine enhances energy metabolism in intestinal cells of DSS-induced mice, thereby maintaining normal physiological functions. Targeted metabolomics analysis of short-chain fatty acids, combined with 16S rRNA gene sequencing, demonstrated that berberine supplementation significantly increases short-chain fatty acid (SCFA) levels in the intestinal environment and selectively enriches the abundance of <i>Akkermansia</i>. Furthermore, single-cell RNA sequencing data indicated that berberine inhibits fibroblast-to-lymphatic transformation and suppresses the expression of interleukin-1<i>β</i>, leading to reduced immune activation in innate immune cells. Drug-target analysis identified shared molecular targets between berberine and various immunotherapeutic agents. <b>Conclusion:</b> This study provides a comprehensive understanding of berberine's multi-target mechanisms and highlights its potential as a therapeutic agent for inflammatory diseases through the modulation of gut microbiota, host metabolism, and immune responses.