Traditional Chinese Medicine-derived berberine-loaded herbzyme ameliorates ulcerative colitis by regulating IL10 and TMAO
TL;DR
By modulating p-STAT3-IL10-NLRP3 pathway and the Klebsiella-TMAO axis to ameliorate UC, this work establishes a foundation for the development of nanomedicines based on active TCM components.
Abstract
Ulcerative colitis (UC) is a common inflammatory bowel disease. The traditional Chinese medicine (TCM) formula Zanglian Wan has demonstrated promising therapeutic effects in clinical practice, yet the synergistic mechanisms among its active components remain to be fully elucidated. Inspired by this formula, this study successfully constructed a novel nanocomplex, BLCDs, through the self-assembly of Sanguisorba officinalis L.-derived carbon dots (LCDs) and berberine (BBR) via electrostatic interactions and hydrogen bonding. Characterization results showed that LCDs possessed a uniform size distribution and were rich in oxygen-containing functional groups (carboxyl, hydroxyl, carbonyl) on their surface. Their SOD-like activity was dependent on these groups and was retained after BBR conjugation. In LPS-stimulated NCM460 cells, RNA-seq identified IL10 as the most significantly upregulated gene upon BLCDs treatment. Mechanistically, BLCDs promoted the phosphorylation of STAT3 (p-STAT3), which transcriptionally upregulated IL10 expression, leading to inhibition of the NLRP3 inflammasome pathway and its downstream inflammatory cytokines. In DSS-induced mouse model, BLCDs significantly ameliorated intestinal inflammation, oxidative stress, and barrier dysfunction. This therapeutic advantage was attributed to enhanced intestinal retention conferred by their larger particle size and charge switching properties. 16S rDNA sequencing indicated that BLCDs increased gut microbiota abundance and diversity, suppressed the growth of harmful bacteria such as Klebsiella, and reduced the generation of trimethylamine N-oxide (TMAO). Colorectal normal organoids (CNOs) experiments further confirmed that BLCDs reversed TMAO-induced inflammatory lesions through an IL10-dependent mechanism. Both in vitro and in vivo safety evaluations demonstrated that BLCDs possess good biocompatibility. Taken together, this study successfully constructed BLCDs nanocomplexes integrating the antioxidant activity of LCDs and the anti-inflammatory properties of BBR. By modulating p-STAT3-IL10-NLRP3 pathway and the Klebsiella-TMAO axis to ameliorate UC, this work establishes a foundation for the development of nanomedicines based on active TCM components.