Multi-aspect therapeutic effects of a polyphenolic herbal formulation Cirsium japonicum, Scutellaria baicalensis, Paeonia japonica, and Glycyrrhiza uralensis on ulcerative colitis: inflammation modulation, gut microbiota remodeling, and metabolite profiling.

Ulcerative Colitis (UC) is a chronic illness that commonly demands the use of medication, sometimes for long term. In a DSS mouse model, we examined 5-aminosalicylic acid (5ASA) in comparison to a defined polyphenol-rich herbal mixture CSPG: Cirsium japonicum, Scutellaria baicalensis, Paeonia japonica, and Glycyrrhizae radix, using a two-phase approach. In phase 1 (days 1-14, without DSS stimulation), the herbal formula CSPG produced a more gut-friendly preventive profile compared to 5ASA in non-inflammatory condition:Unlike 5-ASA, which decreases microbial diversity as previously reported, CSPG preserved overall diversity and maintained protective taxa such as Ruminococcaceae uncultured ; and reduced inflammatory metabolites (uracil, glyceric acid, succinic acid) more effectively than 5ASA. Next, in phase 2 (days 15-24, with DSS inflammatory stimulation), CSPG matched first-line 5-ASA in suppressing inflammation (reduced colon shortening and procalcitonin). Its PI3K-Akt upregulation-together with NF-κB repression-was associated with more continuous ZO-1/ZO-2/occludin proteins expression and normalization of claudin-2 and MUC1/MUC2/MUC4, indicating barrier-repair capacity, a result supported by in vitro HT-29 experiments. Simultaneously, CSPG corrected DSS-induced dysbiosis more effectively than 5ASA: it increased SCFA-linked taxa (Prevotellaceae UCG-001 and Ruminococcus; 5ASA also rose but to a lesser extent), and reduced inflammation-associated groups ( [Eubacterium] siraeum group, and Erysipelotrichaceae). CSPG restored SCFAs and elevated glycine, proline, pyruvate, and myo-inositol, while reducing succinate and uracil-with stronger effects than 5-ASA for pyruvate, myo-inositol, and succinate, and comparable effects for butyrate. Although CSPG is not a single-target, rationally designed drug like 5ASA, it achieved comparable anti-inflammatory and barrier-repair effects and, unlike 5ASA, also improved gut microbiota composition and metabolite profiles, indicating potential advantages for long-term UC management.