The San-Qi-Xue-Shang-Ning formula protects against ulcerative colitis by restoring the homeostasis of gut immunity and microbiota

Ethnopharmacological relevance: Ulcerative colitis (UC) is a major cause of morbidity and mortality due to repetitive remissions and relapses, and many severe complications, including colitis-associated Cancer (CAC). The San-Qi-Xue-Shang-Ning (SQ) formula has been utilized in clinical practice to treat gut diseases, but its pharmacological evidence is limited and awaits elucidation.

Aim of the study: Here, we elucidated the molecular mechanisms of the SQ formula.

Materials and methods: Its therapeutic value in combating UC and CAC was predicted from network pharmacology and weighted gene co-expression network analysis (WGCNA). Experimental colitis models were established by feeding dextran sodium sulfate (DSS) to C57BL/6N mice for 7 days, and they were subjected to the SQ formula for 14 days. High-throughput technologies and biochemical investigations were executed to corroborate the anti-colitis effect.

Results: Network pharmacology and WGCNA demonstrated that the targets of the SQ formula were associated with interleukin-17 (IL-17), tumor necrosis factor (TNF), IL-1b and peroxisome proliferators-activated receptor (PPAR) signaling pathways, and correlated with the survival in patients with colorectal Cancer. In mice with colitis, the SQ treatment hindered colitis progression in a dose-dependent manner, as evidenced by the rescued colon length and weight loss, improved colonic epithelial integrity, and abolished crypt loss. In addition to the suppressed serum IL-17, TNFα, and IL-1b levels, the SQ-treated colitis mice exhibited decreased colonic protein abundance of hypoxia-inducible factor-1α (HIF-1 α), PPARα, and Caspase3 (Casp3) with an increased PPARγ expression. Concurrently, the high dose of SQ promoted the alternative activation of peritoneal macrophages by increasing Arg1 and inhibiting iNOS2, thereby facilitating the migration of NCM460 cells and controlling TNF-induced Reactive Oxygen Species production and Apoptosis in intestinal organoids. In colitis-accompanied dysbiosis, the SQ formula reversed the decreased microbiota diversity indexes and restored the microbiome profile in the murine colitis models.

Conclusion: The SQ formula is a potent anti-colitis drug that facilitates inflammation resolution and restores gut microbiota homeostasis.

Dysbiosis; Inflammation; Reactive oxygen species; San-Qi-Xue-Shang-Ning formula; Ulcerative colitis.