Codonopsis pilosula as the sovereign herb in Shenling Baizhu formula ameliorates DSS-induced ulcerative colitis via spermidine-AMPK-mediated mitophagy to inhibit the cGAS-STING inflammatory axis

  • Int Immunopharmacol. 2026 Sep 1:184:116954. doi: 10.1016/j.intimp.2026.116954.
Xiaohu Xi  1 ,  Jiankuan Li  2 ,  Yingjing Wang  2 ,  Yan Ni  3 ,  Jiangtao Zhou  2 ,  Lingya Cao  2 ,  Wei Wei  4 ,  Jianping Gao  5
Affiliations
  • 1. School of Pharmacy, Shanxi Medical University, Taiyuan 030001, Shanxi, China; Department of Pharmacy, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi, China.
  • 2. School of Pharmacy, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
  • 3. Institute of Formulae of Traditional Chinese Medicine, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi, China.
  • 4. Department of Gastroenterology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China.
  • 5. School of Pharmacy, Shanxi Medical University, Taiyuan 030001, Shanxi, China. Electronic address: [email protected].
PMID: 42217339 DOI: 10.1016/j.intimp.2026.116954
Abstract

Background: Dextran sulfate sodium-induced ulcerative colitis is featured by excessive intestinal inflammation and disrupted mucosal immune homeostasis. Codonopsis pilosula is the sovereign herb in Shenling Baizhu Formula for ulcerative colitis therapy, and Codonopsis pilosula Polysaccharides are its key active components, while their immunomodulatory effects and molecular mechanisms in Shenling Baizhu Formula against ulcerative colitis remain elusive. This study explored the critical role of Codonopsis pilosula Polysaccharides and the spermidine-AMPK-mediated mitophagy-cGAS-STING inflammatory axis in regulating intestinal inflammation and ameliorating ulcerative colitis.

Methods: A dextran sulfate sodium-induced ulcerative colitis mouse model was established to evaluate the indispensable role of Codonopsis pilosula Polysaccharides in Shenling Baizhu Formula. Ultra-high performance liquid chromatography metabolomics and 16S ribosomal RNA Sequencing were performed to identify key metabolites and gut microbiota. In vitro dextran sulfate sodium-induced ulcerative colitis cellular models (human colorectal adenocarcinoma Caco-2 and human normal colonic epithelial NCM460 cells) were constructed to validate the regulatory mechanism of spermidine on AMPK-mediated Mitophagy, inflammatory balance and intestinal epithelial injury.

Results: Codonopsis pilosula Polysaccharides were essential for the anti-ulcerative colitis efficacy of Shenling Baizhu Formula: removal of Codonopsis pilosula significantly aggravated colonic pathological lesions, intestinal inflammatory responses and oxidative stress in ulcerative colitis mice, whereas Codonopsis pilosula Polysaccharides supplementation reversed these abnormal phenotypes (P < 0.05). Metabolomics and microbiomics confirmed that Codonopsis pilosula Polysaccharides exerted therapeutic effects via spermidine (a key metabolite in glutamate metabolism pathway) and Muribaculaceae. Critically, in vitro dual-cell experiments verified that spermidine activated AMPK-mediated Mitophagy to directly inhibit the hyperactivation of cGAS-STING inflammatory axis, thereby restoring intestinal inflammatory homeostasis and alleviating epithelial cell injury in ulcerative colitis.

Conclusion: Codonopsis pilosula Polysaccharides extracted from the sovereign herb Codonopsis pilosula in Shenling Baizhu Formula ameliorate dextran sulfate sodium-induced ulcerative colitis, and the core mechanism depends on spermidine-triggered AMPK-mediated Mitophagy to suppress the cGAS-STING inflammatory signaling axis, which plays a pivotal role in regulating intestinal immunity and repairing mucosal epithelial damage.

Keywords
AMPK; Codonopsis pilosula polysaccharides; Mitophagy; Spermidine; Ulcerative colitis; cGAS-STING.
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