Saikosaponin D Improves Diarrhea-Predominant Irritable Bowel Syndrome by Regulating the Brain-Gut Axis: Based on Changes in the Gut HMGB1-TLR4/NF-κB Pathway and Hypothalamic HPA Axis.

Authors

Guilin Dong, Ao Li, Haizhou Zeng, Xinran Li, Yanli Xiong, Xiaoqing Xu, Jingjing Li, Yunxia Kuang, Chunli Lu, Guoqiang Qian

Published in

Digestive diseases and sciences. Aug 06, 2026. Epub Aug 06, 2026.

Abstract

Diarrhea-predominant irritable bowel syndrome (IBS-D) is characterized by diarrhea and is often accompanied by depression, abdominal symptoms, and emotional comorbidities. Preclinical and clinical studies have shown that dysfunction of the brain-gut axis is a key pathogenic factor in IBS-D, yet the specific mechanisms remain unclear. Saikosaponin D (SSD), a major bioactive component of Bupleurum chinense DC., exhibits anti-inflammatory, antidepressant, and antitumor activities, with multi-target and multi-pathway interactions.
Acetic acid and restraint stress induced an IBS-D mouse model. SSD (purity ≥ 98%, Macklin Inc.) was administered orally at low, medium, and high doses (5, 10, 20 mg/kg). Visceral sensitivity, inflammatory status, intestinal barrier function, HPA axis activity, and gut microbiota composition were systematically evaluated using behavioral tests, Western blot, qRT-PCR, and 16S rRNA sequencing.
SSD significantly alleviated visceral hypersensitivity and depression-like behavior, inhibited the peripheral HMGB1-TLR4/NF-κB inflammatory pathway, and restored intestinal barrier integrity. SSD also downregulated hypothalamic Nesfatin-1/CRH/p-CREB expression, suppressed hyperactivation of the stress-related HPA neuroendocrine axis, and reshaped the gut microbial community structure (β-diversity). Network pharmacology analysis suggested that SSD targets were significantly enriched in brain-gut axis-related pathways.
The present results indicate that SSD could ameliorate IBS-D by synergistically regulating peripheral inflammation, central stress, and intestinal microbes via the brain-gut-microbiota axis, providing experimental evidence for its potential application in TCM-based treatment.

PMID:
42560608
Bibliographic data and abstract were imported from PubMed on 06 Aug 2026.

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