A study conducted by researchers at Beijing University of Chinese Medicine and published in Biomedicine & Pharmacotherapy demonstrates that Si Ni San (四逆散), a classical Chinese herbal formula, effectively mitigates intestinal dysmotility, inflammation, and mucin secretion dysfunction in chronic stress-induced bowel disturbance. [1]
The researchers administered Si Ni San to rats exposed to chronic restraint stress, a validated model for functional gastrointestinal disorders such as irritable bowel syndrome. Their findings showed that Si Ni San significantly improved colonic motility, reduced inflammatory cytokines, restored mucosal barrier function, and normalized serotonin signaling within the gut. [1]
Wistar rats were divided into four groups: a control group, a chronic restraint stress model group, a Si Ni San treatment group (6.9 g/kg/day), and a trimebutine maleate group (100 mg/kg/day). Rats in the treatment groups received oral administration once daily for seven days following a two-week period of stress exposure. The herbal formula was prepared using a concentrated decoction of four herbs: Chái Hú (柴胡, Bupleuri Radix), Bái Sháo (白芍, Paeoniae Radix Alba), Zhǐ Shí (枳实, Aurantii Fructus Immaturus), and Gān Cǎo (甘草, Glycyrrhizae Radix et Rhizoma). [1]
Colonic motility was measured using a charcoal meal propulsion test. Rats in the chronic stress group had a colonic propulsion rate of 56.8 percent, compared to 84.3 percent in the control group. Treatment with Si Ni San improved this rate to 76.4 percent, comparable to the pharmaceutical control group at 78.2 percent. [1]
Inflammatory markers including IL-6, TNF-α, and IL-1β were significantly elevated in colonic tissue of stressed animals. Si Ni San reduced these cytokines to levels near baseline. For example, IL-6 decreased from 221.3 pg/mg in the stress group to 137.6 pg/mg after treatment. TNF-α levels fell from 252.8 pg/mg to 164.5 pg/mg, and IL-1β declined from 187.9 pg/mg to 112.3 pg/mg. These reductions were statistically significant compared to untreated stressed rats (p < 0.01). [1]
Histological analysis revealed damage to the colonic mucosa in the stress group, including goblet cell depletion and epithelial disorganization. Si Ni San reversed these histopathological changes, as confirmed by increased mucin (Muc2) expression and MUC2-positive goblet cell density. Goblet cell counts rose to 48.7 ± 3.1 cells per high-power field in the treatment group, compared to 28.4 ± 2.7 in the untreated model group. [1]
The study also investigated serotonin signaling, which plays a central role in gut motility and sensitivity. Chronic stress elevated colonic 5-HT content and downregulated the serotonin transporter (SERT), resulting in impaired neurotransmitter reuptake. Si Ni San treatment normalized SERT protein expression and reduced 5-HT concentrations, thereby helping to restore serotonergic balance in the enteric nervous system. [1]
Mechanistically, Si Ni San exerted its therapeutic effects through several coordinated actions: suppression of inflammatory cytokines, upregulation of mucin expression, normalization of serotonin metabolism, and stabilization of mucosal mast cells. Immunohistochemical staining for mast cell tryptase indicated a reduction in mast cell activation in the treatment group, which may correlate with decreased visceral hypersensitivity and epithelial inflammation. [1]
The results suggest that Si Ni San may be particularly useful for functional gastrointestinal conditions involving Liver–Spleen disharmony and stress-mediated immune dysregulation. While this was a preclinical study, the data provide a rationale for further clinical investigation in patients with irritable bowel syndrome or related disorders characterized by inflammatory and serotonergic dysfunction.
The herbal composition used in the study followed the traditional formula: Chái Hú (柴胡) to soothe the Liver and relieve constraint, Bái Sháo (白芍) to soften the Liver and preserve yin, Zhǐ Shí (枳实) to break up qi stagnation and regulate the intestines, and Gān Cǎo (甘草) to harmonize the actions of the other herbs. [1] No adverse effects were reported in the rats receiving Si Ni San, and the treatment demonstrated comparable efficacy to trimebutine maleate, a pharmaceutical agent commonly prescribed for gut motility disorders.
This study provides detailed mechanistic and histological evidence to support the clinical use of Si Ni San in the treatment of stress-exacerbated gastrointestinal dysfunction. Although human trials are needed to confirm these findings, the results offer strong preclinical support for the formula’s use in regulating gut motility, restoring mucosal integrity, and resolving inflammation associated with chronic stress responses.
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Reference1. Xu, Y., Zhao, R., Liu, C., Liu, Y., Zhang, Q., Chen, Y., & Li, Y. (2024). Si Ni San, a compound Chinese herbal medicine, alleviates stress-induced intestinal dysmotility, inflammation, and mucin production. Biomedicine & Pharmacotherapy, 173, 115152.
