Abstract
In a prospective, randomized, three-arms, controlled clinical study, Chinese Herbal Medicine MaZiRenWan (MZRW, also known as Hemp Seed Pill) demonstrates comparable efficacy with Senna for functional constipation (FC) during an 8-week treatment period. Both MZRW and Senna are better than a placebo; relative to Senna and a placebo, MZRW displayed a more sustained effect during the 8-week follow-up period. The characteristic pharmacological mechanism responsible for this observation is still unclear. To explore this, we collected pre- and post-treatment serum samples of 85 FC patients from MZRW/Senna/placebo treatment groups for pharmacometabolomic analysis. An ultrahigh-performance liquid chromatography-mass spectrometer (UPLC-MS) was used for metabolic profiling and quantification. In vivo studies were conducted in constipated C57BL/6J mice to verify the effects and corresponding mechanism(s) of the action of MZRW. Pearson correlation analysis, paired t-test, one-way ANOVA analysis, χ2 test, and Student t-test were used to interpret the clinical and preclinical data. Changes in levels of circulating oleamide and its derivatives negatively correlate with improvement in complete spontaneous bowel movement (CSBM) in the MZRW group (Pearson r = -0.59, p = 0.00057). The same did not hold true for either Senna or placebo groups. Oleamide is a known regulator of intestinal motility. MZRW treatment resulted in reduced levels of circulating oleamide in FC patients. Experimental verification showed that MZRW attenuated oleamide-induced slow intestinal motility in mice. MZRW decreased oleamide levels in serum, ileum, and colon in normal mice, but increased expression of colonic fatty acid amide hydrolase (FAAH). In conclusion, MZRW improved bowel movement in FC by down-regulating oleamide, possibly by enhancing FAAH-mediated degradation. Our findings suggest a novel therapeutic strategy for FC.
Highlights
Functional constipation (FC) affects over 14% of adults globally (Suares and Ford, 2011)
By analyzing the pre- and post-treatment serum samples from 85 FC patients, who were randomly selected from the three-armed groups in the three-armed clinical study, we found a representative metabolite identified as oleamide to be highly related to intestinal motility
As one member of the fatty acid amide (FAA) family, oleamide has been known for its role in the regulation of intestinal motility in mice by activating the cannabinoid receptor 1 (CB1) receptor (Capasso et al, 2005)
Summary
Functional constipation (FC) affects over 14% of adults globally (Suares and Ford, 2011). In a three-armed, randomized, and controlled clinical study with 291 FC patients (Zhong et al, 2019), MZRW demonstrated comparable efficacy with Senna (a first-line laxative commonly used in Hong Kong) during the treatment period. The change of serum oleamide is significantly correlated with complete spontaneous bowel movement (CSBM) improvement in the MZRW group, but not with CSBM improvement in the Senna or placebo group This suggests that oleamide signaling could be targeted by MZRW to relieve FC. How oleamide is regulated by MZRW in FC patients and mice was investigated
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