Modulation of gut microbiota and intestinal metabolites by lactulose improves loperamide-induced constipation in mice

Lactulose is a common laxative and has been widely applied to clinical treatment for constipation. This study aimed to explore the improving effect of lactulose on constipation through the mediation of gut microbiota and intestinal metabolites. BALB/c mice with constipation induced by loperamide were orally treated with lactulose for four weeks. After the treatment, the constipation-related factors were determined. The effect of lactulose on the composition of gut microbiota was assessed by 16S rDNA gene sequencing. Gas chromatography or liquid chromatography-mass spectrometer (GC/LC-MS) analysis was used for the quantification of intestinal metabolites. The treatment of constipated mice with lactulose accelerated intestinal motility, suppressed inflammatory responses, protected gut barrier, and improved metabolisms of water and salt in the intestinal tract. These therapeutic effects were attributed to the reversed gut microbiota dysfunction, which conferred the benefit to the production of intestinal metabolites including bile acids, short-chain fatty acids, and tryptophan catabolites. Further, the depletion of intestinal flora from loperamide- or (loperamide + lactulose)-treated mice confirmed the significance of gut microbiota in the mediation of constipation. In summary, this study leads us to propose that lactulose may improve constipation through a prebiotic effect on gut microbiota and intestinal metabolites.