Changes in constipation severity and gut microbiota after lactulose administration in patients with chronic constipation: A prospective single-arm interventional study

Background: Lactulose is an osmotic laxative that may affect gut microbiota through its prebiotic properties. However, few studies have evaluated the changes in clinical symptoms and gut microbiota before and after lactulose administration in patients with chronic constipation. We aimed to evaluate the changes in constipation symptoms and gut microbiota after 8 weeks of lactulose administration in patients with chronic constipation. Methods: This prospective single-arm interventional study included 19 Japanese patients with chronic constipation who were enrolled between April 2019 and December 2024. Lactulose was administered for 8 weeks. The prespecified primary outcome was the change in mean weekly spontaneous bowel movement frequency from baseline to week 8. Secondary outcomes included defecation status, constipation severity assessed using the Constipation Scoring System (CSS), gastrointestinal symptoms assessed using the Gastrointestinal Symptom Rating Scale (GSRS), blood test results, and fecal gut microbiota. Gut microbiota analysis was performed using QIIME2. Nonparametric statistical methods were used, with adjustment for multiple comparisons where appropriate. Results: The prespecified primary outcome, the change in mean weekly spontaneous bowel movement frequency from baseline to week 8, showed no statistically significant difference. No significant changes were observed in overall bowel movement frequency, Bristol Stool Form Scale score, or rescue medication use. After Holm adjustment, significant differences across the 3 time points were observed in the CSS item scores for frequency of bowel movements and time needed per attempt, as well as in the total CSS score. In the GSRS, numerically lower scores were observed in abdominal pain and hard stool scores, but no GSRS item remained statistically significant after Holm adjustment. Gut microbiota analysis showed a significant increase in the relative abundance of Bifidobacteriales. The Simpson index decreased significantly, and weighted UniFrac analysis showed a significant compositional difference between baseline and week 8. No serious adverse events or clinically relevant abnormalities in laboratory test results were observed. Conclusion: Lactulose administration was associated with improvements in selected measures of constipation severity and compositional changes in the gut microbiota, particularly an increase in the relative abundance of Bifidobacteriales.