Constipation is one of the most prevalent gastrointestinal disorders in patients with chronic kidney disease (CKD), due in part to their multiple comorbidities, concomitant medications, low fiber and fluid intake, and altered gut microbiota. Although constipation is usually perceived as a benign condition, recent evidence has challenged this most common perception, demonstrating its independent association with poor clinical outcomes, partly through the altered gut microbiota favoring the production of fecal metabolites. Among patients with CKD whose gut plays an important role in the disposal of uremic toxins and in fluid and electrolyte homeostasis, the presence of constipation can preclude these compensatory mechanisms and may further contribute to their poor clinical outcomes. Importantly, recent experimental studies in uremic animals have shown that constipation treatment with laxatives not only accelerated intestinal motility but also modified the gut microbiota and fecal metabolites, protected the gut barrier, suppressed inflammatory responses, and even ameliorated CKD progression. These findings led to the suggestion that the adequate management of constipation in patients with CKD may provide additional therapeutic and prognostic benefits beyond its conventional defecation control. However, no human studies have yet examined the effects of constipation treatment on clinical outcomes associated with constipation, or on outcome-related biochemical and microbiological parameters in patients with CKD. The central hypothesis of this proposal is that treatment of constipation in patients with CKD not only improves their constipation symptoms but also favorably modifies the relevant biochemical and gut microbial profiles, and ultimately improves clinical outcomes in these patients. As a first step to test this hypothesis, we propose to perform a single-center, open-label, randomized, controlled, parallel-group, pilot feasibility trial of a 4-week intervention of constipation treatment (vs. control) in patients with CKD and constipation, with the following specific aims: 1) Test the feasibility of delivering the proposed interventions and performing the proposed examinations; and 2) Determine the effects of constipation treatment on the changes in constipation-related clinical symptoms, biochemical parameters, and microbial profiles of the gut and circulating microbiota, in a total of 40 patients with CKD stages G3-G5 and constipation, randomized 1:1 to constipation treatment (with lactulose) vs. control (with no treatment except bisacodyl rescue therapy). Consistent with the objectives of the small R01 mechanism, this small, short-term pilot feasibility trial allows us to acquire preliminary data regarding the effects of constipation treatment on various aspects of patients with CKD and feasibility data related to recruitment, retention, and study conduct. Furthermore, the findings of this study will lay the foundation for our long-term goal to...