Constipation Drug Shows Promise in Preserving Kidney Function, Study Finds
A commonly used medication for constipation, lubiprostone, may offer a surprising benefit for individuals with chronic kidney disease: the preservation of kidney function. New research published in Science Advances suggests the drug works not by directly reducing toxins, but by reshaping the gut microbiome and boosting mitochondrial health.
Chronic kidney disease (CKD) affects millions worldwide, and often co-occurs with constipation. This new study offers a potential avenue for treatment that goes beyond simply alleviating gastrointestinal discomfort. “These findings suggest lubiprostone’s kidney effect tracks with a microbiome–polyamine–mitochondrial axis rather than reductions in gut-derived uremic toxins,” researchers noted.
Unveiling the Gut-Kidney Connection
Patients with CKD often experience dysbiosis – an imbalance in gut bacteria – alongside impaired intestinal barrier function and a buildup of harmful uremic toxins like indoxyl sulfate and p-cresyl sulfate. These factors contribute to a decline in estimated glomerular filtration rate (eGFR), a key measure of kidney function, and increase the risk of cardiovascular problems. The study aimed to determine if modulating gut function, independent of laxative effects, could help protect the kidneys.
Phase 2 Trial Design and Key Findings
The multicenter, randomized, double-blind, placebo-controlled phase 2 trial, conducted at nine Japanese hospitals, involved 118 adults with stage IIIb–IV CKD. Participants received either 8 μg/day of lubiprostone, 16 μg/day of lubiprostone, or a placebo for 24 weeks. While the primary endpoint – change in indoxyl sulfate levels – wasn’t significantly affected by lubiprostone, encouraging signals emerged regarding renal function.
Specifically, the 16 μg/day dose of lubiprostone was associated with an increase in eGFR from creatinine (a 1.92 ml/min/1.73 m² difference versus placebo; P=0.046) and preservation of its slope over the 24-week period. Blood urea nitrogen levels also decreased in the 16 μg/day group. Notably, creatinine levels remained stable throughout the trial.
The Role of the Microbiome and Mitochondrial Health
Researchers employed multiomics – integrating metabolomics, 16S ribosomal ribonucleic acid (RNA) sequencing, and shotgun metagenomics – to delve into the underlying mechanisms. The analysis revealed that lubiprostone was associated with increases in gut bacteria that produce short-chain fatty acids (Blautia, Roseburia, Marvinbryantia) and pathways involved in agmatine deiminase production.
These changes coincided with shifts in fecal metabolites indicative of enhanced polyamine synthesis. In participants who responded well to the 16 μg/day dose, levels of spermidine rose in plasma, and beneficial bacteria like Akkermansia muciniphila expanded, while potentially harmful Bacteroides gallinarum declined.
Further mechanistic studies in mice demonstrated that oral spermidine improved creatinine levels, restored tubular area, and boosted mitochondrial function. Renal RNA sequencing confirmed that spermidine down-regulated inflammatory pathways and up-regulated genes related to mitochondrial recovery. .
Safety and Tolerability
Lubiprostone was generally well-tolerated. Adverse events were primarily gastrointestinal, with diarrhea reported in 12.1% of those receiving 8 μg/day and 16% of those receiving 16 μg/day. Discontinuation rates were similar across all groups, and no clinically significant electrolyte disturbances were observed.
Implications for CKD Treatment
These findings suggest that lubiprostone may offer renal benefits beyond constipation relief. The preservation of eGFR without fluid retention or weight gain supports a biological mechanism that could complement existing CKD treatments like angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and newer therapies. “For people living with CKD, even modest, sustained improvements in eGFR slope may potentially delay progression,” researchers stated, highlighting the potential clinical relevance of these changes.
However, larger, longer-term, and more diverse trials are needed to confirm these findings, determine optimal dosing, identify which patients are most likely to benefit, and compare lubiprostone to other constipation therapies.
Journal reference: Watanabe, S., Nakayama, M., Yokoo, T., Sanada, S., Ubara, Y., Komatsuda, A., Asanuma, K., Suzuki, Y., Konta, T., Kazama, J. J., Suzuki, T., Fukuda, S., Soga, T., Yamada, T., Mizutani, S., Matsumoto, M., Naito, Y., Taguchi, K., Fukami, K., Kashiwagi, H., Kikuchi, K., Suzuki, C., Tokuno, H., Urasato, M., Kujirai, R., Matsumoto, Y., Akiyama, Y., Tomioka, Y., Itai, S., Tongu, Y., Mishima, E., Kawabe, C., Kasahara, T., Ogata, Y., Toyohara, T., Sato, T., Tanaka, T., & Abe, T. (2025). Lubiprostone in chronic kidney disease: Insights into mitochondrial function and polyamines from a randomized phase 2 clinical trial. Sci. Adv. 11(35). DOI:10.1126/sciadv.adw3934, https://www.science.org/doi/10.1126/sciadv.adw3934
