Lactulose Improves Renal Function and Gut Microbiota in CKD Original paper

What was studied?

This original research study examined how lactulose improves renal function and gut microbiota dysbiosis and uremic toxin production in adenine-induced chronic kidney disease (CKD) and whether these microbiome shifts translate into measurable improvements in renal function. The investigators used a well-established adenine CKD model, where adenine metabolism produces 2,8-dihydroxyadenine crystals that accumulate in proximal tubules and drive tubulointerstitial injury. After CKD establishment, rats were transitioned to either standard chow or lactulose-supplemented diets (3.0 percent or 7.5 percent), enabling assessment of lactulose’s capacity to alter dysbiosis, reduce serum indoxyl sulfate (IS), p-cresyl sulfate (PCS), and trimethylamine-N-oxide (TMAO), and mitigate renal fibrosis. The study integrated classical nephrology outcomes (serum creatinine, BUN, fibrosis quantification) with microbiome composition profiling using T-RFLP and SCFA quantification, thus offering a translational view of lactulose as a microbiome-targeted intervention (MBTI).

Who was studied?

The study evaluated male Wistar/ST rats induced into CKD through 0.75 percent adenine feeding for three weeks, a model confirmed by marked increases in serum creatinine, BUN, IS, and extensive tubulointerstitial fibrosis documented in the histological micrographs on page 6. After CKD induction, 36 rats were randomized into three groups: control (normal diet), 3.0 percent lactulose, and 7.5 percent lactulose (n=12 per group). An additional normal cohort served as a healthy reference. Fecal and serum sampling occurred at baseline, post-adenine induction, and four weeks after dietary intervention, allowing temporal comparison of renal, metabolic, and microbiome changes. No animals exhibited diarrhea or constipation, supporting model stability.

Most important findings

Lactulose produced dose-dependent improvements in renal function, with both 3.0 percent and 7.5 percent diets lowering serum creatinine and BUN relative to controls, as shown in the plots on page 5. Serum IS, which increased 8.5-fold after adenine, rose further in controls but fell significantly in both lactulose groups by week 4, indicating suppression of indole-producing taxa. PCS levels, markedly elevated in CKD, were likewise reduced. TMAO also trended downward in the 7.5 percent group. These toxin reductions strongly correlated with improvements in creatinine and BUN (scatter plots, page 6).

Microbiota analyses demonstrated that lactulose reduced the relative abundance of Bacteroides and Clostridium cluster XI, both major producers of indole precursors of IS, while increasing Bifidobacterium and Lactobacillales, as shown in the taxa-specific bar graphs on page 10. These represent key beneficial taxa in a CKD microbiome signature and major microbial associations (MMAs) relevant to the suppression of uremic toxins. Despite no large shifts in total SCFA levels across groups, lactulose nonetheless promoted compositional rebalancing toward SCFA-associated genera. Kidney histology (page 8) demonstrated a substantial reduction in tubulointerstitial fibrosis in lactulose groups, consistent with the observed reduction of IS and PCS, which are known drivers of ROS-mediated fibrosis. Lactulose also improved oxidative stress markers, decreasing AOPPs and increasing thiol content and GSH/GSSG ratio.

Key implications

This study provides a mechanistic foundation for using lactulose as an MBTI for CKD, demonstrating dual activity: suppression of IS- and PCS-producing bacterial taxa and restoration of beneficial, SCFA-producing commensals such as Bifidobacterium. The improvement in renal biomarkers aligns with microbiome shifts that reduce indole production and uremic toxin burden. By preventing further tubulointerstitial fibrosis and improving oxidative stress profiles, lactulose addresses upstream drivers of CKD progression rather than only downstream symptoms. Importantly, the findings validate lactulose as an agent capable of reversing core elements of CKD dysbiosis and restoring metabolic homeostasis, supporting its use as a clinically actionable MBTI candidate for nephrology.

Citation

Sueyoshi M, Fukunaga M, Mei M, Nakajima A, Tanaka G, Murase T, et al. Effects of lactulose on renal function and gut microbiota in adenine-induced chronic kidney disease rats.Clin Exp Nephrol. 2019;23:908-919. doi:10.1007/s10157-019-01727-4.