New hypothesis: a gut-lipid-kidney axis in constipated CKD patients-insights from multi-omics triangulation

Patients with chronic kidney disease (CKD) frequently experience constipation, often linked to gut microbiota disruptions. We hypothesized that constipation is not merely a comorbidity but a driver of adverse outcomes through a specific host-microbial metabolic axis. Employing a multi-cohort design for evidence triangulation, we first employed a large U.S. database and mortality data up to 31 December 2019 to investigate the association between constipation and overall mortality in patients with CKD using weighted Cox proportional hazards models. To explore potential microbial and metabolic mechanisms that could underlie such clinical observations, we then used genetic data from the independent FINRISK cohort to investigate causal relationships between specific gut microbiota, their metabolites, and CKD. In the observational cohort, we identified functional constipation as a potent, independent predictor of both all-cause (HR: 1.33; 95% CI: 1.11-1.58) and cardiovascular mortality. This association remained robust across sensitivity analyses and showed a distinct U-shaped dose-response relationship with stool frequency. In the causal inference phase, while the direct causal effect of constipation on CKD was not significant, MR identified a significant causal depletion of the genus Herbidospora driven by constipation. Further analyses revealed that Herbidospora exerts a protective effect against CKD. Crucially, mediation analysis demonstrated that phosphatidylcholine (14:0_18:2) [PC 14:0_18:2] metabolites mediate 12.5% of the protective pathway from Herbidospora to CKD. Constipation is a key and independent predictor of mortality in patients with CKD. We found that constipation leads to a reduction in the number of Herbidospora, thereby disrupting the protective function of the kidney. This is because PC (14:0_18:2) is lacking. This study emphasizes the importance of restoring this microbial metabolic axis as a novel therapeutic strategy for CKD.IMPORTANCEFor millions living with chronic kidney disease (CKD), a common issue such as constipation can be a hidden danger, increasing their mortality risk by over one-third. Our research uncovers why: an unhealthy gut, often indicated by constipation, lacks specific "good"" bacteria essential for producing a protective fat molecule. This natural molecule acts as a key, activating the kidney's own defense and repair systems. This discovery of a "gut-lipid-kidney" connection offers a groundbreaking new strategy: therapies aimed at restoring gut health and supplementing this key protective fat could provide a powerful new way to slow disease progression and improve survival in CKD patients.