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

Functional constipation is an independent predictor of all-cause mortality in patients with CKD.

• Hazard ratio for all-cause mortality: HR 1.33 (95% CI: 1.11–1.58)
• Analysis used weighted Cox proportional hazards models in a large U.S. database with mortality data up to 31 December 2019
• The association remained robust across sensitivity analyses
• Constipation also predicted cardiovascular mortality independently

The relationship between stool frequency and mortality in CKD patients follows a distinct U-shaped dose-response curve.

• This dose-response relationship was identified in the observational cohort analysis
• Both very low and very high stool frequencies were associated with increased mortality risk
• The pattern was identified using weighted Cox proportional hazards models in the large U.S. database

Mendelian randomization identified a significant causal depletion of the gut bacterial genus Herbidospora driven by constipation.

• Causal inference was conducted using genetic data from the independent FINRISK cohort
• The direct causal effect of constipation on CKD itself was not statistically significant
• Constipation was found to causally reduce levels of the genus Herbidospora
• Herbidospora was identified as exerting a protective effect against CKD

Phosphatidylcholine (14:0_18:2) [PC 14:0_18:2] mediates 12.5% of the protective pathway from Herbidospora to CKD.

• Mediation analysis was used to quantify the contribution of PC (14:0_18:2) to the Herbidospora–CKD protective pathway
• PC (14:0_18:2) was identified as a key metabolic intermediary in the gut-lipid-kidney axis
• The mediation proportion was 12.5% of the total protective effect of Herbidospora on CKD
• This finding was derived from multi-omics triangulation combining microbiome and metabolomics data

A multi-cohort, multi-omics triangulation design was employed to investigate the constipation–CKD–mortality relationship.

• The study used a large U.S. database for the observational mortality analysis and the FINRISK cohort for Mendelian randomization causal inference
• Genetic data from FINRISK were used to investigate causal relationships between gut microbiota, their metabolites, and CKD
• The design combined observational epidemiology, Mendelian randomization, and mediation analysis
• The approach was intended to provide evidence triangulation across independent cohorts and methodologies

The authors propose restoring the gut-lipid-kidney microbial metabolic axis as a novel therapeutic strategy for CKD.

• Proposed strategies include therapies aimed at restoring gut health and supplementing PC (14:0_18:2)
• The therapeutic rationale is based on the identified Herbidospora–PC(14:0_18:2)–kidney protective pathway
• The authors suggest this axis could slow disease progression and improve survival in CKD patients
• This recommendation is framed as a 'groundbreaking new strategy' based on the multi-omics findings