Organelle-specific mechanisms and AI-guided stratification in gut-renal-vascular axis modulation

Gut-derived uremic toxins, notably indoxyl sulfate (IS), p-cresyl sulfate (PCS), and trimethylamine N-oxide (TMAO), contribute to multi-organ damage via the gut-renal-vascular axis, exacerbating chronic kidney disease (CKD) and cardiovascular pathologies. The global CKD prevalence exceeds 850 million, yet the evidence remains fragmented. Consequently, this fragmentation highlights a gap in developing integrated, mechanism-targeted strategies.

This narrative review proposes an integrative framework linking subcellular organelle damage to metabolite-driven epigenetic reprogramming within the gut-renal-vascular axis. We synthesize current evidence not as a definitive efficacy assessment, but to construct and substantiate a novel paradigm for precision stratification and intervention, highlighting the gut-derived metabolites IS, PCS, and TMAO as archetypes of this multi-scale pathophysiology.

A structured literature search of PubMed, Cochrane Library, Embase, Web of Science, and ClinicalTrials.gov (inception to May 2025) was conducted. Forty-eight studies were included for thematic synthesis. To enhance transparency, a documented study selection process was followed. Tools for risk-of-bias assessment were used descriptively to contextualize the evidence, acknowledging the interpretive nature of a narrative synthesis.

The synthesis included 48 studies, encompassing approximately 15,000 participants. A descriptive summary of a subset of interventional studies suggests that some interventions may be associated with reduced composite outcome risks (e.g., one trial reported a risk ratio of 0.85). These findings indicate substantial heterogeneity in study designs and populations. Mechanistic literature frequently implicates the attenuation of NLRP3 inflammasome activation and epigenetic reprogramming as potential pathways underlying intervention effects.

This narrative review discusses evidence suggesting that precision-guided combined interventions may represent a potential strategy for mitigating multi-organ damage in CKM cohorts. However, the significant heterogeneity across studies necessitates a cautious, individualized approach when interpreting this evidence for clinical practice.