Gut-Kidney-Brain Axis Emerges as Mechanistic Framework for Excessive Daytime Sleepiness in Parkinson Disease and Chronic Kidney Disease

A review recently published in Frontiers in Aging Neuroscience proposed that the gut-kidney-brain axis can be a unifying pathophysiological framework for excessive daytime sleepiness (EDS) in patients with comorbid Parkinson disease (PD) and chronic kidney disease (CKD).¹

Drawing on data encompassing more than 15,000 participants, the authors argued that gut microbial dysbiosis, uremic toxin accumulation, and blood-brain barrier (BBB) disruption converge to drive EDS through neuroinflammatory, metabolic, and neurotransmitter-mediated pathways. Although the study identified potentially actionable therapeutic targets, including specific probiotic strains and a BBB permeability-based stratification index, significant heterogeneity in the underlying evidence base and a preponderance of preclinical data warrant measured clinical interpretation.

EDS affects the vast majority of patients with PD and represents one of the most functionally impairing nonmotor symptoms of the disease. Its co-occurrence with CKD, which the review estimates affects 40% to 60% of patients with PD, creates a complex clinical scenario that current treatment guidelines do not adequately address.² The current review aimed to fill this gap by synthesizing the mechanistic and interventional literature through the lens of gut-kidney-brain axis dysregulation, an area of growing but still maturing evidence.

Study Overview

Co-led by Canmin Zhu, MD, neurologist at The First People's Hospital of Jiangxia District in China, the study conducted a systematic search of PubMed, Embase, Cochrane Library, Web of Science, and Scopus for studies published between January 2000 and December 2025. The final synthesis included 68 studies, comprising 23 randomized controlled trials (RCTs), 26 observational cohort studies, and 19 qualitative or other study designs, with a total of 15,392 participants.

This study’s patient population carried diagnoses of PD, CKD, or both. Primary end points centered on changes in Epworth Sleepiness Scale (ESS) scores. A random-effects model was applied for quantitative synthesis where methodological conditions permitted; a narrative approach was used for the remainder. Risk of bias was assessed using adapted Cochrane tools, and evidence quality was graded using the GRADE framework.

Key Findings

The most clinically prominent quantitative finding was the association between probiotic supplementation, specifically Clostridium butyricum and Bifidobacterium triple-strain formulations, and a mean reduction in ESS scores of 8.2 points (95% CI: 7.1–9.3; I2 = 65%).¹ On the 24-point ESS, this magnitude of reduction would represent a clinically meaningful shift; however, the heterogeneity statistic of 65% exceeded the threshold the authors themselves set for pooled quantitative analysis (I2 < 50%), raising questions about the interpretability of the pooled estimate.

READ MORE: Solriamfetol Shows No Significant Impact on Nocturnal Sleep Parameters in OSA-Related Excessive Daytime Sleepiness

The review also highlighted a biomarker-guided approach centered on the Blood-Brain Barrier Permeability Index (BBPI), measured via dynamic contrast-enhanced MRI using the transfer constant Ktrans. A Ktrans threshold greater than 0.028 min⁻¹ was associated with a 3.2-fold higher odds of cognitive decline in patients with PD (OR = 3.2, 95% CI: 1.9–5.4).¹ A BBPI-stratified intervention algorithm, directing low-risk patients toward lifestyle modification, intermediate-risk patients toward adjunctive pharmacotherapy, and high-risk patients toward combinatorial regimens, was associated with 68.9% achieving BBPI normalization in a single-center pilot context.

A combination regimen of celecoxib plus probiotics demonstrated a 73.5% ESS improvement rate compared with 41.2% in controls in small RCT data; the mean between-group difference of 32.3 percentage points was statistically significant but derived from a limited, single-center study population. Microglial activation inhibition was separately associated with a 38% reduction in Pittsburgh Sleep Quality Index scores (95% CI: 29–47%; P <.01) across included studies. Safety concerns were also noted including the combination of celecoxib and probiotics carrying renal toxicity risk in patients with CKD, a population with inherently limited pharmacological tolerability.

Interpretation

This review's conceptual contribution, framing gut-kidney-brain axis dysregulation as a mechanistic hub in PD-CKD comorbidity, is clinically compelling and addresses a genuine gap. The proposed BBPI-guided stratification model, if validated, could offer neurologists a practical framework for personalizing non-motor symptom management in this population. However, the preponderance of evidence underpinning the model is preclinical or derived from small, single-center human studies, and the overall GRADE certainty for primary outcomes was rated as moderate at best, with mechanistic and operational metrics rated low.

Clinicians should note that the 8.2-point ESS reduction attributed to probiotics, whereas numerically large, emerges from a heterogeneous pool of studies and does not yet have the multicenter RCT confirmation necessary to inform prescribing decisions. The BBPI threshold of Ktrans > 0.028 min⁻¹ was derived from a single-center cohort of 89 patients and requires external validation before it can be recommended as a clinical decision tool.

Limitations

The review carries several important limitations that the authors acknowledge. Blinding was rated at high risk of bias in 67% of included studies. Study sample sizes were predominantly small (20–100 participants), and most were conducted at single centers, limiting generalizability. The heavy reliance on animal models, particularly for mechanistic claims, introduces a translational gap that the authors themselves caution against minimizing. Individual study heterogeneity in patient populations, gut microbiota composition, and CKD staging further complicates pooled interpretation.

Future Research

The authors call for large-scale multicenter RCTs to validate BBPI thresholds across diverse patient populations and disease stages, and for the development of standardized biomarker quantification protocols for clinical deployment. Integration of multi-omics approaches, including microbiota profiling, cerebrospinal fluid biomarkers, and neuroimaging, are proposed as a path toward precision intervention frameworks. Emerging therapeutic candidates highlighted include miR-21 antagonists targeting BBB tight junction preservation, nanoparticle-based CNS drug delivery systems, and gene therapies directed at GBA and LRRK2 mutations associated with genetic PD subtypes.⁵ AI-driven predictive analytics for therapeutic optimization in PD-depression and related comorbidities are also noted as an area of active investigation.

REFERENCES
1. Yang S, Zhu C, Xiong S, et al. Gut-kidney-brain axis and daytime sleepiness in Parkinson's disease and chronic kidney disease: an expert narrative review. Front Aging Neurosci. 2026;17:1728664. doi:10.3389/fnagi.2025.1728664
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3. Minibajeva O, Zeltina E, Karelis G, Kurjane N, Kenina V. Clinical symptoms influencing Parkinson's patients' quality of life in Latvia: a single-center cohort study. Medicina. 2023;59:935. doi:10.3390/medicina59050935
4. Schreiner SJ, Werth E, Ballmer L, et al. Sleep spindle and slow wave activity in Parkinson disease with excessive daytime sleepiness. Sleep. 2023;46:zsac165. doi:10.1093/sleep/zsac165
5. Schneider SA, Alcalay RN. Precision medicine in Parkinson's disease: emerging treatments for genetic Parkinson's disease. J Neurol. 2020;267:860-869. doi:10.1007/s00415-020-09705-7