Gut Microbiome Signatures in iNPH: Insights from a Shotgun Metagenomics Study

Idiopathic normal pressure hydrocephalus (iNPH), a leading cause of reversible dementia in older adults, is marked by ventriculomegaly, gait disturbances, cognitive decline, and urinary incontinence. Emerging evidence suggests that gut dysbiosis (microbial imbalance) may influence neuroinflammation and cerebrospinal fluid dynamics, potentially contributing to glymphatic system dysfunction and ventricular enlargement. This study used shotgun metagenomics to analyze the gut microbiome in iNPH patients (n=18) compared to healthy controls (n=50), individuals with ventriculomegaly but no iNPH symptoms (n=50), and Alzheimer's disease patients (n=50). Microbiome analysis revealed an enrichment of species previously described as associated with multiple disease states, such as Enterocloster bolteae and Ruminococcus gnavus, indicating general dysbiosis. In contrast, enrichment of specific taxa, including Evtepia gabavorous and Cuneatibacter sp., correlated uniquely with iNPH clinical traits, suggesting potential disease-specific microbial markers. Functional analysis showed enrichment of pathways related to carbohydrate and amino acid metabolism, including the S-adenosyl-L-methionine superpathway, implicating inflammatory and immune processes. The findings provide new insights into distinct gut microbiome signatures in iNPH and show potential gut-brain interactions that may contribute to the disorder's pathophysiology, thus identifying possible targets for future therapeutic strategies.