Size-dependent transcriptomic heterogeneity and microbial dysbiosis in Peutz-Jeghers syndrome colorectal polyps: An exploratory self-controlled multi-omics analysis

BACKGROUNDIn patients with Peutz-Jeghers syndrome (PJS), larger colorectal polyps carry a higher risk of malignant transformation.However, the molecular changes that occur with lesion growth remain poorly understood. AIMTo investigate the transcriptomic and microbial differences in polyps of varying size and normal tissues from a single PJS patient. METHODSWe performed RNA sequencing on three representative polyps of different sizes (small, medium, and large) and three matched normal mucosal tissue samples.For microbiome profiling, we conducted 16S rRNA gene sequencing on the five available polyps and the same three normal tissue samples.We then examined host-microbiome interactions through differential gene expression, functional enrichment, and multi-omics correlation network analyses. RESULTSIn this patient, transcriptional dysregulation intensified with increasing polyp size.All polyps shared 107 core differentially expressed genes, with disrupted cell adhesion and metabolic reprogramming.Large polyps displayed a complex expression pattern with downregulation of most genes (719 downregulated vs 145 upregulated) but selective enrichment of specific immune-inflammatory pathways, including the nuclear factor kappa B, B-cell receptor, and immunoglobulin A-mediated pathways.The microbiota profiles of small and medium polyps were similar, whereas those of large polyps were distinct.4 / 35 CONCLUSION Our preliminary data reveal size-dependent heterogeneity among polyps in a patient with PJS.Small lesions displayed metabolic shifts, while large polyps showed transcriptional repression, immune activation, and dysbiosis.Further validation in a cohort of PJS patients is needed.