The pathogenesis of type 2 diabetes is characterized by insulin resistance and a progressive decline in β-cell function. A key driver of this dysfunction is the loss of β-cell identity, which reduces functional β-cell mass and leads to inadequate insulin secretion. Periodontal pathogens have been implicated in promoting insulin resistance; however, their role in the transformation of β-cell identity remains poorly understood. This study aims to investigate the impact of periodontal pathogen Fusobacterium nucleatum (F. nucleatum) on β-cell identity maintenance and the underlying molecular mechanisms. Single-cell RNA sequencing (scRNA-seq) data from human pancreatic islets of nondiabetic (ND), prediabetic (Pre-T2D), and type 2 diabetes (T2D) donors were analyzed to assess changes in β-cell proportion, differentiation trajectory, and associated molecular pathways. The Single-cell Analysis of Host-Microbiome Interactions (SAHMI) method was used to detect F. nucleatum sequences in pancreatic islets. Pearson correlation analysis identified key genes associated with the action of F. nucleatum, followed by in vitro validation using a co-culture model of F. nucleatum and MIN6 cells to elucidate the underlying mechanisms. scRNA-seq analysis revealed a reduced proportion of β-cells and decreased expression of key β-cell identity-maintenance genes in the T2D group. The expression levels of transdifferentiation markers and β-cell disallowed genes were elevated, alongside a trend toward α-cell transdifferentiation. The NF-κB signaling pathway was significantly activated in the T2D group, accompanied by a significant increase in the SPP1 inflammatory signal, while the WNT pathway was markedly diminished. Integrated Pearson correlation and in vitro analyses identified the cell cycle regulator CDKN1C as a central mediator through which F. nucleatum promotes β-cell identity loss. Mechanistically, F. nucleatum activated the NF-κB pathway, leading to downregulation of CDKN1C expression and thereby promoting loss of β-cell identity, which played an important role in the progression of diabetes associated with periodontitis. This study demonstrates that β-cells in T2D primarily undergo transdifferentiation towards α-cells, and the periodontal pathogen F. nucleatum promotes β-cell identity loss via NF-κB-mediated downregulation of CDKN1C.
Wei et al. (Mon,) studied this question.