Multi-omics analysis of gut microbiota and gene expression reveals that TBK1 promotes colorectal tumorigenesis by activating glycolysis.

Abstract

Colorectal cancer (CRC) is a prevalent malignancy with intricate connections to gut microbiota (GM) dysbiosis, though the specific mechanisms linking microbiota-induced gene expression changes to CRC progression remain unclear. This study employed a multi-omics approach to investigate the interplay between GM alterations and host gene expression in CRC. C57BL/6J male mice were used to establish CRC models via dextran sulfate sodium (DSS)/azoxymethane (AOM) induction. 16S rRNA sequencing was performed to characterize GM changes in CRC mouse models, revealing dysbiosis characterized by reduced Akkermansia muciniphila (Akkermansia) and elevated Desulfovibrio desulfuricans (Desulfovibrio) abundance. Transcriptomic analysis following microbiota transplantation identified significant upregulation of TANK-binding kinase 1 (TBK1) in CRC-associated microbiota recipients. In vitro experiments utilizing CRC cell models demonstrated that TBK1 overexpression activated glycolysis, as evidenced by increased extracellular acidification rate, lactate production, and elevated expression of glycolytic enzymes hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1). Functionally, TBK1 promoted cell proliferation and colony formation while inhibiting apoptosis, which were attenuated by the glycolytic inhibitor 2-deoxy-D-glucose. These findings establish TBK1 as a critical mediator linking GM dysbiosis to metabolic reprogramming in CRC, suggesting that targeting the TBK1-glycolysis axis may represent a promising therapeutic strategy for delaying CRC progression.