The food-derived metabolite trimethylamine and trimethylamine-N-oxide promote colorectal cancer progression via SREBF1

Colorectal cancer (CRC) is characterised by microbial dysbiosis. Trimethylamine (TMA) and trimethylamine-N-oxide (TMAO) are gut microbiota-derived metabolites produced from dietary precursors that are implicated in CRC progression. However, the underlying mechanisms by which TMA or TMAO affect CRC progression remain largely unexplored. Therefore, in this study, we aimed to investigate the effects of TMA and TMAO on CRC progression. The methods used included real-time PCR, western blotting, cell viability and migration assays, apoptosis analysis, single-cell RNA sequencing, and tumor xenograft models. We demonstrated that exposure to both TMA and TMAO promoted CRC cell proliferation. Notably, treatment with 1 μM TMA and 100 μM TMAO had the greatest effect on enhancing CRC cell invasion and migration, while also reducing apoptosis. Mechanistically, TMA and TMAO modulated the expression of sterol regulatory element-binding factor 1 (SREBF1) and activated the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signalling pathway, thereby contributing to CRC progression. In mouse subcutaneous tumour experiments, a high-TMAO diet accelerated CRC progression, leading to significantly larger tumour volumes than those in the control group. Collectively, these findings suggest a potential correlation between elevated serum TMAO levels and CRC progression. Notably, we provide the first evidence that TMA and TMAO promote CRC cell proliferation via activation of the PI3K/AKT signalling pathway, with SREBF1 serving as a key mediator of TMA- and TMAO-induced CRC proliferation. Reducing TMA and TMAO intake through dietary intervention and the use of SREBF1 inhibitors may delay CRC progression, offering considerable clinical potential for therapeutic applications.