Lactobacillus johnsonii Synthesizes Chenodeoxycholic Acid to Reduce Susceptibility to High-Fat Diet-Induced Colorectal Cancer

High-fat diet (HFD) is positively correlated with colorectal cancer (CRC), but there are notable inter-individual differences in susceptibility to the tumor-promoting effects of HFD. A better understanding of the mechanisms that modulate the outcomes of HFD could help inform precision prevention strategies for CRC. Here, we found a key role for the gut microbiota in the individual differences observed in the tumor-promoting effects of HFD. Analysis of the gut bacteria enriched in mice resistant to HFD-induced cancer identified Lactobacillus johnsonii (L. johnsonii) as an effective protector. Colonization of L. johnsonii increased intestinal chenodeoxycholic acid (CDCA) concentrations in HFD-exposed mice, which decelerated HFD-induced CRC progression. Mechanistically, L. johnsonii converted conjugated bile acid to CDCA via bile salt hydrolase (BSH), and CDCA induced mitochondrial dysfunction and oxidative stress to promote apoptosis, effectively suppressing tumor development. These results establish the gut microbiota as a mediator of inter-individual differences in cancer susceptibility induced by HFD and reveal a probiotic strategy with the ability to inhibit tumorigenesis, suggesting a possible route to reduce HFD-induced CRC progression.