Men demonstrate higher incidence and mortality rates of colorectal cancer (CRC) than women. This study aims to explain the potential causes of such sexual dimorphism in CRC from the perspective of sex‐biased gut microbiota and metabolites. The results show that sexual dimorphism in colorectal tumorigenesis is observed in both Apc^Min/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)‐treated mice with male mice have significantly larger and more tumors, accompanied by more impaired gut barrier function. Moreover, pseudo‐germ mice receiving fecal samples from male mice or patients show more severe intestinal barrier damage and higher level of inflammation. A significant change in gut microbiota composition is found with increased pathogenic bacteria Akkermansia muciniphila and deplets probiotic Parabacteroides goldsteinii in both male mice and pseudo‐germ mice receiving fecal sample from male mice. Sex‐biased gut metabolites in pseudo‐germ mice receiving fecal sample from CRC patients or CRC mice contribute to sex dimorphism in CRC tumorigenesis through glycerophospholipids metabolism pathway. Sexual dimorphism in tumorigenesis of CRC mouse models. In conclusion, the sex‐biased gut microbiome and metabolites contribute to sexual dimorphism in CRC. Modulating sex‐biased gut microbiota and metabolites could be a potential sex‐targeting therapeutic strategy of CRC.

During colorectal cancer (CRC) progression, probiotics support gut microbial balance, enhance intestinal barrier integrity, and exert antioxidant and anti‐inflammatory effects. Such supplementation may slow tumor growth and serve as an adjunctive therapy for CRC. In this study, we evaluated the impact of Lactobacillus johnsonii ‐FM1 in Apc ^Min/+ and azoxymethane/dextran sulfate sodium‐induced CRC mouse models. Our results demonstrate that L. johnsonii ‐FM1 markedly reduces tumor number, size, and volume in both models. Shotgun metagenomic sequencing showed that L. johnsonii ‐FM1 increases the abundance of potentially beneficial taxa while decreasing opportunistic pathogens, thereby preserving gut barrier function. Moreover, untargeted metabolomics paired with liquid chromatography‐tandem mass spectrometry identified vanillic acid (VCA) as a key bioactive metabolite produced by L. johnsonii ‐FM1. In vitro, VCA inhibits CRC cell line proliferation, diminishes colony formation, induces cell‐cycle arrest, and promotes apoptosis. Mechanistically, VCA attenuates CRC progression by suppressing Wnt/β‐catenin signaling. Our findings suggest a promising probiotic‐based adjunctive strategy for CRC prevention and treatment.

Healthy ageing GWAS meta-analysis. GWAS results from Singapore Chinese subjects. Data includes chr, rsid, pos, allele_a, allele_b (test allele), p_value, beta and se. P_value, beta and se were from meta-analysis.