Butyrate and probiotic metabolites counteract colorectal cancer progression: insights into β-catenin pathway, autophagy and immune crosstalk

Genetic alterations in the WNT/β-Catenin pathway play a pivotal role in colorectal cancer (CRC) development, leading to β-Catenin accumulation and nuclear translocation, which drives tumor proliferation and migration. The gut microbiota has emerged as a key player in CRC progression, with dysbiosis creating a pro-inflammatory environment and metabolic disruptions that impact autophagy, a crucial process for intestinal homeostasis that is often deregulated in cancer. Here, we investigate the molecular mechanisms underlying the anti-proliferative effects of butyrate, a microbiota-derived short-chain fatty acid, with a specific focus on autophagy. Butyrate inhibits proliferation by inducing autophagy-mediated degradation of β-Catenin. To establish translational relevance, we further assess the ability of the probiotic strain Lactiplantibacillus plantarum OC01 to inhibit CRC progression. Our findings highlight the functional role of autophagy in mediating the protective and anticancer effects of probiotic metabolites. This suggests that probiotic-based strategies enhancing autophagy could serve as promising adjuvant therapies, particularly for CRC patients harboring WNT pathway mutations. Given the critical role of tumor-associated macrophages (TAMs) in shaping the tumor microenvironment (TME), we also evaluate the impact of L. plantarum OC01 metabolites on macrophage polarization, and how it influences cancer cell proliferation and migration. Our results demonstrate that L. plantarum OC01 metabolites can modulate the TME, shifting TAMs toward a more inflammatory and anti-tumoral phenotype. Overall, our study point out the therapeutic potential of microbiota-derived metabolites in CRC management. By targeting key pathways such as WNT/β-Catenin and reshaping the TME, butyrate and probiotics emerge as promising candidates for novel CRC treatment strategies.