Enhancing Colorectal Cancer Treatment: The Role of Bifidobacterium in Modulating Gut Immunity and Mitigating Capecitabine‐Induced Toxicity

ABSTRACT Colorectal cancer (CRC) is the third leading cause of cancer‐related mortality globally and presents significant challenges in treatment and patient care. Capecitabine, a widely used prodrug of 5‐fluorouracil (5‐FU), offers targeted delivery with reduced systemic toxicity compared to traditional chemotherapies. However, capacitabine is associated with adverse effects, such as hand‐foot syndrome, gastrointestinal issues, and mucositis. Emerging evidence suggests that probiotics, particularly Bifidobacterium, play a pivotal role in gut microbiota modulation, promoting anti‐inflammatory cytokines and short‐chain fatty acids, such as butyrate, which possess both intestinal protective and anti‐cancer properties. In this review, we explored the potential of Bifidobacterium to improve chemotherapy outcomes by mitigating inflammation and enhancing mucosal immunity in CRC patients. Furthermore, we demonstrated in silico approaches, including molecular docking and protein–protein interaction analysis, for Bifidobacterium and Toll‐like receptor 2 (TLR‐2), a key mediator of intestinal immunity. Docking results revealed strong binding affinity, suggesting the activation of anti‐inflammatory pathways. Notably, this interaction enhanced IL‐10 production while reducing pro‐inflammatory cytokines, such as IL‐6 and TNF‐α, fostering gut homeostasis and mitigating chronic inflammation, a key driver of CRC progression. Therefore, future research should focus on personalized probiotics and validating their synergy with chemotherapy and immunotherapy to improve CRC treatment outcomes.