The Gut Microbiome in Gastrointestinal Cancer: Unravelling the Hidden Drivers of Tumorigenesis and Therapeutic Response

Gastrointestinal (GI) cancers represent 26% of all cancer cases worldwide and are responsible for 35% of cancer deaths. These types of cancer have significant clinical challenges due to late detection and treatment resistance. The gut microbiome is a complex and adaptable ecosystem crucial for metabolism, intestinal barrier maintenance, and immune function, and establishes a strong two-way interaction within the host. Tumors affect both local and systemic microbial environments, and dysbiosis, an imbalance in microbiota, contributes to cancer development, immune evasion, and progression across different GI regions. In upper GI malignancies, microbial species such as Fusobacterium nucleatum and Porphyromonas gingivalis promote chronic inflammation, while gastric carcinogenesis develops from Helicobacter pylori-induced atrophy through secondary colonization by bacteria such as Streptococcus anginosus. In hepatopancreatobiliary and colorectal cancers, barrier disruption allows bacteria and lipopolysaccharides to translocate, disrupts bile acid metabolism, and causes genotoxic damage through agents like colibactin. These are just a few examples covered in this review. We covered a comprehensive and up to date overview of the major gut microbial communities associated with GI cancers and their role in oncogenesis. Additionally, the gut-derived microbial communities play an active role in cancer treatment outcomes. The microbiome influences patient responses to and side effects of chemotherapy, radiotherapy, and immune checkpoint blockades through drug metabolism, modulation of mucosal injury, and immune remodeling. Strategies like prebiotics, probiotics, and fecal microbiota transplantation (FMT) offer promising approaches to reduce treatment-related toxicities and overcome therapeutic resistance. These strategies are under active evaluation to address therapeutic resistance and reduce toxicity, highlighting the potential of microbiome-directed cancer medicine.