Therapeutic potential of fecal microbiota transplantation in colorectal cancer based on gut microbiota regulation: from pathogenesis to efficacy

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide, with its progression intricately linked to gut microbiota dysbiosis. Disruptions in microbial homeostasis contribute to tumor initiation, immune suppression, and inflammation, establishing the microbiota as a key therapeutic target. Fecal microbiota transplantation (FMT) has emerged as a transformative approach to restore microbial balance, enhance immune responses, and reshape the tumor microenvironment. This review explores the mechanisms underlying FMT's therapeutic potential, evaluates its advantages over other microbiota-based interventions, and addresses challenges such as donor selection, safety concerns, and treatment standardization. Looking forward, the integration of FMT into personalized CRC therapies requires robust clinical trials and the identification of predictive biomarkers to optimize its efficacy and safety.

Keywords: colorectal cancer; fecal microbiota transplantation; gut microbiome; microbiota–gut–brain.

Figure 1.

A schematic representation of the intestinal barrier. The intestinal barrier includes a microbial barrier, a mechanical barrier, and an immune barrier, and plays a significant role in regulating the gut microbiota. The microbial barrier exists in a mucous layer acting as a scaffold, including Escherichia coli, Helicobacter pylori, and Fusobacterium nucleatum, to name a few. The mechanical barrier is made up of a single layer of intestinal epithelial cells that is sealed by tight junctions, the cells of which include stem cells (ISCs), progenitor cells (TA cells), and specialized cells (enterocytes, M cells, goblet cells, Paneth cells, enteroendocrine cells, and tuft cells). Immune cells in the lamina propria constitute the immune barrier and support the gut barrier by helping to maintain the host–microbiota interface. Source: Created with figdraw.com.

Figure 2.

Several groups of intestinal bacteria with carcinogenic effects. (a) Escherichia coli. Escherichia coli is a genotoxic substance produced by strains of E. coli carrying the pathogenicity island polyketide synthase (pks+). Its pathogenic mechanism is to cross-link DNA and induce DNA ds breaks, leading to DNA damage in colonic epithelial cells and tumor induction. (b) Campylobacter jejuni. Campylobacter jejuni produces CDT, genotoxins that also cause DNA ds breaks. (c) Bacteroides fragilis. ETBF treatment of colorectal cancer cells promoted Th17 cell differentiation by down-regulating miR-149-3p in exosomes in vitro and in vivo, which was dependent on METTL14-mediated m6A methylation. ETBF down-regulation of miR-149-3p and further promotion of PHF5A-mediated RNA variable shearing of KAT2A ultimately induced colorectal carcinogenesis. Source: Created with figdraw.com. ds, double-strand; ETBF, enterotoxigenic Bacteroides fragilis; METTL14, RNA methyltransferase 14.

Figure 3.

Mechanisms of microbiota disruption leading to an inflammatory environment. (1) The NF-κB heterodimer is usually composed of the p50 and p65 subunits. It is present in the cytoplasm and is inactivated by the inhibitory molecule IkBα. The IkB protein is activated when a specific IKK acts on the IkB protein. This causes NF-κB to translocate to the nucleus and initiate transcription of the target gene. (2) JAK/STAT signaling pathway. Cytokine binding induces receptor dimerization. Upon ligand binding, JAKs are activated and phosphorylate each other, then recruit, bind, and phosphorylate STATs in the cytoplasm, which are then dimerized and transported to the nucleus. The dimerized STATs bind directly to DNA, altering chromatin structure and inducing gene expression of inflammatory mediators. (3) MAPK signaling pathway. The pathway of MAPK consists of MAPK kinase (MKKK), MAPK kinase (MKK), and MAPK, that is, the MAP3K-MAP2K-MAPK chain. These three kinases can be activated sequentially to transmit signals from upstream to downstream. Of the four MAPK signaling pathways, those associated with inflammation, apoptosis, and growth are JNK and p38. (4) PIK3CA/AKT/mTOR signaling pathway. AKT is activated by phosphorylation of PDK1 and also by the RAS/MAPK pathway. On the cell surface, members of the tyrosine kinase receptor activate intracellular cofactors that regulate the PIK3 pathway. MAPK interacts with transcription factors in the nucleus, thereby affecting gene expression. Source: Created with figdraw.com. IKK, IkB kinase.

Figure 4.

Bidirectional lines of communication between the microbiota, gut, and brain primarily involve neural, endocrine, and immune pathways. When gut microbes are out of balance, a wide range of microbial products including metabolites, neurotransmitters, and cytokines, including 5-HT, SCAF, and GABA, enter the brain through the bloodstream. The unidirectional and bidirectional movement of metabolites in the gut and brain or distal organs in direct press constitutes a co-metabolic interaction. Source: Created with figdraw.com.

Figure 5.

The main path of the operation of fecal bacteria transplantation is (1) through the introduction of enteroscopy to the end of the small intestine where the immune tissues and cells are particularly high, put the bacteria liquid; (2) through the upper digestive tract, to reach the jejunum nutrient tube or nasojejunostomy tubes; and (3) an enema, but the enema can only be enrolled in a small section. Currently, many companies are also trying to do fecal bacteria capsules. Source: Created with figdraw.com.