• Engineering Probiotics: A Promising Strategy for Modulating Colorectal Cancer Through Balancing the Microbiome
  • Sahar Hemati,1 Mehran Mahooti,2 Davood Zare,3,*
    1. Department of Biology, Islamshahr Branch, Islamic Azad University, Islamshahr, Iran
    2. Department of Biotechnology, Iranian Research Organization for Science and Technology, Tehran, P. O. Box 3353-5111, Iran
    3. Department of Biotechnology, Iranian Research Organization for Science and Technology, Tehran, P. O. Box 3353-5111, Iran


  • Introduction: Colorectal cancer (CRC) is third in incidence and second in cancer-related deaths globally, making it one of the most prevalent and fatal cancers (Cheng et al., 2024; Gonzalez-Gutierrez et al., 2024). CRC develops when specific alterations in intestinal epithelial cells result in the growth of malignant tumors (Pandey & Bhattacharyya, 2024). The colon microbiota, a diverse ecosystem of bacteria, fungi, and viruses, differs significantly in CRC patients compared to healthy individuals. Dysbiosis, characterized by compositional and functional changes along with the presence of pathogens and pathogenic microbial metabolites, contributes to the initiation and progression of CRC (Cheng et al., 2024; La Vecchia et al., 2024). Since stability in the gut microbiome is essential for health, interventions aimed at rebalancing the intestinal microbiota hold great promise for both the prevention and therapy of colorectal cancer (Fong et al., 2020). Probiotics help to prevent colon cancer and protect against carcinogenic infections by restoring gut flora equilibrium (Nair et al., 2024). Probiotic microorganisms exhibit immune-modulating and health-promoting properties by interacting with intestinal epithelial cells, stimulating immune responses, and reducing inflammatory reactions. These probiotics influence signaling pathways such as Wnt/β-catenin and IL-10, which modulat inflammation and promote immune tolerance, thus contributing to gut health. A 4-week clinical trial demonstrated that probiotics containing Lactobacillus and Bifidobacteria strains modulated the intestinal microenvironment and decreased proinflammatory cytokines in postoperative CRC patients (Han, Zhang, et al., 2024). Furthermore, advances in genetic engineering and synthetic biology have enabled the development of engineered probiotics with enhanced therapeutic effects through targeted genetic modifications. These engineered probiotics can specifically modulate biological functions in the gut microbiota, offering more effective treatments with fewer side effects and reduced costs compared to conventional therapies (Fong et al., 2020; Han, Zhang, et al., 2024). Overall, formulating and engineering probiotics stand out as promising adjuncts in colorectal cancer prevention and control through maintaining microbiome homeostasis, steering immune functions, and improving treatment efficacy.
  • Methods: In this review article, a comprehensive literature search was conducted across reputable databases including Google Scholar, PubMed, Scopus, and Nature to identify studies related to colorectal cancer (CRC), probiotics, gut microbiome, and engineered probiotics. Keywords relevant to these topics were used to ensure thorough coverage. After screening and removing duplicates and irrelevant studies, a total of 142 high-quality peer-reviewed articles with rigorous experimental designs were selected for detailed analysis. Data extraction concentrated on compiling current evidence regarding the interactions between the gut microbiota, probiotics, and CRC.
  • Results: A healthy gut microbiota is vital for intestinal function, whereas dysbiosis involving a loss of beneficial bacteria and rise of pathogens contributing to colorectal cancer development through sustained inflammation and generation of carcinogenic metabolites (Śliżewska et al., 2020). Advances in synthetic biology and genetic engineering have enabled the creation of engineered probiotics capable of modulating the gut microenvironment more precisely than traditional strains. These engineered microbes produce bioactive compounds that regulate key inflammatory pathways such as NF-κB, restore microbial homeostasis, and inhibit tumor progression (Arnold et al., 2023; Han et al., 2020). For instance, Escherichia coli Nissle 1917 has been genetically modified using CRISPR-Cas to enhance therapeutic gene expression and produce anti-cancer molecules like GABA and GLP-1 (Rahmati et al., 2025). In vitro and in vivo studies show that mixtures of Lactobacillus and Bifidobacterium strains suppress CRC cell proliferation, invasion, and migration, supporting their complementary use in CRC treatment (Shang et al., 2020). These findings highlight the potential of microbiome engineering as a targeted and personalized strategy for CRC management (Wang et al., 2024).
  • Conclusion: Colorectal cancer (CRC) remains a major global health threat. Although significant progress has been made, prevention and therapy still face hurdles. Probiotics have attracted interest as adjunct, low‑cost interventions by boosting beneficial Firmicutes, rebalancing the microbiome, and regulating inflammatory mediators like NF‑κB and IL‑10, thereby enhancing treatment results. Genetic modification of probiotics allows more precise targeting and immune stimulation, which may help lower the risk of cancer recurrence. Therefore, probiotics and their engineered strains not only restore the microbiome but also strengthen immunity and decrease the risk of CRC recurrence. However, comprehensive evaluation and deeper understanding of their biological mechanisms at different disease stages require further research.
  • Keywords: Colorectal cancer (CRC), Microbiota, Probiotics, Engineered probiotics