Dysbiosis and colorectal cancer: conducive factors, biological and molecular role, and therapeutic prospectives

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States. Emerging evidence highlights the significant role of gut microbiota dysbiosis, characterized by a reduction in beneficial bacteria and an increase in pro-inflammatory and pro-carcinogenic bacteria, in CRC pathogenesis. Both genetic and environmental factors, including diet, antibiotic use, physical activity, aging, and obesity, contribute to this microbial imbalance. Dysbiosis promotes chronic inflammation and immune dysregulation, which facilitates tumor initiation and progression. This review examines the intricate interactions between gut microbiota, immune modulation, and CRC development. It explores current and emerging therapeutic strategies that target the microbiome to enhance treatment efficacy, discusses interventions aimed at restoring healthy microbiota in CRC patients, and outlines future directions for microbiome-based therapies to improve clinical outcomes.

Keywords: Colorectal cancer; dysbiosis; immunomodulation; inflammation; intestinal microbiome; therapeutics.

Figure 1

Risk factors and pathophysiology of CRC. Gut microbiota dysbiosis, influenced by environmental and lifestyle factors, creates a favorable environment for CRC. The presence of risk factors, including diabetes, smoking, alcoholism, chronic inflammation, and others, leads to the alteration of the intestinal microbiota termed dysbiosis. Gut dysbiosis increases the secretion of proinflammatory cytokines such as IL-6 and TNF-α, expression of TLRs, and oxidative stress by increasing the production of ROS. This disrupts the intestinal barrier and increases the propensity for CRC. Further, the presence of polyps in the intestine also increases the risk of CRC. CRC: colorectal cancer; IL: interleukin; ROS: reactive oxygen species; TLRs: toll-like receptors; TNF: tumor necrosis factor. Created in BioRender. Rai, V. (2025) https://BioRender.com/it0zune

Figure 2

Intestinal immunity and microbiota in gut health. (A) The mucus layer forms the first line of defense in the GI tract to prevent microbial attachment to epithelial cells. (B) Antimicrobial peptides, including defensins, cathelicidins, and C-type lectins, secreted by Paneth cells and other epithelial cells, inhibit microbes. (C) Secretory IgA traps pathogens and toxins in the mucus. Polysaccharide A and butyrate from commensal bacteria promote Treg-mediated anti-inflammatory responses. (D) Pattern recognition receptors like TLRs and NLRs detect microbial-associated molecular patterns. This triggers the immune response pathway involving MyD88, TRIF, MAPK, and NFκB to protect intestinal cells. Activation of these pathways regulates immune responses and inflammation, and the acute immune response protects the intestinal epithelium. However, in the presence of chronic inflammation, this regulation is lost and results in IBD. AMPs: antimicrobial peptides; DAMP: damage-associated molecular pattern; GI: gastrointestinal; IBD: inflammatory bowel disease; IL: interleukin; LPS: lipopolysaccharide; MAPK: mitogen-activated protein kinases; MyD88: myeloid differentiation primary response 88; NLR: NOD-like receptor; PAMP: pathogen-associated molecular pattern; TGF-β: transforming growth factor beta; TLR: Toll-like receptor; Treg: regulatory T; TRIF: TIR-domain-containing adapter-inducing interferon-β. Created in BioRender. Rai, V. (2025) https://BioRender.com/e7t5oem

Figure 3

Molecular changes in intestinal dysbiosis contributing to IBD. Gut dysbiosis, an imbalance in the gut microbiota, significantly increases the risk of developing IBD, which is characterized by chronic inflammation in the gut. This imbalance can lead to a breakdown of the intestinal barrier, allowing harmful bacteria to penetrate the lining and trigger inflammation. Inflammation is mediated by increased recruitment of immune cells secreting pro-inflammatory cytokines. A decrease in anti-inflammatory cytokines and growth factors, an increase in oxidative stress, and activation of inflammatory mediators such as TLRs contribute to the chronicity of inflammation and the development of IBD. CRP: C-reactive protein; IBD: inflammatory bowel disease; IL: interleukin; MPO: myeloperoxidase; NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3; ROS: reactive oxygen species; TGF: transforming growth factor; TLRs: toll-like receptors; TNF: tumor necrosis factor; Treg: regulatory T. Created in BioRender. Rai, V. (2025) https://BioRender.com/lumhuep