Gut dysbiosis in cancer immunotherapy: microbiota-mediated resistance and emerging treatments

Abstract

Cancer is a multifaceted disease driven by a complex interplay of genetic predisposition, environmental factors and lifestyle habits. With the accelerating pace of cancer research, the gut microbiome has emerged as a critical modulator of human health and immunity. Disruption in the gut microbial populations and diversity, known as dysbiosis, has been linked with the development of chronic inflammation, oncogenesis, angiogenesis and metastasis. This review discusses the microbial species associated with various types of cancer and the pathways involved in their tumorigenic effect including mechanisms like inflammatory cytokine response, immune modulation, genotoxicity and modification of the tumor microenvironment. Diagnostic tools such as metagenomics, metabolomics, and the use of dysbiosis indexes help in the detection of gut bacterial imbalances, enabling early detection of cancer and potential intervention. Gut dysbiosis diminishes the efficacy of cancer treatments including immunotherapies, and creates immunotherapy resistance by altering drug metabolism and driving immunometabolic reprogramming, allowing tumor cells to evade immune attack. Immunometabolic reprogramming through gut microbiota modulation provides a new avenue to be explored that can restore anti-tumor immunity and reverse resistance to cancer treatments. This review also highlights the use of fecal microbiota transplantation and probiotics to mitigate chances of dysbiosis-related cancer progression. Through a comprehensive assessment of the role of gut microbiota in cancer, this review underscores the need for the use of gut microbial biomarkers for cancer detection and microbiome-targeting strategies to individualize cancer treatment.

Keywords: cancer; gut dysbiosis; immunotherapy; microbiota; therapeutic potential; tumor microenvironment.

Figure 1

Mechanism of gut dysbiosis leading to inflammation and cancer initiation. Factors such as diet, lifestyle and antibiotic use can disrupt the delicate balance of beneficial and pathogenic gut microbes, leading to dysbiosis. This increases intestinal permeability, allowing pathogens, bacterial metabolites and toxins to move across the epithelial barrier. These microbial-associated molecular patterns (MAMPs) or pathogen- associated molecular patterns (PAMPs) are recognized by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) (e.g., TLR4 recognizes lipopolysaccharide (LPS) produced by certain bacteria). Inflammatory signaling cascades are triggered (such as NF-κB, STAT3 and Wnt/β-catenin pathways), promoting the release of inflammatory cytokines, and eventually leads to carcinogenesis (e.g., colorectal, gastric and oesophageal cancers). This inflammation can turn into systemic inflammation when pathogenic and immune components enter the blood stream and travel to other organs causing cancers like liver, pancreatic, lung, breast and brain cancers.

Figure 2

The angiogenesis pathway triggered by Afa/Dr diffusely adhering E. coli (DAEC) begins with bacterial adhesion to intestinal epithelial cells via specific surface receptors like Decay-Accelerating Factor (Daf). This interaction activates intracellular signaling cascades, i.e. the MAPK and NF-κB pathways, which increase the transcription of hypoxia-inducible factor-1 alpha (HIF-1α). This induces the expression of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines like IL-8. These molecules collectively drive inflammation, promote epithelial-mesenchymal transition (EMT) through the upregulation of Snail and Twist pathways, and stimulate angiogenesis, supporting tumor progression.

Figure 3

Gut microbiota dysbiosis can be managed and prevented in several ways to reduce the risk of developing dysbiosis-induced cancer. Probiotic treatments (live single strain bacteria or bacterial consortia), prebiotic and dietary interventions, and fecal microbiota transplantation (FMT) can help reverse and avoid dysbiosis. FMT involves transplanting fecal/gut bacteria from a healthy individual to a host with dysbiosis to restore their microbial balance (eubiosis). These strategies not only enhance the efficacy of chemotherapy and immune checkpoint inhibitor (ICI) therapy (anti-CTLA-4 and anti-PD-1/anti-PD-L1) but also reduce complications associated with cancer therapy such as colitis and diarrhoea caused by chemo and radiation.