Effect of Nematodes-Bacteria Complex Metabolites on Cancer and Tumor Progression

Abstract

Helminths that inhabit the gastrointestinal (GI) tract represent some of the most significant infectious agents impacting health. The interaction between the human microbiota, GI helminths, and their host occurs through multiple complex pathways, altering the host's immune system and the dynamics of the commensal gut microbiota (GM). These interactions also largely influence a balanced state of homeostasis and health promotion and robustly activate the immune system, facilitating tumor eradication and mitigating the challenges of drug resistance. Furthermore, incorporating microbial metabolites into radiotherapy and chemotherapy reduces the intense adverse effects of these treatments while enhancing their overall effectiveness. The interplay between GM and helminths, as well as their metabolites, significantly impacts the development, prognosis, and treatment of cancer. The interaction mechanisms between GI helminths and the GM are not fully elucidated. Thus, understanding a beneficial biological relationship can reveal hidden mechanisms for controlling and inhibiting cancer pathways in humans by providing insights into cellular processes and potential therapeutic targets. This knowledge can be applied to develop more effective cancer treatments. This review outlines the existing research on GM metabolites in cancer, intending to offer innovative pathways for future cancer treatment.

Keywords: apoptosis; cancer; gastrointestinal helminths; gastrointestinal microbiota; gut microbiota.

Figure 1

The flowchart outlines the essential steps in conducting a critical literature review, encompassing inclusion and exclusion criteria as well as filtering stages. It is important to note that scientific rigor within the inclusion criteria is assessed through the application of appropriate scientific methods. These methods ensure unbiased and robust design, methodology, analysis, interpretation, and reporting throughout the review process. This figure was generated using BioRender software version 04.

Figure 2

Examining SCFAs in combating NF-κB-associated inflammation and cancer risk is crucial due to the complexity of inflammatory pathways in carcinogenesis. NF-κB up-regulates matrix metalloproteinases (MMPs), aiding metastasis, enhances VEGF for angiogenesis, and affects STAT signaling for cell proliferation while inhibiting apoptosis—key cancer progression traits. SCFAs counteract these by promoting T-cell differentiation into regulatory cells, stimulating anti-inflammatory cytokines, and upregulating tissue inhibitors of metalloproteinases (TIMPs) to reduce metastasis and block NF-κB and STAT pathways. Activation of NF-κB and the NLRP3 inflammasome is essential but concerning for TMAO-induced vascular calcification. The NLRP3 inflammasome’s role in inflammation complicates understanding chronic inflammation’s impact on blood vessels. This figure was created with BioRender software version 04.

Figure 3

The effects of short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate on the tumor immune microenvironment (TIME). Erk activation enhances the levels of vimentin and N-cadherin, thereby driving the occurrence of EMT. The presence of microorganism-associated molecular patterns (MAMPs) on microbes allows macrophages to identify them using Toll-like receptors (TLRs). The production of reactive oxygen species (ROS) can occur in macrophages, or the activation of different signaling pathways can lead to the release of proinflammatory cytokines, including IL-1, IL-6, IL-8, IL-23, and TNF. The activation of STAT3 and NF-κB signaling pathways by proinflammatory cytokines triggers the expression of the c-myc oncogene and MMP13, which subsequently contributes to epithelial-mesenchymal transition (EMT), persistent inflammation, and ultimately the development of cancer. At the same time, FadA and BFT, acting as virulence factors, can hinder E-cadherin functionality, which activates the β-catenin/Wnt signaling pathways and subsequently leads to the activation of the STAT3 and NF-κB pathways. Short-chain fatty acids (SCFAs) promote the production of IL-22 in CD4+ T-cells and innate lymphoid cells (ILCs) through mechanisms involving HIF-1α and AhR, as well as the participation of Stat3 and mTOR. This figure was generated using BioRender software version 04.

Figure 4

The intricate relationship between the GM and roundworms presents a dual-edged sword in the context of inflammation, necrosis, and apoptosis. While excretory/secretory (ES) products from roundworms encourage anti-inflammatory bacterial taxa and suppress pro-inflammatory ones, the complexity deepens with the Th2 immune response. This response, characterized by elevated levels of IL-4 and IL-13, stimulates goblet cells to increase mucus production, altering the gut lumen’s environment. Such changes support the proliferation of regulatory T-cells (Tregs) via TGF-β and IL-10 release, promoting an anti-inflammatory milieu strengthened by short-chain fatty acids like butyrate. However, this balance is precarious; any breakdown of the intestinal barrier can allow harmful microbial compounds such as lipopolysaccharides to infiltrate systemic circulation. The ensuing cascade involves reactive oxygen species and pro-inflammatory cytokines like TNF-α and IL-1β being released through TLR4 signaling in macrophages. Despite this turmoil, roundworms contribute to regulating immune cell apoptosis at a cellular level; they help sustain Treg survival through IL-10 and TGF-β signaling during infection. Ultimately, while specific mechanisms foster immunological tolerance and curb inflammation, they also highlight vulnerabilities that could exacerbate systemic inflammatory responses if not carefully modulated. This figure was generated using BioRender software version 04.