Immunomodulation by Gut Microbiome on Gastrointestinal Cancers: Focusing on Colorectal Cancer

Abstract

Gastrointestinal cancer (GI) is a global health disease with a huge burden on a patient's physical and psychological aspects of life and on health care providers. It is associated with multiple disease related challenges which can alter the patient's quality of life and well-being. GI cancer development is influenced by multiple factors such as diet, infection, environment, and genetics. Although activating immune pathways and components during cancer is critical for the host's survival, cancerous cells can target those pathways to escape and survive. As the gut microbiome influences the development and function of the immune system, research is conducted to investigate the gut microbiome-immune interactions, the underlying mechanisms, and how they reduce the risk of GI cancer. This review addresses and summarizes the current knowledge on the major immune cells and gut microbiome interactions. Additionally, it highlights the underlying mechanisms of immune dysregulation caused by gut microbiota on four major cancerous pathways, inflammation, cellular proliferation, apoptosis, and metastasis. Overall, gut-immune interactions might be a key to understanding GI cancer development, but further research is needed for more detailed clarification.

Keywords: anti-cancer; colorectal cancer; gastrointestinal cancer; gut microbiome; immune system; immune–gut interaction.

Figure 1

Schematic illustration of regional diversity of the microbiome along the GI tract. The figure is divided into different regions of the GI tract and highlights the microbial concentration ranges, common phylum and genus, relative abundance [27], and immune regulations specific to each region. “Created with BioRender.com”.

Figure 2

Summary of the most reported gut microbiome and immune interactions. While the left side of the figure illustrates the influence of segmented filamentous bacteria (SFB) and antimicrobial peptides (AMP) on the host immune system through the activation of Th17 and MyD88 signaling, respectively, the right section of the figure highlights the role of dietary fibers and short chain fatty acids (SCFA) on T cells expression. The role of bacterial antigens on the production of IgA dimer is shown in the middle part of the figure. “Created with BioRender.com”.

Figure 3

Schematic representation of the immune—gut interactions during GI cancer and how it influences the inflammatory responses. Due to gut dysbiosis, the low level of short chain fatty acids can lead to the activation of inflammatory pathway, the production of cytokines and chemokines and the activation of STAT3 and NF-kB signaling pathways. “Created with BioRender.com”.

Figure 4

Schematic illustration of two pathways in which two bacteria Fusobacterium nucleatum and Holdemanella biformis facilitate cancer progression and cellular proliferation through FadA- E-cadherin interaction and short chain fatty acids (SCFA), respectively. (A) represent the proliferative example while (B) the anti-proliferative example. “Created with BioRender.com”.

Figure 5

Summarizes the influence of Fusobacterium nucleatum on cancer metastasis either by targeting sugar residues Gal-GalNAc on cancerous cells or targeting receptors that are overexpressed on natural killer cells (NK). “Created with BioRender.com”.

Figure 6

Illustrations of the role of short-chain fatty acids specifical butyrate on cellular apoptosis. The figure highlights the Gpr109a receptor and the pathways that lead to the reduction of mucosal tissue repair and Caspase 3 activation. “Created with BioRender.com”.

Figure 7

Illustrations of the gut bacteria and their role in modulating the efficacy of the currently used anti-cancer drugs. The figure summarizes the influence of the reported bacteria on immunotherapy and chemotherapy treatments. “Created with BioRender.com”.