Gut microbiota - bidirectional modulator: role in inflammatory bowel disease and colorectal cancer

Abstract

The gut microbiota is a diverse ecosystem that significantly impacts human health and disease. This article focuses on how the gut microbiota interacts with inflammatory bowel diseases and colorectal tumors, especially through immune regulation. The gut microbiota plays a role in immune system development and regulation, while the body's immune status can also affect the composition of the microbiota. These microorganisms exert pathogenic effects or correct disease states in gastrointestinal diseases through the actions of toxins and secretions, inhibition of immune responses, DNA damage, regulation of gene expression, and protein synthesis. The microbiota and its metabolites are essential in the development and progression of inflammatory bowel diseases and colorectal tumors. The complexity and bidirectionality of this connection with tumors and inflammation might render it a new therapeutic target. Hence, we explore therapeutic strategies for the gut microbiota, highlighting the potential of probiotics and fecal microbiota transplantation to restore or adjust the microbial community. Additionally, we address the challenges and future research directions in this area concerning inflammatory bowel diseases and colorectal tumors.

Keywords: CRC; IBD; SCFAs; gut microbiota; immune modulation.

Figure 1

NTBF promotes immunologic tolerance. NTBF releases PSA through outer membrane vesicles, promoting the production of IL-10 through TLR2 signaling on CD4 Foxp3 Tregs, and inhibiting RORγt Th17, reducing the production of IL-17A, thereby promoting immune tolerance. (Foxp3, Forkhead Box P3, a key transcription factor for Treg, which is usually used as the marker for Treg. RORγt, retinoic acid related orphan receptor γt, a key transcription factor for the differentiation and function of Th17).

Figure 2

Overview of genera associated with CD or UC. To classify genera based only on their abundance being higher or lower in CD or UC compared to healthy individuals.

Figure 3

ETBF promotes tumorigenesis by distinct mechanisms. BFT can activate the STAT3 and NF-κB pathways, increasing the production of cytokines IL-17A and IL-8, thereby creating a pro-inflammatory environment. ETBF can upregulate JMJD2B levels in the TLR4-NFAT5-dependent pathway. JMJD2B regulates the stemness of tumor cells by enhancing NANOG expression through demethylation. ETBF can also promote cancer progression by downregulating miR-149-3p through METTL14 methylation. On one hand, it facilitates the differentiation of Th17 cells via exosomes; on the other hand, it further promotes the RNA selective splicing of KAT2A mediated by PHF5A.

Figure 4

Microbiome therapies correct dysbiosis caused by colorectal cancer. Here are various methods listed from non-selective modification to targeted treatment, and they can enhance the efficacy of other colorectal tumor treatments.

Figure 5

Fn involved in immunotherapy. Fn can activate the cGAS-STING signaling pathway in CRC cells, thereby upregulating PD-L1 expression through NF-κB (p65) transcription and enhancing anti-tumor effects. Fn can also recruit IFN-γ+ CD8+ TILs, increasing IFN-γ production and enhancing the efficacy of anti-PD-L1 therapy, thereby killing tumor cells.