Fusobacterium nucleatum Affects Cell Apoptosis by Regulating Intestinal Flora and Metabolites to Promote the Development of Colorectal Cancer

Abstract

Background/AimsIntestinal flora, especially Fusobacterium nucleatum (Fn), can affect the development of colorectal cancer (CRC). In this study, we examined the composition of intestinal flora and their metabolites in the tissues, serum and feces of CRC patients.Materials and MethodsCRC tissues, adjacent normal colonic tissues, fecal and serum samples were collected from CRC patients who received surgical treatment between January 2018 and January 2020. Fecal and serum samples were collected from healthy individuals for comparison. In addition, fecal samples were collected from BALB/c female mice. SW480, a human CRC cell line, was utilized for in vitro studies. The experiments involved 1H-NMR-based metabolomics analysis, targeted and untargeted mass spectrometry analysis, and intestinal flora 16S rDNA V4 region sequencing.ResultsThe abundance of Bacteroides and propionic acid concentration were decreased and that of Lactobacillus and lactic acid concentration were increased in CRC tissues. In addition, the abundances of Ruminococcus, Prevotella, and Sutterell were decreased in CRC patients. The levels of leucine and isoleucine were decreased in the serum and tumor tissues of CRC patients. Aspartate, glutamate and glutathione levels were elevated in the tissues of CRC patients only. The serum glutamine, tyrosine, valine, alanine, and histidine levels were decreased significantly. Lactic acid inhibited and propionic acid promoted apoptosis among SW480 CRC cells.ConclusionFn affected the apoptosis of CRC cells and promoted the progression of CRC by affecting the distribution of intestinal flora, which altered the concentrations of metabolites such as lactic acid, propionic acid. Intestinal flora could regulate amino acid metabolism.

Anti-tumour effect of Huangqin Decoction on colorectal cancer mice through microbial butyrate mediated PI3K/Akt pathway suppression

“…Clinical evidences have proved that lower faecal concentrations of SCFAs are associated with higher risk of CRC and incidence of CRC [45]. Propionic acid, the main metabolite of Bacteroides , could promote apoptosis among SW480 CRC cells and exhibited a lower content in CRC [46]. Moreover, butyrate has substantial anti-tumorigenesis effects, including inhibition of tumour cell proliferation, initiation of apoptosis in tumour cells, and mediation of T-regulatory cell homeostasis [47, 48].…”

Intratumoral Microbiome: Foe or Friend in Reshaping Tumor Microenvironment Landscape?

“…In this context many bacterial species, which inhabit human tumors, carry out lactate production as a fermentation end product, including the dominant phyla of Bacteroidetes, Firmicutes and Proteobacteria [17,89,90]. Indeed, lactate accumulation has been observed in many cancer types [91,92], contributing to acidification of the TME due to its low dissociation constant pKa 3.85. The production of SCFAs is another metabolic feature of specific bacterial genera.…”

The Role of Fusobacterium nucleatum in Colorectal Cancer Cell Proliferation and Migration

“…One of the most striking characteristics of tumor cells is their ability to adapt to changing environmental conditions by utilizing a wide range of nutrients to maintain their demanding anabolic demands [ 52 ]. With the exception of various tumor-infiltrating immune cells and cytokines, tumor metabolism, including amino acid metabolism [ 53 ] and glycolysis [ 54 , 55 ], also play important roles in CRC invasion and metastasis. Fn can regulate amino acid metabolism by intervening in the distribution of the intestinal microbiota.…”

“…In SW480 cells exposed to Fn, the levels of lactic acid, aspartic acid, and anti-apoptotic protein Bcl-2 are increased, whereas concentrations of propionic acid and the apoptotic protein Bax are decreased; in the tumor tissues and serum of CRC patients, the levels of isoleucine and leucine are decreased. These findings in vivo/in vitro suggest that Fn inhibits cancer cell apoptosis, promoting CRC progression, mainly by regulating propionic acid and lactic acid metabolism [ 53 ]. The enrichment and persistence of Fn bacterial community in CRC is essential for tumor progression.…”

“…The significant enrichment of potentially pathogenic taxa (e.g., phylum Proteobacteria , Stenotrophomonas , Denitrifaciens , and unidentified Enterobacteriaceae ) and depletion of probiotic bacteria (such as Lactobacillus ) are features of the mucosal microbiota caused by Fn infection, which further worsening the dysbiosis of the colonic mucosal microbiota [ 3 ]. Yu et al [ 53 ] collected feces of mice infected with Fn, and they foud that the abundance of Fn was positively correlated with the abundance of Gemmatimonadetes while negatively correlated with the abundance of Tenericutes and Euryarchaeota . Bullman et al [ 57 ] confirmed that the relative abundance of the overall dominant microbiome (e.g., Bacterium , Prevotella and Selenomonas species), including Fn, was nearly identical in the primary CRC and their matched metastatic cancers.…”