Gut Microbiota Alteration Influences Colorectal Cancer Metastasis to the Liver By Remodeling the Liver Immune Microenvironment

Abstract

Background: The gut microbiota regulates the liver immune microenvironment in colorectal cancer (CRC) through gut-liver axis. Kupffer cells (KCs) contribute significantly to the formation of pre-metastatic niches (PMNs) for CRC liver metastasis. The aim of our study was to explore the effect of gut microbiota regulating KCs in CRC liver metastasis. Results: Mice treated with different antibiotics were divided into Control group, vancomycin (Vanc) group, colistin (Coli) group, and a group of ampicillin, streptomycin and colistin (ASC). Fewer liver metastases were identified in mice in the ASC group and Coli group than in those in the Control group (P = 0.003, P = 0.041, respectively). An increased proportion of Parabacteroides_goldsteinii, Bacteroides_vulgatus, Bacteroides_ thetaiotaomicron, Bacteroides_uniformis in mice of the Coli group were observed in 16S rDNA sequencing. Consistent with the Tax4Fun functional prediction, a prominent expansion of hepatic KCs was identified in mice in the ASC and Coli groups compared to those in the Control group (P = 0.001, P = 0.038, separately). Meanwhile, Bacteroides_vulgatus was a positive correlation with KCs contents (P = 0.011, r = 0.705). On the other hand, more liver metastases were observed in mice of the Vanc group than those in the Control group (P = 0.028). An increased abundance of Parabacteroides_distasonis, Proteus_mirabilis and a remarkable reduction of hepatic KCs were observed in mice in the Vanc group (P = 0.027). Pearson correlation analysis showed Proteus_mirabilis was a negative related to KCs contents (P = 0.028, r = 0.632). Conclusions: An increased abundance of Proteus_mirabilis and a decreased abundance of Bacteroides_vulgatus may be a key factor in CRC liver metastasis, which may be related to the reduction of KCs in the liver.

Emerging mechanisms progress of colorectal cancer liver metastasis

“…However, most current studies have demonstrated that KC plays a role in promoting the occurrence of CRC liver metastasis. This contrary conclusion may be caused by different immune components being activated in different experimental systems, or the interaction of other cell populations with KC is ignored ( 86 ). LSECs line the sinusoidal vessels with characteristic holes that allow liver cells and HSCs residing in the Disse space to have complete contact with the blood ( 87 ).…”