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.