Abstract
Colitis-associated cancer (CAC) is the most serious outcome of inflammatory bowel disease, which has an alteration of commensal intestinal microbiota. However, the role of intestinal microbiota on CAC progression is not well-understood. Fecal microbiota transplantation (FMT) was used for treating murine azoxymethane–dextran sodium sulfate (AOM-DSS) model of CAC. Composition of gut microbiota during FMT treatment was analyzed. RT-PCR and ELISA were used to detect the inflammatory factors, and immunofluorescence was applied to examine the phospho-nuclear factor (NF)-κB p65/p100 and Ki67-positive cells in the colons. In addition, flow cytometry was performed to analyze the immune cell after FMT treatment. Rehabilitation of the intestinal microbiota by FMT restored both the ratio and diversity of microbiota during CAC progression. Remarkably, a favorable morphometric outcome characterized by decreased tumor load and size was observed in CAC mice with FMT treatment. In addition, an anti-inflammatory function of FMT was demonstrated by decreasing pro-inflammatory factors but increasing anti-inflammatory factors through inhibiting canonical NF-κB activity and cellular proliferation in colons of CAC mice. The expression of CD4+CD25+Foxp3+ regulatory T cells (Tregs) was significantly increased after FMT treatment in CAC mice, but not T helper (Th)1/2/17 cells. Our study aids in the understanding of CAC pathogenesis and reveals a previously unrecognized role for FMT in the treatment of CAC through restoring the intestinal microbiota and inducing regulatory T cells.
Highlights
Colorectal cancer (CRC) is one of the most common fatal malignancies globally (Weir et al, 2003)
To determine the impact of AOM/dextran sodium sulfate (DSS) protocol on mice’s gut microbiota and whether Fecal microbiota transplantation (FMT) would interfere with its abundance and diversity, we analyzed the bacterial communities in fecal samples
The abundance of the two major phyla was returned to normal level after FMT treatment, suggesting that the ratio of Firmicutes and Bacteroidetes was restored after FMT treatment and appeared in a donor-like manner (Figures 1B,D)
Summary
Colorectal cancer (CRC) is one of the most common fatal malignancies globally (Weir et al, 2003). The colitis-associated cancer (CAC), as one major subset of CRC, is closely related to chronic or dysregulated inflammation (Potack and Itzkowitz, 2008). Studies showed that inflammation is a critical cause for initiation and/or regulation of the progress of CAC (Kraus and Arber, 2009). The excessive Th2/Th17 cells in intestinal mucosa are the main reasons for chronic inflammation and promote CAC progression (Amicarella et al, 2017). While Tregs, which are important in the limitation and regulation of immune responses, are believed to play an important role in maintaining gut homeostasis and reducing inflammatory responses (Salama et al, 2009; Erdman et al, 2010; van Herk and Te Velde, 2016)
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