Gavage of Fecal Samples from Patients with Colorectal Cancer Promotes Intestinal Carcinogenesis in Germ-Free and Conventional Mice
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AbstractBackground & Aims: Altered gut microbiota is implicated in development of colorectal cancer (CRC). Some intestinal bacteria have been reported to potentiate intestinal carcinogenesis by producing genotoxins, altering the immune response and intestinal micro-environment, and activating oncogenic signaling pathways. We investigated whether stool from patients with CRC could directly induce colorectal carcinogenesis in mice.

Methods: We obtained stored stool samples from participants in a metagenome study performed in Hong Kong. Conventional (male C57BL/6) mice were given azoxymethane to induce colon neoplasia after receiving a course of antibiotics in drinking water. Mice were gavaged twice weekly with stool from 5 patients with CRC or 5 healthy individuals (controls) for 5 weeks. Germ-free C57BL/6 mice were gavaged once with stool from 5 patients with CRC or 5 controls. We collected intestinal tissues from mice and performed histology, immunohistochemistry, expression microarray, quantitative PCR, immunoblot, and flow cytometry analyses. We performed 16S rRNA gene sequencing analysis of feces from mice.

Results: Significantly higher proportions of conventional mice fed with stool from individuals with CRC than control stool developed high-grade dysplasia (P<.05) and macroscopic polyps (P<.01). We observed a higher proportion of proliferating (Ki-67-positive) cells in colons of germ-free mice fed with stool from patients with CRC vs those fed with stool from controls (P<.05). Feces from germ-free and conventional mice fed with stool from patients with CRC vs controls contained different microbial compositions, with lower richness in mice fed with stool from patients with CRC. Intestines collected from conventional and germ-free mice fed with stool from patients with CRC had increased expression of cytokines that modulate inflammation, including C-X-C motif chemokine receptor 1 (CXCR1), CXCR2, interleukin 17A (IL17A), IL22, and IL23A. Intestines from conventional and germ-free mice fed with stool from patients with CRC contained higher proportions of T-helper 1 (Th1) cells (2.25% vs 0.44%) and Th17 cells (2.08% vs 0.31%) (P<.05 for each) than mice fed with stool from controls. Real-time PCR arrays revealed upregulation of genes involved in cell proliferation, stemness, apoptosis, angiogenesis, invasiveness and metastasis in mice fed with stool from CRC patients.

Conclusions: We fed stool samples from patients with CRC and heathy individuals to germ-free mice and conventional mice with azoxymethane. We found stool from patients with CRC to increase the numbers of polyps, levels of intestinal dysplasia and proliferation, markers of inflammation, and proportions of Th1 and Th17 cells in colon, compared with stool from individuals without CRC. This study provides evidence that the fecal microbiota from patients with CRC can promote tumorigenesis in germ-free mice and mice given a carcinogen.
Acceptance Date09/08/2017
All Author(s) ListSunny H. Wong, Liuyang Zhao, Xiang Zhang, Geicho Nakatsu, Juqiang Han, Weiqi Xu, Xue Xiao, Thomas NY Kwong, Ho Tsoi, William KK. Wu, Benhua Zeng, Francis KL. Chan, Joseph JY Sung, Hong Wei, Jun Yu
Journal nameGastroenterology
Volume Number153
Issue Number6
Pages1621 - 1633.e6
LanguagesEnglish-United States

Last updated on 2021-12-09 at 23:58