Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria

Abstract

Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of Escherichia coli and Bacteroides fragilis. Genes for colibactin (clbB) and Bacteroides fragilis toxin (bft), encoding secreted oncotoxins, were highly enriched in FAP patients’ colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with E. coli (expressing colibactin), and enterotoxigenic B. fragilis showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.

The role of microbiota in the development of colorectal cancer

“…Infection with pks + E. coli induces anaphase bridging, chromosome aberrations, aneuploidy, and tetraploidy . Mucus degradation enables an increase in pks + E. coli adhesion, triggering increased DNA damage in colonic epithelial cells by colibactin . Bacteria‐host cell contact is required for the genotoxic effect of pks; therefore, an environment where bacteria can more readily take root in the epithelial layer could deliver more of the pks product colibactin to host cells in the epithelium .…”

The Gut Microbiome in Pancreatic Disease

“…57 In the colon, adherent bacteria such as Bacteroides fragilis are thought to promote adenomas and cancers as they produce enterotoxins that have tumorigenic effects including effects on signaling, cell adhesion molecules and cytokine alterations. 58, 59 Consistent with their role in modulating the immune response, gut bacterial profiles are recognized as influencing the immune response directed towards tumors. 15, 60 Several studies have shown that gut microbiome profiles influence the immune therapy response to checkpoint inhibitor therapy.…”

Mutagenicity of Helicobacter hepaticus infection in the lower bowel mucosa of 129/SvEv Rag2−/‐Il10−/−gpt delta mice is influenced by sex

“…In addition, elevation of the iNos‐mediated nitrate respiration pathway provides a growth advantage to E. coli in the inflamed intestine of DSS‐treated C57BL/6 mice . Furthermore, the population of pks+ E. coli in the colonic biofilms of patients with familial adenomatous polyposis and Apc MinΔ716/+ mice is enriched by concurrent colonization of Bacteroides fragilis . In the current study, H. hepaticus infection increased levels of fecal pks+ E. coli , presumably due to inflamed large bowel of H. hepaticus ‐infected RagIl10gpt mice.…”