Colon cancer ranks as the third most prevalent and deadliest type of cancer. Alarmingly, its incidence is rising, particularly among young people. Emerging evidence indicates that certain bacteria in the gut microbiota (the collection of primarily healthy bacteria in our intestines) can promote the development of colon cancer, through largely unknown mechanisms.
One of the suspected cancer-promoting bacteria is pks+ E. coli, which produces a genotoxin called ‘colibactin’. Colibactin is capable of binding and damaging human DNA, causing mutations that can increase the risk of cancer. These bacteria and the mutations they induce are remarkably overabundant in patients with colon cancer.
Until now, it was unclear how pks+ E. coli could reach and damage the gut wall to promote cancer development. The experiments by the teams of Prof. Lars Vereecke (VIB-UGent) and Prof. Han Remaut (VIB-VUB) revealed that these bacteria switch between a free-swimming state and a mode where they attach to the gut tissue lining (the intestinal epithelium). This attachment is made possible by specific bacterial pili, long thin protein fibers on the bacterial surface that end in adhesins that can bind receptors on the cells of the intestinal epithelium.
"We found that this pilus binding significantly increases the number, size, and aggressiveness of colon tumors," says Maude Jans (VIB-UGent), first author of the study.
"Our experiments reveal that the binding of pks+ E. coli to the intestinal epithelium can be regarded as a critical step in the development of colon cancer," says Prof. Lars Vereecke (VIB-UGent), senior author of the study. "We found that by interfering with these bacterial attachment mechanisms, tumor development could be strongly attenuated."
"We were able to identify the specific bacterial adhesins that mediate binding to colon cells: FimH and FmlH," says Dr. Magdalena Kolata (VIB-VUB), co-first author of the study. "We hypothesized that the binding by these adhesins allows bacteria to produce the genotoxin colibactin nearby epithelial cells, which leads to DNA damage and cancer development."
Sure enough, the team demonstrated that the removal of the adhesins takes away the ability of the bacteria to deliver colibactin and cause DNA damage.
"Based on our discoveries, we tested a therapeutic approach to prevent bacterial attachment using molecules that block the binding of these essential bacterial adhesins. Remarkably, we could drastically suppress DNA damage and tumor development in preclinical models," says Jans. "This therapy approach is very promising since it successfully targets harmful E. coli strains, without affecting beneficial gut microbes, unlike antibiotics."
The researchers also highlight that a Western lifestyle can make our intestinal wall more accessible to harmful bacteria, including pks+ E. coli.
The new results also shed a precautionary light on a prevailing mystery in the field: some E. coli strains that are approved and used as probiotics (live bacteria thought to promote health) carry the pks genes but do not result in increased cancer risk in laboratory experiments.
"We show that such strains do indeed make colibactin and that they express the FimH and FmlH adhesins used by the pathogenic strains to deliver the toxin to the epithelial cells," says co-senior author Prof. Han Remaut (VIB-VUB). "It turns out these strains hold a FimH variant that is not very good in binding so that the colibactin toxin does not reach its target."
However, the authors demonstrate that just a few mutations suffice to restore strong FimH binding and the genotoxic activity of these strains, highlighting that their consideration as benign probiotics may need to be reconsidered.
Jans M, Kolata M, Blancke G, D'Hondt A, Gräf C, Ciers M, Sze M, Thiran A, Petta I, Andries V, Verbandt S, Shokry E, Sumpton D, Vande Voorde J, Berx G, Tejpar S, van Loo G, Iliev ID, Remaut H, Vereecke L.
Colibactin-driven colon cancer requires adhesin-mediated epithelial binding.
Nature. 2024 Nov 6. doi: 10.1038/s41586-024-08135-z