Genotoxic E. coli may play a role in colorectal cancer

Last Updated: 2020-03-05

By Will Boggs MD

NEW YORK (Reuters Health) - Strains of E. coli that carry pks, which encodes a genotoxic set of enzymes, might play a pathogenic role in human colorectal cancer (CRC), according to studies in human intestinal organoids.

"pks-positive E. coli is the first example of a bacterium that directly mutates human DNA," Dr. Hans Clevers of the Royal Netherlands Academy of Arts and Sciences and UMC Utrecht told Reuters Health by email. "It does so by secreting colibactin, which we show to leave a specific mark in the DNA of human cells, a so-called mutational signature."

pks+ E. coli is present in about 20% of healthy individuals, about 40% of patients with inflammatory bowel disease, and about 60% of patients with familial adenomatous polyposis and CRC.

Dr. Clevers and colleagues exposed human intestinal organoids to genotoxic pks+ E. coli by repeated luminal injection over a period of five months.

Exposure to pks+ E. coli was associated with a variety of mutations that together made up a characteristic mutational signature in these organoids, the researchers report in Nature.

Interrogation of a whole-genome sequencing (WGS) database of 3,668 solid cancer metastases identified strong enrichment of two pks signatures in CRC-derived metastases.

Moreover, 2.4% of the most common driver mutations found in seven CRC patient cohorts matched the pks colibactin target motif, and 5.3% of driver mutations matched mutations in APC, the most commonly mutated gene in CRC.

"The fact that the same signature is seen in a subset of colorectal-cancer patients implies that the pks+ E. coli is causally involved in those cancer cases," Dr. Clevers said.

"Careful screening of larger populations should establish the prevalence of pks+ E coli in the general population," he said. "It would be of interest to test antibiotic therapy on pks+ individuals in order to 'purge' the pks+ E. coli and replace it by pks- E. coli. This strategy resembles treatment of Helicobacter in stomach-ulcer patients, which prevents against stomach cancer."

Dr. Clevers added, "Somewhat astonishingly, a pks+ E. coli strain with the name Nissle 1917 is quite widely used (and even prescribed by gastroenterologists) as a probiotic for a variety of gut-related (and other) diseases. There are multiple scientific publications that show that Nissle is 'genotoxic,' i.e., it is known to cause DNA breaks. How is it possible that a known mutagen is used as a pseudo-drug?"

SOURCE: https://go.nature.com/2VJMTHS Nature, online February 27, 2020.