Thought all those probiotics were good? Think again. At least that’s what a new study published in Cell Death and Disease suggests. Scientists from Jamia Hamdard, New Delhi and Institute of Liver and Biliary Sciences, New Delhi show that otherwise deemed ‘friendly’ bacteria, under certain conditions, might contribute to development of colorectal or bowel cancer (CRC).
As the name suggests, CRC is a cancer of colon and rectum that often develops as small abnormal growths on the inner lining of the large intestine. Evidence linking virulent strains of gut flora with colon cancer has been around for some time. The virulent forms of E.coli, for example, release genotoxins, such as colibactin, that damage intestinal cell’s DNA. Benign bacteria, on the other hand, act as commensals, i.e. while they grow and live in the gut, they also help with metabolism, synthesis of vitamins and a variety other functions. The ‘friendly’ tag assigned to these bacteria would then make sense, right? Not quite, according to the authors of this study. “It is assumed that benign bacteria do not harm the body. With certain pre-existing conditions, friendly E.coli in the colon can turn rogue too”, says, Sudeshna Kar of Jamia Hamdard, who is also the principal investigator of this study. The pre-existing conditions might be an inflamed tissue, a mechanical breach or certain mutations in the intestinal cells that lead to lowering of cellular defence. The ‘friendly’ E.coli can then repeatedly invade cells that were otherwise protected.
“Modelling conditions of lowered cell defence that would allow benign E.coli to repeatedly invade and cause harm isn’t easy,” admits Kar. To overcome this, the team developed a system where intestinal cell lines were exposed to an E.coli strain that was mutated to be highly invasive. Over long term, the population of cancerous stem cells in the intestinal cell line and the number of tumours grew. Similar tumours were also observed when these infected cells were injected into immuno-compromised mice.
So, what transpires inside invaded cells to turn them cancerous? The researchers studied proteins of invaded cells and found certain transcription factors and signalling proteins, such as NF-κB and β‑catenin, were present in higher amount. In normal cells, these proteins are essential for cellular homeostasis and survival. However, when a cell gets repeatedly invaded, these pathways end up getting flipped in ways, that convert a normal intestinal cell back to its stem cell state. These stem cells eventually turn tumourigenic as they acquire traits such as increased ability to survive starvation, ability to migrate and form tumours and increased resistance to agents that cause cell death. In addition, the authors also saw an increase in survival related proteins such as Mcl1, Bim and Puma. “With repeated invasion, these pro-life pathways get activated and stabilised, diverging cellular machinery towards a cancerous state”, says Kar.
Interestingly, all these tumourigenic changes in the intestinal cells were only seen with benign strains of E.coli. When intestinal cells were infected with strains producing virulent factors, they simply didn’t survive. Kar therefore cautions against use of probiotics as a silver bullet for good colon health.
There are limitations, however, to the conclusions one can draw from this study. “The findings do widen the field of microbial connection to cancer but extending them to clinical outreach would require additional research”, says Christian Jobin, Professor at Department of Medicine, University of Florida. More evidence is needed to show that, “infection of the invasive strain alone, in vivo, in an animal will cause cancer”, and for establishing the “stem cell connection in mice completely”, he adds.
For extending the research into a clinical perspective, Kar wants to map out biomarkers that vary with different stages of infection with E.coli. She hopes that matching this signature of genes with patient samples, especially during different stages of colon cancer, might be a step forward in its treatment.