Gut Bacteria, the Immune System and the Development of Cancer

As I mentioned last week, there isn’t a whole lot of great new biome research coming out these days, for obvious reasons.  The only story over the last few days that really interested me was out of the University of Michigan, which looked at how specific gut bacteria affect susceptibility to colon cancers.[i]

Certain gut bacteria stimulate the production of a kind of immune cell called CD8+, which ordinarily help protect against the formation of cancer.  However, excess stimulation of the CD8+ cells can actually cause inflammation which promotes cancer development.  Like so many things in the body, balance is key.

These researchers compared two groups of mice with different microbiota compositions and found that when exposed to a carcinogen, one group developed an average of 5 tumors whereas the other developed an average of 15, and had a much higher level of inflammation.  To definitively ascertain that the causative agent was the differing gut bacteria, the scientists transplanted the gut bacteria from these 2 groups into new mice that were genetically identical but had been raised in a germ-free environment.  Sure enough, the group given gut bacteria from the mice that had averaged more inflammation and more tumors showed exactly the same, faring far worse than the mice that had received fecal transplants from the less-susceptible group.

Some of the bacterial differences discovered:   “The less-susceptible mice had increased levels of Anaeroplas-mataceae, Erysipelotrichaceae, Clostridiales, and Sutterellaceaebacteria.  The mice with more tumors and inflammation had increased levels of Prevotellaceae and Helicobacteraceaebacteria.  Further research led them to isolate 9 specific bacterial populations that “…may have tumor-suppressive or tumor-promoting activities.”  To name a few, high tumor susceptibility was associated with Bacteroidetes Alistipes, Firmicutes Ruminoccus, whereas low susceptibility was associated with Firmicutes Lachnospiraceae.  Interestingly, their findings do overlap some known dysbiotic elements already associated with disease in humans.  For example, low levels of “…Lachnospiraceae have been found in IBD [inflammatory bowel disease] and CRC [colo-rectal cancer] patients…”  whereas, “…a member of the Ruminococcaceae was associated with high tumor burdens, and Ruminococcaceae have also been found to be enriched in IBD and CRC patients.”

In order to understand exactly what was causing the high levels of inflammation and increased cancer susceptibility in the second group of mice, the researcher took a closer look at their immune systems.  They discovered that the animals had more T immune cells in their colon tissue, including way more CD8+ cells.  This was puzzling since, as I mentioned above, ordinarily CD8+ cells help us fight cancer.  To find out then whether or not the increased number of these cells was driving the development of cancer, they transplanted gut bacteria from these animals into mice that were genetically engineered to lack CD8+ cells and sure enough, these latter mice develop far fewer tumors.  “Although CD8 T cells are known for their cytotoxic, anti-tumor activity, our results suggest that in the presence of dysbiosis, they can also have a pathogenic role by promoting damaging, chronic inflammation and consequently tumor development.”

The scientists discovered that “…that these cells get over-activated in the presence of certain bacteria and then exhausted, leaving them less capable of killing tumor cells.”[ii]

The authors conclude that “…these studies suggest that microbial dysbiosis can contribute to colon tumor susceptibility by hyperstimulating CD8 T cells to promote chronic inflammation and early T cell exhaustion, which can reduce anti-tumor immunity.”  Once again, we see that incredible effect of the microbiome on the immune system and the development of disease.

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[i] Amy I. Yu, Lili Zhao, Kathryn A. Eaton, Sharon Ho, Jiachen Chen, Sara Poe, James Becker, Allison Gonzalez, Delaney McKinstry, Muneer Hasso, Jonny Mendoza-Castrejon, Joel Whitfield, Charles Koumpouras, Patrick D. Schloss, Eric C. Martens, Grace Y. Chen. Gut Microbiota Modulate CD8 T Cell Responses to Influence Colitis-Associated Tumorigenesis. Cell Reports, 2020; 31 (1): 107471 DOI: 10.1016/j.celrep.2020.03.035

[ii] https://labblog.uofmhealth.org/lab-report/identical-mice-different-gut-bacteria-different-levels-of-cancer