U of A researchers discover the role of gut-derived metabolites in treating colon cancer

"What short-chain fatty acids seem to be doing is helping the cancer cells produce molecules that are activating the T-cells, drawing them inside the tumour,” U of A researcher says.

University of Alberta researchers have discovered that colorectal cancer cells (CRC) become increasingly sensitive to certain bacteria produced during food digestion. Known as gut-derived metabolites, they induce the activation of T-cells, which can eliminate CRCs. This highlights a potential new therapy for treating colon cancer.

According to Kristi Baker, an associate professor in the department of oncology, T-cells are “like the snipers of the immune system.” They are able to directly kill cancer cells and virally infected cells without damaging other cells nearby.

T-cells able to “eliminate a very specific population of cells”

Colon cancer is the second-leading cause of cancer-related deaths worldwide. Consuming highly-processed foods, leading a sedentary lifestyle, and having a low intake of fresh produce can contribute to colon cancer development. 

Short-chain fatty acids are gut-derived metabolites produced from the digestion of dietary fibre. They activate immune cells known as cluster of differentiation (CD8+) T-cells. According to the study led by Baker’s team, CD8+ T-cells go to areas with CRCs and help kill the tumour cells. They’re able to do so because T-cells can “eliminate a very specific population of cells,” Baker said.

When short-chain fatty acids activate the CD8+ T-cells, it causes an anti-tumour response against CRCs. This response makes CRCs easily detectable for immune cells that kill tumour cells. It also prevents histone deacetylation, which allows the CRCs to send a signal and activate an anti-tumour immune response.

According to Baker, it’s important for T-cell therapies to successfully get T-cells into a tumour.

“A lot of the time the tumours will have defensive walls that try to prevent the T-cells from getting in there. What short-chain fatty acids seem to be doing is helping the cancer cells produce molecules that are activating the T-cells, drawing them inside the tumour.”

Baker’s lab investigated how gut microbiome influences colorectal cancer

The gut microbiome’s possible role in colon cancer also interested Baker’s lab. During the digestive process, the gut microbiome produces these short-chain fatty acids. According to Baker, nobody definitively knew “how they changed the way cancer interacts with the immune system.” 

Baker’s study tested two types of short-chain fatty acids, butyrate and propionate, on CRCs from three sources: CRC cell lines, CRCs from mice with colon cancer, and human CRCs.

“We were a little bit surprised by how strong the effect was. Even 48 to 72 hours after we had removed the short-chain fatty acids, the cancer cells were still doing a much better job of stimulating the T-cells,” Baker said. “It seemed to be a very long duration effect. That is something I definitely had not expected.”

Baker hopes that the study will make the relationship between cancer cells and the immune system clearer. This could lead to the development of effective therapies for colon cancer in the future.

“I think the better understanding we have of what helps and hurts that interaction will give us a good idea for building therapies in the future.”

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