Chronic Cellular Stress and Its Impact on Gut Microbiome in Cancer Development

Recent research from the Technical University of Munich has shed light on how prolonged cellular stress influences the composition of the gut microbiome, potentially promoting cancer. The study focuses on a cellular protein called Activating Transcription Factor 6 (ATF6), which normally acts to protect cells by managing faulty proteins. Under typical conditions, ATF6 remains inactive, activating only when cell stress occurs. However, in certain diseases, this protective protein can remain permanently active, leading to significant changes in cellular metabolism.

This sustained activity alters lipid metabolism in intestinal cells, increasing the production of long-chain fatty acids. These fatty acids become a source of nourishment for specific bacteria, notably Desulfovibrio fairfieldensis, which thrive on these lipids. An overgrowth of such bacteria can disturb the gut microbiome balance, as these microbes release hydrogen sulfide—a gas that, at elevated levels, damages intestinal cells and contributes to an environment conducive to cancer.

Experimental studies in mice demonstrated that continuous activation of ATF6 leads to microbiome changes favoring tumor-promoting bacteria. When lipid metabolism was pharmacologically blocked in these mice, the development of cancer was prevented, indicating a direct link between cellular stress, lipid metabolism alterations, microbiome shifts, and cancer progression.

Further, researchers analyzed data from over 1,000 cancer patients and found that up to 38% of those over 50 exhibited chronic activation of ATF6. Many long-chain fatty acids associated with ATF6 activity were also found in human cancer tissues, suggesting the mechanisms observed in animal models are relevant in human disease.

While these discoveries are promising, further research is necessary to explore therapeutic approaches, such as microbiota-modulating treatments or dietary interventions, to mitigate cancer risks associated with cellular stress and microbiome imbalance. Currently, the focus remains on understanding how diet and other factors influence these pathways to develop effective future therapies.

Sources: ScienceX - Medical Xpress