How chronic cellular stress alters the gut microbiome
- Permanently activated protective protein alters lipid metabolism in intestinal cells.
- This results in increased production of long-chain fatty acids.
- Cancer-promoting bacteria feed on these and change the composition of the microbiome.
It is well established that gut microbiome composition plays a pivotal role in human health – yet the precise connections are still not fully elucidated. Researchers at the Technical University of Munich (TUM) have moved a step closer to understanding these complex interactions: they have identified a cellular mechanism that alters the gut microbiome in a way that promotes cancer. An analysis of patient data shows that the findings also apply to humans.
At the starting point of the observed microbiome changes is a protein that normally has a protective function: ATF6 (Activating Transcription Factor 6). As long as everything in the cells runs normally, it remains inactive. However, when too many faulty proteins accumulate, it becomes active and initiates processes that help the cell repair or remove these proteins. The cell is thus temporarily stressed, but then returns to its resting state.
In some diseases, however, this protective protein remains permanently active. The gut microbiome then shifts toward a state that can trigger cancer. A team led by Dirk Haller, Professor of Nutrition and Immunology, and Dr. Olivia Coleman, research associate in Haller's department, had already shown this in earlier studies. Now the researchers were able to demonstrate how this change in the microbiome occurs. Their results have been published in Nature Metabolism.
Long-chain fatty acids as favorite food of certain bacteria
A central role is played by lipid metabolism in the intestinal cells. Normally, it supplies the cells with energy and provides important building blocks and signaling molecules. Under chronic activation of the protective protein ATF6, however, lipid metabolism changes and generates more long-chain fatty acids. These then serve as food for certain bacteria, above all Desulfovibrio fairfieldensis. They multiply and displace other microbes – thus changing the composition of the microbiome. Earlier studies have shown that these bacteria, when present in large amounts, can negatively affect the intestine because they release hydrogen sulfide – a gas that damages intestinal cells at high concentrations.
The team was able to demonstrate this process, which begins with disturbed cell function, continues through altered lipid metabolism, and ultimately leads to an adaptation of the microbiome in favor of certain bacteria, through various experiments with intestinal organoids and mice. For example, mice bred without a microbiome did not develop cancer even with permanent ATF6 activation, while mice with a microbiome did. When lipid metabolism was blocked with drugs in the mice with a microbiome, interrupting the process, these animals also remained cancer-free because no excess long-chain fatty acids were produced.
Shown also in humans
In a further step, the team examined whether the results are transferable to humans. The researchers analyzed data from more than 1,000 cancer patients. Up to 38 percent of patients over the age of 50 in the studied cohorts showed chronic ATF6 activation. Furthermore, numerous long-chain fatty acids showed overlap between ATF6-activated mice and human cancer tissue.
Can measures already be derived from these results – for example, the application of microbiotia preparations that inhibit the growth of bacteria such as Desulfovibrio fairfieldensis? Dirk Haller says: "On the basis of this study we cannot yet recommend a therapy. At present, we are researching, among other things, the influence of diet on these processes and whether chronic ATF6 activation also plays a role in other cancers. Building on these results, we hope to develop effective therapies in the future through clinical testing and methods."
