For years, we’ve talked about diet, genetics, and screening as the major defenses against colorectal cancer. But what if one of the most significant risks for this deadly disease is driven by something far more intimate: a breakdown in your cells’ ability to handle stress?
A landmark new paper in the journal Nature Metabolism has uncovered a shocking biological chain reaction that links chronic internal cellular stress directly to the growth of cancer-promoting bacteria in the gut. The core finding is provocative: When a specific “protective” protein in the gut lining gets stuck in the “on” position, it acts like a broken factory, churning out specialized fat molecules. These fats then become a super-food, causing certain dangerous bacteria in the colon to thrive and, ultimately, trigger tumors.
This discovery moves colorectal cancer (CRC) from a singular, unlucky genetic event to a complex, preventable ecological disaster, where our damaged cells are actively feeding the enemy within. The finding underscores that to fight CRC, we may need to stop feeding the bacteria first.
The Cell’s Broken Alarm System
Inside every cell is a structure called the Endoplasmic Reticulum (ER)—a protein-folding assembly line. When that assembly line gets overwhelmed with faulty proteins, the cell signals for an emergency shutdown and repair. This process is known as cellular stress.
The study focuses on the main emergency responder: a protein called ATF6 (Activating Transcription Factor 6). Normally, ATF6 is the repair crew chief. It activates, fixes the problem, and then goes dormant. But when stress becomes chronic, such as in certain inflammatory diseases, the ATF6 switch jams “on.”
Researchers confirmed this malfunction isn’t a niche finding in human patients. Their analysis of several large German CRC patient cohorts established that this chronic, permanent ATF6 activation was present in up to 38 percent of individuals with colorectal cancer. That’s a significant portion of cancer cases driven by this specific internal stress signal.
Toxic Fat: A High-Octane Meal for Bad Bugs
When the ATF6 protein stays perpetually active in the epithelial cells (the single layer lining your colon), it dramatically shifts the cell’s internal operations, turning the gut lining into a specialized fat-producing factory.
The over-activated ATF6 orders the ramp-up of an enzyme called Fatty Acid Synthase (FASN), which is responsible for building fat molecules. This process results in the overproduction and release of long-chain fatty acids (LCFAs).
These excess LCFAs aren’t just metabolic waste. They are the prized food source for some of the gut’s worst residents. The research team identified a specific bacterial species that thrives on these stressed-out fats: Desulfovibrio fairfieldensis. When overfed, this bacterium creates high levels of a toxic gas, which erodes the colon lining and creates an environment where tumors can easily start to grow.
The ability of ATF6 to change the cell’s environment and favor dangerous microbes causes an imbalance in the gut known as dysbiosis, a condition long suspected of fueling cancer growth.
The Proof: Shutting Down the Fat Factory Stops Cancer
The study provides the crucial evidence to prove this link is causal.
Researchers engineered special mice to have the ATF6 protein permanently activated in their colons, mimicking the high-stress state found in human patients. They then compared two identical groups: one with a normal gut microbiome and one raised entirely Germ-Free (without any bacteria).
The results showed that the mice with chronic ATF6 activation and a normal microbiome developed spontaneous colon tumors. In contrast, the genetically identical mice with chronic ATF6 activation but no gut bacteria remained completely tumor-free. This finding establishes that the stress signal alone does not cause cancer; it needs the bacteria to complete the destructive cycle.
The scientists then tested a therapeutic approach. Since the problem starts with the overproduction of LCFAs, they treated the cancer-susceptible mice with a drug that inhibits FASN, the fat-building enzyme. By blocking the flow of fat, they starved the bad bacteria. The outcome was that the FASN inhibitor prevented tumor formation in the mice. They stopped the cancer not by repairing the ATF6 protein, but by interrupting the communication pathway between the stressed cell and the opportunistic microbe.
The groundbreaking implication here is that colorectal cancer is an ecosystem disease. A breakdown in our internal cellular machinery (ATF6) creates a metabolic opportunity (LCFAs) that a tumor-promoting bacteria (Desulfovibrio fairfieldensis) seizes. For decades, cancer treatment has focused on killing the tumor. Now, we have evidence that a new avenue for therapy could involve blocking the fat-based food supply and starving the bacteria, even while the initial cellular stress remains.
The research team, which analyzed data from over 1,000 cancer patients to confirm their findings, is currently investigating how diet might influence this stress-fat-bacteria axis. While this work identifies a powerful, actionable target for future clinical trials, Professor Dirk Haller provides a note of caution: “On the basis of this study we cannot yet recommend a therapy.”. Future cancer treatments won’t just kill tumors; they’ll involve changing the toxic environment that allowed them to grow in the first place.
Paper Summary
Methodology
The study employed a multi-pronged approach, using transgenic mice (nATF6IEC) with chronic ATF6 activation in colon cells, comparing them in Specific Pathogen-Free (SPF) and Germ-Free (GF) conditions to prove the role of gut bacteria. Untargeted Metabolomics confirmed the presence of excess long-chain fatty acids (LCFAs) in mouse models, colon organoids, and human tumor tissue. The team also analyzed data from over 1,000 German colorectal cancer (CRC) patient cohorts and The Cancer Genome Atlas (TCGA). Finally, a Fatty Acid Synthase (FASN) inhibitor was used in mice to test therapeutic intervention.
Results
Chronic ATF6 activation in colon cells led to the overproduction and accumulation of LCFAs, a process confirmed in human tumor tissue. The resulting tumor development was microbiota-dependent, as SPF mice developed tumors while GF mice remained tumor-free. The LCFAs selectively fostered the growth of tumor-associated bacteria, particularly Desulfovibrio fairfieldensis. When researchers blocked LCFA production using the FASN inhibitor, it successfully prevented tumor formation in mice, even with ATF6 still active.
Limitations
The study noted that some human tissue samples were from advanced CRC cases, potentially limiting insights into the earliest stages of the disease. Complex human data required careful correction for confounding factors like microsatellite instability (MSI) status. The specific influence of diet on the stress-fat-bacteria pathway is an area that requires further investigation.
Funding and Disclosures
The authors have declared no competing interest. The research was a collaborative effort primarily led by the Chair of Nutrition and Immunology, School of Life Sciences, at the Technische Universität München (TUM) in Germany, alongside several associated European research institutions.
Publication Information
The paper is titled: “ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation”. It was published in the journal Nature Metabolism on September 1, 2025, with the digital object identifier (DOI) 10.1038/s42255-025-01350-6.
