Abstract The induction of endoplasmic reticulum unfolded protein responses (UPR ER ) contributes to cancer development and progression. We recently linked microbiota-related triggers to the tumor-promoting role of signal transducer activating transcription factor 6 (ATF6) in the colon. Here we substantiate the clinical relevance of ATF6 and related bacterial genera in colorectal cancer patient cohorts. Spatial and longitudinal bacterial profiling in ATF6 transgenic mice (nATF6 IEC ) identified tumor-initiating and tumor-progressing shifts in the mucosa-associated microbiota. Transcriptional analysis in intestinal epithelial cells (IEC) of germ-free and specific pathogen-free nATF6 IEC mice defined bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics, isotope-labeling in intestinal organoids and FASN inhibition confirmed ATF6-mediated involvement of long-chain fatty acids in tumorigenesis. Multi-omics data integration identified a bacteria-lipid network characterized by fatty acid efflux, catabolism and detoxification. We postulate chronic ATF6 signaling to drive a clinically relevant pathologic response altering lipid metabolism to select for a tumor-promoting microbiota. Graphical Abstract Chronic ATF6 signaling in the colonic epithelium alters lipid metabolism to select a tumor-promoting microbiota nATF6 expression is induced in intestinal epithelial cells in transgenic mice (nATF6 IEC ) Biallelic nATF6 IEC germ-free mice (grey circle) and floxed or monoallelic specific pathogen-free mice (black circle) remain in a state of homeostasis (yellow circle), while biallelic specific pathogen-free mice (black circle) develop spontaneous colon tumorigenesis (red circle) Mechanistically, biallelic nATF6 IEC mice in the presence of an intestinal microbiota alter colonic lipid metabolism, including the upregulation of Fasn The microbial lipid-response to the altered lipid milieu results in dysbiosis and the subsequent formation of colon adenomas Inhibition of FASN in biallelic nATF6 IEC mice prevents colon tumor formation (yellow arrow) Created with BioRender.com nATF6: activated activating transcription factor 6; LCFA: long-chain fatty acids; SAFA: saturated fatty acids; Fasn: fatty acid synthase; C75 i.p.: intraperitoneal injection of the Fasn inhibitor C75.

ATF6 activation alters colonic lipid metabolism causing tumor-associated microbial adaptation