Epithelial Cell-Specific Induction of Activating Transcription Factor 6 Signaling Promotes Intestinal Dysbiosis and Colonic Tumorigenesis

Activation of the endoplasmic reticulum unfolded protein response (erUPR) might contribute to the oncogenic transformation of tissues. However, a causative tumor-promoting role has not been demonstrated. To address the role of activating transcription factor (ATF)6-mediated erUPR signaling in intestinal epithelial cells (IEC), we generated Villin-Cre-driven IEC-specific transgenic mice overexpressing the activated form of ATF6 (nATF6^IEC).

Homozygous nATF6^IEC-tg/tg mice spontaneously developed colonic adenomas independent of major inflammatory processes, with an incidence of 100% at 12 weeks of age. In contrast, heterozygous nATF6^IEC-wt/tg mice showed no tumor formation but a tumorigenic response to both IL-10 deficiency and chemical wounding using dextran sodium-sulfate.

In nATF6^IEC-tg/tg mice, erUPR-related gene expression and increased proliferation of IEC preceded tumor formation. Further, loss of mucin-filled goblet cells was associated with increased microbial penetration of the mucus barrier. High-throughput 16S-rRNA gene sequencing of cecal microbiota revealed a clear separation of bacterial communities according to genotype with reduced bacterial diversity. Finally, antibiotic treatment and germfree housing was shown to alleviate or even prevent tumor formation.

In conclusion, the novel nATF6^IEC mouse model demonstrates for the first time a causal contribution of altered erUPR signaling to colonic tumorigenesis linked to changes in the gut microbiota.