Farnesoid X Receptor Activation Upregulates Expression of the Transcription Elongation Factor, TCEA2, in Intestinal Epithelial Cells

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BACKGROUND: Oxidative DNA damage occurs during mucosal inflammation, with such lesions stalling RNA polymerase II and impairing transcription fidelity, thereby driving genomic instability, a hallmark of cancer. TCEA2 (TFIIS) is a transcription elongation factor that rescues stalled polymerases by stimulating transcript cleavage, enabling lesion bypass and transcription-coupled repair. Dysregulated TCEA2 may worsen transcription stress and mutagenesis under inflammatory conditions. Farnesoid X receptor (FXR), a bile acid–activated nuclear receptor, preserves intestinal barrier integrity, prevents mucosal inflammation and colitis-associated colorectal cancer by regulating immune signaling and epithelial homeostasis. This suggests FXR may influence transcriptional stress pathways, including TCEA2 regulation, linking bile acid signaling to genome stability. AIM: To determine whether FXR activation modulates TCEA2 expression in intestinal epithelial cells. METHODS: Differentiated and undifferentiated ileal and colonic enteroids were grown as monolayers and treated with the FXR agonist, obeticholic acid (OCA; 10 µM) for 6 – 24 hrs. Changes in gene expression were analysed by bulk RNASeq and were expressed as fold change in Reads Per Kilobase of Transcript (RPKM) compared to untreated controls (n = 3 throughout). TCEA2 expression in T84 cell monolayers was analyzed by qPCR. RESULTS: Treatment with OCA increased TCEA2 expression in UD colonic enteroids by 17.7 ± 10.9 fold after 6 hrs and 53.0 ± 33.1 fold after 24 hrs compared to unstimulated cells (n = 9; p< 0.001). Similarly, in DF colonic enteroids OCA treatment increased TCEA2 expression by 24.8 ± 5.4 and 33.4 ± 7.3 fold over controls at 6 and 24 hrs, respectively. OCA also stimulated TCEA2 expression in ileal enteroids with maximal responses occurring after 24 hrs of 127.5 ± 41.5 and 782.2 ± 303.2 fold of control in UD and DF cells, respectively (n = 3; p < 0.05). The effects of OCA were specific to TCEA2 as the agonist did not increase expression of the related elongation factors, TCEA1 or TCEA3. In cultured monolayers of T84 colonic epithelial cells the synthetic FXR agonist, GW4064 (5 µM; 3 - 48 hrs), also increased TCEA2 mRNA expression with a maximal effect of 390.3 ± 75.4 fold over controls occurring after 24 hrs of treatment (n = 4; p < 0.05). The effects of GW4064 on TCEA2 expression were significantly inhibited by pretreatment with the NF-κB inhibitor, BMS 345541, from 405.3 ± 60.7 to 96.4 ± 34.1 fold of controls (n = 5; p < 0.01). CONCLUSION: These data demonstrate FXR activation to strongly upregulate TCEA2 mRNA expression in colonic epithelial cells, with effects confirmed across enteroid and T84 cell models. The response is specific to TCEA2 and, at least partially, NF-κB–dependent, suggesting a novel FXR–NF-κB–TCEA2 regulatory axis. These findings indicate FXR may enhance transcriptional resilience under conditions of stress, an effect that may contribute to its anti-inflammatory and anti-cancer effects in vivo. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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