P0143 Isotretinoin treatment protects against Crohn’s disease development and suppresses pro-inflammatory cytokines that drive experimental enteritis
Authors: Meyer M , Grabherr F , Hadjihannas M V , Schwärzler J , Mayr L , Jukic A , Enrich B , Scheffauer L , Zundel L , Zollner A , Grander C , Franke A , Tilg H , Adolph T E 
Published: January 2025

Abstract

Background
The rising incidence of Crohn’s disease (CD) is paralleled by a Westernization of diet including an increased consumption of long-chain polyunsaturated fatty acids (PUFA). Previous research demonstrated that PUFA consumption is positively correlated with clinical disease activity in CD patients1 and mice lacking antioxidant GPX4 in their intestinal epithelial cells develop CD like enteritis when fed a PUFA enriched Western diet2. In this study we investigated whether blocking PUFA signalling through the PUFA receptor RXRα could alleviate experimental enteritis and provide protection against CD development in a Western cohort.

Methods
We generated mice lacking GPX4 (Gpx4ΔPC) specifically in Paneth cells, fed them a PUFA enriched Western-style diet (PUFA-WD) to induce experimental enteritis and treated them with 9-cis retinoic acid, administered by oral gavage. MODE-K cells (murine IECs) were subjected to GPX4 and RXRα silencing using siRNA and then stimulated with PUFA, 9-cis retinoic acid or isotretinoin (which is partly metabolised to 9-cis retinoic acid3). Cytokine expression was measured using ELISA. Additionally, we conducted a retrospective analysis of electronic health records via TriNetX4 to evaluate how isotretinoin treatment in US acne patients influences the likelihood of CD development later in life.

Results
After one month of PUFA-WD feeding, Gpx4ΔPC mice developed CD-like enteritis which was significantly ameliorated when treated with 9-cis retinoic acid during the last 3 days of the experiment. In GPX4 deficient IECs, PUFA induced expression of the neutrophil attracting chemokine CXCL1 was suppressed by RXRα silencing and dose dependently reduced by treatment with the RXRα modulators 9-cis retinoic acid or isotretinoin. This indicates a competitive interaction between PUFA and these modulators for RXRα binding, leading to cytokine production. 85,338 acne patients treated with isotretinoin were compared to 85,259 age and sex matched isotretinoin-untreated acne patients. We analysed outcomes for diagnosis of inflammatory bowel disease within 1 year in these two cohorts. Isotretinoin therapy was significantly associated with protection from Crohn’s disease (OR 0,641, 95% CI (0.509, 0.806)), but not from ulcerative colitis (OR 0.981, 95% CI (0.789, 1.219)).

Conclusion
Our findings reveal that PUFA-induced cytokine production mediated by RXRα plays a key role in the development of diet-induced gut inflammation. This process can be mitigated through the use of RXRα modulators, including isotretinoin. Additionally, isotretinoin use is associated with a reduced risk of Crohn’s disease development in US acne patients.

References
1.Schwärzler J, Mayr L, Vila AV, et al. PUFA-induced metabolic enteritis as a fuel for Crohn's disease. Gastroenterology. Jan 11 2022;doi:10.1053/j.gastro.2022.01.004
2.Mayr L, Grabherr F, Schwarzler J, et al. Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease. Nat Commun. Apr 14 2020;11(1):1775. doi:10.1038/s41467-020-15646-6
3.Allenby G, Bocquel MT, Saunders M, et al. Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. Jan 1 1993;90(1):30-4. doi:10.1073/pnas.90.1.30
4.Palchuk MB, London JW, Perez-Rey D, et al. A global federated real-world data and analytics platform for research. JAMIA Open. Jul 2023;6(2):ooad035. doi:10.1093/jamiaopen/ooad035