Infliximab treatment significantly increased UCP1 expression in Crohn's disease creeping fat, enhancing thermogenesis and reducing pro-inflammatory markers.
Does infliximab promote mitochondrial activation, thermogenesis, and anti-inflammatory reprogramming in Crohn's disease creeping fat?
Anti-TNF therapy with infliximab promotes metabolic and immune reprogramming of Crohn's disease creeping fat, enhancing mitochondrial activation and thermogenesis while reducing inflammation.
Absolute Event Rate: 0% vs 0%
Abstract Background Creeping fat in Crohn’s disease is a metabolically active perilesional adipose tissue that contributes to intestinal inflammation. Creeping fat can acquire a thermogenic (“browning”) phenotype, characterised by increased mitochondrial activity and anti-inflammatory functions.1,2,3 Anti-TNF therapy may influence not only intestinal inflammation but also the metabolic programming of creeping fat.4 This study investigates whether anti-TNF treatment, specifically infliximab, modulates mitochondrial activation, thermogenesis, and immune reprogramming in creeping fat. Methods Two independent human cohorts were analysed. (1) Observational cohort: Creeping fat biopsies from infliximab-treated and anti-TNF–naïve Crohn’s disease patients (n = 6 per group) were clinically characterised (Montreal classification, C-reactive protein, faecal calprotectin) and analysed for metabolic and inflammatory gene and protein expression. Mature Creeping fat -derived adipocytes were isolated to evaluate mitochondrial and browning markers. (2) Ex vivo cohort: Creeping fat explants from CD patients undergoing surgery (n = 5) were treated with infliximab (5 mg/kg, 24 h) to assess direct effects on gene expression by RT-qPCR. Comparisons between groups were performed using non-parametric tests as appropriate (GraphPad Prism 10.0). Statistical significance was defined as p 0.05. Results Infliximab-treated patients exhibited significantly higher expression of the thermogenic marker UCP1 at both mRNA and protein levels compared with naïve patients. Creeping fat-derived adipocytes from treated individuals showed increased expression of mitochondrial biogenesis (TFAM, NRF1), thermogenic (UCP1, PPARG), and anti-inflammatory (IL4, IL13, ADIPOQ) markers, together with reduced pro-inflammatory mediators (TNF, LEP). Ex vivo, infliximab directly upregulated browning and mitochondrial genes (UCP1, PPARG, CIDEA, NAMPT, TFAM, NRF1) and induced an anti-inflammatory shift (increase IL10 and IL4; decrease TNF and CCL2). Conclusion Anti-TNF therapy promotes metabolic and immune reprogramming of Crohn’s disease creeping fat, enhancing mitochondrial activation and thermogenesis while reducing inflammation. These findings suggest that the therapeutic benefits of infliximab extend beyond mucosal healing to include adipose tissue modulation. References: 1. D. Monfort-Ferré et al. J Crohn Colitis., 2022;16(10):1571–83, 2. Zuo L et al. J Crohn Colitis. 2023 21;17(8):1179-1192. 3. Tschurtschenthaler M, et al. J Crohns Colitis. 2023 Aug 21;17(8):1177-1178. 4. A. Boronat-Toscano et al. Int J Mol Sci. 2022 Sep 22;23(19):11170. Conflict of interest: Ms. Montfort-Ferré, Diandra: No conflict of interest Ginés Mir, Iris: No conflicts Cepero, Claudia: No conflict of interest Menacho, Margarita: No conflicts Clua, Laura: No conflict of interest Moliné Pallarés, Alicia: No conflict of interest Cabré, Laia: No conflict of interest Caro, Aleidis: No conflict of interest Ferreres, Joan: No conflict of interest Manyé Almero, Josep: no conflict of interest Suau, Roger: I declare that no conflicts of interest exist related to the authors’ work, study, or project, and that have no financial or personal relationships that could compromise objectivity. Serena, Carolina: No conflict of interest
Montfort-Ferré et al. (Thu,) reported a other. Infliximab treatment significantly increased UCP1 expression in Crohn's disease creeping fat, enhancing thermogenesis and reducing pro-inflammatory markers.