Anti‐TNF Therapy Is Associated With Browning‐ and Immune‐Related Changes in Creeping Fat in Crohn's Disease
Diandra Monfort‐Ferré, Iris Ginés, Claudia Cepero, Laia Cabré, Aledis Caro, Margarita Menacho, Miriam Gené, Montserrat Garcia, Maria del Carmen Lahoz, Maria José Mañas, Marc Martí, Aitana Tarzán, Roger Suau, Joan Ferreres, Josep Manyé, Carolina SerenaABSTRACT
Background
Creeping fat (CrF) in Crohn's disease (CD) is a metabolically active perilesional adipose tissue involved in intestinal inflammation. Whether biological therapies modify its browning‐associated phenotype remains largely unexplored. We investigated whether anti‐TNF treatment is associated with changes in browning‐, mitochondrial biogenesis‐ and immune‐related pathways in CrF and whether similar molecular changes occur following ex vivo infliximab exposure.
Methods
Two independent human cohorts were analysed. (1) Observational cohort: CrF biopsies from anti‐TNF‐treated and anti‐TNF–naïve CD patients ( n = 14 and n = 19, respectively) were analysed for metabolic and inflammatory gene and protein expression. AdMSCs and mature CrF‐derived adipocytes were isolated, and UCP1 protein abundance was assessed by immunohistochemistry and western blotting. (2) Ex vivo cohort: Paired CrF explants from anti‐TNF‐naïve patients with CD undergoing surgery were cultured with or without infliximab (5 mg/kg‐equivalent, 24 h) and analysed by RT‐qPCR and immunohistochemistry.
Results
Anti‐TNF‐treated patients showed higher UCP1 expression in CrF at mRNA and protein levels. CrF‐derived mature adipocytes from treated patients exhibited increased expression of browning‐/thermogenesis‐ and mitochondrial biogenesis‐associated genes, together with reduced selected pro‐inflammatory markers. AdMSCs also showed exploratory differences in their conditioned‐medium protein profile, although no protein remained significant after FDR correction. Ex vivo infliximab exposure was associated with changes in selected browning‐, mitochondrial biogenesis‐ and immune‐related markers.
Discussion
Together, the observational and ex vivo findings identify CrF as an anti‐TNF‐responsive immunometabolic compartment in CD, characterised by coordinated browning‐, mitochondrial biogenesis‐ and immune‐related molecular changes. Functional studies are needed to establish the metabolic significance of these changes.