Kynurenic acid derived from mesentery regulates mesenteritis and colitis via inducing white adipose browning in Crohn’s disease

Hypertrophied mesenteric adipose tissue (MAT) wrapped around the inflamed intestine, also known as creeping fat (CrF), is a classic pathological characteristic of Crohn's disease (CD). Recent studies revealed that the abnormal mesentery in CD exhibits a white-to-beige transformation (known as white adipose browning), which may be a compensatory mechanism for disease attenuation. However, its underlying causes and mechanisms remain unknown. The beige MAT samples from patients with CD and normal white MAT samples from patients without CD were collected, and targeted metabolome analysis was performed. Interleukin-10 gene knockout (IL-10-/-) and 2,4,6-trinitrobenzenesulphonic acid solution (TNBS)-induced colitis mice were used to evaluate the effects of kynurenic acid (KYNA) on mesenteritis and colitis. Mesenteric explants and adipocytes were collected and cultured to assess the effects of KYNA on adipose tissue browning and macrophage inflammation. Targeted metabolomic sequencing revealed that KYNA exhibited the highest level of upregulation in the beige MAT of CD, which was tightly correlated with the browning marker UCP-1, inflammatory factors, and adipokines. In vivo experiments demonstrated that KYNA triggered the white-to-beige transformation of MAT in IL-10-/- and TNBS-induced colitis mice, which further alleviated mesenteritis and colitis. Additionally, mesenteric explants and adipocytes displayed a browning phenotype with KYNA co-incubation, and their supernatants significantly induced M2 macrophage polarization and inhibited inflammation. Mechanistically, KYNA induced MAT browning and regulated disease procession of CD via GPR35-ERK1/2-PGC-1α signaling pathway. This study provides novel insights into the browning transformation of the mesentery in CD and suggests a potential approach for clinical therapy.