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P497 IL-33/ST2 levels and gut microbiota characterisation can predict mucosal response to anti-TNF therapy in ulcerative colitis

L. R. Lopetuso*1, V. Petito1, C. Graziani1, A. Quagliariello3, F. Del Chierico3, L. Putignani3, T. T. Pizarro4, A. Armuzzi1, F. Scaldaferri1, A. Gasbarrini1

1Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, UOC Internal Medicine, Gastroenterology and Hepatology Gastroenterological and Oncological Area, Gastroenterological and Endocrino-Metabolical Sciences Department, Roma, Italy, 3Ospedale Pediatrico Bambino Gesù IRCCS, Unità per lo studio del Microbioma Umano, Roma, Italy, 4Case Western Reserve University, Cleveland, USA


IL-33/ST2 axis and gut microbiota are important factors in the pathogenesis of IBD. Anti-TNF are able to modulate the IL-33/ST2 axis as well as gut microbiota in inflammatory conditions and are effective in inducing mucosal healing in patients with moderate-to-severe ulcerative colitis (UC). The aim of our study was to explore the potential role of the IL-33/ST2 axis and gut microbiota in the mucosal healing process mediated by anti-TNF therapy in UC.


Endoscopic MAYO score was calculated before the first anti-TNF infusion (T0) and after 6 weeks (T2). Twenty-six UC patients (MAYO score at T0 ≥ 2), grouped into 14 responders (R) with mucosal healing (MAYO score ≤ 1) and 12 non-responders (NR) to anti-TNF at T2 (MAYO score ≥ 2) were enrolled. Ten healthy controls were also enrolled. At each time point, serum and faecal samples were collected. ELISA and western blot were performed. Intestinal biopsies were also taken from the rectum and IHC was done. Genomic DNA was extracted from faecal samples and V3-V4 regions of the 16S rRNA gene were sequenced by MiSeq Illumina platform for microbiota characterisation.


IL-33 protein levels were significantly increased in R vs. NR, both at T0 and T2. Among R, IL-33 protein was slightly reduced at T2 vs. T0, while unchanged in NR. Interestingly, significantly higher levels of ST2 were found in R vs. NR at T0, while no differences between groups were found at T2. Among R, ST2 levels were dramatically reduced at T2 vs. T0. No significant differences were found in NR at both time points. Controls showed significantly lower levels of both IL-33 and ST2 compared with other groups. Full-length, bioactive IL33 (31 kDa), ST2L (76 kDa) and sST2 (52 kDa) were expressed in all experimental groups; the cleaved, less active form of IL33 (24 kDa) was increased in only NR vs. R and healthy controls. IHC confirmed these observations. IL-33 and ST2 staining was more intense within the inflamed and ulcerated mucosa of R compared with NR at T0. After 6 weeks, ST2 staining was even more evident in R, notably localised to the healed mucosa and in close proximity to areas of re-epithelialization. Little to no staining for both IL-33 and ST2 was present in healthy controls. Microbiota analysis showed an increased biodiversity at T0 in R vs. NR. At T0, NR showed lower levels of Verrucomicrobia (Akkermansia municiphila) and Firmicutes, with an increased abundance of Bacteroidetes vs. R.


Our results suggest a possible role for IL-33/ST2 and gut microbiota in predicting gut mucosal wound healing in patients with moderate-to-severe UC treated with anti-TNF. IL-33/ST2 axis and gut microbiota could thus represent a useful diagnostic tool to evaluate therapeutical options in IBD patients.