1 SCIENTIFIC REPORTS | (2019) 9:12792 | https://doi.org/10.1038/s41598-019-49129-6 www.nature.com/scientificreports Flightless I exacerbation of infammatory responses contributes to increased colonic damage in a mouse model of dextran sulphate sodium-induced ulcerative colitis Z. Kopecki 1,2 , G. Yang 1 , S. Treloar 3 , S. Mashtoub 4,5 , G. S. Howarth 2 , A. G. Cummins 6 & A. J. Cowin 1,2 Ulcerative colitis (UC) is a chronic infammatory bowel disease characterized by cytokine driven infammation that disrupts the mucosa and impedes intestinal structure and functions. Flightless I (Flii) is an immuno-modulatory protein is a member of the gelsolin family of actin-remodelling proteins that regulates cellular and infammatory processes critical in tissue repair. Here we investigated its involvement in UC and show that Flii is signifcantly elevated in colonic tissues of patients with infammatory bowel disease. Using an acute murine model of colitis, we characterised the contribution of Flii to UC using mice with low (Flii +/- ), normal (Flii +/+ ) and high Flii (Flii Tg/Tg ). High levels of Flii resulted in signifcantly elevated disease severity index scores, increased rectal bleeding and degree of colon shortening whereas, low Flii expression decreased disease severity, reduced tissue infammation and improved clinical indicators of UC. Mice with high levels of Flii had signifcantly increased histological disease severity and elevated mucosal damage with signifcantly increased infammatory cell infltrate and signifcantly higher levels of TNF-α, IFN-γ, IL-5 and IL-13 pro-infammatory cytokines. Additionally, Flii overexpression resulted in decreased β-catenin levels, inhibited Wnt/β-catenin signalling and impaired regeneration of colonic crypts. These studies suggest that high levels of Flii, as is observed in patients with UC, may adversely afect mucosal healing via mechanisms involving Th 1 and Th 2 mediated tissue infammation and Wnt/β-catenin signalling pathway. Ulcerative colitis (UC) is a chronic infammatory bowel disease (IBD) with incidences of 7.6 to 13.9 cases per 100,000 people in Westernised industrialized nations. It is defned as a lifelong condition with periods of remis- sion, which manifests in bloody diarrhoea, mucus and abdominal pain 1 . It peaks in young adults and to lesser extent in the elderly. Pathogenesis of UC is unknown, although genetic susceptibility, environmental factors, microorganisms, immune dysregulation and chemical mediators have all been suggested as possible contributing factors 2 . Symptoms may relapse and remit, but mucosal infammation continues with spontaneous remission being uncommon. Treatment includes corticosteroids, aminosalicylates, immunomodulators and biologics such as anti-tumour necrosis factor-α (TNF-α) antibody, and surgical resection 3 . Randomised controlled trials have 1 Regenerative Medicine, Future Industries Institute, University of South Australia, Mawson Lakes, Adelaide, South Australia, Australia. 2 School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia. 3 School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, Adelaide, South Australia, Australia. 4 Department of Gastroenterology, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia. 5 Discipline of Physiology, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia. 6 Department of Gastroenterology and Hepatology, The Queen Elizabeth Hospital, Woodville South, Adelaide, South Australia, Australia. Z. Kopecki and A. J. Cowin contributed equally. Correspondence and requests for materials should be addressed to Z.K. (email: zlatko.kopecki@unisa.edu.au) Received: 8 April 2019 Accepted: 15 August 2019 Published: xx xx xxxx OPEN