Poster Presentation Australian & New Zealand Obesity Society 2016 Annual Scientific Meeting

IL-22 Therapy Reverses High Fat Diet Induced Colonic Epithelial Cell Stress and Inflammation. (#244)

Sahar Keshvari 1 , Max Gulhane 1 , Lydia Murray 1 , Rohan Lourie 1 , Hui Tong 1 , Yong Sheng 1 , Ran Wang 1 , Alicia Kang 2 , Veronika Schreiber 1 , Kuan Yau Wang 1 , Graham Magor 1 , Stuart Denman 3 , Jakob Begun 1 , Timothy Florin 1 , Andrew Perkins 1 , Páraic Ó Cuív 2 , Michael McGuckin 1 , Sumaira Hasnain 1
  1. Mater Research_UQ, Woolloongabba, QLD, Australia
  2. University of Queensland Diamantina Institute, Brisbane
  3. The Commonwealth Scientific and Industrial Research Institute, Brisbane

In Type 2 diabetes β-cell dysfunction is accompanied by adverse cellular responses to high concentration of lipids and glucose, oxidative stress, endoplasmic reticulum (ER) stress and local inflammation. Furthermore, prolonged high fat diets (HFD) induce low-grade chronic intestinal inflammation in mice, and diets high in saturated fat are a risk factor for the development of human inflammatory bowel diseases. Previously we showed that IL-22 is a natural regulator of β-cell insulin biosynthesis and secretion, protecting the β-cell from stress, preventing hypersecretion of poor quality insulin, and suppressing innate islet inflammation1. To further investigate extra-pancreatic effects of IL-22 we hypothesized that HFD-induced endoplasmic reticulum (ER)/oxidative stress occur in intestinal secretory goblet cells, triggering inflammatory signalling and reducing synthesis/secretion of proteins that form the protective mucus barrier.

A prolonged HFD was accompanied by an increase in circulating triglyceride levels in-vitro in cultured intestinal goblet cells. Non-esterified long-chain saturated fatty acids directly increased oxidative/ER stress leading to protein misfolding. We noted an increase in the intestinal inflammatory cytokine signature, alongside compromised mucosal barrier integrity, loss in the tight junction protein, claudin-1 and increased serum endotoxin levels when mice were kept on HFD for 22 weeks. Obese mice treated with IL-22, not only had an improvement in hyperglycaemia but this was accompanied by reduced ER/oxidative stress in the intestine which overall led to an improvement in the integrity of the mucosal barrier. IL-22 treatment also reversed microbial changes associated with obesity and diabetes with an increase in Akkermansia muciniphila and decrease in E. coli and Prevotella spp. Consistent with epidemiological studies, our experiments suggest that HFDs are likely to impair intestinal barrier function, particularly in early life, which partially involves direct effects of free fatty acids on intestinal secretory cells, and this can be reversed by IL-22 therapy.

  1. Hasnain, S. Z. et al. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nature medicine 20, 1417-1426, doi:10.1038/nm.3705 (2014).