Title

Exclusive Enteral Nutrition Alleviates Th17-Mediated Inflammation via Eliminating Mechanical Stress–Induced Th17-Polarizing Cytokines in Crohn’s-like Colitis

Authors

Ramasatyaveni Geesala, PhD, Ke Zhang, MSc, You-Min Lin, MD, PhD John C. Johnson, BSc, Yingzi Cong, PhD, Steven Cohn, MD, PhD and Xuan-Zheng Shi, MD, MSc

Journal

Inflammatory Bowel Disease

Abstract

Background and Aims: Exclusive enteral nutrition (EEN) with a liquid diet is the only established dietary treatment for Crohn’s’ disease (CD). However, the mechanism of action of EEN in CD is unclear. T helper 17 (Th17) immune response plays a critical role in CD. We hypothesized that EEN alleviates Th17 response by eliminating mechanical stress–induced expression of Th17-polarizing cytokines.

Methods: A rat model of Crohn’s-like colitis was established by intracolonic instillation of TNBS (65 mg/kg in 250 µL of 40% ethanol). Control rats were treated with saline. We characterized immunophenotypes and molecular changes of the colon in control and colitis rats with and without EEN treatment. Th17 differentiation was determined using coculture assays.

Results: TNBS instillation induced transmural inflammation with stenosis in the inflammation site and a marked increase of Th17-polarizing cytokines interleukin (IL)-6 and osteopontin and the Th17 cell population in the mechanically distended preinflammation site (P-site). EEN treatment eliminated mechanical distention and the increase of IL-6, osteopontin, and Th17 response in the P-site. IL-6 and osteopontin expression was found mainly in the muscularis externa. Mechanical stretch of colonic smooth muscle cells in vitro induced a robust increase of IL-6 and osteopontin. When naïve T cells were cultured with conditioned media from the P-site tissue or stretched cells, Th17 differentiation was significantly increased. Inhibition of IL-6, but not deletion of osteopontin, blocked the increase of Th17 differentiation.

Conclusions: Mechanical stress induces Th17-polarizing cytokines in the colon. EEN attenuates Th17 immune response by eliminating mechanical stress–induced IL-6 in Crohn’s-like colitis. Key Words: exclusive enteral nutrition, Crohn’s disease, Th17 immune response, mechanical stress, IL-6.