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Zachariah M. Raouf*, Steven N. Steinway, Dan Scheese, Hannah Moore, Carla M. Lopez, Maame Sampah, Koichi Tsuboi, Johannes Duess, Hee-Seong Jang, William B. Fulton, Meghan Wang, Peng Lu, Sanxia Wang, Thomas Prindle, Chhinder P. Sodhi, David Hackam
Surgery, Johns Hopkins University, Baltimore, MD

Inflammatory bowel disease and disorders of gastrointestinal motility overlap significantly in the clinical setting. While ileus is commonly seen, the mechanisms involved remain poorly understood, in part due to a lack of robust in vivo models. Prior studies have shown that serotonergic signaling plays a role in control of intestinal motility, although the precise mechanisms by which colonic and ileal motility are linked during inflammatory processes remain unclear. We hypothesize that the small intestinal dysmotility seen in a colonic inflammation model is precipitated through aberrant changes in serotonergic signaling from the inflamed colon to the small intestine.

Four-week-old C57BL/6 mice were randomized into control and DSS groups. DSS groups received 7-day exposure to DSS (MW 40,000–50,000 kDa) ad libitum at concentrations of 2.5% and 5% in 0.5% sucrose drinking water. Mice were sacrificed on day 7. 70kda fluorescein-dextran was administered and animals were sacrificed 30 minutes later; the whole intestine was divided into 2cm sections. Sections were homogenized, and FITC-fluorescence measured in the supernatant. The small intestinal transit time was derived from the position of the geometric (Geom) center (GC) of FITC-dextran. Colon length was measured, and samples of stomach, ileum, and colon were taken. mRNA expression of interleukin 6 (IL-6), interleukin 1ß (IL1ß), and lipocalin-2 (LCN2) as well as serotonergic pathway genes tryptophan hydroxylase (Tph1), and serotonin transporter (5'HTT) were normalized to ribosomal protein large P0 (Rplp0).

Compared to controls, mice receiving 2.5% or 5% DSS gained less percent weight (Ctrl=24.50 vs 2.5%DSS=5.18 vs 5%DSS= -7.41; p<0.0001), had shorter colons (Ctrl=59.35mm vs 2.5%DSS=50.57mm vs 5%DSS=41.00mm; p<0.05) and showed significant upregulation of antimicrobial peptide, LCN2 (Ctrl=38.50 vs 2.5%DSS= 218.40; p<0.01) and pro-inflammatory cytokines IL6 (Ctrl=0.94 vs 2.5%DSS=4.38; p<0.05) and IL1ß (Ctrl=9.61 vs 2.5%DSS=69.95; p<0.01). DSS significantly reduced intestinal motility (Ctrl, GC=10.5 vs 2.5%DSS, GC=8 vs 5%DSS, GC=6; p<0.01). Ileal serotonergic markers showed significant alteration in DSS groups with Tph1 gene expression upregulated (Ctrl=4.01 vs 2.5%DSS=6.25; p<0.05) and serotonin transporter (5'HTT) expression downregulated (Ctrl=91.68 vs 2.5%DSS=52.04; p<0.05). However, no significant changes in key pro-inflammatory cytokines (IL6, IL1β and TNFα) were found in the terminal ileum.

Colonic inflammation induced significant intestinal dysmotility that was associated with changes in the expression of genes that regulate serotonergic signaling. These findings suggest the potential for novel approaches for the control of colitis associated ileus through modulation of the serotonergic signaling system.

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