Volume 126, Issue 7, Pages (June 2004)

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Volume 126, Issue 7, Pages 1657-1664 (June 2004) Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome 1 Matthew D. Coates, Christine R. Mahoney, David R. Linden, Joanna E. Sampson, Jason Chen, Hagen Blaszyk, Michael D. Crowell, Keith A. Sharkey, Michael D. Gershon, Gary M. Mawe, Peter L. Moses Gastroenterology Volume 126, Issue 7, Pages 1657-1664 (June 2004) DOI: 10.1053/j.gastro.2004.03.013

Figure 1 Colonic mucosal 5-HT is decreased in UC, IBS-C, and IBS-D. (A) The 5-HT concentration per milligram of wet weight was significantly decreased in colonic mucosa of individuals with UC, IBS-C, and IBS-D. Furthermore, 5-HT content was significantly lower in the severe UC group compared with the nonsevere UC group (n values: control, 24; UC, 19; IBS-D, 12; IBS-C, 15; nonsevere UC, 11; severe UC, 8; ∗P < 0.01 compared with control, ANOVA; †P < 0.001 compared with control, ANOVA; ††P < 0.01 nonsevere vs. severe UC, t test). (B) Consistent with the findings related to 5-HT concentrations, there was a significant decrease in mRNA encoding TpH, the rate-limiting enzyme in the biosynthesis of 5-HT, in the UC, IBS-D, and IBS-C samples (n values: control, 22; UC, 19; IBS-D, 14; IBS-C, 16; nonsevere UC, 13; severe UC, 6; ∗P < 0.05 compared with control, ANOVA). The TpH-1 level was significantly different when the severe UC group was compared with the nonsevere UC group (note that the scale is expanded for the UC subgroup data). Gastroenterology 2004 126, 1657-1664DOI: (10.1053/j.gastro.2004.03.013)

Figure 2 The number of EC cells is decreased in severe UC but is unchanged in nonsevere IC as well as IBS-C and IBS-D. (A) There were no significant changes in the number of epithelial cells per colonic gland in the UC, IBS-D, or IBS-C groups relative to healthy controls (P = 0.06 for control vs. UC). However, when the UC group was divided into severe and nonsevere subgroups, the severe UC samples had more epithelial cells than controls (†P < 0.01, ANOVA) and the severe UC group had significantly more epithelial cells than the nonsevere UC group (††P < 0.01, t test). These data show that UC samples were obtained from nonulcerated regions. (B) There was a decrease in EC cells per millimeter muscularis mucosa versus control in the severe UC group (†P < 0.01, ANOVA), and the severe UC group had fewer EC cells per millimeter than the nonsevere UC group (††P < 0.02, t test). (C) The percentage of 5-HT—positive epithelial cells was significantly lower in the severe UC group versus control (†P < 0.01, ANOVA), and the severe UC group had a lower percentage of EC cells than the nonsevere UC group (††P < 0.005, unpaired t test). (D) The percentage of enteroendocrine cells that are EC cells was also decreased versus control in the severe UC group (†P < 0.01), and the severe UC group had a lower percentage of enteroendocrine cells that were EC cells than the nonsevere UC group (††P < 0.01, unpaired t test). n values: control, 14; UC, 19; IBS-D, 13; IBS-C, 11; nonsevere UC, 12; severe UC, 7. Gastroenterology 2004 126, 1657-1664DOI: (10.1053/j.gastro.2004.03.013)

Figure 3 Mucosal 5-HT release was not altered in UC or IBS or in the UC subgroups. No significant changes were detected in the 5-HT release from colonic mucosa relative to control in any of the experimental groups under (A) basal or (B) stimulated conditions. Furthermore, there was no significant difference in basal or stimulated 5-HT release between the severe and nonsevere UC subgroups. Stimulation of 5-HT release involved 3 minutes of mild agitation on a vortex machine. Stimulation resulted in a significant increase in 5-HT release relative to the samples from the same individuals under basal conditions (control, P < 0.01; UC, P < 0.001; IBS-D, P < 0.01; IBS-C, P < 0.05; paired t test). Histologic evaluation of specimens that underwent this procedure showed that there was no change in the cellular integrity of the tissue samples. n values: control, 19; UC, 19; IBS-D, 13; IBS-C, 12; nonsevere UC, 11; severe UC, 8. Gastroenterology 2004 126, 1657-1664DOI: (10.1053/j.gastro.2004.03.013)

Figure 4 Mucosal 5-HT transporter expression was reduced in UC and IBS. SERT mRNA levels were significantly reduced in all 3 experimental groups (n values: control, 23; UC, 19; IBS-D, 14; IBS-C, 16; ∗P < 0.01). In addition, SERT immunoreactivity was diminished in all experimental groups (n values: control, 11; UC, 10; IBS-D, 7; IBS-C, 10; †P < 0.001). Micrographs show representative SERT immunoreactivity levels. There were no differences in SERT mRNA or immunoreactivity levels in the nonsevere versus severe UC groups. All images were obtained with identical camera settings, and brightness and contrast levels were not altered. Gastroenterology 2004 126, 1657-1664DOI: (10.1053/j.gastro.2004.03.013)