Ulcerative colitis patients in remission have an altered secretory capacity in the proximal colon despite macroscopically normal mucosa

Abstract

Background: One of the hallmarks of acute colitis is loss of epithelial transport. For unknown reasons, many patients still suffer from GI symptoms during remission, indicating a sustained imbalance between absorption and secretion. We hypothesize that the colonic epithelium becomes more reactive to secretagogues to compensate for a failing barrier.

Methods: Biopsies from ascending colon and sigmoid colon of UC patients in remission and controls were mounted in Ussing chambers. Membrane current (Im) and epithelial capacitance (Cp) were used as markers for anion secretion and mucus exocytosis. Carbachol (1 mmol L(-1) ) and forskolin (10 μmol L(-1) ) were used to study Ca(2+) and cAMP-mediated secretion.

Key results: Baseline values showed segmental patterns with higher Im in ascending colon and higher Cp in sigmoid colon of both UC patients and controls, but the patterns did not differ between the groups. The Im response to forskolin was increased (+35%) in the ascending colon of UC patients and the Im response to carbachol was decreased (-40%) in the same segment. No group differences were seen in the distal colon for either the forskolin or carbachol-induced Im responses. The Cp response to carbachol was instead up-regulated in the distal colon of UC patients, but remained unaffected in the proximal colon.

Conclusions & inferences: The proximal colonic mucosa of UC patients in remission seems to shift its reactivity to secretagogues, becoming more sensitive to cAMP-dependent secretion and less sensitive to Ca(2+) -dependent secretion. This phenomenon may contribute to residual diarrhea in this patient group, despite resolution of inflammation.

Figure 1

Basal electrophysiological parameters in the ascending colon and sigmoid colon of controls (n = 32) and UC patients (n = 24). (A) Membrane current (Im), (B) Epithelial resistance (Rp) (C) Epithelial capacitance (Cp). Data are presented as mean ± SEM, ns = non significant.

Figure 2

Forskolin effect on membrane current in human colon. (A) Total response over time in the ascending colon of control n = 12) and UC (n = 15) patients. (B) Delta max response in the ascending colon during 30 min incubation. (C) Total response over time in the sigmoid colon of control (n = 10) and UC (n = 13) patients. (D) Delta max response in the sigmoid colon during 30-min incubation. Data are presented as mean ± SEM, *P < 0.05.

Figure 3

Carbachol effect on membrane current in human colon. (A) Total response over time in the ascending colon of control (n = 21) and UC patients (n = 18). (B) Delta response to carbachol divided into the peak response (max value - baseline) and sustained response (average of three last recordings) baseline). (C) Total response over time in the sigmoid colon of control (n = 17) and UC patients (n = 19). (D) Delta response to carbachol divided into peak response (max value – baseline) and sustained response (average of three last recordings) baseline). Data are presented as mean ± SEM, *P < 0.05, **P < 0.01.

Figure 4

Carbachol effect on epithelial capacitance in human colon. (A) Delta increase in capacitance in the ascending colon of control (n = 21) and UC patients (n = 18). (B) Secretion rate during the first (0–2 min) and second (2–7 min) time points in the ascending colon. (C) Delta increase in capacitance in the sigmoid colon of control (n = 17) and UC patients (n = 19). (D) Secretion rate during the first (0–2 min) and second (2–7 min) time points in the sigmoid colon. Data are presented as mean ± SEM, ***P < 0.001.

Figure 5

Carbachol-induced effect on epithelial capacitance in mouse colon. (A) Delta increase in capacitance in the proximal colon of WT (n = 6), CF (n = 9) and Muc2^−/− (n = 3) mice. (B) Secretion rate during the first (0–2 min) and second (2–7 min) time points in the proximal colon. (C) Delta increase in capacitance in the distal colon of WT (n = 9), CF (n = 9) and Muc2^−/− mice (n = 6). (D) Secretion rate during the first (0–2 min) and second (2–7 min) time points in distal colon. Data are presented as mean ± SEM, **P < 0.01, ns = non significant.