Mucosal healing did not predict sustained clinical remission in patients in whom the biological therapies had been stopped.

Abstract:Bile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhea. In this study our aim was to characterise the cellular pathomechanism of bile-induced diarrhea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileumresected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na+/H+ exchanger (NHE) and Cl-/HCO3-exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhea, compared to control patients. Acute treatment of colonic crypts with 0.3mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 AbstractBile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhea. In this study our aim was to characterise the cellular pathomechanism of bile-induced diarrhea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na + /H + exchanger (NHE) and Cl -/HCO 3 -exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhea, compared to control patients. Acute treatment of colonic crypts with 0.3mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. This concentration of chenodeoxycholate did not cause morphological changes in colonic epithelial cells, although significantly reduced the intracellular ATP level, decreased mitochondrial transmembrane potential and caused sustained intracellular Ca 2+ elevation. We also showed that chenodeoxycholate induced Ca 2+ release from the endoplasmic reticulum and extracellular Ca 2+ influx contributing to the Ca 2+ elevation. Importantly, our results suggest that the chenodeoxycholate induced inhibition of NHE activities was ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained Ca 2+ elevation.We suggest that bile acids inhibit the function of ion transporters via cellular energy breakdown and Ca 2+ overload in human colonic epithelial cells, which can reduce fluid and electrolyte absorption in the colon and promote ...

On the basis of the present study, we suggest that the simultaneous measurement of serum TNF-α level, serum anti TNF-α concentration, and antibodies against anti TNF-α may further help to optimize the therapy in critical situations.

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