Background Diarrhea is a common clinical feature of ulcerative colitis resulting from unbalanced intestinal fluid and salt absorption and secretion. The Cl-/HCO3- exchanger SLC26A3 is strongly expressed in the mid-distal colon and plays an essential role in colonic Cl- absorption and HCO3- secretion. Slc26a3 expression is up-regulated by lysophosphatidic acid (LPA) in vitro. Our study was designed to investigate the effects of LPA on SLC26A3 expression and the diarrheal phenotype in a mouse colitis model. Methods Colitis was induced in C57BL/6 mice by adding 4% of dextran sodium sulfate (DSS) to the drinking water. The mice were assigned to LPA treatment DSS group, phosphate-buffered saline (PBS) treatment DSS group, DSS only group and untreated mice with a completely randomized design. Diarrhea severity was evaluated by measuring mice weight, disease activity index (DAI), stool water content and macroscopic evaluation of colonic damage. The effect of LPA treatment on Slc26a3 nnRNA level and protein expression in the different groups of mice was investigated by quantitative PCR and Western blotting. Results All mice treated with DSS lost weight, but the onset and severity of weight loss was attenuated in the LPA treatment DSS group. The increases in stool water content and the macroscopic inflammation score in LPA treatment DSS group were significantly lower compared to DSS control group or PBS treatment DSS group ((18.89 +/- 8.67)% vs. (28.97 +/- 6.95)% or (29.48 +/- 6.71)%, P=0.049, P=0.041, respectively and 2.67 +/- 0.81 vs. 4.5 +/- 0.83 or 4.5 +/- 0.54, P=0.020, P=0.006, respectively), as well as the increase in DAI (P=0.004, P=0.008, respectively). LPA enema resulted in higher Slc26a3 mRNA and protein expression levels compared to PBS-treated and untreated DSS colitis mice. Conclusion LPA increases Slc26a3 expression in the inflamed intestine and reduces diarrhea severity in DSS-induced colitis, suggesting LPA might be a therapeutic strategy in the treatment of colitis associated diarrhea.