Do Probiotics Reduce PPAR-γ in Ulcerative Colitis? An Open Labeled Pilot Study

Abstract

Purpose: Evidence is mounting that bacteria play a role in the pathogenesis of IBD. Probiotics have shown efficacy in the treatment of ulcerative colitis (UC) although the mechanism of action is unknown. PPAR-γ is expressed in colonic epithelial cells and inhibits cytokine activation. In UC, PPAR-γ levels are low. The aim of this study was to determine whether probiotics (VSL#3) up-regulate PPAR-γ as their mechanism of action. Methods: Patients with active and inactive UC were screened for eligibility, consented and the disease activity index (DAI) calculated from a questionnaire and a sigmoidoscopy with biopsy. In this open labeled study, patients were treated with VSL#3 orally for 4 weeks. Concurrent use of mesalamine was permitted, but steroids, antibiotics or immunomodulators were prohibited. At the end of 4 weeks, a sigmoidoscopy with biopsy was repeated and the DAI calculated. Real time PCR was performed to assess the level of PPAR-γ from the biopsy samples pre and post VSL#3. Results: 15 patients were enrolled; 8 with active and 7 inactive disease. Baseline DAI was 5.6 ± 2.6 for patients with active disease and 0.7 ± 0.8 in the inactive group (p = 0.001). Following VSL#3 treatment, 75% of patients with active disease achieved remission (DAI ≤2) with the DAI decreasing by 66% from 5.6 ± 2.6 to 1.5 ± 1.8 (p = 0.01). This was due to statistically significant reductions in stool frequency, sigmoidoscopy scores and global assessment. DAI also decreased in those with inactive disease (p = ns). However, only the endoscopic subscore was significantly decreased at 4 weeks (p = 0.04). At baseline, PPAR-γ levels were similar between patients with active and inactive disease (p = 0.8). Following VSL#3, PPAR-γ RNA levels were reduced by 45% (p = 0.001) in active disease and by 45.6% (p = 0.1) in those with inactive disease. At 4 weeks, PPAR-γ levels were similar between patients with active disease that achieved remission and patients with inactive disease (p = 0.6). Conclusions: 75% of patients with active disease achieved remission with VSL#3. This was associated with a significant reduction in PPAR-γ levels from baseline in patients with active disease. Overall there was no significant correlation (p = 0.25) between reduction in the DAI and reduction in PPAR-γ. This data indicates that the mechanism of action of probiotics is not through an upregulation in PPAR-γ but is perhaps the result of immune tolerance. Supported by NIH grant M01-RR0132.