L. VAN DEN BOSSCHE (1), P. HINDRYCKX (1), L. DEVISSCHER (1), S. DEVRIESE (1), S. VAN WELDEN (1), T. HOLVOET (1), R. VILCHEZ-VARGAS (2), M. VITAL (3), D. PIEPER (3), J. VANDEN BUSSCHE (4), L. VANHAECKE (4), T. VAN DE WIELE (2), M. DE VOS (1), D. LAUKENS (1) / [1] Ghent University, Ghent, Belgium, Department of Gastroenterology, [2] Ghent University, Ghent, Belgium, Center for Microbial Ecology and Technology, [3] Helmholtz Centre for Infection Research (HZI), , Germany, Department of Medical Microbiology, [4] Ghent University, Ghent, Belgium, Department of Veterinary Public Health and Food Safety
Introduction: The promising results with secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (IBD). However, the exact mechanism by which bile acid therapy confers protection from colitogenesis is currently unknown.
Aim: Since the gut microbiota plays a crucial role in the pathogenesis of IBD, and exogenous bile acid administration may affect the community structure of the microbiota, we examined the impact of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine/glycine conjugates on the fecal microbial community structure during experimental colitis.
Methods: Acute colitis was induced in mice by administration of 4% dextran sodium sulfate to the drinking water for 7 days. Mice were treated with 500 mg/kg/d UDCA, tauroursodeoxycholic acid (TUDCA), glycoursodeoxycholic acid (GUDCA), or placebo by oral gavage. At day 9 of colitis, fecal microbiota profiles were determined through 16S rRNA Illumina MiSeq sequencing and mice were sacrificed at day 10 to assess the severity of inflammation. Ultra-high performance liquid chromatography and high resolution mass spectrometry were performed on fecal samples to analyze the extent of biotransformation of orally administered UDCA, TUDCA and GUDCA.
Results: Daily administration of UDCA, TUDCA and GUDCA equally lowered the severity of colitis, as evidenced by reduced body weight loss, colonic shortening and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile acid therapy during colitis did not restore fecal bacterial richness and diversity but normalized the colitis-associated increased ratio of Firmicutes to Bacteroidetes. Interestingly, administration of bile acids prevented the loss of Clostridium cluster XIVa and increased the abundance of Akkermansia muciniphila, bacterial species known to be particularly decreased in IBD patients. Orally administered UDCA, TUDCA and GUDCA were extensively metabolized in vivo, resulting in a similar fecal bile acid composition.
Conclusions: We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and improve inflammation in human IBD.