Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice

ABSTRACT The promising results seen in studies of 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. 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 or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic acid (TUDCA), or glycoursodeoxycholic acid (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, 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. However, bile acid therapy 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. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human IBD. IMPORTANCE Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile acid therapy on the fecal microbiota during colitis has not yet been considered. Here, we studied the alterations in the fecal microbial abundance in colitic mice following the administration of secondary bile acids. Our results show that secondary bile acids reduce the severity of colitis and ameliorate colitis-associated fecal dysbiosis at the phylum level. This study indicates that secondary bile acids might act as a safe and effective drug for inflammatory bowel disease.

Tandem Mass Spectrometric Determination of Atypical 3β-Hydroxy-Δ5-Bile Acids in Patients with 3β-Hydroxy-Δ5-C27-Steroid Oxidoreductase Deficiency: Application to Diagnosis and Monitoring of Bile Acid Therapeutic Response

BACKGROUND3β-Hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency, a progressive cholestatic liver disease, is the most common genetic defect in bile acid synthesis. Early diagnosis is important because patients respond to oral primary bile acid therapy, which targets the negative feedback regulation for bile acid synthesis to reduce the production of hepatotoxic 3β-hydroxy-Δ5-bile acids. These atypical bile acids are highly labile and difficult to accurately measure, yet a method for accurate determination of 3β-hydroxy-Δ5-bile acid sulfates is critical for dose titration and monitoring response to therapy.METHODSWe describe a electrospray ionization LC-MS/MS method for the direct measurement of atypical 3β-hydroxy-Δ5-bile acid sulfates in urine from patients with HSD3B7 deficiency that overcomes the deficiencies of previously used GC-MS methods.RESULTSSeparation of sulfated 3β-hydroxy-Δ5-bile acids was achieved by reversed-phase HPLC in a 12-min analytical run. The mean (SE) urinary concentration of the total 3β-sulfated-Δ5-cholenoic acids in patients with HSD3B7 deficiency was 4650 (1711) μmol/L, approximately 1000-fold higher than in noncholestatic and cholestatic patients with intact primary bile acid synthesis. GC-MS was not reliable for measuring 3β-hydroxy-Δ5-bile acid sulfates; however, direct analysis of urine by fast atom bombardment mass spectrometry yielded meaningful semiquantitative assessment of urinary excretion.CONCLUSIONSThe tandem mass spectrometry method described here for the measurement of 3β-hydroxy-Δ5-bile acid sulfates in urine can be applied to the diagnosis and accurate monitoring of responses to primary bile acid therapy in HSD3B7 patients.