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.

Ameliorative effect of animal bile preparations on dextran sulfate sodium‐induced colitis in mice

“…Sato et al ., have shown that UDCA exerts its preventive effect on DSS‐induced colitis through its bacterial conversion into LCA, which is a TGR5 agonist . In addition, Van den Bossche et al ., showed that UDCA ameliorates DSS‐induced colitis in mice by improving colitogenic dysbiosis in the colon . This also supports the present observation that BB, which contains abundant UDCA (Table ), increased both UDCA and LCA content in the cecum and exerted ameliorative effects on DSS‐induced colitis.…”

“…Therefore, the animal bile preparations containing different types of bile acid are assumed to exert distinct effects on the pathophysiology of gastrointestinal tissues. Indeed, the beneficial effects of bile acids in animal bile preparations have been recently demonstrated using a dextran sulfate sodium (DSS)‐induced colitis model , which is extensively used as an experimental model of inflammatory bowel diseases . No study, however, has yet examined whether the animal bile preparations have therapeutic efficacy against inflammatory bowel disease experimentally or clinically.…”

Emerging roles of bile acids in mucosal immunity and inflammation

“…For example, UDCA ameliorates DSS-induced colitis in mice, and this is associated with expansion of antiinflammatory enteric bacterial species, including cluster XIVa Clostridium and Akkermansia muciniphila, which are generally depleted in IBD patients. 158,159 Whether the therapeutic effects of UDCA in rodent colitis models is translatable to human IBD patients, and the extent to which this activity involves direct effects on hepatic BA production, the gut flora, and/or the mucosal immune system remains to be elucidated. Nonetheless, these data raise the possibility that elevated BA accumulation in the intestinal mucosa, due to either altered BA metabolism or increased intestinal permeability, contribute to IBD-associated mucosal inflammation.…”

Manipulating resident microbiota to enhance regulatory immune function to treat inflammatory bowel diseases

“…Bile acids are also bacterial metabolites with pleotropic functions, including the regulation of metabolism and inflammation through interactions with both microbial and host receptors [60]. Ursodeoxycholic acid, a hydrophilic secondary bile acid, ameliorates mouse experimental colitis by expanding anti-inflammatory cluster XIVa Clostridium and Akkermansia muciniphila [61]. Dysbiosis in enteric bacteria changes bile acid receptor FXR expression, which is protective for experimental colitis models through inhibiting NF-kB signaling [62].…”