Could gut microbiota protect against sclerosing cholangitis?

Abstract

Potential conflict of interest: Dr. Backhed consults and received grants from Albireo. He owns stock and holds intellectual property rights with Metabogen. He consults for Boehringer Ingelheim and Merck and received grants from Danone. See Article on Page 185 Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease characterized by an inflammatory and fibrotic process affecting both intra‐ and extrahepatic bile ducts that eventually develops into liver cirrhosis and liver failure.1 Up o 80% of PSC patients have concomitant inflammatory bowel disease (IBD) that, in the majority of cases, is diagnosed as ulcerative colitis; therefore, PSC is considered the classic hepatobiliary manifestation of IBD.2 During the past decade, the gut microbiota has been implicated as an environmental factor that can protect against or promote different diseases, including IBD.3 Recent data from a number of basic and clinical studies have suggested a pathogenetic relationship between PSC and gut microbiota,4 and indeed, the gut microbiota of PSC patients was found to show significantly less diversity compared to the healthy population and UC patients without biliary disease.5 Interestingly, reduced diversity seems to be associated with both obesity and IBD.3 To address the hypothesis that gut microbiota directly contributes to PSC, Tabibian et al.6 rederived the multidrug resistance 2 knockout (Mdr2−/−), a well‐established animal model of PSC7 and low phospholipid‐associated cholelithiasis,8 as germ free (GF). Surprisingly, GF Mdr2−/− mice exhibited a substantially more severe PSC phenotype compared with conventionally raised (CONV‐R) counterparts. Compared with CONV‐R Mdr2−/−, GF animals had higher serum markers of cholestasis and more advanced histological damage, such as increased liver fibrosis, ductular reaction, and ductopenia. Otherwise, there were no gross differences reported between GF and CONV‐R Mdr2−/− mice, apart from increased cecal weight, a well‐documented phenotype of GF mice. It should be noted that whereas GF mice were bred at Taconic and shipped during GF conditions to the investigators before the end of the experiment, the conventional counterparts were bred and raised in the lab of the investigators. Furthermore, it would have been interesting to investigate whether colonization with an unfractionated microbiota from CONV‐R mice would have rescued the phenotype to further demonstrate the protective role of the gut microbiota. The investigators then studied differences in cholangiocyte senescence, a mechanism that they recently described as characteristic for the development and progression of PSC,9 and found senescence to be increased in GF Mdr2−/−. To further address potential mechanisms, Tabibian et al. studied bile acid (BA) composition. The gut microbiota is essential for BA metabolism and regulates both the levels of primary BA synthesis, through modulation of the nuclear receptor, farnesoid X receptor, as well as production of secondary BAs, such as deoxycholic acid (DCA), that are absent in GF mice.10 In contrast to previous published articles, the present study did not observe increased levels of tauro‐betamuricholic acid or (tauro‐) ursodeoxycholic acid (UDCA) in GF mice,10 which may be attributed to different genetic backgrounds of the mice in the present study. DCA has previously been linked to induction of hepatocyte senescence,11 but this metabolite did not affect senescence in the cultured cholangiocytes. In contrast, (unconjugated) UDCA was protective against cholangiocyte injury and senescence. Taken together, this study highlights the possibility that the gut microbiota, which is altered in humans with PSC, may contribute to disease progression. However, Mdr2−/− mice represent an extreme variant completely lacking phospholipids in bile that are needed for the formation of mixed micelles with cholesterol and toxic BAs. This is not the case in the vast majority of patients with PSC, where variants or mutations in the human homologue gene, MDR3, are very rare findings.2 Thus, the role of BAs in the pathogenesis of PSC still is unclear. It would have been interesting to colonize GF Mdr2−/− mice with microbiota from patients and controls to determine whether microbiota from control subjects can prevent development of sclerosing cholangitis. Finally, this article is likely to set a flurry of studies to further address the role of microbiota in PSC, which may eventually lead to novel therapeutic avenues for treating this disease.