Fecal Microbiota Transplantation for the Treatment of Primary Sclerosing Cholangitis.

Background and Significance:

Primary sclerosing cholangitis (PSC) is a progressive, chronic cholestatic liver disease characterized by inflammatory and fibrotic destruction of the intrahepatic and/or extrahepatic bile ducts. PSC will progress to biliary cirrhosis, portal hypertension and liver failure (1) . It is a common indication for liver transplantation. In up to 90% of patients, ulcerative colitis or Crohn's disease will also be present (2) . Medications used for the treatment of ulcerative colitis such as sulfasalazine, corticosteroids and azathioprine or 6-mercaptopurine have not been effective in reducing inflammation or bringing about remission in PSC (3) . A number of studies of other anti-inflammatory agents have failed to demonstrate any benefit. In standard dosing, ursodeoxycholic acid (UDCA) may be of benefit in delaying the progression of disease, although a recent study showed that high dose UDCA was not only ineffective, it may also be harmful (4) . Currently there is no medical therapy that has been shown to be effective in PSC and no therapy has won FDA approval for this indication.

It has been postulated that bacterial components may stimulate an aberrant immune response resulting in the perpetuation of the biliary inflammation seen in PSC. Bacteria gain access to the liver and biliary tree through translocation across an abnormal and inflamed intestinal mucosa into the portal venous system (5) . Studies have shown an increased risk of portal venous bacteremia in patients with PSC. Animal models have demonstrated that enteric dysbiosis can lead to hepatobiliary inflammation with various features of PSC (6) . The pathways through which bacteria might then induce the pathology characteristic of PSC are speculative.

Bacteria might cause direct injury through colonization, though studies have not identified any particular pathogen or a consistent set of bacteria. Another potential pathway may be that a certain set of bacteria generate secondary bile acids, such as deoxycholic acid and lithocholic acid, which are injurious to the biliary system (7) . We recently found an altered serum bile acid composition in patients with PSC compared to non-cholestatic controls. Treatment with UDCA in PSC patients decreases the concentration of the toxic primary bile acid chenodeoxycholic acid but also increased the toxic secondary bile acid lithocholic acid (Abstract DDW 2014). Alteration of the gut microbiota may minimize or eliminate this injury.

There is limited experience in the use of antibiotics in treating PSC. Metronidazole has been shown to result in improvement in liver function tests (8) . Oral vancomycin has also been advanced as a potentially promising therapy (9) . An initial report of three pediatric patients and a subsequent small, uncontrolled series of oral vancomycin in 14 children showed improvement in liver tests and symptoms (10, 11) . We recently completed a study of oral vancomycin was given to 10 adults with PSC found mild improvement in serum alkaline phosphatase levels (Abstract DDW 2011).