Following the interest in the microbiome in many areas of medicine, FMT is tested in a wide variety of conditions, within or outside clinical trials. Besides providing a new treatment option, well-designed FMT trials also provide the strongest evidence for a role of the gut microbiome in the development or progression of human disease. A landmark study from the Netherlands, the randomized controlled FAT-LOSE trial, provided such evidence in metabolic diseases by showing that allogenic FMT from lean people to obese people improved insulin sensitivity [33]. No studies of FMT have so far been published in biliary diseases, but based on the close relationship with IBD, the first trials are likely to be performed in PSC.

For chronic conditions, a drug-like agent targeting the gut microbiome is probably more attractive. Possible agents include probiotics, prebiotics and antibiotics. Probiotics are defined as live microorganisms that are not constituents of the host microbiome but confer a health benefit to the host [34]. The bacterial strains currently available are of limited value, and, in line with this, no effect has been observed in small trials in PSC. The prospects do however include new and more effective bacterial cocktails designed on the basis of effects observed in FMT trials or experimental studies, or even bacterial strain genetically engineered to produce beneficial metabolites. Prebiotics are nondigestible food components (typically dietary fibre) that are selectively metabolized by beneficial members of the gut microbial community and therefore act to stimulate their growth [34]. Prebiotics have been shown to alter the gut microbiome, but only modest clinical effects have so far been observed in, e.g. type 2 diabetes. Choice of prebiotic in treatment trials could be motivated by the microbiome alterations, e.g. intending to increase microbiome diversity in the gut. Antibiotics have strong impact on the gut microbiome and may influence the disease process in, e.g. PSC (see above). While still not ruled out as a possible drug option in PSC, the major impact on the microbiome (with unknown consequences for host physiology) and risk of antibiotic resistance make chronic antibiotic treatment unattractive long term.

The importance of diet in the shaping of the gut microbiome opens the door for more efficient disease preventive lifestyle advice on the population level (“eat yourself healthy”) but also protective or disease-targeted diets in patients. Extraordinary examples of diets causing microbiome-related disease include an experimental model of obesity-driven hepatocellular carcinoma, which was shown to be caused by increased deoxycholic acid levels produced by increased numbers of gram-positive bacteria able to generate secondary bile acids [35], and a milk fat-driven model of colitis caused by diet-related increases of taurin-conjugated bile acids with subsequent increases of the bacterium Bilophila wadsworthia [15]. In biliary diseases, with a possible exception for gallstone disease, little is known about disease-associated and healthy diets. Importantly, the same diet is not necessarily advisable for everyone, and gut microbial profile or other biomarkers could be speculated to provide guidance. Needless to say, there is a lot of work undone in this field.