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In the last decades, the proportion of host–microbiota interaction studies in biomedical research continuously increased, mainly driven by the quest for a better understanding of microbiota-associated human diseases. Among the numerous medical conditions the courses of which have been shown to be influenced by the microbiota, GI disorders and especially IBDs have been studied extensively, either in experimental murine models or in clinical studies (reviewed in ref 1). Among the plethora of immune pathways impacted and dysregulated by the microbiota and thus leading to pathologies, inflammasome signalling has been shown to severely affect the progression of GI disorders2 and to be associated with microbiota composition.3 Primary sclerosing cholangitis (PSC) represents a rare disease characterised by chronic inflammation and concomitant fibrosis of the biliary tree with a poor outcome. A microbiota-dependent pathogenesis of PSC, similar to that of IBD, has been suggested.4 However, the number of clinical and experimental studies addressing host–microbiota interactions in PSC remains limited. Rederivation of PSC models into germ-free conditions caused either attenuation or aggravation of the phenotype,5 emphasising the microbiota-dependent character of this pathology and the urgent need for a better understanding. The microbiota-mediated mechanisms remain to be revealed in order to allow for the design of new therapeutic approaches.
In Gut, Liao et al 6 investigated the functional role of the microbiota in the development of PSC using Mdr2−/− mice, a well-characterised animal model for PSC.7 Genetic deletion of the multidrug resistance protein 2 (Mdr2) increases the biliary concentration of free bile acids through the absence of phosphatidylcholine, resulting in cholangitis. Given the established impact of the crosstalk between bile acid metabolism and the gut microbiota on the immune system,8 the authors hypothesised that dysbiosis associated with the pathological biliary composition of Mdr2−/− mice may play a causal role in the development of the disease.
Mdr2−/− mice showed extensive liver damage with infiltration of inflammatory immune cells and enhanced activation of caspase-8, a mediator of apoptosis. Increased NRLP3 inflammasome activation markers were detected in PSC patient samples, indicating a higher degree of activity in these patients compared with healthy subjects. A similar phenotype was observed in the animal model.
Concurrent with increased intrahepatic immune activation, Mdr2−/− animals exhibited a decreased intestinal barrier function resulting in higher translocation of bacterial DNA and other bacterial products such as lipopolysaccharide into the portal system.
In addition, Mdr2−/− mice harboured a different caecal microbiota than their heterozygous littermates. The use of specific pathogen-free (SPF) animals to study host–microbiota interactions may be subject to many pitfalls biasing standardisation and interpretation of the data, mostly because of unappreciated intrinsic and extrinsic factors influencing the host, its immune system and the microbiota.9 Through experiments including littermate controls and careful analysis of confounding factors, such as cage effects, the authors were able to show that the genotype contributed indeed to a significant extent to the difference in microbiota composition observed between Mdr2-deficient and sufficient animals (figure 1A).
To address the functional effect of the changes in microbiota composition, Liao et al took advantage of faecal microbiota transfer (FMT) from either Mdr2-deficient mice or their sufficient littermates into SPF wild-type animals. Recipients of faecal microbiota originating from Mdr2-deficient animals developed an immunological phenotype similar to Mdr2-deficient animals, whereas recipients of faeces derived from Mdr2-suffcient animals stayed healthy (figure 1B). Given the tremendous effect of FMT on the development of liver damage, it is evident that FMT could also be considered as a therapeutic approach for PSC in humans. A recent small clinical study suggested a possible improvement of the cholestatic parameters through FMT in patients suffering from IBD-associated PSC.10
Sequence-based taxonomic profiling does not allow to discriminate bystander variations from functionally relevant changes of the microbiota composition. The FMT experiment, as performed in the study of Liao et al, provided very convincing evidence that the compositional changes observed are relevant for the pathogenesis of the disease.
Treatment of Mdr2-deficient animals with a pan-caspase inhibitor reduced hepatic injury and tended to normalise the microbiota composition when compared with wild-type animals (figure 1C).
This piece of work sets solid foundations for further work on the host–microbiota interactions in the setting of PSC, both in humans and in the animal model. In-depth study of the microbiota, involving further dimensions, may open new perspectives in the understanding of the pathogenesis of PSC, as it did for IBD.11–13 We believe that unravelling so far unexplored aspects of the host–microbiota interactions in the setting of PSC may pave the path for translational progresses, such as the development of microbiota-based diagnostics, monitoring and therapeutic approaches (figure 1D).
Contributors CM and SCGV wrote the manuscript.
Funding CM received an MD-PhD fellowship of the Swiss National Science Foundation (323530_158124). SCGV is supported by the Directorate for Teaching and Research of the Inselspital and by the Johanna Dürmüller-Bol Foundation.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
Patient consent for publication Not required.
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