Reply: The mucosal gut signature in primary sclerosing cholangitis before and after liver transplantation. Is the dysbiosis index really predictive for the recurrence of PSC?

We read with interest the letter from Mammadov et al1, commenting on our recent publication on the mucosal gut microbiome in primary sclerosing cholangitis (PSC) before and after liver transplantation and their comment that we understate the importance of the pretransplant mucosal microbiota on posttransplant liver health in PSC.2 We acknowledge the likely important role of the pretransplant microbiome also for posttransplant health; and indeed, we believe our study corroborates this. Our finding of a shared mucosal gut microbiome before and after liver transplantation highlights the possibility that an unhealthy gut microbial ecology with disease-modifying properties present before the transplant could persist after transplantation and potentially drive the development of recurrent primary sclerosing cholangitis (rPSC). The cited article by Visseren et al3 on rPSC raises the interesting possibility that individual gut bacteria present in transplant-naive individuals may alter disease courses after liver transplantation. Contraintuitive to conventional medical microbiological wisdom, they found that transplanted PSC patients without recurrence had an increased abundance of the enteropathogen Shigella, suggestive of a protective role of this enteropathogen. Upon revisiting our own transplanted PSC cohort, we found no evidence of an association between either Moraxellaceae or Fusobacteriaceae with rPSC (compared with liver-transplanted PSC without recurrence). However, we saw that a diagnosis of rPSC at inclusion was associated with reduced relative abundance of mucosal Escherichia-Shigella (p = 0.053, padjusted = 0.53, Figure 1). Moreover, in our nontransplanted group, Escherichia-Shigella associated with reduced Mayo PSC score (β: −3.9, 95% CI: −6.5 to −1.4, linear regression), while we found no such relationship in our posttransplant group.FIGURE 1: MaAsLin2 analysis of the mucosal gut microbiota in transplanted primary sclerosing cholangitis patients with rPSC at inclusion as a predictor (adjusted for multiple sampling sites per patient). Labeled if p < 0.1 and abs (β coefficient) >0.3. Abbreviation: rPSC, recurrent primary sclerosing cholangitis.While studying how specific microbial taxa associate with indices of disease severity and clinical outcomes is an interesting strategy, it has several limitations. First, we believe individual features in metagenomics studies are prone to being spurious and should be cautiously interpreted unless several studies have produced similar results, preferably in cohorts from different regions. In addition, we believe that the disease-modifying effects of mucosal microbiota are likely the result of a complex interplay between microbial ecology, substrate availability, and host physiology. However, we also believe further disentanglement of the gut-liver axis in PSC may improve our diagnostic and prognostic tool kit in the personalized management of the disease, but this will require large studies with careful assessment of external validity before translation to clinical care.