{'fraction_non_alphanumeric': 0.020330712930333422, 'fraction_numerical': 0.0056925996204933585, 'mean_word_length': 5.808118081180812, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Editorial: gut microbial profile associated with primary sclerosing cholangitis—what is new and how do we progress from here?

Uncovering the aetiopathogenesis of primary sclerosing chol‐ angitis (PSC) is one of the major challenges we currently face in haepatology. Although ulcerative colitis (UC) occurs in up to 80% of patients with PSC (PSC‐IBD) there are crucial differences in clinical manifestation of colonic inflammation and clear distinc‐ tions among genetic polymorphisms identified through genome‐ wide association studies.1 Several single centre studies, consisting of relatively small cohorts, have described significant differences in gut microbial profiles in patients with PSC compared to UC and healthy controls.2‐5 The differences in microbial taxa identified are however not consistent among studies. This makes it challeng‐ ing to explore specific microbiota‐mediated disease mechanisms in PSC. Rühlemann et al presented the largest study to date in this field consisting of 388 individuals (137 with PSC) based in Norway and Germany.6 They confirmed that the gut (faecal) microbial pro‐ files of patients with PSC were distinct to UC and healthy controls and this was independent of medication or presence of colitis, although there was a higher median faecal calprotectin level in the UC cohort. Intriguingly they found no differences in the gut mi‐ crobiota between PSC and PSC‐IBD proposing that this dysbiosis seen in PSC was independent of colitis. Through a meta‐analysis, they identified both known and novel differences in taxa in PSC that may potentially have pathophysiological significance such as increases in the pro‐inflammatory lipopolysaccharide containing Gammaproteobacteria. Furthermore, they identified enrichment of the amine oxidase expressing Veillonella and bile salt hydrolase expressing Lactobacillales in PSC compared to controls suggesting that the proposed PSC disease mechanisms of aberrant gut‐liver lymphocyte trafficking and dysregulation of bile acid pathways, respectively, deserve detailed consideration. This study is important and provides valuable insight into gut microbiota associated with PSC. However, the lack of a non‐PSC cholestatic control group makes it challenging to conclude if these findings are PSC‐specific. By analysing cohorts across two differ‐ ent geographical regions, the authors attempted to control for environmental factors that could potentially explain the inconsis‐ tencies in findings from earlier studies exploring PSC gut microbi‐ ota. However, various limitations, specifically differences in DNA extraction kits and protocols at the two sites, the potential for “batch effects” and differences in dietary pattern make interpre‐ tation of inter‐regional differences challenging. This limitation was further underscored by their observation of significant differences in gut microbial profiles between healthy controls in Norway and Germany. A study of over 7000 individuals concluded that the host location determined the strongest associations with variations in microbiota.7 There is accumulating evidence demonstrating that PSC is as‐ sociated with differences in gut microbiota. In order to understand what this actually means, we now need to move towards carefully conducted studies that explore causation. Very early exploratory clinical trials investigating modulation of gut microbiota with van‐ comycin and faecal microbiota transplantation in PSC have shown potential.8‐10 Harnessing such studies for mechanistic exploration of changes in host pathophysiology in relation to shifts in gut mi‐ crobiota may hold a key to understanding and treating this complex disease better (Figure 1).