Characterization of the Gut Microbiota and Mycobiota in Italian Pediatric Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis.

Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis, often associated with inflammatory bowel diseases. Recent evidence ascribes, together with immunologic and environmental components, a significant role to the intestinal microbiota or its molecules in the PSC pathogenesis. By metagenomic sequencing of 16S rRNA and ITS2 loci, we describe the fecal microbiota and mycobiota of 26 pediatric patients affected by PSC and concomitant ulcerative colitis (PSC-UC), 27 patients without PSC but with UC (UC), and 26 healthy subjects (CTRLs). Compared with CTRL, the bacterial and fungal gut dysbiosis was evident for both PSC-UC and UC groups; in particular, Streptococcus, Saccharomyces, Sporobolomyces, Tilletiopsis, and Debaryomyces appeared increased in PSC-UC, whereas Klebsiella, Haemophilus, Enterococcus Collinsella, Piptoporus, Candida, and Hyphodontia in UC. In both patient groups, Akkermansia, Bacteroides, Parabacteroides, Oscillospira, Meyerozyma and Malassezia were decreased. Co-occurrence analysis evidenced the lowest number of nodes and edges for fungi networks compared with bacteria. Finally, we identified a specific patient profile, based on liver function tests, bacterial and fungal signatures, that is able to distinguish PSC-UC from UC patients. We describe the gut microbiota and mycobiota dysbiosis associated to PSC-UC disease. Our results evidenced a gut imbalance, with the reduction of gut commensal microorganisms with stated anti-inflammatory properties (ie, Akkermansia, Bacteroides, Parabacteroides, Oscillospira, Meyerozyma, and Malassezia) and the increase of pathobionts (ie, Streptococcus, Saccharomyces, and Debaryomyces) that could be involved in PSC progression. Altogether, these events may concur in the pathophysiology of PSC in the framework of UC.

Del Chierico F ，Cardile S ，Baldelli V ，Alterio T ，Reddel S ，Bramuzzo M ，Knafelz D ，Lega S ，Bracci F ，Torre G ，Maggiore G ，Putignani L ... -  《-》

Outcome of Very Early Onset Inflammatory Bowel Disease Associated With Primary Sclerosing Cholangitis: A Multicenter Study From the Pediatric IBD Porto Group of ESPGHAN.

Catassi G ，D'Arcangelo G ，Norsa L ，Bramuzzo M ，Hojsak I ，Kolho KL ，Romano C ，Gasparetto M ，Di Giorgio A ，Hussey S ，Yerushalmy-Feler A ，Turner D ，Matar M ，Weiss B ，Karoliny A ，Alvisi P ，Tzivinikos C ，Aloi M ... -  《-》

Sishen Pill & Tongxieyaofang ameliorated ulcerative colitis through the activation of HIF-1α acetylation by gut microbiota-derived propionate and butyrate.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease closely related to gut microbiota dysbiosis and intestinal homeostasis imbalance. Sishen Pill&Tongxieyaofang (SSP-TXYF) has a long history of application in traditional Chinese medicine and is widely used in UC clinics. However, its mechanism of action is still unclear. This study aimed to explore the potential regulatory role of SSP-TXYF in protecting against UC through metabolites produced by the intestinal microbiota, and elucidate its underlying molecular mechanism. 16S rRNA and UPLC-QE-Orbitrap-MS were used to assess the microbiota and short-chain fatty acids (SCFAs). A rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced gut microbiota dysbiosis was used to study the effects of SSP-TXYF on UC in vivo. Intestinal epithelial cells-6 (IEC-6) were treated with lipopolysaccharide (LPS). The intestinal mucosal barrier (IMB) functions were investigated by alcian blue staining and western blot analysis. The mechanism of SSP-TXYF influenced the HIF-1α acetylation pathway was examined by real-time fluorescence quantitative PCR (qPCR), Western blotting, and Co-immunoprecipitation. Using 16S rRNA gene-based microbiota analysis, we found that SSP-TXYF ameliorated TNBS-induced gut microbiota dysbiosis. We found that SSP-TXYF significantly inhibited the decreased abundance of Firmicutes in UC rats, in addition, the abundance of Actinobacteria was also improved. The mechanism of SSP-TXYF-treated TNBS-induced UC resulted from improved IMB functions via the activation of hypoxia-inducible factor-1 (HIF-1α) acetylation. Notably, SSP-TXYF Enriched microbiota-derived metabolites propionate and butyrate, which could activate HIF-1α acetylation in IEC. Furthermore, exogenous treatment of propionate and butyrate reproduced similar protective effects as SSP-TXYF to UC through improving HIF-1α-dependent IMB functions. Overall, our findings suggest that the gut microbiota-propionate/butyrate-HIF-1α-IMB axis plays an important role in SSP-TXYF-maintaining intestinal homeostasis, which may represent a novel approach for UC prevention via the intervention of any link in this axis.

Liu H ，Wang D ，Feng X ，Liu L ，Liu B ，Zhu L ，Sun J ，Zuo X ，Chen S ，Xian J ，Zhang C ，Yang W ... -  《-》

Outcomes of oral vancomycin therapy in children with atypical ulcerative colitis with or without confirmed primary sclerosing cholangitis: a real-world observational study.

Atypical ulcerative colitis (UC) presenting reverse gradient colitis, backwash ileitis, or rectal sparing and/or positive atypical antineutrophil cytoplasmic antibody serology is often associated with primary sclerosing cholangitis (PSC) and can be resistant to conventional medical therapies (CMT) for inflammatory bowel diseases. We report short-term and long-term outcomes of oral vancomycin therapy (OVT) in children with atypical UC and confirmed PSC in imaging/biopsy (PSC-UC) or treatment-resistant atypical UC without detectable PSC (aUC-non-PSC). In this retrospective real-world observational study from a tertiary paediatric centre in Brisbane, Australia, 44 children with aUC (29 PSC-UC, 15 aUC-non-PSC) received 79 OVT courses between 2014 and 2023. Pre-post-OVT characteristics were compared and relapses/repeated courses were recorded. Pre-OVT, all had active colitis by Paediatric Ulcerative Colitis Activity Index (PUCAI), Feacal Calprotectin (FC) and/or colonoscopy. Post-OVT, PUCAI reduced from 15 (IQR 5-33) to 0 (IQR 0-5); 85% of children with pre-OVT PUCAI ≥10 achieved clinical remission (100% PSC-UC vs 64% aUC-non-PSC, p=0.019). FC reduced from 995 (IQR 319-1825) to 44 (IQR 16-79) µg/g; 83% of children with pre-OVT FC ≥100 µg/g achieved biochemical remission (92% PSC-UC vs 64% aUC-non-PSC, p=0.063). Colonoscopy confirmed Mayo 0 healing in 62% (67% PSC-UC vs 54% aUC-non-PSC, p=0.443) and 46% achieved pan-colonic histological remission (54% PSC-UC vs 31% aUC-non-PSC, p=0.173). All pre-post-OVT changes in these four markers were significant in both groups. After ceasing first OVT, 25/44 relapsed within 8.2 (IQR 1.9-14.5) months. Recommencing OVT regained biomarker remission in 13/25. During 3.8 (IQR 2.0-5.3) years of follow-up, 79 OVT courses in conjunction with CMT maintained deep remission in 67%. Routine stool testing (n=138) detected no vancomycin-resistant Enterococcus (VRE). OVT induced and reinduced remission in children with atypical UC. Relapse often followed ceasing vancomycin, half responded to reinduction. No VRE was developed.

Räisänen L ，Balouch F ，McLaren-Kennedy A ，Clark JE ，Lewindon P ... -  《-》

Multiomic Sequencing Reveals Distinctive Gene Expression and Epigenetic Alterations Associated With Primary Sclerosing Cholangitis Development in Treatment-Naïve Pediatric Ulcerative Colitis.

Primary sclerosing cholangitis (PSC) is a progressive cholestatic disease with up to 80% of patients also suffering from ulcerative colitis (PSC-UC). The difficulty in the diagnosis along with the increased risk for developing cancer represents a clinical challenge. Furthermore, the precise molecular factors regulating the phenotype of this disease subtype remain unknown. We applied methyl-capture sequencing and mRNA sequencing to colonic mucosal biopsies from 3 groups of treatment-naïve children at diagnosis from the Determinants and Outcomes in CHildren and AdolescentS study: UC (n = 10), PSC-UC (n = 10), and healthy controls (n = 10). Differential gene expression between UC and PSC-UC showed significantly higher gene expression changes in PSC-UC patients when compared to UC. Specifically, expression of these genes was regulated by master transcriptional regulators (NLRP3, DLL1) and transcription factors (RELA, Myogenin, and FOXO1), which are shown to regulate expression of inflammatory response and immune-associated genes in PSC-UC patients exclusively. Differential methylation analysis between PSC-UC and UC demonstrated >2000 differentially methylated regions with a large proportion of them enriched in gene promoter and enhancer regions. We further show no difference in epigenetic age between PSC-UC and UC. Finally, we identify KLHL17 as hypomethylated and upregulated in PSC-UC patients. Our study, for the first time, identifies distinct gene expression and DNA methylation alterations that differentiate UC from PSC-UC at diagnosis in treatment-naïve pediatric patients. We show the gene expression differences observed between PSC-UC and UC are modulated by intricate molecular mechanisms involving master transcriptional regulator-mediated signaling through transcription factors. These findings suggest the potential utility of these molecular markers as predictive biomarkers for PSC development in UC at an early stage of development. Further validation in larger patient cohorts is warranted.

Rodriguez-Sosa A ，Lawal O ，McDonnell C ，Grant L ，O'Brien J ，Ali M ，Stephens I ，Kirwan G ，Genua F ，Kel A ，Dominik A ，Stack R ，Yochum G ，McDermot M ，Doherty G ，Hussey S ，Das S ... -  《-》