BACKGROUND:The study sought to prospectively examine clinical, biochemical, and transmural outcomes. Transmural outcomes are assessed by ultrasound after 1 year in patients with inflammatory bowel disease (IBD) treated in line with standard of care. METHODS:The TRUST BEYOND study is a prospective, multicenter, noninterventional study at 49 sites in Germany, Austria, and Switzerland and includes 282 patients with IBD who have active disease at baseline. For this analysis, 163 patients with IBD (74 with Crohn's disease, 89 with ulcerative colitis) were followed up for 1 year. At baseline and at every 3 months, clinical, biochemical, and ultrasound parameters, such as bowel wall thickness and color Doppler sonography, were assessed. RESULTS:Patients with IBD demonstrated vast improvements in clinical, biochemical, and ultrasound assessments as early as week 12. Rates of transmural response and healing progressively increased over the study period to up to 77.5% and 39.3%, respectively, in patients with ulcerative colitis and to 66.2% and 27.0%, respectively, in patients with Crohn's disease. Patients with early transmural response achieved numerically higher rates of various outcomes at week 52 than patients without early transmural response. In a multivariate analysis, transmural response at week 12 predicted clinical remission at week 52 (odds ratio, 4.3; 95% confidence interval, 2.45-7.52; P < .001). CONCLUSIONS:These results suggest that intestinal ultrasound is a suitable noninvasive modality to monitor patients with IBD in routine care. Transmural endpoints can be achieved in patients with IBD treated with standard of care and can predict outcomes after 1 year.

Abstract Microbial dysbiosis is a hallmark of inflammatory bowel diseases (IBD); however, its drivers and impact on disease pathophysiology are poorly understood. Applying neural network-based feature attribution to metabolomics and metagenomics datasets from >5000 individuals, we identified epimerized host derived bile acids (BAs) produced by microbial hydroxysteroid dehydrogenases (HSDHs) as a novel hallmark of IBD-associated dysbiosis. Epimerized BAs reduce FXR activity in intestinal epithelial cells and dampen their production of FGF19, a negative feedback regulator of host-derived bile acid (HBA) production in the liver. Increased HBA levels drive colonic epithelial remodeling by impacting goblet cell maturation and select for HSDH-carrying bacteria that transform bactericidal HBA into less toxic, epimerized forms. Confirming the translational relevance of these findings, we demonstrated that high HBA levels limit fecal microbiota transplant engraftment and show that BA sequestering drugs support microbiome recovery in patients with high HBA levels. Together, we discover that elevated HBAs deplete BA-sensitive commensals and favor the growth of HSDH-encoding pathobionts that disrupt host BA feedback signaling, establishing a causal link between changes in microbial ecology and IBD pathophysiology.

A woman in her 60s developed diarrhoea after receiving amoxicillin/clavulanic acid for biliary pancreatitis. After a diagnosis of Clostridioides difficile infection, she was treated with fidaxomicin. Despite initial improvement, her diarrhoea recurred, with increased severity, and repeated testing for C. difficile was negative. Further diagnostic workup yielded negative results for infectious, autoimmune or endocrine causes of diarrhoea, but a CT scan showed extensive walled-off necrosis (WON) due to the pancreatitis. Colonoscopy revealed two colonic fistulae, which were later confirmed by magnetic resonance cholangiopancreatography as pancreaticocolonic fistulae (PCF). The patient was treated with the placement of a lumen-apposing metal stent, multiple endoscopic necrosectomies and broad-spectrum antibiotics. The patient’s diarrhoea resolved after the reduction in the size of the WON. She was discharged in good condition after a prolonged hospital course. This case highlights the importance of considering PCF in patients with WON and persistent diarrhoea, as a rare complication of necrotising pancreatitis.

The fecal microbiome of patients with inflammatory bowel diseases (IBD) is characterized by longitudinal variability. It remains unknown if this is caused by decreased resilience of the microbiome to external factors. We investigated the influence of osmotic diarrhea induced by bowel preparation as a disruptive factor on the fecal microbiome in IBD patients and healthy comparators. We conducted a prospective, single-center study including IBD patients and healthy controls scheduled for colonoscopy with uniform bowel preparation. Fecal samples were collected at 7 time points prior, during, and until 3 months after the intervention. 16S rRNA was isolated from stool and sequenced using the Illumina technique. Twenty-two IBD patients and 17 healthy controls were included in the study. Baseline diversity was higher in healthy controls. Bowel preparation longitudinally decreased alpha diversity and altered beta diversity and taxonomic composition in both groups. Alterations were more pronounced in healthy controls, and the microbial composition converged between the 2 groups. Bowel preparation resulted in an increased relative abundance of Anaerostipes and Coprococcus in both groups and in decreased relative abundance of Bifidobacterium and Clostridium sensu stricto in IBD patients and of Eubacterium hallii group and Ruminococcus in healthy controls. Changes largely restored to baseline composition within 1 week in both groups and remained stable thereafter. Bowel preparation induced reversible short-term microbial perturbations which were less pronounced in IBD patients than in healthy comparators suggesting that a single external disruptive factor may have less impact on an already altered fecal microbiome.

The gut microbiome contributes to chronic inflammatory responses in ulcerative colitis (UC), but molecular mechanisms and disease-relevant effectors remain unclear. Here we analyze the pro-inflammatory properties of colonic fluid obtained during colonoscopy from UC and control patients. In patients with UC, we find that the pelletable effector fraction is composed mostly of bacterial extracellular vesicles (BEVs) that exhibit high IgA-levels and incite strong pro-inflammatory responses in IgA receptor-positive (CD89+) immune cells. Biopsy analyses reveal higher infiltration of CD89+ immune cells in the colonic mucosa from patients with UC than control individuals. Further studies show that IgA-coated BEVs, but not host-derived vesicles nor soluble IgA, are potent activators of pro-inflammatory responses in CD89+ cells. IgA-coated BEVs also exacerbate intestinal inflammation in a dextran sodium sulfate colitis model using transgenic mice expressing human CD89. Our data thus implicate a link between IgA-coated BEVs and intestinal inflammation via CD89+ immune cells, and also hint a potential new therapeutic target for UC.

Factor XIII plays a key role within the coagulation cascade. We aimed to investigate the relevance of factor XIII activity on the outcome of patients with gastrointestinal bleedings. In this retrospective, single-center study patients with gastrointestinal bleeding and measurement of factor XIII activity were included. The primary endpoint was the number of red blood cell transfusions in patients with reduced factor XIII activity (< 70

Background Corticosteroids are used for induction of remission in patients with moderately to severely active ulcerative colitis. However, up to one-third of patients fail to this therapy. We investigated if fecal microbial composition or its metabolic capacity are associated with response to systemic corticosteroids. Methods In this prospective, multicenter study, patients with active ulcerative colitis (Lichtiger score ≥4) receiving systemic corticosteroids were eligible. Data were assessed and fecal samples collected before and after 4 weeks of treatment. Patients were divided into responders (decrease of Lichtiger Score ≥50%) and nonresponders. The fecal microbiome was assessed by the 16S rRNA gene marker and analyzed with QIIME 2. Microbial metabolic pathways were predicted using parsimonious flux balance analysis. Results Among 93 included patients, 69 (74%) patients responded to corticosteroids after 4 weeks. At baseline, responders could not be distinguished from nonresponders by microbial diversity and composition, except for a subgroup of biologic-naïve patients. Within 4 weeks of treatment, responders experienced changes in beta diversity with enrichment of ascribed beneficial taxa, including Blautia, Anaerostipes, and Bifidobacterium, as well as an increase in predicted butyrate synthesis. Nonresponders had only minor longitudinal taxonomic changes with a significant increase of Streptococcus salivarius and a microbial composition shifting away from responders. Conclusion Baseline microbial diversity and composition seem to be of limited use to predict response to systemic corticosteroids in active ulcerative colitis. Response is longitudinally associated with restoration of microbial composition and its metabolic capacity.

STW 5, a blend of nine medicinal plant extracts, exhibits promising efficacy in treating functional gastrointestinal disorders, notably irritable bowel syndrome (IBS). Nonetheless, its effects on the gastrointestinal microbiome and the role of microbiota on the conversion of its constituents are still largely unexplored. This study employed an experimental ex vivo model to investigate STW 5's differential effects on fecal microbial communities and metabolite production in samples from individuals with and without IBS. Using 560 fecal microcosms (IBS patients, n = 6; healthy controls, n = 10), we evaluated the influence of pre-digested STW 5 and controls on microbial and metabolite composition at time points 0, 0.5, 4, and 24 h. Our findings demonstrate the potential of this ex vivo platform to analyze herbal medicine turnover within 4 h with minimal microbiome shifts due to abiotic factors. While only minor taxonomic disparities were noted between IBS- and non-IBS samples and upon treatment with STW 5, rapid metabolic turnover of STW 5 components into specific degradation products, such as 18β-glycyrrhetinic acid, davidigenin, herniarin, 3-(3-hydroxyphenyl)propanoic acid, and 3-(2-hydroxy-4-methoxyphenyl)propanoic acid occurred. For davidigenin, 3-(3-hydroxyphenyl)propanoic acid and 18β-glycyrrhetinic acid, anti-inflammatory, cytoprotective, or spasmolytic activities have been previously described. Notably, the microbiome-driven metabolic transformation did not induce a global microbiome shift, and the detected metabolites were minimally linked to specific taxa. Observed biotransformations were independent of IBS diagnosis, suggesting potential benefits for IBS patients from biotransformation products of STW 5. IMPORTANCE:STW 5 is an herbal medicinal product with proven clinical efficacy in the treatment of functional gastrointestinal disorders, like functional dyspepsia and irritable bowel syndrome (IBS). The effects of STW 5 on fecal microbial communities and metabolite production effects have been studied in an experimental model with fecal samples from individuals with and without IBS. While only minor taxonomic disparities were noted between IBS- and non-IBS samples and upon treatment with STW 5, rapid metabolic turnover of STW 5 components into specific degradation products with reported anti-inflammatory, cytoprotective, or spasmolytic activities was observed, which may be relevant for the pharmacological activity of STW 5.

Colitis ulcerosa ist eine chronisch entzündliche Darmerkrankung mit Befall des Kolons. Die häufigsten Symptome sind blutige und schleimige Durchfälle, Stuhldrang sowie abdominelle Schmerzen. Diese Symptome stellen für die Betroffenen oft eine wesentliche gesundheitliche Beeinträchtigung dar. Filgotinib ist ein Medikament, das in oraler Form zur Behandlung der moderat bis schwer aktiven Colitis ulcerosa angewendet wird. Es zählt zur Klasse der Januskinase-Inhibitoren und blockiert bevorzugt das Enzym Januskinase 1, das zytokinvermittelte Inflammationsprozesse bei Colitis ulcerosa aufrechterhält. Die Wirksamkeit und Sicherheit von Filgotinib im Vergleich zu Placebo zur Behandlung der moderat bis schwer aktiven Colitis ulcerosa wurden in der SELECTION-Studie über 58 Wochen untersucht. Filgotinib 200 mg führte im Vergleich zu Placebo bei signifikant mehr Patienten zu einer schnellen Verbesserung klinischer Symptome innerhalb der ersten 3–4 Tage der Anwendung. Es führte weiters zu einer höheren Rate an klinischer, endoskopischer und histologischer Remission sowohl nach 10 als auch nach 58 Wochen. Das Sicherheitsprofil der Substanz wurde in einer Langzeitstudie evaluiert. Dabei wurden am häufigsten Übelkeit, Infektionen der oberen Atemwege und der Harnwege, Schwindelgefühl und Lymphopenie berichtet. Die Häufigkeiten von schwerwiegenden Infektionen, Thrombosen und schweren kardialen Nebenwirkungen waren gering und vergleichbar zwischen Filgotinib und Placebo. Besondere Merkmale von Filgotinib sind die einmal tägliche orale Anwendung, die gute Steuerbarkeit aufgrund der kurzen Halbwertzeit sowie die nicht vorhandene Immunogenität im Gegensatz zu den Biologika.

Archaea are vital components of the human microbiome, yet their study within the gastrointestinal tract (GIT) is limited by the scarcity of cultured representatives. Our study presents a method for the targeted enrichment and isolation of methanogenic archaea from human fecal samples. The procedure combines methane breath testing, in silico metabolic modeling, media optimization, FACS, dilution series, and genomic sequencing through Nanopore technology. Additional analyzes include the co-cultured bacteriome, comparative genomics of archaeal genomes, functional comparisons, and structure-based protein function prediction of unknown differential traits. Successful establishment of stable archaeal cultures from 14 out of 16 fecal samples yielded nine previously uncultivated strains, eight of which are absent from a recent archaeome genome catalog. Comparative genomic and functional assessments of Methanobrevibacter smithii and Candidatus Methanobrevibacter intestini strains from individual donors revealed features potentially associated with gastrointestinal diseases. Our work broadens available archaeal representatives for GIT studies, and offers insights into Candidatus Methanobrevibacter intestini genomes' adaptability in critical microbiome contexts.

Bipolar disorder (BD) is a chronic mood disorder characterized by recurrent episodes of depression and (hypo-) mania. The gut microbiome is a potential avenue through which metabolic signaling, inflammatory pathways, environmental factors, and genetics influence BD pathogenesis via the gut-brain axis. Fecal microbiota transplantation (FMT) is a powerful translational tool for investigating the connections between the gut microbiome and BD, and there is evidence FMT can transfer affective symptoms of BD from humans to mice. In this study, we compared the behavior, gut-brain metabolomic profiles, and inflammatory marker expression in two groups of adult female C57BL/6J mice, one receiving FMT from a human donor with BD in a mixed episode ( HAM-D = 20, YMRS = 14) and another receiving FMT from a mentally healthy weight and age-matched control donor without BD (HAM-D and YMRS = 0). Here, we demonstrate that mice receiving FMT from individuals with BD had an increased abundance of Bacteroidota and decreased abundances of Parabacteroides merdae and Akkermansia muciniphila associated with altered levels of fecal metabolites, short-chain fatty acids, and related gut hormone expression relative to mice receiving control donor FMT. BD mice also exhibited differential regulation of several metabolites and inflammatory markers in the amygdala, with glycine being the most prominently affected. Furthermore, BD mice displayed increased anxiety-like behavior and decreased sociability, indicating that aspects of the behavioral phenotype of BD are transferable from humans to mice via FMT. Taken together, these findings implicate gut-brain signaling in the physiological and behavioral changes observed in our BD-FMT mouse model.

Background The gut microbiome of patients with inflammatory bowel diseases (IBD) is characterized by increased longitudinal variability. It remains unknown if this is caused by increased instability of the microbiome to external factors. We investigated the influence of osmotic diarrhea induced by bowel preparation as an external source of irritation on the gut microbiome in IBD patients and healthy comparators.

Background: Among patients with ulcerative colitis, 30–50% receive corticosteroids within the first five years after diagnosis. We aimed to reconsider their effectiveness in the context of the biologic era. Methods: In this prospective, multicenter study, patients with active ulcerative colitis (Lichtiger score ≥ 4) were eligible if initiating systemic corticosteroids. The primary endpoint was clinical response (decrease in the Lichtiger score of ≥50%) at week 4. Secondary endpoints included combined response defined as clinical response and any reduction in elevated biomarkers (CRP and/or calprotectin). Steroid dependence was assessed after three months. Results: A total of 103 patients were included. Clinical response was achieved by 73% of patients, and combined response by 68%. A total of 15% of patients were steroid-dependent. Activity of colitis did not influence short-term response to treatment but increased the risk for steroid dependence. Biologic-naïve patients responded better than biologic-experienced patients. Past smoking history (OR 5.38 [1.71, 20.1], p = 0.003), hemoglobin levels (OR 0.76 [0.57, 0.99] for higher levels, p = 0.045), and biologic experience (OR 3.30 [1.08, 10.6], p = 0.036) were independently associated with nonresponse. Conclusion: Disease activity was not associated with short-term response to systemic corticosteroids but was associated with steroid dependence in patients with active ulcerative colitis. Exposure to biologics negatively affects response rates.

OBJECTIVES:In infants with suspected food protein induced proctocolitis (sFPIP) only a minority of patients are finally diagnosed with the disease following diagnostic dietary intervention (DDI). There is a need for a pathophysiological explanation for the cause of hematochezia in the majority of sFPIP infants.METHODS:We prospectively recruited infants with sFPIP and healthy controls. Fecal samples were collected at inclusion, week 4 (end of DDI in sFPIP), and week 8. For 16S rRNA sequencing (515F/806R) we used Illumina MiSeq sequencing system. Amplicon sequence variants were generated using Qiime2 and DADA2. Qiime diversity alpha and beta group comparisons and linear discriminant analysis effect size analysis was performed. For shotgun metagenomic analysis on species level we used KneadData and MetaPhlAn2.RESULTS:Fourteen sFPIP infants were compared to 55 healthy infants. At inclusion overall microbial composition of sFPIP infants differed significantly from controls (weighted UniFrac; Pairwise PERMANOVA, P = 0.002, pseudo- F = 5.008). On genus level healthy infant microbiota was significantly enriched with Bifidobacterium ( B ) compared to sFPIP patients (linear discriminant analysis [LDA] = 5.5, P < 0.001, 31.3% vs 12.1%). sFPIP stool was significantly enriched by Clostridium sensu stricto 1 over controls (LDA = 5.3, P = 0.003, 3.5% vs 18.3%). DDI caused a significant and sustained increase of Bifidobacterium (LDA = 5.4, P = 0.048, 27.9%) in sFPIP infants. Species level analysis revealed significant reduction of abundance of B longum in sFPIP patients, which after DDI was reversed by B. species other than B longum .CONCLUSIONS:We revealed a gut microbiota dysbiosis phenomenon in sFPIP infants. DDI induces a microbiota composition comparable to that of healthy infants. In most sFPIP infants hematochezia might be triggered by a gut microbiota dysbiosis phenomenon.

Background Faktor XIII ist ein Gerinnungsfaktor der für die Stabilisierung des Thrombus notwendig ist. Die globalen Gerinnungstests (Prothrombinzeit und partielle Thromboplastinzeit) bilden die Faktor XIII Aktivität nicht ab. Daten aus der Traumatologie und nach herzchirurgischen Eingriffen legen nahe, dass die Faktor XIII Substitution Blutungen positiv beeinflussen kann. Das Ziel der Studie war es, den Einfluss der Faktor XIII Aktivität und dessen Substitution auf den Verlauf von gastrointestinalen Blutungen zu untersuchen.

Klebsiella oxytoca is a ubiquitous bacterium that is increasingly associated with inflammatory diseases. Here, we report the hybrid assembled genome for cytotoxic K. oxytoca strain AHC-6. The genome comprises a total of 5.7 Mbp, with a GC content of 55.2% and 5,258 coding sequences after assembly and annotation.

Abstract Background and aims Immunological treatment failure of anti-TNF therapy negatively influences treatment persistence of a second anti-TNF in IBD patients. So far it is unknown if this effect is also observed for other monoclonal antibodies. We assessed the influence of immunogenicity to anti-TNFs on treatment persistence of subsequent ustekinumab and vedolizumab therapy. Methods IBD patients with and without immunogenicity to anti-TNFs (undetectable trough levels and antibody titers ≥20 ng/mL) and subsequent ustekinumab (UST) and/or vedolizumab (VDZ) therapy were included in this retrospective, single-center study. The Kaplan-Meier method with the log-rank test and Cox proportional hazards were used as statistical methods. Results One hundred patients (Crohn’s disease: 62, Ulcerative colitis: 31, IBD unclassified: 7) with 127 treatment lines (62 with UST, 65 with VDZ) were included in the analysis. Immunogenicity to previous anti-TNFs did not influence treatment persistence of subsequent ustekinumab and vedolizumab therapy (UST: Log rank: p = .95, Immunogenicity: HR for treatment discontinuation: 0.97 [95% CI 0.31–3.04]; VDZ: p = .65, HR: 0.85 [0.41–1.75]; total cohort [UST and VDZ]: p = .62, HR: 0.86 [0.47–1.57]). Azathioprine co-treatment did not lengthen treatment persistence (UST: Log rank: p = .77, azathioprine: HR: 1.20 [0.34–4.27]; VDZ: p = .92, HR: 0.58 [0.17–1.99]; total cohort: p = .79, HR: 1.10 [0.55–2.20]). In this anti-TNF experienced cohort, patients with ustekinumab remained longer on treatment than patients receiving vedolizumab (Log rank: p = .005, UST: HR: 0.43 [0.23–0.79]). Conclusions Immunogenicity to anti-TNFs does not influence treatment persistence of subsequent ustekinumab and vedolizumab therapy.

Summary Ulcerative colitis (UC) is one of the main forms of inflammatory bowel disease (IBD). Despite the widening range of drug treatment options, primary nonresponse, secondary loss of response as well as adverse events call for additional treatment alternatives. Tofacitinib is an oral small-molecule drug of the class of Janus kinase inhibitors which, in the European Union, was approved for the treatment of moderate to severe active UC in August 2018. This position paper, drawn up by the IBD Working Group of the Austrian Society of Gastroenterology and Hepatology, summarizes the mechanism of action, clinical development, marketing authorization status, efficacy and safety of tofacitinib. Also, by providing a synopsis of available data from both pivotal and post-marketing studies, clinical aspects of specific interest are highlighted and discussed. The available body of evidence indicates that tofacitinib is an additional effective medication for the treatment of UC that exhibits a good safety profile. This position paper aims at optimizing the safe and effective use of tofacitinib in daily clinical practice.