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Background: While surgery plays a pivotal role in the management of ileal Crohn's disease, the risk of endoscopic recurrence following an ileocaecal resection can be greater than 65% within 12 months of surgery. More than 90% of patients with Crohn's disease have a concomitant diagnosis of bile acid diarrhea following an ileal resection. This pilot study aimed to assess whether the use of bile acid sequestrants in patients with Crohn's disease who have undergone a primary terminal ileal resection with concomitant bile acid diarrhea can alter the microbiome and prevent disease recurrence., Methods: Patients with Crohn's disease who underwent a primary terminal ileal resection and had symptoms of diarrhea within 1-3 months of surgery underwent 75SeHCAT testing for bile acid diarrhea. If positive (75SeHCAT ≤ 15%), patients were treated with colesevelam and stool samples were collected at 4 weeks, 8 weeks, and 6-12 months posttreatment. If negative (75SeHCAT > 15%), treatment was not given and were reviewed in the clinic as per local guidelines. All patients underwent a 6-12 month postoperative colonoscopy where further stool samples and mucosal biopsies were taken. Disease activity was established using the endoscopic Rutgeert's score, with disease remission defined as Rutgeert's score

Background: We conducted a single-arm interventional study, to explore mucosal changes associated with clinical remission under oral vancomycin (OV) treatment, in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD); NCT05376228., Methods: Fifteen patients with PSC and active colitis (median fecal calprotectin 459 µg/g; median total Mayo score 5) were treated with OV (125 mg QID) for 4 weeks and followed-up for a further 4 weeks of treatment withdrawal (8 weeks, end-of-study). Colonic biopsies were obtained at baseline and Week 4. Clinical assessments, and serum and stool samples (metagenomics, metatranscriptomics, and metabolomics) were collected at Weeks 0, 2, 4, and 8. The primary efficacy outcome measure was the induction of clinical remission., Results: Oral vancomycin resulted in clinical remission in 12/15 patients and significant reductions in fecal calprotectin. Oral vancomycin was associated with reduced abundances of Lachnospiraceae, genera Blautia and Bacteroides; and enrichment of Enterobacteriaceae, and genera Veillonella, Akkermansia, and Escherichia. Oral vancomycin treatment was associated with the downregulation of multiple metatranscriptomic pathways (including short-chain fatty acid [SCFA] metabolism and bile acid [BA] biotransformation), along with host genes and multiple pathways involved in inflammatory responses and antimicrobial defence; and an upregulation of genes associated with extracellular matrix repair. Oral vancomycin use resulted in the loss of specific fecal SCFAs and secondary BAs, including lithocholic acid derivatives. Colitis activity relapsed following OV withdrawal, with host mucosal and microbial changes trending toward baseline., Conclusions: Four weeks of OV induces remission in PSC-IBD activity, associated with a reduction in gut bacterial diversity and compositional changes relating to BA and SCFA homeostasis., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Introduction: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD). The strong association between gut and liver inflammation has driven several pathogenic hypotheses to which the intestinal microbiome is proposed to contribute. Pilot studies of faecal microbiota transplantation (FMT) in PSC and IBD are demonstrated to be safe and associated with increased gut bacterial diversity. However, the longevity of such changes and the impact on markers of disease activity and disease progression have not been studied. The aim of this clinical trial is to determine the effects of repeated FMT as a treatment for PSC-IBD., Methods and Analysis: FAecal micRobiota transplantation in primary sclerosinG chOlangitis (FARGO) is a phase IIa randomised placebo-controlled trial to assess the efficacy and safety of repeated colonic administration of FMT in patients with non-cirrhotic PSC-IBD. Fifty-eight patients will be recruited from six sites across England and randomised in a 1:1 ratio between active FMT or FMT placebo arms. FMT will be manufactured by the University of Birmingham Microbiome Treatment Centre, using stool collected from rigorously screened healthy donors. A total of 8 weekly treatments will be delivered; the first through colonoscopic administration (week 1) and the remaining seven via once-weekly enema (up to week 8). Participants will then be followed on a 12-weekly basis until week 48 from the first treatment visit. The primary efficacy outcome will be to determine the effect of FMT on serum alkaline phosphatase values over time (end of study at 48 weeks). Key secondary outcomes will be to evaluate the impact of FMT on other liver biochemical parameters, PSC risk scores, circulating and imaging markers of liver fibrosis, health-related quality of life measures, IBD activity and the incidence of PSC-related clinical events. Key translational objectives will be to identify mucosal metagenomic, metatranscriptomic, metabolomic and immunological pathways associated with the administration of FMT., Ethics and Dissemination: The protocol was approved by the South Central-Hampshire B Research Ethics Committee (REC 23/SC/0147). Participants will be required to provide written informed consent. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications., Trial Registration Number: The trial was registered at ClinicalTrials.gov on 23 February 2024 (NCT06286709). Weblink: Study Details | FAecal Microbiota Transplantation in primaRy sclerosinG chOlangitis | ClinicalTrials.gov., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Primary sclerosing cholangitis (PSC) is one of the leading indications for liver transplantation in Europe, and a major risk factor for cancer in inflammatory bowel disease (IBD). However, it is not known how the epidemiology of PSC will change as that of IBD evolves. The aim of this study is to provide nationwide statistics on the past and current prevalence of PSC and IBD across England, and forecast how this is likely to change over time., Methods: We accessed and analysed a nationwide population-based administrative healthcare registry, which houses prospectively accrued data since April 1st 2001. In so doing, the past and current prevalence of PSC-IBD and IBD alone was determined among 18-60-year-olds in England, alongside average annual percentage change rates (AAPC), between the 1st of January 2015 and 2020. Past and current prevalence data, alongside trends in incidence and event-free survival rates, were then used to forecast future prevalence between 2021 and 2027., Findings: In 2015, the prevalence of PSC with prior IBD diagnosis was 5.0 per 100,000 population, rising to 5.7 when including those with IBD diagnosed after PSC. In 2020, prevalence increased to 7.6 (8.6 accounting for IBD developing after PSC), yielding an AAPC of 8.8. In 2027, PSC-IBD prevalence is forecast to be 11.7 (95% prediction interval [PI]: 10.8-12.7), and 13.3 when accounting for IBD developing after PSC (AAPC: 6.4; 95% PI: 5.3-7.5). Comparatively, the prevalence of IBD alone rose among 18-60-year-olds from 384.3 in 2015 to 538.7 in 2020 (AAPC 7.0), and forecast to increase to 742.5 by 2027 (95% PI: 736.4-748.0; AAPC: 4.7, 95% PI: 4.6-4.8)., Interpretation: The rate of growth in PSC-IBD is predicted to exceed IBD-alone. Further research is needed to understand changes in disease epidemiology, including aetiological drivers of developing (invariably progressive) liver disease in IBD, and the implications of rising case burden on health care resources., Funding: This study was supported by an unrestricted grant provided by Gilead Sciences., Competing Interests: All authors have completed the ICMJE disclosure form and declare as follows: PJT receives institutional salary support from the NIHR Birmingham BRC. This paper presents independent research supported by the Birmingham NIHR BRC based at the University Hospitals Birmingham National Health Service Foundation Trust and the University of Birmingham, UK. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. This study was supported by an unrestricted grant from Gilead sciences, provided to the host institution. No conflicts of interests are declared for the other co-authors., (© 2024 The Author(s).)

The first British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS)-endorsed faecal microbiota transplant (FMT) guidelines were published in 2018. Over the past 5 years, there has been considerable growth in the evidence base (including publication of outcomes from large national FMT registries), necessitating an updated critical review of the literature and a second edition of the BSG/HIS FMT guidelines. These have been produced in accordance with National Institute for Health and Care Excellence-accredited methodology, thus have particular relevance for UK-based clinicians, but are intended to be of pertinence internationally. This second edition of the guidelines have been divided into recommendations, good practice points and recommendations against certain practices. With respect to FMT for Clostridioides difficile infection (CDI), key focus areas centred around timing of administration, increasing clinical experience of encapsulated FMT preparations and optimising donor screening. The latter topic is of particular relevance given the COVID-19 pandemic, and cases of patient morbidity and mortality resulting from FMT-related pathogen transmission. The guidelines also considered emergent literature on the use of FMT in non-CDI settings (including both gastrointestinal and non-gastrointestinal indications), reviewing relevant randomised controlled trials. Recommendations are provided regarding special areas (including compassionate FMT use), and considerations regarding the evolving landscape of FMT and microbiome therapeutics., Competing Interests: Competing interests: BHM has received consultation honoraria from Ferring Pharmaceuticals, Finch Therapeutics, Summit Therapeutics and speaker fees from Yakult. BMerrick received speaker fees from New Scientist. MNQ received speaker fees from BMS, Parapharm, Tillotts, Janssen and Takeda. NTE has received speaker fees from a company not related to the topic of this guideline. JPS received speaker fees from Takeda, AbbVie, Pfizer and BMS. NS received consultancy fees for advisory board for Pharmacosmos. ALH received fees for consultancy and speaker for AbbVie, Arena, Atlantic, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Galapagos, Lilly, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda; and also serves on the Global Steering Committee for Genentech. CS is a chair for the Healthcare Infection Society. JJK received consultancy fees from Vedanta Biosciences and Microviable Therapeutics and received a research grant from Vedanta Biosciences; and is a member of the scientific committee of European Helicobacter Microbiota Study group, member of the Scientific Advisory Board of 'Microviable Therapeutics', a member of a steering committee scientific study VE202 for ulcerative colitis (Vedanta Biosciences) and a founder and board member of Netherlands Donor Feces Bank (academic, non-profit). PH received consultancy and speaker fees from commercial companies and is a director of Modusmedica (since 2010 onwards). THI received consultancy fees from Ferring and speaker fees from Pharmacosmos and is a member of BSG/HIS microbiome for health expert panel and a director of University of Birmingham Microbiome Treatment Centre. SDG received consultancy honoraria from Enterobiotix and AstraZeneca, received speaker fees from Tillotts and has investments in biomedical company not related to the topic of this guideline. All other authors declared no conflicts of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The fecal microbiota and metabolome are hypothesized to be altered before late-onset neonatal meningitis (LOM), in analogy to late-onset sepsis (LOS). The present study aimed to identify fecal microbiota composition and volatile metabolomics preceding LOM., Methods: Cases and gestational age-matched controls were selected from a prospective, longitudinal preterm cohort study (born <30 weeks' gestation) at nine neonatal intensive care units. The microbial composition (16S rRNA sequencing) and volatile metabolome (gas chromatography-ion mobility spectrometry (GC-IMS) and GC-time-of-flight-mass spectrometry (GC-TOF-MS)), were analyzed in fecal samples 1-10 days pre-LOM., Results: Of 1397 included infants, 21 were diagnosed with LOM (1.5%), and 19 with concomitant LOS (90%). Random Forest classification and MaAsLin2 analysis found similar microbiota features contribute to the discrimination of fecal pre-LOM samples versus controls. A Random Forest model based on six microbiota features accurately predicts LOM 1-3 days before diagnosis with an area under the curve (AUC) of 0.88 (n=147). Pattern recognition analysis by GC-IMS revealed an AUC of 0.70-0.76 (P<0.05) in the three days pre-LOM (n=92). No single discriminative metabolites were identified by GC-TOF-MS (n=66)., Conclusion: Infants with LOM could be accurately discriminated from controls based on preclinical microbiota composition, while alterations in the volatile metabolome were moderately associated with preclinical LOM., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Inflammatory bowel disease (IBD) is a multisystem disease impacting various body systems including musculoskeletal, ocular, skin, hepatobiliary, pulmonary, cardiac, and haematological systems. The extraintestinal manifestations of IBD are frequent, common in both ulcerative colitis (UC) and Crohn's disease (CD), and impact the morbidity and mortality of patients., Methods: The Embase, Embase classic, and PubMed databases were searched between January 1979 and December 2021. A random effects model was performed to find the pooled prevalence of joint, ocular, and skin extraintestinal manifestations of UC and CD., Results: Fifty-two studies were included that reported on 352 454 patients. The prevalence of at least 1 joint, ocular, or skin extraintestinal manifestation in all IBD, UC, and CD was 24%, 27%, and 35% respectively. The prevalence between UC and CD were similar for pyoderma gangrenosum and axial joint manifestations. Ocular manifestations were found to be more common in CD than in UC. Peripheral joint manifestations and erythema nodosum were found to be more common in CD than UC., Discussion: To our knowledge, this is the first meta-analysis that reports on the prevalence of at least 1 joint, ocular, or skin extraintestinal manifestation in IBD. Our results are largely consistent with figures and statements quoted in the literature. However, our findings are based on significantly larger cohort sizes. Thus, our results have the potential to better power studies and more accurately counsel patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The aim of this systematic review and meta-analysis is to assess the efficacy and safety of faecal microbiota transplantation [FMT] in the treatment of chronic pouchitis., Methods: A PRISMA-compliant systematic review and meta-analysis was conducted using the following databases and clinical trial registers: Medline, Embase, Scopus, Cochrane Database of Systematic Reviews [CENTRAL], clinical trials.gov, ScienceDirect, and VHL [virtual health library]. The primary outcome was clinical response/remission in patients treated with FMT. Secondary outcomes included safety profile, quality of life, and changes in the gut microbiome., Results: Seven observational cohort studies/case series and two randomised, controlled trials with a total of 103 patients were included. The route, preparation, and quantity of FMT administered varied among the included studies. Clinical response rate of 42.6% with a remission rate of 29.8% was estimated in our cohort following FMT therapy. Minor, self-limiting, adverse events were reported, and the treatment was well tolerated with good short- and long-term safety profiles. Successful FMT engraftment in recipients varied and, on average, microbial richness and diversity was lower in patients with pouchitis. In some instances, shifts with specific changes towards abundance of species, suggestive of a 'healthier' pouch microbiota, were observed following treatment with FMT., Conclusion: The evidence for FMT in the treatment of chronic pouchitis is sparse, which limits any recommendations being made for its use in clinical practice. Current evidence from low-quality studies suggests a variable clinical response and remission rate, but the treatment is well tolerated, with a good safety profile. This review emphasises the need for rationally designed, well-powered, randomised, placebo-controlled trials to understand the efficacy of FMT for the treatment of pouchitis., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

The gut microbiota is a reservoir for antimicrobial resistance genes (ARGs). With current sequencing methods, it is difficult to assign ARGs to their microbial hosts, particularly if these ARGs are located on plasmids. Metagenomic chromosome conformation capture approaches (meta3C and Hi-C) have recently been developed to link bacterial genes to phylogenetic markers, thus potentially allowing the assignment of ARGs to their hosts on a microbiome-wide scale. Here, we generated a meta3C dataset of a human stool sample and used previously published meta3C and Hi-C datasets to investigate bacterial hosts of ARGs in the human gut microbiome. Sequence reads mapping to repetitive elements were found to cause problematic noise in, and may importantly skew interpretation of, meta3C and Hi-C data. We provide a strategy to improve the signal-to-noise ratio by discarding reads that map to insertion sequence elements and to the end of contigs. We also show the importance of using spike-in controls to quantify whether the cross-linking step in meta3C and Hi-C protocols has been successful. After filtering to remove artefactual links, 87 ARGs were assigned to their bacterial hosts across all datasets, including 27 ARGs in the meta3C dataset we generated. We show that commensal gut bacteria are an important reservoir for ARGs, with genes coding for aminoglycoside and tetracycline resistance being widespread in anaerobic commensals of the human gut.

Background and Aims: Healthcare quality improvement (QI) is the systematic process to continuously improve the quality of care and outcomes for patients. The landmark Inflammatory Bowel Disease (IBD) UK National Audits provided a means to measure the variation in care, highlighting the need to define the standards of excellence in IBD care. Through a consensus approach, we aimed to establish key performance indicators (KPIs), providing reliable benchmarks for IBD care delivery in UK., Methods: KPIs that measure critical aspects of a patient journey within an IBD service were identified though stakeholder meetings. A two-stage Delphi consensus was then conducted. The first involved a multidisciplinary team of IBD clinicians and patients to refine definitions and methodology. The second stage assessed feasibility and utility of the proposed QI process by surveying gastroenterology services across UK., Results: First, the four proposed KPIs were refined and included time from primary care referral to diagnosis in secondary care, time to treatment recommendation following a diagnosis, appropriate use of steroids and advanced therapies prescreening and assessment. Second, the Delphi consensus reported >85% agreement on the feasibility of local adoption of the QI process and >75% agreement on the utility of benchmarking of the KPIs., Conclusions: Through a structured approach, we propose quantifiable KPIs for benchmarking to improve and reduce the individual variation in IBD care across the UK., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Bile acid diarrhoea (BAD) is a common disorder that results from an increased loss of primary bile acids and can result in a change in microbiome. The aims of this study were to characterise the microbiome in different cohorts of patients with BAD and to determine if treatment with a bile acid sequestrant, colesevelam, can alter the microbiome and improve microbial diversity., Materials and Methods: Patients with symptoms of diarrhoea underwent 75-selenium homocholic acid ( 75 SeHCAT) testing and were categorised into four cohorts: idiopathic BAD, post-cholecystectomy BAD, post-operative Crohn's disease BAD and 75 SeHCAT negative control group. Patients with a positive 75 SeHCAT (<15%) were given a trial of treatment with colesevelam. Stool samples were collected pre-treatment, 4-weeks, 8-weeks and 6-12 months post-treatment. Faecal 16S ribosomal RNA gene analysis was undertaken., Results: A total of 257 samples were analysed from 134 patients. α-diversity was significantly reduced in patients with BAD and more specifically, in the idiopathic BAD cohort and in patients with severe disease (SeHCAT <5%); p < 0.05. Colesevelam did not alter bacterial α/β-diversity but patients who clinically responded to treatment had a significantly greater abundance of Fusobacteria and Ruminococcus , both of which aid in the conversion of primary to secondary bile acids., Conclusion: This is the first study to examine treatment effects on the microbiome in BAD, which demonstrated a possible association with colesevelam on the microbiome through bile acid modulation in clinical responders. Larger studies are now needed to establish a causal relationship with colesevelam and the inter-crosstalk between bile acids and the microbiome., Competing Interests: MB has received grants and travel expenses from Vifor International and Tillotts Pharma, outside of the submitted work. The research department of MB also received funding from Tillotts Pharma to support part of the described work. HS has received travel and conference expenses from Tillotts Pharma, Norgine, MSD, Abbvie and Janssen outside of the submitted work. JS has received speaker fees for Abbvie, Takeda and Janssen outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kumar, Quraishi, Al-Hassi, El-Asrag, Segal, Jain, Steed, Butterworth, Farmer, Mclaughlin, Beggs and Brookes.)

Autoimmune diseases have long been known to share a common pathogenesis involving a dysregulated immune system with a failure to recognize self from non-self-antigens. This immune dysregulation is now increasingly understood to be induced by environmental triggers in genetically predisposed individuals. Although several external environmental triggers have been defined in different autoimmune diseases, much attention is being paid to the role of the internal micro-environment occupied by the microbiome, which was once termed "the forgotten organ." In this regard, the gut microbiome, serving as an intermediary between some of those external environmental effectors and the immune system, helps programming of the immune system to be tolerant to innocent external and self-antigens. However, in the presence of perturbed gut microbiota (dysbiosis), the immune system could be erroneously directed in favor of pro-inflammatory pathways to instigate different autoimmune processes. An accumulating body of evidence, including both experimental and human studies (observational and interventional), points to the role of the gut microbiome in different autoimmune diseases. Such evidence could provide a rationale for gut microbiome manipulation with therapeutic and even preventative intent in patients with established or predisposed to autoimmune diseases, respectively. Perturbations of the gut microbiome have been delineated in some immune mediated diseases, IBD in particular. However, such patterns of disturbance (microbiome signatures) and related pathogenetic roles of the gut microbiome are context dependent and cannot be generalized in the same exact way to other autoimmune disorders, and the contribution of the gut microbiome to different disease phenotypes has to be precisely defined. In this review, we revise the evidence for a role of the gut microbiome in various autoimmune diseases and possible mechanisms mediating such a role., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Faecal microbiota transplantation (FMT) has previously been explored as a treatment for ulcerative colitis (UC) however, biomarkers that predict and / or are associated with clinical response are poorly defined. The aim of this systematic review was to identify donor and recipient clinical, microbial and metabolomic predictive biomarkers of response to FMT in UC., Methods: A systematic search of the relevant literature of studies exploring FMT in UC was conducted. Data on microbial diversity, taxonomic changes, metabolic changes, donor and recipient microbiota relationship and baseline predictors was examined., Findings: 2852 studies were screened, and 25 papers were included in this systematic review. Following FMT, alpha diversity was seen to increase in responders along with increases in the abundance of Clostridiales clusters (order) and Bacteroides genus. Metabolomic analysis revealed short chain fatty acid (SCFA) production as a marker of FMT success. Donors or FMT batches with higher microbial alpha diversity and a greater abundance of taxa belonging to certain Bacteroides and Clostridia clusters were associated with clinical response to FMT. Baseline clinical predictors of response in patients with UC included younger age, less severe disease and possibly shorter disease duration. Baseline recipient microbial predictors at response consisted of higher faecal species richness, greater abundance of Candida and donor microbial profile similarity., Interpretation: Distinct changes in gut microbiota profiles post-FMT indicate that certain baseline characteristics along with specific microbial and metabolomic alterations may predispose patients towards a successful therapeutic outcome. Opportunities towards a biomarker led precision medicine approach with FMT should be explored in future clinical studies., Funding: There no specific funding to declare., Competing Interests: Declaration of interests All authors declare no relevant conflict of interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: In this article, we provide a contemporary overview on PSC pathogenesis, with a specific focus on the role of mucosal immunity., Recent Findings: The extent of enteric dysbiosis in PSC has been extensively quantified, with evidence of reduced bacterial diversity and enrichment of species capable of driving lymphocyte recruitment from the gut to the liver. Integrative pathway-based analysis and metagenomic sequencing indicate a reduction in butyrate-producing species, near absence of bacteria that activate the nuclear bile acid receptor FXR, and depletion of species that regulate the synthesis of vitamin B6 and branched-chain amino acids. Immunotyping of the cellular inflammatory infiltrate has identified a population of intrahepatic naive T cells, with tendency to acquire a Th17 polarisation state, paralleled by heightened responses to pathogen stimulation. Moreover, the search for antigen specificity has revealed the presence of overlapping nucleotide clonotypes across the gut and liver, highlighting the ability to recognize a common pool of epitopes bearing structural similarities across afflicted sites., Summary: Understanding the complex mechanisms that underpin mucosal immune responses between the liver and gut will help identify new druggable targets in PSC, centring on gut microbial manipulation, bile acid therapies, and restoration of immune homeostasis., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Primary sclerosing cholangitis (PSC) is a rare immune-mediated cholestatic disease for which no medical therapy has been shown to slow disease progression. Consequently, liver transplantation is the only lifesaving intervention for patients, and despite being a rare disease, PSC is the lead indication for transplantation across several European countries. The vast majority of patients (>70%) also develop inflammatory bowel disease (IBD) at some point in their lifetime, which imparts added lifetime risks of hepatobiliary malignancy and colorectal cancer. The rare disease nature, variable and often slow rates of disease progression (years rather than months), and lack of robust surrogate biomarkers for early stage yet high risk disease, represent critical challenges in trial design that have long precluded the development of effective medical treatment. However, the horizon for new treatments is encouraging, given innovative clinical trial programmes led by industry, alongside several investigator-initiated studies. Herein, we outline the current platform of interventional trials in PSC, before discussing emerging areas of therapeutic interest., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: TI is the director of the University of Birmingham Microbiome Treatment Centre and the lead for faecal microbiota transplantation for the UK Microbiome for Health Expert Panel. All other authors declare no competing interests.

Vedolizumab is a gut-selective monoclonal antibody approved for the management of Crohn's disease and ulcerative colitis. The available data demonstrate a favourable response to dose escalation in patients with primary non-response or secondary loss of response to vedolizumab. While therapeutic drug monitoring has a proven clinical utility for tumour necrosis factor antagonists, the available guidance for therapeutic drug monitoring and dose escalation of vedolizumab is rather limited. The present review proposes a practical algorithm to use vedolizumab trough levels in the management of treatment failure. Therapeutic drug monitoring can differentiate underexposed patients from those with mechanistic failure. Underdosed patients can respond to dose escalation instead of unnecessarily switching to other treatment modalities. We also review the safety and potential cost-effectiveness of vedolizumab dose escalation, the role of antidrug antibodies and the possible applicability of this strategy to subcutaneous vedolizumab., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Screening for colorectal cancer (CRC) reduces its mortality but has limited sensitivity and specificity. Aims We aimed to explore potential biomarker panels for CRC and adenoma detection and to gain insight into the interaction between gut microbiota and human metabolism in the presence of these lesions., Methods: This multicenter case-control cohort was performed between February 2016 and November 2019. Consecutive patients ≥18 years with a scheduled colonoscopy were asked to participate and divided into three age, gender, body-mass index and smoking status-matched subgroups: CRC (n = 12), adenomas (n = 21) and controls (n = 20). Participants collected fecal samples prior to bowel preparation on which proteome (LC-MS/MS), microbiota (16S rRNA profiling) and amino acid (HPLC) composition were assessed. Best predictive markers were combined to create diagnostic biomarker panels. Pearson correlation-based analysis on selected markers was performed to create networks of all platforms., Results: Combining omics platforms provided new panels which outperformed hemoglobin in this cohort, currently used for screening (AUC 0.98, 0.95 and 0.87 for CRC vs controls, adenoma vs controls and CRC vs adenoma, respectively). Integration of data sets revealed markers associated with increased blood excretion, stress- and inflammatory responses and pointed toward downregulation of epithelial integrity., Conclusions: Integrating fecal microbiota, proteome and amino acids platforms provides for new biomarker panels that may improve noninvasive screening for adenomas and CRC, and may subsequently lead to lower incidence and mortality of colon cancer.

The risk of recurrent dysplastic colonic lesions is increased following polypectomy. Yield of endoscopic surveillance after adenoma removal is low, while interval colorectal cancers occur. To longitudinally assess the dynamics of fecal microbiota and amino acids in the presence of adenomatous lesions and after their endoscopic removal. In this longitudinal case-control study, patients collected fecal samples prior to bowel preparation before scheduled colonoscopy and 3 months after this intervention. Based on colonoscopy outcomes, patients with advanced adenomas and nonadvanced adenomas (0.5-1.0 cm) who underwent polypectomy during endoscopy ( n = 19) were strictly matched on age, body-mass index, and smoking habits to controls without endoscopic abnormalities ( n = 19). Microbial taxa were measured by 16S RNA sequencing, and amino acids (AA) were measured by high-performance liquid chromatography (HPLC). Adenoma patients were discriminated from controls based on AA and microbial composition. Levels of proline ( p = .001), ornithine ( p = .02) and serine ( p = .02) were increased in adenoma patients compared to controls but decreased to resemble those of controls after adenoma removal. These AAs were combined as a potential adenoma-specific panel (AUC 0.79(0.64-0.94)). For bacterial taxa, differences between patients with adenomas and controls were found ( Bifidobacterium spp.↓, Anaerostipes spp.↓, Butyricimonas spp.↑, Faecalitalea spp.↑ and Catenibacterium spp.↑), but no alterations in relative abundance were observed after polypectomy. Furthermore, Faecalitalea spp. and Butyricimonas spp. were significantly correlated with adenoma-specific amino acids. We selected an amino acid panel specifically increased in the presence of adenomas and a microbial signature present in adenoma patients, irrespective of polypectomy. Upon validation, these panels may improve the effectiveness of the surveillance program by detection of high-risk individuals and determination of surveillance endoscopy timing, leading to less unnecessary endoscopies and less interval cancer.

The ability of SARS-CoV-2 to infect the gastrointestinal tract is well described. Inflammatory bowel diseases (IBD) are believed to represent a disorganised immune response in genetically predisposed individuals, which are triggered by various environmental factors, notably infections. Here we report a case of chronic watery diarrhoea that was triggered by a SARS-CoV-2 infection. The work-up confirmed a new diagnosis of lymphocytic colitis, and the patient responded favourably to a course of oral budesonide. Clinicians should become vigilant to the possibility of triggered IBD in patients with persistent diarrhoea following a SARS-CoV-2 infection., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Breastfeeding is associated with long-term health benefits, such as a lower incidence of childhood infections, asthma, obesity and autoimmune disorders. However, little is known regarding how the maternal and neonatal immune systems interact after parturition when the neonate receives nutrition from maternal breast milk., Methods: We undertook a comparative analysis of immune repertoire and function at birth and 3 weeks of age in a cohort of 38 term neonates born by caesarean section grouped according to feeding method (breast milk versus formula). We used flow cytometry to study the immune phenotype in neonatal and maternal blood samples and mixed lymphocyte reactions to establish the proliferation response of neonatal versus maternal lymphocytes and vice versa. The microbiome of neonatal stool samples was also investigated using 16S rRNA sequencing., Results: We show that the proportion of regulatory T cells (Tregs) increases in this period and is nearly twofold higher in exclusively breastfed neonates compared with those who received formula milk only. Moreover, breastfed neonates show a specific and Treg-dependent reduction in proliferative T-cell responses to non-inherited maternal antigens (NIMA), associated with a reduction in inflammatory cytokine production. We also observed the enrichment of short chain fatty acid producing taxa (Veillonella and Gemella) in stool samples of exclusively breastfed neonates., Conclusions: These data indicate that exposure of the neonate to maternal cells through breastfeeding acts to drive the maturation of Tregs and 'tolerizes' the neonate towards NIMA., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: 5-Aminosalicylates [5-ASAs] are the mainstay of treatment for ulcerative colitis [UC]. The optimum preparation, dose, and route of administration for UC remain unclear. We conducted a network meta-analysis to examine this issue., Methods: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials from inception to December 2020. We included randomised controlled trials [RCTs] comparing oral, topical, or combined oral and topical 5-ASAs, with each other or placebo for induction of remission or prevention of relapse of UC. Results were reported as pooled relative risks [RRs] with 95% confidence intervals [CIs] to summarise effect of each comparison tested, with treatments ranked according to P-score., Results: We identified 40 RCTs for induction of remission and 23 for prevention of relapse. Topical mesalazine [P-score 0.99], or oral and topical mesalazine combined [P-score 0.87] ranked first and second for clinical and endoscopic remission combined. Combined therapy ranked first in trials where ≥50% of patients had left-sided/extensive disease, and topical mesalazine first in trials where ≥50% of patients had proctitis/proctosigmoiditis. High-dose [≥3.3 g/day] oral mesalazine ranked third in most analyses, with the most trials and most patients. For relapse of disease activity, combined therapy and high-dose oral mesalazine ranked first and second, with topical mesalazine third. 5-ASAs were safe and well tolerated, regardless of regimen., Conclusions: Our results support previous evidence; however, higher doses of oral mesalazine had more evidence for induction of remission than combined therapy and were significantly more efficacious than lower doses. Future RCTs should better establish the role of combined therapy for induction of remission, as well as optimal doses of oral 5-ASAs to prevent relapse., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This study aims to determine differences in the on- and off-tumor microbiota between patients with right- and left-sided colorectal cancer. Microbiome profiling of tumor and tumor-adjacent biopsies from patients with right-sided ( n = 17) and left-sided ( n = 7) colorectal adenocarcinoma was performed using 16S ribosomal RNA sequencing. Off-tumor alpha and beta diversity were significantly different between right- and left-sided colorectal cancer patients. However, no differences in on-tumor diversity were observed between tumor locations. Comparing the off-tumor microbiota showed the right colon to be enriched with species of the Lachnoclostridium, Selenomonas, and Ruminococcus genera. Whereas the left colon is enriched with Epsilonbacteraeota phylum, Campylobacteria class, and Pasteurellales and Campylobacterales orders, in contrast, the on-tumor microbiota showed relatively fewer differences in bacterial taxonomy between tumor sites, with left tumors being enriched with Methylophilaceae and Vadin BE97 families and Alloprevotella, Intestinibacter, Romboutsia, and Ruminococcus 2 genera. Patients with left-sided colorectal cancer had large taxonomic differences between their paired on- and off-tumor microbiota, while patients with right-sided colorectal cancer showed relatively fewer taxonomic differences. Collectively, this suggests that the right and left colon show distinctive bacterial populations; however, the presence of a colonic tumor leads to a more consistent microbiota between locations.

Iron deficiency anemia is a common complication of colorectal cancer and may require iron therapy. Oral iron can increase the iron available to gut bacteria and may alter the colonic microbiota. We performed an intervention study to compare oral and intravenous iron therapy on the colonic tumor-associated (on-tumor) and paired non-tumor-associated adjacent (off-tumor) microbiota. Anemic patients with colorectal adenocarcinoma received either oral ferrous sulphate ( n = 16) or intravenous ferric carboxymaltose ( n = 24). On- and off-tumor biopsies were obtained post-surgery and microbial profiling was performed using 16S ribosomal RNA analysis. Off-tumor α- and β-diversity were significantly different between iron treatment groups. No differences in on-tumor diversity were observed. Off-tumor microbiota of oral iron-treated patients showed higher abundances of the orders Clostridiales, Cytophagales, and Anaeroplasmatales compared to intravenous iron-treated patients. The on-tumor microbiota was enriched with the orders Lactobacillales and Alteromonadales in the oral and intravenous iron groups, respectively. The on- and off-tumor microbiota associated with intravenous iron-treated patients infers increased abundances of enzymes involved in iron sequestration and anti-inflammatory/oncogenic metabolite production, compared to oral iron-treated patients. Collectively, this suggests that intravenous iron may be a more appropriate therapy to limit adverse microbial outcomes compared to oral iron.

Fecal microbiota transplantation involves the infusion of intestinal microorganisms via the transfer of a stool from a healthy individual into a diseased individual, with the intent of restoring normal intestinal flora. Fecal transplant is proposed for the treatment of refractory Clostridioides difficile infection. At present, recurrent Clostridioides difficile infection is the only indication supported by solid scientific evidence. Regulations by healthcare authorities vary among different countries. Considering that Romania does not have an available national guideline to offer standardization, this paper aimed to create a national fecal microbiota transplantation guideline concerning indications, techniques and donor screening, developed by international and local scientific working groups.