Severe Fatigue in Inflammatory Bowel Disease: Dopaminergic Therapy With Modafinil or Vitamin Therapy With Thiamine.

We found Moulton et al's1 illustrative case series of 10 patients with inflammatory bowel disease (IBD) and chronic fatigue, all presenting with depression, particularly interesting. 1 Among the patients, 8 previously had undergone treatment with multiple psychotropic medications, and 2 had active IBD as indicated by increased fecal calprotectin levels. Remarkably, all 10 patients responded positively to open-label treatment with modafinil, a central nervous system stimulant that blocks dopamine reuptake transport, which resulted in an impressive improvement in their fatigue symptoms. At baseline, the self-reported mean fatigue score was 16, measured on the IBD Fatigue Assessment Scale (IBD-FAS), which ranges up to 20, and with levels higher than 11 indicating severe fatigue. After 6 months of modafinil treatment, the mean fatigue score was 6.7.1.

Real-world Effectiveness of Fecal Microbiota Transplantation for First or Second Clostridioides difficile Infection.

BACKGROUND & AIMS: Clostridioides difficile infection (CDI) is associated with high mortality. Fecal microbiota transplantation (FMT) is an established treatment for recurrent CDI, but its use for first or second CDI remains experimental. We aimed to investigate the effectiveness of FMT for first or second CDI in a real-world clinical setting. METHODS: This multi-site Danish cohort study included patients with first or second CDI treated with FMT from June 2019 to February 2023. The primary outcome was cure of C. difficile-associated diarrhea (CDAD) 8 weeks after the last FMT treatment. Secondary outcomes included CDAD cure 1 and 8 weeks after the first FMT treatment and 90-day mortality following positive C. difficile test. RESULTS: We included 467 patients, with 187 (40%) having their first CDI. The median patient age was 73 years (interquartile range [IQR], 58-82 years). Notably, 167 (36%) had antibiotic-refractory CDI, 262 (56%) had severe CDI, and 89 (19%) suffered from fulminant CDI. Following the first FMT treatment, cure of CDAD was achieved in 353 patients (76%; 95% confidence interval [CI], 71%-79%) at week 1. At week 8, 255 patients (55%; 95% CI, 50%-59%) maintained sustained effect. In patients without initial effect, repeated FMT treatments led to an overall cure of CDAD in 367 patients (79%; 95% CI, 75%-82%). The 90-day mortality was 10% (95% CI, 8%-14%). CONCLUSION: Repeated FMT treatments demonstrate high effectiveness in managing patients with first or second CDI. Forwarding FMT in CDI treatment guidelines could improve patient survival. CLINICALTRIALS: gov, Number: NCT03712722.

Effects of smoking on clinical treatment outcomes amongst patients with chronic inflammatory diseases initiating biologics: secondary analyses of the prospective BELIEVE cohort study.

The prevalence and disease burden of chronic inflammatory diseases (CIDs) are predicted to rise. Patients are commonly treated with biological agents, but the individual treatment responses vary, warranting further research into optimizing treatment strategies. This study aimed to compare the clinical treatment responses in patients with CIDs initiating biologic therapy based on smoking status, a notorious risk factor in CIDs. In this multicentre cohort study including 233 patients with a diagnosis of Crohn's disease, ulcerative colitis, rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis or psoriasis initiating biologic therapy, we compared treatment response rates after 14 to 16 weeks and secondary outcomes between smokers and non-smokers. We evaluated the contrast between groups using logistic regression models: (i) a "crude" model, only adjusted for the CID type, and (ii) an adjusted model (including sex and age). Among the 205 patients eligible for this study, 53 (26%) were smokers. The treatment response rate among smokers (n = 23 [43%]) was lower compared to the non-smoking CID population (n = 92 [61%]), corresponding to a "crude" OR of 0.51 (95% CI: [0.26;1.01]) while adjusting for sex and age resulted in consistent findings: 0.51 [0.26;1.02]. The contrast was apparently most prominent among the 38 RA patients, with significantly lower treatment response rates for smokers in both the "crude" and adjusted models (adjusted OR 0.13, [0.02;0.81]). Despite a significant risk of residual confounding, patients with CIDs (rheumatoid arthritis in particular) should be informed that smoking probably lowers the odds of responding sufficiently to biological therapy. Registration: Clinical.Trials.gov NCT03173144.

Impact of gluten intake on clinical outcomes in patients with chronic inflammatory diseases initiating biologics: Secondary analysis of the prospective multicentre BELIEVE cohort study.

Chronic inflammatory diseases (CIDs) pose a growing healthcare challenge, with a substantial proportion of patients showing inadequate response to biological treatment. There is renewed interest in dietary changes to optimize treatment regimens, with a growing body of evidence suggesting beneficial effects with adherence to a gluten-free diet. This study compared the likelihood of achieving clinical response to biological treatment after 14-16 weeks in patients with CID with high versus low-to-medium gluten intake. Secondary outcomes of interest included changes in disease activity, health-related quality of life and C-reactive protein. The study was a multicentre prospective cohort of 193 participants with a CID diagnosis (i.e. Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis, Axial Spondyloarthritis, Psoriatic Arthritis or Psoriasis) who initiated biological treatment between 2017 and 2020. Participants were stratified based on their habitual gluten intake: the upper 33.3% (high gluten intake) and the remaining 66.6% (low-to-medium gluten intake). The proportion of patients achieving clinical response to biological treatment after 14-16 weeks was compared using logistic regression models. The median gluten intake differed significantly between groups (12.5 g/day vs. 5.9 g/day, standardized mean difference = 1.399). In total, 108 (56%) achieved clinical response to treatment, with no difference between 35 (55%) in the high gluten group and 73 (57%) in the medium-to-low gluten group (OR = 0.96 [0.51-1.79], p = 0.897). No differences were found with secondary outcomes. In conclusion, this study found no association between gluten intake and response to biological treatment in patients with CID.

Microfibrillar-associated protein 4 as a predictive biomarker of treatment response in patients with chronic inflammatory diseases initiating biologics: secondary analyses based on the prospective BELIEVE cohort study.

BACKGROUND: Currently, there are no reliable biomarkers for predicting treatment response in chronic inflammatory diseases (CIDs). OBJECTIVE: To determine whether serum microfibrillar-associated protein 4 (MFAP4) levels can predict the treatment response to biological therapy in patients with CIDs. METHODS: The BELIEVE study was originally designed as a prospective, multi-center cohort study of 233 patients with either rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, Crohn's disease, or ulcerative colitis, initiating treatment with a biologic agent (or switching to another). Clinical assessment and blood sample collection were performed at baseline and 14-16 weeks after treatment initiation. The primary analyses included participants with available blood samples at baseline; missing data were handled as non-responders. The patients were stratified into the upper tertile of serum MFAP4 (High MFAP4) versus a combined category of middle and lower tertiles (Other MFAP4). The primary outcome was the proportion of patients with clinical response to biologic therapy after 14-16 weeks. RESULTS: 211 patients were included in the primary analysis population. The mean age was 43.7 (SD: 14.8) years, and 120 (59%) were female. Positive treatment response was observed in 41 (59%) and 69 (49%) for High MFAP4 and Other MFAP4, respectively. When adjusting for pre-specified variables (CID, age, sex, smoking status, and BMI), the adjusted OR was 2.28 (95% CI: 1.07 to 4.85) for a positive treatment outcome in the High MFAP4 group. CONCLUSION: A high MFAP4 status before initiating biological treatment is associated with a positive clinical response, when adjusting for confounding factors.

B-vitamins, related vitamers, and metabolites in patients with quiescent inflammatory bowel disease and chronic fatigue treated with high dose oral thiamine.

BACKGROUND: High doses of oral thiamine improve clinical fatigue scores in patients with quiescent inflammatory bowel disease (IBD) and chronic fatigue. In this study we analysed plasma samples obtained in a randomised clinical trial and aimed compare levels of vitamins B1, B2, B3 and B6, and their related vitamers and metabolites in patients with IBD, with or without chronic fatigue and with or without effect of high dose oral thiamine for chronic fatigue. METHODS: Blood samples from patients with fatigue were drawn prior and after thiamine exposure and only once for patients without fatigue. A wide panel of analysis were done at Bevital AS Lab. RESULTS: Concentration of flavin mononucleotide (FMN) was lower in patients with chronic fatigue compared to patients without fatigue (p = 0.02). Patients with chronic fatigue who reported a positive effect on fatigue after 4 weeks of high dose thiamine treatment had a statistically significantly lower level of riboflavin after thiamine treatment (p = 0.01). CONCLUSION: FMN and Riboflavin were associated with chronic fatigue in patients with quiescent IBD. Levels of other B vitamins and metabolites were not significantly different between the investigated groups or related to effect of the thiamine intervention. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov study identifier NCT036347359. Registered 15 August 2018, https://clinicaltrials.gov/study/NCT03634735?cond=Inflammatory%20Bowel%20Diseases&intr=Thiamine&rank=1.

Sodium depletion and secondary hyperaldosteronism in outpatients with an ileostomy: a cross-sectional study.

OBJECTIVE: Patients with an ileostomy may experience postoperative electrolyte derangement and dehydration but are presumed to stabilise thereafter. We aimed to investigate the prevalence of sodium depletion in stable outpatients with an ileostomy and applied established methods to estimate their fluid status. METHODS: We invited 178 patients with an ileostomy through a region-wide Quality-of-Life-survey to undergo outpatient evaluation of their sodium and fluid status. The patients delivered urine and blood samples, had bioelectrical impedance analysis performed and answered a questionnaire regarding dietary habits. RESULTS: Out of 178 invitees, 49 patients with an ileostomy were included; 22 patients (45%, 95% CI, 31-59%) had unmeasurably low urinary sodium excretion (<20 mmol/L), indicative of chronic sodium depletion, and 26% (95% CI, 16-41%) had plasma aldosterone levels above the reference value. Patients with unmeasurably low urinary sodium excretion had low estimated glomerular filtration rates (median 76, IQR 63-89, mL/min/1.73m2) and low venous blood plasma CO2 (median 24, IQR 21-26, mmol/L), indicative of chronic renal impairment and metabolic acidosis. Bioelectrical impedance analysis, plasma osmolality, creatinine and sodium values were not informative in determining sodium status in this population. CONCLUSION: A high proportion of patients with an ileostomy may be chronically sodium depleted, indicated by absent urinary sodium excretion, secondary hyperaldosteronism and chronic renal impairment, despite normal standard biochemical tests. Sodium depletion may adversely affect longstanding renal function. Future studies should investigate methods to estimate and monitor fluid status and aim to develop treatments to improve sodium depletion and dehydration in patients with an ileostomy.IMPACT AND PRACTICE RELEVANCE STATEMENTSodium depletion in otherwise healthy persons with an ileostomy was identified in a few publications from the 1980s. The magnitude of the problem has not been demonstrated before. The present study quantifies the degree of sodium depletion and secondary hyperaldosteronism in this group, and the results may help guide clinicians to optimise treatment. Sodium depletion is easily assessed with a urine sample, and sequelae may possibly be avoided if sodium depletion is detected early and treated. This could ultimately help increase the quality of life in patients with an ileostomy.

Long-term maintenance treatment with 300 mg thiamine for fatigue in patients with inflammatory bowel disease: results from an open-label extension of the TARIF study.

OBJECTIVE AND AIMS: Fatigue is common in inflammatory bowel disease (IBD). In a RCT we demonstrated reductions in fatigue after 4 weeks' treatment with high-dose oral thiamine. We aimed to investigate whether 300 mg thiamine daily for 12 weeks could maintain the achieved levels of fatigue in patients with IBD after a 4-week intervention with high-dose thiamine; and evaluate the effect of a 6-month period where patients were free to take oral thiamine. METHODS: A randomised, open-label, controlled trial, performed as a long-term extension (LTE) study of an initial randomised, high-dose thiamine trial. Patients were allocated 1:1 to 300 mg oral thiamine or no thiamine for 12 weeks. Subsequently, the patients were allowed to self-treat with over-the-counter (OTC) oral thiamine 6-month. RESULTS: Regardless of allocation in the LTE study fatigue severity increased in the study period. No significant effect of 300 mg oral thiamine were found, when stratifying for initial allocation in the high-dose study or fatigue level at entry in the LTE study. Patients who took OTC thiamine had lower level of fatigue 6 month later (7.8; 95% CI: 5.5-10.1) when compared to the remains (11.0; 95% CI: 9.2-12.8) (p = .02). After the 6-months follow-up without restrictions, 66% of patients had reached normal fatigue levels. CONCLUSIONS: We found no beneficial effect on fatigue from thiamine taken in doses of 300 mg per day for 12 weeks following high-dose treatment. After a 6-months follow-up without restrictions 66% had reached a normal level of fatigue. CLINICAL TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov under study identifier NCT03634735.

Danish national guideline for the treatment of Clostridioides difficile infection and use of faecal microbiota transplantation (FMT).

Aim: This Danish national guideline describes the treatment of adult patients with Clostridioides (formerly Clostridium) difficile (CD) infection and the use of faecal microbiota transplantation (FMT). It suggests minimum standard for implementing an FMT service.Method: Four scientific societies appointed members for a working group which conducted a systematic literature review and agreed on the text and recommendations. All clinical recommendations were evalluated for evidence level and grade of recommendation.Results: In CD infection, the use of marketed and experimental antibiotics as well as microbiota-based therapies including FMT are described. An algorithm for evaluating treatment effect is suggested. The organisation of FMT, donor recruitment and screening, laboratory preparation, clinical application and follow-up are described.Conclusion: Updated evidence for the treatment of CD infection and the use of FMT is provided.

Fecal Microbiota Transplantation Is Superior to Fidaxomicin for Treatment of Recurrent Clostridium difficile Infection.

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is recommended for treatment of recurrent Clostridium difficile infection (rCDI). We performed a single-center randomized trial to compare the effects of FMT with those of fidaxomicin and vancomycin. METHODS: We studied consecutive adults with rCDI seen at a gastroenterology clinic in Denmark from April 5, 2016 through June 10, 2018. Patients were randomly assigned to a group that received FMT, applied by colonoscopy or nasojejunal tube, after 4-10 days of vancomycin (125 mg 4 times daily; FMTv; n = 24), 10 days of fidaxomicin (200 mg twice daily; n = 24), or 10 days of vancomycin (125 mg 4 times daily; n = 16). Patients who had rCDI after this course of treatment and patients who could not be randomly assigned to groups were offered rescue FMTv. The primary outcome was combined clinical resolution and a negative result from a polymerase chain reaction test for Clostridium difficile (CD) toxin 8 weeks after the allocated treatment. Secondary end points included clinical resolution at week 8. RESULTS: All 64 patients received their assigned treatment. The combination of clinical resolution and negative results from the test for CD were observed in 17 patients given FMTv (71%), 8 patients given fidaxomicin (33%), and 3 patients given vancomycin (19%; P = .009 for FMTv vs fidaxomicin; P = .001 for FMTv vs vancomycin; P = .31 for fidaxomicin vs vancomycin). Clinical resolution was observed in 22 patients given FMTv (92%), 10 patients given fidaxomicin (42%), and 3 patients given vancomycin (19%; P = .0002; P < .0001; P = .13). Results did not differ significantly between patients who received FMTv as their initial therapy and patients who received rescue FMTv. There was 1 serious adverse event that might have been related to FMTv. CONCLUSIONS: In a randomized trial of patients with rCDI, we found the FMTv combination superior to fidaxomicin or vancomycin based on end points of clinical and microbiological resolution or clinical resolution alone. ClinicalTrials.gov, number NCT02743234; EudraCT, j.no 2015-003004-24.

Faecal microbiota transplantation for eradication of co-infection with Clostridioides difficile and extensively drug-resistant KPC-producing Klebsiella pneumoniae.

Clostridioides difficile infection may be complicated by co-infection with other pathogens. We here describe the successful use of faecal microbiota transplantation to eradicate concomitant C. difficile and extensively drug-resistant (XDR) KPC-producing Klebsiella pneumoniae. Donor microbiota efficiently engrafted in the patient, and a donor-like microbial assemblage persisted in the patient during six months follow-up. The report explores the potential for the donor microbiota to eradicate and replace multi-resistant microorganisms.

Faecal microbiota transplantation as a home therapy to frail older people.

BACKGROUND: Clostridioides (Clostridium) difficile infection (CDI) is a leading cause of antibiotics-associated diarrhoea. Faecal microbiota transplantation (FMT) is effective for recurrent CDI and may be provided as a home treatment to frail, older people. METHODS: We present four consecutive patients with recurrent CDI, treated at home using nasojejunal tube-delivered or encapsulated donor faeces. The primary outcome was combined clinical resolution and a negative CD toxin test 8 weeks post-treatment. RESULTS: All four patients had severe CDI and all improved clinically following one FMT. Sustained resolution following one FMT was observed in one patient. Two patients had recurrence and received a second FMT using capsules; both achieved resolution. One patient who had recurrence declined from further FMT due to fear of relapse and was established on long-term vancomycin. No adverse events related to FMT were observed. CONCLUSION: Frail older people may benefit from FMT. Home treatment is a viable option and may be considered both for clinical cure and for palliation.

Banking feces: a new frontier for public blood banks?

Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridioides difficile infection and is potentially beneficial in other microbiota-related disorders. The provision of FMT in routine clinical practice requires an extensive infrastructure that is reliant on voluntary donors. Alongside an increasing demand for FMT, the logistic barriers of a large-scale donor-dependent operation and the difficulties among health authorities to regulate FMT limit the dissemination of sustainable FMT services. Blood centers are large organizations that handle a multitude of donor-dependent operations on a daily basis. Blood and feces share many of the same dependencies, and feces may present a new opportunity for the blood services to handle. In this paper, we describe how an FMT service may be established and embedded within the blood service infrastructure, and we explain the benefits of using blood donors as feces donors. We further explore the current indications of FMT, the challenges related to the lack of legislation, and the future perspectives for blood banks to meet a new and increasing demand.

Helicobacter pylori infection is associated with reduced prevalence of colonic diverticular disease.

BACKGROUND: Colonic diverticular disease is a common disorder with increasing incidence in Western societies. The intestinal microbiome may be among etiological factors. Helicobacter pylori may protect against some intestinal diseases, and incidence of H. pylori is decreasing in Western societies. Thus, we aimed to determine whether H. pylori is associated to decreased prevalence of registered colonic diverticular disease. MATERIALS AND METHODS: In a historical cohort study, patients were enrolled from primary health care centers after urea breath test for H. pylori and then followed for a median of 6 years. The patient's diagnostic codes and country of birth were acquired from nationwide Danish administrative registries. We used logistic regression to compare prevalence and Cox regression to compare incidence of diverticular disease between H. pylori-positive and H. pylori-negative patients, adjusting for confounding variables. RESULTS: Patients infected with H. pylori had lower prevalence of colonic diverticular disease (0.87% vs 1.14%, OR=0.62, 95% CI: 0.50-0.78). This phenomenon was observed whether we studied all registered diagnoses or only cases registered as primary diagnoses at discharge. After urea breath test, we observed no statistical difference in incidence rates of diverticular disease. CONCLUSION: H. pylori is associated with reduced prevalence of colonic diverticular disease. The inverse association was absent after the urea breath test. Thus, we speculate that H. pylori may provide protection from colonic diverticular disease. Alternatively, H. pylori is a marker for other factors affecting disease development.

Gastrointestinal and liver disease in Adult Life After Childhood Cancer in Scandinavia: A population-based cohort study.

Survival after childhood cancer diagnosis has remarkably improved, but emerging evidence suggests that cancer-directed therapy may have adverse gastrointestinal late effects. We aimed to comprehensively assess the frequency of gastrointestinal and liver late effects among childhood cancer survivors and compare this frequency with the general population. Our population-based cohort study included all 1-year survivors of childhood and adolescent cancer in Denmark, Finland, Iceland, Norway and Sweden diagnosed from the 1940s and 1950s. Our outcomes of interest were hospitalization rates for gastrointestinal and liver diseases, which were ascertained from national patient registries. We calculated standardized hospitalization rate ratios (RRs) and absolute excess rates comparing hospitalizations of any gastrointestinal or liver disease and for specific disease entities between survivors and the general population. The study included 31,132 survivors and 207,041 comparison subjects. The median follow-up in the hospital registries were 10 years (range: 0-42) with 23% of the survivors being followed at least to the age of 40 years. Overall, survivors had a 60% relative excess of gastrointestinal or liver diseases [RR: 1.6, 95% confidence interval (CI): 1.6-1.7], which corresponds to an absolute excess of 360 (95% CI: 330-390) hospitalizations per 100,000 person-years. Survivors of hepatic tumors, neuroblastoma and leukemia had the highest excess of gastrointestinal and liver diseases. In addition, we observed a relative excess of several specific diseases such as esophageal stricture (RR: 13; 95% CI: 9.2-20) and liver cirrhosis (RR: 2.9; 95% CI: 2.0-4.1). Our findings provide useful information about the breadth and magnitude of late complications among childhood cancer survivors and can be used for generating hypotheses about potential exposures related to these gastrointestinal and liver late effects.

Biological therapy increases the health-related quality of life in patients with inflammatory bowel disease in a clinical setting.

OBJECTIVE: Inflammatory bowel diseases (IBDs) have a considerable impact on the health-related quality of life (HRQoL) of patients. We aimed to investigate the effect of biological therapy on HRQoL in IBD patients followed in an out-patient clinical setting and to compare the HRQoL scores to that of IBD patients without disease activity. MATERIALS: Observational and retrospective study in patients treated with biologics. A Short Health Scale (SHS) questionnaire on HRQoL consisting of four items (bowel symptoms, interference in daily life, worry, and general well-being) was completed and registered in each patient's medical journal. Data on HRQoL was collected at the beginning of treatment and every 3 months thereafter. The biologically treated group was compared with a control group of IBD patients without disease activity. RESULTS: We identified 114 patients who began a new round of biological treatment. These were either naïve to biologics or had a break in treatment for more 3 months. After 3 months of therapy, significant improvements in HRQoL compared to baseline were observed for every item on the SHS (p value < 0.01). Subgroup analysis showed a poorer HRQoL performance in women, patients with Crohn's disease, and smokers. The median HRQoL score regarding bowel symptoms and interference in daily life was similar to the control group after 6 months of treatment. CONCLUSION: Treatment with biological therapy leads to a statistically and clinically significant improvement in HRQoL in all parameters. After 6 months of treatment, bowel symptoms and interference in daily life were similar to patients without disease activity.

Adherence and quality of care in IBD.

OBJECTIVE: In inflammatory bowel disease (IBD), adherence to both medical treatment and other aspects of care has a substantial impact on the course of the disease. Most studies of medical adherence have reported that 30-45% of patients with IBD were non-adherent. Our study aimed to investigate the different aspects of adherence and to identify predictors of non-adherence, including the quality of care, for outpatients with IBD. MATERIALS AND METHODS: An anonymous electronic questionnaire was used to investigate different aspects of adherence, the quality of care, patient involvement and shared decision making among 377 IBD outpatients. RESULTS: Three hundred (80%) filled in the questionnaire. The overall adherence rate was 93%. Young age (< 35 years old) and smoking were significantly associated with non-adherence (prevalence odds ratio (POR) 2.98, 95% CI 1.04-8.52, p < 0.05 and POR 3.88, 95% CI 1.36-11.05, p < 0.05, respectively). The lowest medical adherence rates were found for 5-ASA and topical treatments among patients with inactive disease. A large majority of patients stated that treatment strategies were agreed upon as a shared decision between the patient and the health care professionals. CONCLUSIONS: Predictors for non-adherence were young age and smoking. High adherence rates could be explained by a high patient satisfaction and a high degree of shared decision making.

Pirfenidone inhibits the proliferation of fibroblasts from patients with active Crohn's disease.

OBJECTIVE: One-third of Crohn's disease (CD) patients develop intestinal strictures that require repeated surgical intervention. Current anti-inflammatory therapies have limited effect on stricture development, which necessitates the exploration of new pharmacological approaches. Pirfenidone (PFD), a novel anti-fibrotic agent, was recently approved in Europe for the treatment of idiopathic pulmonary fibrosis (IPF). We hypothesized that observations in IPF could be transferable to intestinal fibrosis and that PFD inhibits the proliferation and extracellular matrix (ECM) turnover of gut-derived fibroblasts from CD patients. MATERIAL AND METHODS: Fibroblasts were isolated from biopsies of inflamed (n = 8) and non-inflamed (n = 5) colonic mucosa. Expression of CD90 and alpha-smooth muscle actin (αSMA) expression was determined by flow cytometry. The fibroblasts were cultured with PFD (0.5, 1.0 and 2.0 mg/ml). Proliferation was evaluated with CellTiter 96(®) AQueous One Solution Cell Proliferation Assay. Production of matrix metalloproteinase-3 (MMP-3), tissue inhibitor of metalloproteinases-1 (TIMP-1) and collagen were assessed using ELISA and calorimetric assays, respectively. RESULTS: The majority of the fibroblasts were αSMA-positive myofibroblasts. PFD inhibited fibroblast proliferation [0.94 (PFD 0.5 mg/ml); 0.76 (1.0 mg/ml); 0.58 (2.0 mg/ml)] and production of MMP-3 [0.85 (0.5 mg/ml); 0.74 (1.0 mg/ml); 0.63 (2.0 mg/ml)] dose-dependently (both p = 0.0001). The anti-proliferative effect of PFD was reversible (p = 0.0001), indicating that PFD does not act by an irreversible cytotoxic mechanism. PFD did not influence neither TIMP-1 nor collagen production. CONCLUSION: PFD inhibited the proliferation and the production of MMP-3 dose-dependently in gut-derived fibroblast from CD patients. Our observations support further studies on PFD in stricturing CD.

High-dose fast infusion of parenteral iron isomaltoside is efficacious in inflammatory bowel disease patients with iron-deficiency anaemia without profound changes in phosphate or fibroblast growth factor 23.

OBJECTIVE: Iron isomaltoside (Monofer(®)) is a high-dose intravenous iron preparation with good tolerability and efficacy in inflammatory bowel disease (IBD) patients with iron deficiency anaemia (IDA). This trial evaluates the safety and efficacy, including effect on intact fibroblast growth factor 23 (iFGF23) of a high single dose and cumulative doses of iron isomaltoside in IBD patients with IDA. MATERIALS AND METHODS: The trial was a prospective, open-label, multi-centre trial conducted in IBD patients with IDA. Based upon haemoglobin (Hb) levels at baseline and weight, the patients received 1500, 2000, 2500 or 3000 mg of iron isomaltoside infused in single doses up to 2000 mg. The outcome measurements included adverse drug reactions (ADRs) and changes in haematology and biochemistry parameters. RESULTS: Twenty-one IBD patients with IDA were enrolled, receiving 1500 (seven patients), 2000 (eight patients), 2500 mg (four patients) or 3000 (two patients) mg of iron. No serious ADRs were observed. Four patients experienced nine mild to moderate ADRs (hypersensitivity, pyrexia, vomiting, constipation, abdominal pain, dyspepsia (two events) and eye allergy (two events)). In total, 15 (75%) patients had an increase in Hb of ≥2.0 g/dL during the trial, with normalisation of ferritin. No changes in iFGF23 or clinically significant hypophosphataemia were found. CONCLUSION: Rapid infusions of high-dose iron isomaltoside, administered as single doses up to 2000 mg and cumulative doses up to 3000 mg, were without safety concerns and were efficacious in increasing Hb levels in IBD patients. Iron isomaltoside did not induce profound phosphate wasting via increased iFGF23 levels.

Encapsulated donor faeces for faecal microbiota transplantation: the Glyprotect protocol.

Background: Faecal microbiota transplantation (FMT) is a highly effective treatment for Clostridioides difficile infection. Its use is backed by solid evidence, but application methods differ. Encapsulated FMT is a non-invasive, patient-friendly and scalable application method that may be preferred over colonoscopy or nasoduodenal tube application. Objectives: We describe a detailed protocol, the Glyprotect protocol, for producing glycerol-based capsules to increase FMT accessibility. Design: Using iterative quality improvement methods, we developed and validated the Glyprotect protocol as a reproducible protocol for cryopreserving minimally processed donor faeces in a standard hospital laboratory setting. Methods: We describe detailed standard operating procedures for producing glycerol-based capsules, including all necessary materials and troubleshooting guidelines. Capsule integrity was tested at various temperatures and pH levels. Flow cytometry was used to measure microbiota counts and dose accuracy. Results: The Glyprotect protocol has been used for more than 2500 capsule-based FMT treatments and complies with European tissue and cell standards. The protocol is optimised to preserve microbes and minimise modulation of the donated microbiota by removing debris and water, which also reduces the number of capsules needed per FMT treatment. The intestinal microbiota is preserved in glycerol for cryoprotection and to prevent capsule leakage. Each capsule contains 650 µL microbe-glycerol mass, estimated to contain an average of 2.5 × 108 non-specified bacteria. Conclusion: The Glyprotect protocol enables hospitals and tissue establishments to set up capsule production in a standard laboratory, improving patients' access to FMT. The protocol facilitates the scalability of FMT services because capsule FMT is less time-consuming and less expensive than liquid-suspension FMT applied by colonoscopy or nasojejunal tube. Trial registration: Not applicable.

A protocol for production of encapsulated donor faeces for faecal microbiota transplantation We provide a detailed description of how to produce encapsulated donor faeces for faecal microbiota transplantation (FMT). FMT is a highly effective treatment for diseases where the intestinal microbiota is compromised, in particular Clostridioides difficile infection. Encapsulated application is patient-friendly and non-invasive, but protocols for the production of FMT capsules have not been published or are not reproducible. We here provide detailed guidance for standard-equipped hospital laboratories to enable capsule production under the current regulatory framework for substances of human origin in Europe. The dissemination of this protocol will increase patients' access to a life-saving therapy.