Selective Uptake Into Inflamed Human Intestinal Tissue and Immune Cell Targeting by Wormlike Polymer Micelles.

Inflammatory bowel disease (IBD) has become a globally prevalent chronic disease with no causal therapeutic options. Targeted drug delivery systems with selectivity for inflamed areas in the gastrointestinal tract promise to reduce severe drug-related side effects. By creating three distinct nanostructures (vesicles, spherical, and wormlike micelles) from the same amphiphilic block copolymer poly(butyl acrylate)-block-poly(ethylene oxide) (PBA-b-PEO), the effect of nanoparticle shape on human mucosal penetration is systematically identified. An Ussing chamber technique is established to perform the ex vivo experiments on human colonic biopsies, demonstrating that the shape of polymeric nanostructures represents a rarely addressed key to tissue selectivity required for efficient IBD treatment. Wormlike micelles specifically enter inflamed mucosa from patients with IBD, but no significant uptake is observed in healthy tissue. Spheres (≈25 nm) and vesicles (≈120 nm) enter either both normal and inflamed tissue types or do not penetrate any tissue. According to quantitative image analysis, the wormlike nanoparticles localize mainly within immune cells, facilitating specific targeting, which is crucial for further increasing the efficacy of IBD treatment. These findings therefore demonstrate the untapped potential of wormlike nanoparticles not only to selectively target the inflamed human mucosa, but also to target key pro-inflammatory cells.

Glucocorticoids regulate lipid mediator networks by reciprocal modulation of 15-lipoxygenase isoforms affecting inflammation resolution.

Glucocorticoids (GC) are potent anti-inflammatory agents, broadly used to treat acute and chronic inflammatory diseases, e.g., critically ill COVID-19 patients or patients with chronic inflammatory bowel diseases. GC not only limit inflammation but also promote its resolution although the underlying mechanisms are obscure. Here, we reveal reciprocal regulation of 15-lipoxygenase (LOX) isoform expression in human monocyte/macrophage lineages by GC with respective consequences for the biosynthesis of specialized proresolving mediators (SPM) and their 15-LOX-derived monohydroxylated precursors (mono-15-OH). Dexamethasone robustly up-regulated pre-mRNA, mRNA, and protein levels of ALOX15B/15-LOX-2 in blood monocyte-derived macrophage (MDM) phenotypes, causing elevated SPM and mono-15-OH production in inflammatory cell types. In sharp contrast, dexamethasone blocked ALOX15/15-LOX-1 expression and impaired SPM formation in proresolving M2-MDM. These dexamethasone actions were mimicked by prednisolone and hydrocortisone but not by progesterone, and they were counteracted by the GC receptor (GR) antagonist RU486. Chromatin immunoprecipitation (ChIP) assays revealed robust GR recruitment to a putative enhancer region within intron 3 of the ALOX15B gene but not to the transcription start site. Knockdown of 15-LOX-2 in M1-MDM abolished GC-induced SPM formation and mono-15-OH production. Finally, ALOX15B/15-LOX-2 upregulation was evident in human monocytes from patients with GC-treated COVID-19 or patients with IBD. Our findings may explain the proresolving GC actions and offer opportunities for optimizing GC pharmacotherapy and proresolving mediator production.

Fatigue in patients with inflammatory bowel disease-strongly influenced by depression and not identifiable through laboratory testing: a cross-sectional survey study.

BACKGROUND: Fatigue is a debilitating and highly relevant symptom in patients with inflammatory bowel disease (IBD). However, awareness of fatigue and treatment options remains limited. This study was aimed at elucidating the influence of disease activity and common complications (pain, anemia, depression, anxiety and quality of life) on fatigue in patients with IBD to identify potential interventional targets for treating physicians. METHODS: A cross-sectional survey including five questionnaires (HADS, Fatigue Assessment Scale, McGill Pain Questionnaire, IBDQ and general well-being) was performed on patients with IBD (n = 250) at a university IBD clinic. Additionally, demographic data, laboratory data, IBD history, treatment and current disease activity (Harvey-Bradshaw Index, partial Mayo Score, calprotectin and CRP) were recorded. RESULTS: A total of 189 patients were analyzed (59.8% with Crohn's disease (CD) and 40.2% with ulcerative colitis (UC)). A total of 51.3% were fatigued, and 12.2% were extremely fatigued. Multiple factors showed significant correlations in univariate analysis. Multivariate analysis revealed that fatigue was correlated with depression (CD, p = 0.002; UC, p = 0.02), diminished quality of life (CD, p = 0.015), female sex (CD, p = 0.015) and younger age (UC, p = 0.024), whereas the influence of anemia or disease activity was non-significant. CONCLUSIONS: Fatigue is burdensome and highly prevalent in patients with active and inactive IBD. Considerations for fatigue treatment, beyond targeting inflammation and anemia, should include investigation of underlying sub-clinical depression.

Treatment Strategies in Inflammatory Bowel Diseases.

BACKGROUND: The prevalence of inflammatory bowel disease (IBD) is rising globally. In Germany, these conditions affect 0.7% of the population, or approximately 600 000 patients. Treatment strategies have become more diversified as a result of an improved understanding of disease pathogenesis. It remains unclear how the currently available drugs should best be used in each individual patient. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, with special attention to phase III and IV trials and to the German and European guidelines on the treatment of IBD. RESULTS: An improved understanding of the immunological mechanisms of disease underlies the current treatment strategies in patients with IBD. For those with a complex clinical course, monoclonal antibodies against pro-inflammatory cytokines (TNF, IL-12/IL-23, IL-23) and cell adhesion molecules (α4ß7) are of established therapeutic value, along with "small molecules" such as JAK inhibitors and sphingosine-1-phosphate receptor modulators. The numerous studies that have been performed, only a few of which have been head-to-head comparison trials, and the (network) meta-analyses that have been published to date do not imply that any single one of these drugs can be considered the universal, primary treatment for all patients with IBD. In this review, we discuss the available substances and certain important differential-therapeutic aspects of the treatment of IBD. CONCLUSION: The treatment of a patient with IBD must take his or her prior treatment(s) and comorbidities into account, along with individual patient characteristics and treatment goals. Rational decision-making is required on the basis of the mechanism of action and the side-effect profile of the various drugs that are now available for use.

Immunomodulator comedication promotes the reversal of anti-drug antibody-mediated loss of response to anti-TNF therapy in inflammatory bowel disease.

PURPOSE: Loss of therapeutic response (LOR) due to anti-drug antibodies (ADA) against tumor necrosis factor (TNF) inhibitors is common in patients with inflammatory bowel disease (IBD). We aimed to investigate whether immunomodulator comedication can reverse the immunogenic LOR to TNF inhibitors in IBD. METHODS: In this real-world retrospective cohort study, 123 IBD patients with neutralizing ADA to infliximab or adalimumab and concomitant subtherapeutic trough levels were screened for clinical LOR. Subsequent ADA and trough level measurements and clinical outcomes were analyzed for patients who received either immunomodulator comedication or dose intensification of infliximab or adalimumab to overcome LOR. RESULTS: Following immunogenic LOR, the initial anti-TNF regimen was optimized in 33 patients. In univariable and multivariable logistic regression analyses, immunomodulator comedication was identified as the crucial factor for regaining clinical remission and ADA clearance. Detectable trough levels (≥ 0.98 or ≥ 1.00 mg/L, respectively) had optimal predictive performance for both endpoints in receiver operating characteristics curves [area under the curve 0.86 (95% confidence interval 0.68-1.00) for regaining clinical remission, 0.87 (0.71-1.00) for ADA clearance]. Furthermore, 11/20 patients (55%) on a comedication with azathioprine or methotrexate and 2/13 patients (15%) receiving anti-TNF dose intensification exclusively (P = 0.032) exhibited ADA elimination, regain of therapeutic trough levels, and clinical remission. Regain of clinical remission alone was achieved in 17/20 (85%) patients receiving comedication and 2/13 (15%) patients receiving anti-TNF dose intensification (P = 1.6 × 10-4). CONCLUSION: Immunogenic LOR to infliximab or adalimumab in IBD can be successfully reversed using immunomodulator comedication.

[Fecal microbiota transplantation: indications, risks and opportunities]. / Fäkaler Mikrobiomtransfer ­ Indikationen, Risiken und Chancen.

Fecal microbiome transfer (FMT) involving the transfer of the microbiome of healthy stool donors to patients with various diseases has been performed in Germany in clinical studies and individual treatment attempts. There is no doubt that FMT is an effective therapeutic principle for recurrent Clostridium difficile infection and ulcerative colitis. From a medico-legal point of view, it should be stressed that, in Germany, the microbiome to be transferred is regarded as a drug, the manufacture of which is subject to the Medicines Act and the risk information from the Federal Institute for Drugs and Medical Devices. The background of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and the potential risk of transmitting pathogens must also be considered. There is an obligation to notify the competent state authorities to perform FMTs in the context of individual treatment attempts. In the context of the limited availability and the fundamental problem of infection, future studies aim to identify the therapeutically active components in the microbiome. Recombinant production is the aim. Initial results represent preliminary steps, as these concepts are not yet established in clinical practice.

Transfer of FRozen Encapsulated multi-donor Stool filtrate for active ulcerative Colitis (FRESCO): study protocol for a prospective, multicenter, double-blind, randomized, controlled trial.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with significant morbidity and mortality. Although the precise cause remains unknown, disturbances in the intestinal microbial community have been linked to its pathogenesis. Randomized controlled trials in UC and relapsing Clostridioides difficile infection (CDI) have established fecal microbiota (FM) transfer (FMT) as an effective therapy. In this context, preliminary results indicated that the transfer of sterile fecal microbiota filtrates (<0.2 µm; FMF, FMFT) of donor stool also drives gastrointestinal microbiota changes and eliminates symptoms in CDI patients. However, along with the success of FMT, regulatory agencies issued safety alerts following reports of serious adverse events due to transmission of enteric pathogens through FMT. To reduce this risk, we established an extensive test protocol for our donors and quarantine regulations for the produced capsules, but alternative concepts are desirable. METHODS: Our project is a randomized, controlled, longitudinal, prospective, three-arm, multicenter, double-blind study to determine the safety and efficacy of repeated long-term, multi-donor FM or FMF transfers compared to placebo using oral, frozen capsules in 174 randomized patients with mild to moderate active UC. The primary outcome will be clinical remission at week 12. DISCUSSION: This proposal aims to examine (a) the efficacy of encapsulated transfer of FM and FMF as a therapy for mild to moderate UC, (b) the short- and long-term safety of FMT and FMFT in patients with UC, and (c) the microbial and immunologic changes that occur after FMT and FMFT to help understand how and why it affects inflammatory bowel disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03843385 . DRKS (Deutsches Register für Klinische Studien) DRKS00020471.

[Inflammatory bowel disease during the COVID-19 pandemic: manifestations and management]. / Chronisch-entzündliche Darmerkrankungen in der COVID-Pandemie: Manifestationen und Management.

The COVID-19 pandemic is significantly affecting the lives of patients with inflammatory bowel disease (IBD). Those affected and their relatives have numerous questions about the risk of the disease, the course of a possible SARS-CoV-2 infection or the influence of CED-specific therapy on these. Many IBD patients also have additional questions about the safety and effectiveness of a vaccination against SARS-CoV-2. The aim of this review is to summarize the latest findings on COVID-19 and IBD, but also to discuss vaccine response (humoral/cellular), the influence of ongoing therapy on the vaccine response as well as the frequency of side effects and the importance of booster immunizations and to create an evidence-based basis for discussion with patients.

[Effects of SARS-CoV-2 Infection on Symptoms and Therapy of Inflammatory Bowel Disease]. / Auswirkungen einer SARS-CoV-2-Infektion auf Symptomatik und Therapie chronisch-entzündlicher Darmerkrankungen.

INTRODUCTION: The influence of a SARS-CoV-2 infection on inflammatory bowel disease (IBD) has not yet been well characterized and it is unclear whether this requires an adaptation of the immunosuppressive therapy. METHODS: A national register was established for the retrospective documentation of clinical parameters and changes in immunosuppressive therapy in SARS-CoV-2 infected IBD patients. RESULTS: In total, only 3 of 185 IBD patients (1.6 %) were tested for SARS-CoV-2 infection because of abdominal symptoms. In the course of COVID-19 disease, 43.5 % developed diarrhea, abdominal pain or hematochezia (risk of hospitalization with vs. without abdominal symptoms: 20.0 % vs. 10.6 %, p < 0.01). With active IBD at the time of SARS-CoV-2 detection, there was an increased risk of hospitalization (remission 11.2 %, active IBD 23.3 % p < 0.05). IBD-specific therapy remained unchanged in 115 patients (71.4 %); the most common change was an interruption of systemic therapy (16.2 %). DISCUSSION: New abdominal symptoms often appeared in SARS-CoV-2 infected IBD patients. However, these only rarely led to SARS-CoV-2 testing. A high IBD activity at the time of SARS-CoV-2 detection was associated with an increased risk of hospitalization.

Results from the German registry for refractory celiac disease.

Refractory celiac disease (RCD) refers to a rare subgroup of patients with celiac disease who show clinical signs of malabsorption despite a gluten-free diet. RCD is divided into an autoimmune phenotype (RCD type I) and pre-lymphoma (RCD type II). To reflect the clinical reality in managing this disease in Germany, a national register was established based on a questionnaire developed specifically for this purpose. Between 2014 and 2020, a total of 53 patients were registered. The diagnosis of RCD was confirmed in 46 cases (87%). This included 27 patients (59%) with RCD type I and 19 patients (41%) with RCD type II. A wide range of diagnostic and therapeutic measures was used. Therapeutically, budesonide was used in 59% of the RCD patients regardless of the subtype. Nutritional therapy was used in only 5 patients (11%). Overall mortality was 26% (12 patients) with a clear dominance in patients with RCD type II (9 patients, 47%). In summary, RCD needs to become a focus of national guidelines to increase awareness, establish standards, and thus enable the treating physician to make the correct diagnosis in a timely manner. Moreover, we concluded that when treating such patients, contacting a specialized center is recommended to ensure sufficient management.

An Update for Pharmacologists on New Treatment Options for Inflammatory Bowel Disease: The Clinicians' Perspective.

The introduction of anti-tumor necrosis factor antibodies resulted in a considerable expansion of the options available for the treatment of inflammatory bowel disease. Unfortunately, approximately one third of treated patients do not respond to these modalities, and drug efficacy may be lost over time. These drugs are also associated with contraindications, adverse events, and intolerance. As such, there is an ongoing need for new therapeutic strategies. Despite several recent advances, including antibodies against pro-inflammatory cytokines and cell adhesion molecules, Janus kinase inhibitors, and modulators of sphingosine-1-phosphate receptors, not all problems associated with IBD have been solved. In this manuscript, we review the current state of development of several new treatment options. Ongoing evaluation will require specific proof of efficacy as well as direct comparisons with established treatments. Results from head-to-head comparisons are needed to provide clinicians with critical information on how to formulate effective therapeutic approaches for each patient.

The COVID-19 Pandemic: Fears and Overprotection in Pediatric Patients with Inflammatory Bowel Disease and Their Families.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has influenced the lives of people worldwide. Little is known about the effects of the COVID-19 pandemic on the behavior and fears of pediatric patients with inflammatory bowel disease (IBD) and their families. We conducted a survey to determine the COVID-19 exposure, related perceptions, and information sources; medication compliance; and patients' and parents' behaviors, fears, and physician contact. METHODS: An anonymous cross-sectional survey of pediatric patients with IBD and their parents at one pediatric gastroenterology unit of a university medical center was performed. RESULTS: A total of 46 pediatric patients with IBD and 44 parents completed the survey. Parents of pediatric patients with IBD had high fear of their children becoming infected with severe acute respiratory syndrome coronavirus 2. They perceived schools as the most hazardous environment, whereas the children did not. Half the pediatric patients with IBD feared infection. Patients and parents felt sufficiently informed about COVID-19. The primary source of guidance for pediatric patients was their parents (43%), followed by television and social media, whereas the parents mainly consulted internet news websites (52.2%), television, and public health institutes. Pediatric patients with IBD adhered to their prescribed medication. They also showed cautious behavior by enhancing hand hygiene (84%) and leaving the house less frequently than before. However, in-person medical visits remained favored over video consultations. CONCLUSION: Although parents expressed overprotective concerns, both parents and pediatric patients with IBD are coping well with the COVID-19 pandemic. IBD-relevant information should be actively conveyed.

[A surgically relevant summary of the addendum to the S3 guidelines of the DGVS on Crohn's disease and ulcerative colitis : Treatment of chronic inflammatory bowel diseases in the COVID-19 pandemic]. / Eine chirurgisch relevante Zusammenfassung des Addendums zu den DGVS-S3-Leitlinien Morbus Crohn und Colitis ulcerosa : Therapie chronisch entzündlicher Darmerkrankungen in der COVID-19-Pandemie.

In order to improve the care of patients with chronic inflammatory bowel diseases during the coronavirus disease 2019 (COVID-19) pandemic, the currently valid guidelines of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) on Crohn's disease and ulcerative colitis were extended within a virtual conference to include current and practically relevant recommendations. The addendum addresses in particular the risk of COVID-19 infections in patients with chronic inflammatory bowel diseases, the diagnostics under the conditions of the pandemic, the consequences for the pharmacotherapy and operative treatment of the underlying disease. It also addresses general measures for protection against infections and for adjunctive treatment of patients with chronic inflammatory bowel diseases.

Self-assessment of treatment targets in patients with inflammatory bowel disease using a survey.

BACKGROUND: Physicians can improve their relationships with patients by understanding and meeting patients' treatment targets, leading to higher adherence to therapy and improved disease prognosis. In the current study, we performed a questionnaire-based survey to further understand treatment targets in patients with inflammatory bowel disease (IBD). METHODS: We created a questionnaire based on a point-allocation scale with 10 treatment target items. A total of 234 patients with IBD [Crohn's disease (n = 129) and ulcerative colitis (n = 105)] participated in three German IBD centers. Patients were asked to allocate a total of 10 points across the 10 items, with more points indicating more importance. RESULTS: The most important treatment targets for patients regarding their therapy were quality of life (2.78 points), control of defecation (1.53 points), and avoidance of IBD-related surgery (1.69 points). Avoiding surgery for IBD was less important in patients who had already undergone a surgical procedure than in those who had not (1.26 points versus 1.89 points, p < 0.001). Typical treatment targets, including mucosal healing (0.52 points) and normal biochemical markers (0.39 points), were not scored high by patients. The least important item was the possibility of all-oral therapy (0.19 points in 33 patients, 0 points in 201 patients). CONCLUSION: Treatment targets for patients were primarily related to quality of life, such as therapy side effects. Knowing these targets may improve patient-physician relationships and communication, and consequently, adherence to therapy.

Towards an Interpretable Classifier for Characterization of Endoscopic Mayo Scores in Ulcerative Colitis Using Raman Spectroscopy.

Ulcerative colitis (UC) is one of the main types of chronic inflammatory diseases that affect the bowel, but its pathogenesis is yet to be completely defined. Assessing the disease activity of UC is vital for developing a personalized treatment. Conventionally, the assessment of UC is performed by colonoscopy and histopathology. However, conventional methods fail to retain biomolecular information associated to the severity of UC and are solely based on morphological characteristics of the inflamed colon. Furthermore, assessing endoscopic disease severity is limited by the requirement for experienced human reviewers. Therefore, this work presents a nondestructive biospectroscopic technique, for example, Raman spectroscopy, for assessing endoscopic disease severity according to the four-level Mayo subscore. This contribution utilizes multidimensional Raman spectroscopic data to generate a predictive model for identifying colonic inflammation. The predictive modeling of the Raman spectroscopic data is performed using a one-dimensional deep convolutional neural network (1D-CNN). The classification results of 1D-CNN achieved a mean sensitivity of 78% and a mean specificity of 93% for the four Mayo endoscopic scores. Furthermore, the results of the 1D-CNN are interpreted by a first-order Taylor expansion, which extracts the Raman bands important for classification. Additionally, a regression model of the 1D-CNN model is constructed to study the extent of misclassification and border-line patients. The overall results of Raman spectroscopy with 1D-CNN as a classification and regression model show a good performance, and such a method can serve as a complementary method for UC analysis.

Fecal Microbiota Transfer.

BACKGROUND: Fecal microbiota transfer (FMT) is increasingly being used in Ger- many, as in other countries, for the treatment of recurrent Clostridioides difficile infection (rCDI). FMT is now being performed both for research and in individual patients outside of clinical trials. No compulsory standards have been established to date for donor screening or for the method of fecal transfer. Given the potential dangers of FMT, this would seem to be urgently necessary. METHODS: This review is based on pertinent literature retrieved by a selective search, including the reports of consensus conferences from Germany and abroad. RESULTS: Because of its high efficacy, FMT is the treatment of choice for rCDI. It is largely free of adverse side effects, even in immune-deficient patients, as long as comprehensive and repeated donor screening has been carried out, with extensive clinical and microbiological testing and with the use of structured questionnaires. The ingestion of frozen, encapsulated microbiota is just as effective as other modes of delivery for the treatment of rCDI. CONCLUSION: Encapsulation of the fecal microbiome (FM) and storage at -20°C is the method of choice, because it can be standardized with the necessary quality controls and it is readily available. Patients with rCDI should undergo FMT by orally ingesting the capsules. There are ongoing research efforts to identify the active e FM. It is not yet clear when the ultimate goal of recombinant production can be achieved.

[Ulcerative colitis: Does the modulation of gut microbiota induce long-lasting remission?] / Colitis ulcerosa: Kann eine Modulation der intestinalen Mikrobiota eine langfristige Remission bedingen?

Although the pathogenesis of ulcerative colitis (UC) remains elusive, substantial progress in understanding its development and progression has been achieved in the past decades, and novel effective treatment strategies have been developed. Changes in gut microbiota, environmental triggers, deregulation of immunological responses, and genetic predisposition have been identified as pathogenic key factors. There are several lines of clinical observations, which support a close connection of altered gut microbiota with the development and course of UC. Despite a plethora of microbiota alterations in UC, it is currently unclear whether the observed changes in inflammation are cause or effect of the altered microbiota state.Fecal microbiota transplantation (FMT) provides a novel, perhaps complementary, strategy to restore gut microbial diversity, bacterial richness, and microbial homeostasis in UC. FMT is an already established treatment option for recurrent Clostridioides difficile infection, and several case series and randomized controlled trials have described its use in UC. In this review, we evaluate recent efficacy and safety data on FMT for UC, discuss possible pitfalls and show possible areas of future development. Although FMT could become a promising treatment modality for UC, based on currently available data, FMT should be only performed in clinical trials as controlled studies focusing on long-term outcomes and safety are warranted.