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.

[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.

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.

[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.