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The treatment of inflammatory bowel diseases (IBD) can be challenging, especially in elderly multimorbid patients. Since incidence and prevalence rates of IBD are rising steadily, treatment of older patients with relevant and also rare comorbidities will be of increasing relevancy for caregivers. Here we report on a 74-year-old multimorbid patient with severe ulcerative colitis (UC) and hemophilia A. Because of the chronic active disease, therapy with a tumor necrosis factor-α inhibitor was started. He suffered from a severe infectious complication (pneumonia) under therapy with infliximab. The therapy was changed to vedolizumab, with which the patient stayed in long-term clinical and endoscopic remission. Because the patient had a non-ST-segment elevation myocardial infarction in April 2016, he received dual platelet inhibitor therapy with aspirin and clopidogrel. Because of consecutive aspirin intolerance, the therapy was changed to clopidogrel monotherapy. Although the UC was treated appropriately with vedolizumab and the patient was in endoscopic mucosal remission, recurrent bleeding episodes from multiple inflammatory pseudopolyps occurred. The bleeding episodes resolved quickly after immediate treatment with factor VIII (Kogenate®). In conclusion, we describe the first patient in the literature with UC and hemophilia A who stayed in long-term remission under therapy with vedolizumab. From our point of view, vedolizumab can be safely administered in the setting of UC and hemophilia A. Antiplatelet drugs which inhibit primary hemostasis must be used with caution in this setting. Bleeding episodes can be treated safely and effectively with factor VIII (Kogenate®).

Clostridium difficile is the most frequent cause of nosocomial antibiotic-associated diarrhea. The incidence of C. difficile infection (CDI) has been rising worldwide with subsequent increases in morbidity, mortality, and health care costs. Asymptomatic colonization with C. difficile is common and a high prevalence has been found in specific cohorts, e.g., hospitalized patients, adults in nursing homes and in infants. However, the risk of infection with C. difficile differs significantly between these cohorts. While CDI is a clear indication for therapy, colonization with C. difficile is not believed to be a direct precursor for CDI and therefore does not require treatment. Antibiotic therapy causes alterations of the intestinal microbial composition, enabling C. difficile colonization and consecutive toxin production leading to disruption of the colonic epithelial cells. Clinical symptoms of CDI range from mild diarrhea to potentially life-threatening conditions like pseudomembranous colitis or toxic megacolon. While antibiotics are still the treatment of choice for CDI, new therapies have emerged in recent years such as antibodies against C. difficile toxin B and fecal microbial transfer (FMT). This specific therapy for CDI underscores the role of the indigenous bacterial composition in the prevention of the disease in healthy individuals and its role in the pathogenesis after alteration by antibiotic treatment. In addition to the pathogenesis of CDI, this review focuses on the colonization of C. difficile in the human gut and factors promoting CDI.

OBJECTIVE: Dysbiosis is a common feature in the pathogenesis of inflammatory bowel diseases (IBD). Environmental factors, such as vitamin D deficiency, seem to play a role in the intestinal inflammation of IBD. The aim of this study was to investigate whether vitamin D administration has an impact on the bacterial composition in Crohn’s disease (CD) compared to healthy controls (HC). METHODS: A prospective, longitudinal, controlled interventional analysis was conducted in seven patients with CD in clinical remission and 10 HC to investigate the effect of orally administrated vitamin D on the intestinal bacterial composition using 16S ribosomal RNA gene amplicon sequencing. Clinical parameters were assessed. RESULTS: In contrast to HC, microbial communities of CD patients changed significantly during early vitamin D administration. However, a further increase in vitamin D level was associated with a reversal of this effect and additionally with a decrease in the bacterial richness in the CD microbiome. Specific species with a high abundancy were found during vitamin D administration in CD, but not in HC; the abundancy of Alistipes, Barnesiella, unclassified Porphyromonadaceae (both Actinobacteria), Roseburia, Anaerotruncus, Subdoligranulum and an unclassified Ruminococaceae (all Firmicutes) increased significantly after 1-week vitamin D administration in CD. CONCLUSIONS: Vitamin D has a specific influence on the bacterial communities in CD, but not in HC. Administration of vitamin D may have a positive effect in CD by modulating the intestinal bacterial composition and also by increasing the abundance of potential beneficial bacterial strains. The authors would like to thank Jana NORMANN for excellent technical assistance and the SILVA_NGS team for bioinformatic support. Purchase of the Illumina MiSeq was kindly supported by the EU-EFRE (European Funds for Regional Development) program and funds from the University Medicine Rostock. H.S. received a research grant from the Damp Foundation (2016–04). The study was registered in the German Clinical Trials Register (Registration number DRKS00013485). The authors would like to thank Jana NORMANN for excellent technical assistance and the SILVA_NGS team for bioinformatic support. Purchase of the Illumina MiSeq was kindly supported by the EU-EFRE (European Funds for Regional Development) program and funds from the University Medicine Rostock. H.S. received a research grant from the Damp Foundation (2016–04). The study was registered in the German Clinical Trials Register (Registration number DRKS00013485).

Clostridium difficile is the most frequent cause of nosocomial antibiotic-associated diarrhea. The incidence of C. difficile infection (CDI) has been rising worldwide with subsequent increases in morbidity, mortality, and health care costs. Asymptomatic colonization with C. difficile is common and a high prevalence has been found in specific cohorts, e.g., hospitalized patients, adults in nursing homes and in infants. However, the risk of infection with C. difficile differs significantly between these cohorts. While CDI is a clear indication for therapy, colonization with C. difficile is not believed to be a direct precursor for CDI and therefore does not require treatment. Antibiotic therapy causes alterations of the intestinal microbial composition, enabling C. difficile colonization and consecutive toxin production leading to disruption of the colonic epithelial cells. Clinical symptoms of CDI range from mild diarrhea to potentially life-threatening conditions like pseudomembranous colitis or toxic megacolon. While antibiotics are still the treatment of choice for CDI, new therapies have emerged in recent years such as antibodies against C. difficile toxin B and fecal microbial transfer (FMT). This specific therapy for CDI underscores the role of the indigenous bacterial composition in the prevention of the disease in healthy individuals and its role in the pathogenesis after alteration by antibiotic treatment. In addition to the pathogenesis of CDI, this review focuses on the colonization of C. difficile in the human gut and factors promoting CDI.

Der Krankheitsverlauf bei CED-Patienten lässt sich aktuell nur unzureichend vorhersagen, prädiktive Marker stehen nur eingeschränkt zur Verfügung. Die hier vorgestellten Arbeiten beschäftigen sich mit dem Zusammenhang zwischen Darmmikrobiom, Vitamin D und genetischen Risikofaktoren, wie Mutationen im NOD2 Gen bei CED. Aus den hier durchgeführten Untersuchungen resultiert u.a. ein besseres Verständnis darüber, wie sich die einzelnen Faktoren gegenseitig beeinflussen und eine Auswirkung auf den Krankheitsverlauf bei CED haben.

Die Zahl von invasiven Candida albicans Infektionen ist in den letzten Jahren erheblich angestiegen. Die parallel dazu zu beobachtende Resistenzentwicklung insbesondere gegen das gut verträgliche und in Prophylaxe und Therapie breit eingesetzte Fluconazol ist in diesem Zusammenhang von großer klinischer Bedeutung. Für den Erfolg einer Fluconazol-Therapie sind aber nicht allein die MHK-Werte eines Isolates entscheidend, sondern darüber hinaus auch die Virulenz charakterisierende Faktoren. Den wichtigsten Pathogenitätsfaktor von C. albicans stellt die aus 10 Isoenzymen bestehende Familie der Sekretorischen Aspartylproteinasen (SAPs) dar. Ziel dieser Arbeit war es, einen Zusammenhang zwischen Fluconazol-Resistenz vermittelt durch Überexpression des Effluxpumpengens MDR1 und den SAPs sowohl auf RNA-Ebene (Genexpression) als auch auf Protein-Ebene (Enzymaktivität) zu untersuchen. Es wurden sensible Wildtypstämme, durch konstitutive und chemisch induzierte MDR1-Expression resistente Isolate sowie isogene MDR1-negative Mutanten vergleichend geprüft. Die Expression der Zielgene wurde durch RT-PCR bestimmt sowie die extrazelluläre SAP-Aktivität in einem Proteinase-Assay gemessen. Es konnte ein Zusammenhang sowohl zwischen der konstitutiven als auch chemisch induzierten MDR1-Expression und der Expression von Sekretorischen Aspartylproteinasen Typ 1 (SAP1) dargestellt werden. Die sowohl durch konstitutive als auch durch chemisch induzierte MDR1-Expression verstärkte Transkription von SAP1-Genen weist auf eine gemeinsame Regulation der beiden Gene MDR1 und SAP1 durch einen übergeordneten Transkriptionsfaktor hin. Ein Einfluss des Mdr1p auf Transkription und Sekretion von SAP1 konnte dagegen ausgeschlossen werden. Die verschiedenen SAPs werden im Verlaufe einer Infektion zu unterschiedlichen Zeitpunkten produziert und unterliegen einer differenzierten Regulation. Eine veränderte Expression von SAP1 bedingt daher nicht zwangsläufig eine gesteigerte Virulenz eines MDR1-exprimierenden, fluconazol-resistenten Stammes. Die Bedeutung der MDR1-assoziierten Hochregulation von SAP1 für die Virulenz von C. albicans und die Pathogenese von Candida-Infektionen muss daher in folgenden Arbeiten geprüft werden. During the last decades invasive infections caused by Candida albicans have emerged as an increasing problem especially in hematological and oncological patients. Azoles have arised as first line antimycotics for prophylaxis and treatment of invasive candida infections. As the number of patients treated with azoles have increased during the last years, azole resistance and especially resistance to fluconazole has emerged as a major problem. Overexpression of efflux pumps encoded by MDR1 leading to a decreased intracellular azole concentration have been identified as an important mechanism contributing to fluconazole resistance in C. albicans. Whereas early studies in animal infection models have described decreased virulence of fluconazole resistant C. albicans strains, some recent publications have indicated that there might be a connection between azole resistance, efflux pump expression and virulence in C.albicans. In Candida the most significant hydrolytic enzymes linked to virulence are the secreted aspartic proteinases (SAPs). C. albicans possesses 10 SAP genes which are differentially expressed during infection. It was the aim of the study to test the influence of MDR1-expression on transcription and protein expression of SAP genes. We examined fluconazole sensitive wildtype strains of C. albicans, strains which were fluconazole resistant due to constitutively and chemically induced overexpression of MDR1 as well as related MDR1 knock out mutants. Expression of the target genes was analysed by RT-PCR and determination of extracellulary proteinase activity. We found a relationship between constitutively and chemically induced MDR1 expression and the expression of SAP1 which was indicative for a combined regulation of both genes. An influence of Mdr1p on the transcription and secretion of SAP1 was not confirmed. SAP genes are differentially expressed in various stages of Candida infections. Further studies are therefore necessary to analyse the influence of MDR1 associated SAP1 upregulation on virulence of C. albicans.

In dieser retrospektiven Genotyp-Phänotyp-Assoziationsstudie wurden 161 Patienten mit Morbus Crohn eingeschlossen und über einen Zeitraum von 2 Jahren auf verschiedene klinische Merkmale hin untersucht. Sämtliche Patienten wurden dazu entsprechend genotypisiert und hinsichtlich der drei Hauptmutationen SNP8, SNP12 und SNP13 hin überprüft. Es sollte nun speziell erfasst werden, ob Patienten mit Mutationen im NOD2-Gen mit einem besonderen klinischen Phänotyp vergesellschaftet sind und so auch einen schwereren Krankheitsverlauf aufweisen. NOD2 als ein möglicher Biomarker und Vorhersageparameter?

Morbus Crohn steht mit seiner noch ungeklärten Pathogenese aktuell im Fokus intensiver Forschung. In dieser Arbeit wurde die in vitro Reaktion von mononukleären Zellen des Blutes auf Bestandteile pathogener Mikroorganismen aus Morbus Crohn Patienten mit denen von gesunden Kontrollen verglichen. Die Daten sollen zur Grundlagenforschung bezüglich der Pathogenese der Erkrankung beitragen. Um genauere Aussagen über einen supportiv-therapeutischen Einsatz von Vitamin D treffen zu können, wurde außerdem die immunregulatorische Rolle von Cholecalciferol an diesem Modell überprüft., Crohn's disease is currently the focus of intensive research, with its exact pathogenesis yet unexplained. In this work, the in vitro reaction of blood mononuclear cells to components of pathogenic microorganisms from Crohn's disease patients was compared with that of healthy controls. With this data it is intended to contribute to basic research into the pathogenesis of the disease. In order to be able to make more precise statements about the supportive therapeutic use of vitamin D, the immunoregulatory role of cholecalciferol was also further examined in this model.