HIF-1α Pathway Orchestration by LCN2: A Key Player in Hypoxia-Mediated Colitis Exacerbation.

In this study, we investigated the role of hypoxia in the development of chronic inflammatory bowel disease (IBD), focusing on its impact on the HIF-1α signaling pathway through the upregulation of lipocalin 2 (LCN2). Using a murine model of colitis induced by sodium dextran sulfate (DSS) under hypoxic conditions, transcriptome sequencing revealed LCN2 as a key gene involved in hypoxia-mediated exacerbation of colitis. Bioinformatics analysis highlighted the involvement of crucial pathways, including HIF-1α and glycolysis, in the inflammatory process. Immune infiltration analysis demonstrated the polarization of M1 macrophages in response to hypoxic stimulation. In vitro studies using RAW264.7 cells further elucidated the exacerbation of inflammation and its impact on M1 macrophage polarization under hypoxic conditions. LCN2 knockout cells reversed hypoxia-induced inflammatory responses, and the HIF-1α pathway activator dimethyloxaloylglycine (DMOG) confirmed LCN2's role in mediating inflammation via the HIF-1α-induced glycolysis pathway. In a DSS-induced colitis mouse model, oral administration of LCN2-silencing lentivirus and DMOG under hypoxic conditions validated the exacerbation of colitis. Evaluation of colonic tissues revealed altered macrophage polarization, increased levels of inflammatory factors, and activation of the HIF-1α and glycolysis pathways. In conclusion, our findings suggest that hypoxia exacerbates colitis by modulating the HIF-1α pathway through LCN2, influencing M1 macrophage polarization in glycolysis. This study contributes to a better understanding of the mechanisms underlying IBD, providing potential therapeutic targets for intervention.

[Primary sclerosing cholangitis-Diagnosis and treatment 2024]. / Primär sklerosierende Cholangitis ­ Diagnose und Therapie 2024.

The etiology of primary sclerosing cholangitis (PSC) remains unclear, which explains in part the lack of a causal treatment. The differential diagnostic distinction from the even rarer immunoglobulin 4 (IgG4)-associated cholangitis (IAC) is becoming increasingly more successful. Advances in the understanding of different clinical courses, improvements in noninvasive diagnostics through modern magnetic resonance imaging (MRI) and the introduction of liver elastography have led to the development of improved prognostic models. The evidence for recommendations on medicinal (e.g., ursodeoxycholic acid) or endoscopic treatment (e.g., balloon dilatation and/or stent insertion) for PSC is still low. In contrast, the long-term results of liver transplantation in PSC patients are constantly improving. Due to the lack of highly sensitive and specific screening methods the early recognition of cholangiocellular carcinoma (CCC) as the most important complication is rarely successful. The continuous improvement of endoscopic retrograde cholangiopancreatography (ERCP) and direct cholangioscopy in combination with molecular biological and fluorescence in situ hybridization (FISH) analyses of bile duct tissue samples are promising for refined diagnostics. Due to the significantly increased risk of colorectal cancer, an annual colonoscopy is recommended in the presence of inflammatory bowel disease. Improvement of the early diagnostics of PSC and successful testing of new treatment strategies raise hope for a continuous improvement in the medical support of these complex patients.

Analysis of the Accuracy of Magnetic Resonance Enterography for the Detection of Active Inflammation and Disease Activity in Patients With Crohn's Disease: A Single-Center Experience in Najran, Saudi Arabia.

BACKGROUND: Magnetic resonance enterography (MRE) is a non-invasive diagnostic imaging modality that has been used for the detection of active inflammation and disease activity in patients with Crohn's disease. However, its diagnostic accuracy in the Najran population has not been well-studied. STUDY AIM: This study aimed to assess the diagnostic accuracy of MRE in detecting active inflammation and disease activity in patients with Crohn's disease in the Najran population. METHODS: The study included 51 patients with Crohn's disease, and their demographic, clinical, radiological, laboratory, and endoscopic data were analyzed. RESULTS: The results showed that MRE findings, such as the radiological score for active inflammation and the presence of extra-intestinal manifestations, were significantly associated with the final diagnosis of active inflammation. Furthermore, the timing of MRE in relation to symptom activity and the indication for performing MRE were significantly associated with the final diagnosis. The study findings demonstrate the potential of MRE as a valuable tool for diagnosing and assessing disease activity in Crohn's disease patients in the Najran population.

[A rare association of Takayasu's disease and inflammatory bowel disease in Gabon]. / Association rare d'une maladie de Takayasu et d'une maladie inflammatoire chronique intestinale au Gabon.

Takayasu's disease is a vasculitis affecting large vessels, particularly the aorta and its main branches, for which the role of Mycobacterium tuberculosis has been suggested as a trigger by a hypersensitivity reaction. Inflammatory bowel diseases, which in sub-Saharan Africa can be confused with parasitic diseases, can rarely be found in association with Takayasu's disease. We report an association between both diseases in the Gabonese population.

Primary colonic MALT lymphoma associated with Crohn's disease: Case report and review of the literature.

Key Clinical Message: To date, the pathogenic mechanisms of the association between Crohn's disease and MALT lymphoma are ambiguous and yet remain to be elucidated. The publication of other cases illustrating this rare association would be interesting to properly plan therapeutic strategies and to better understand the pathogenesis and the prognosis of this association. Abstract: Crohn's disease is a progressive disease, with increasing incidence, that leads to bowel damage and disability. Primary colonic MALT lymphoma is a low-grade B lymphoma, representing only 2.5% of all MALT lymphomas. The pathogenesis of these two cancers is still not clearly elucidated and their association is rare. To our knowledge, only two cases have illustrated synchronous Crohn's disease and MALT lymphoma. The possible role of Crohn's disease as a precursor of MALT lymphoma is still debated; some studies proposed that immunosuppressive drugs used in Crohn's disease are involved in the lymphomagenesis of MALT lymphoma. Other studies supposed no relation between these two neoplasms.We present a rare case of association between Crohn's disease and primary colonic MALT lymphoma in an elderly female patient who had not received any immunosuppressive therapy. The patient presented with chronic diarrhea, epigastric pain, and weight loss. A colonoscopy with biopsies was performed. The histopathologic examination concluded with the diagnosis of not only Crohn's disease but also MALT lymphoma. This discovery of MALT lymphoma was incidental. We highlight the clinical and histopathological features, and we discuss the association between Crohn's disease and MALT lymphoma, which may provide additional information about pathogenic mechanisms.

Improved HPLC Quantification of 6-Mercaptopurine Metabolites in Red Blood Cells: Monitoring Data and Literature Analysis.

Thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (6-MP) are used extensively in pediatric and adult patients with inflammatory and neoplastic diseases. They are metabolized to 6-thioguanine nucleotides (6-TGN) or to 6-methyl-mercaptopurine nucleotides (6-MMPN). The balance between 6-TGN and 6-MMPN is highly variable and monitoring is recommended, but its benefit in outcome gives rise to conflicting results, potentially increased by differences in quantifying 6-MP metabolism. Our aim was to report (1) the HPLC-UV procedure used in our laboratory to quantify red blood cells (RBCs) with 6-TGN and 6-MMPN (as its derivate: 6-MMP(d)) in patients treated with thiopurines and (2) additional tests, sometimes confirmatory, to improve method standardization. The comparison of two methods to count RBCs shows that metabolite concentrations were slightly lower in the washed and resuspended RBCs than in whole blood. Perchloric acid (0.7 M), dithiothreitol (DTT, final 0.013 M sample concentration) and 60 min hydrolysis were selected for acid hydrolysis. (3) Monitoring data from 83 patients receiving AZA or 6-MP showed that at steady state, only 53/183 (29%) had 6-TGN and 6-MMPN in the recommended therapeutic range. Our method is discussed in light of the technical conditions and sample stability data from 17 publications identified since the first analytical report in 1987. Monitoring data demonstrate, if required, that inter-patient variability in 6-TGN and 6-MMPN concentrations is high in samples from treated patients.

[Kaposi sarcoma-a complication of treatment refractory ulcerative colitis]. / Das Kaposi-Sarkom ­ eine Komplikation bei therapierefraktärer Colitis ulcerosa.

We report on the incidental finding of Kaposi sarcoma of the colon in the setting of refractory ulcerative colitis treatment. The patient was under long-term immunosuppression with infliximab, vedolizumab, and prednisolone. Serologic analysis excluded human immunodeficiency virus (HIV) infection.

[Gut microbiota and chronic inflammatory bowel disease]. / Darmmikrobiom und chronisch- entzündliche Darmerkrankung.

Intestinal dysbiosis remains the focus of research into the pathogenesis of chronic inflammatory bowel disease (IBD). The potential role of gut microbiota in the development of IBD includes interaction with the host genome and immune system, as well as various environmental factors, diet, drugs, industrialization, etc. Other organs are negatively affected by intestinal dysbiosis via gut-brain axis. The composition of microbiota and its metabolic activity has a significant impact on the effectiveness of anti-inflammatory therapies. Microbiome-based treatment for IBD includes the use of diet, antibiotics, pre-, pro- and synbiotics, and faecal transplantation (FMT). The development of effective therapies for IBD patients will only be possible once the interactions between the microbiota and its metabolites and the host immune system are better understood.

Care of Women with Chronic Inflammatory Bowel Disease (Chronic IBD) During Pregnancy: Recommendations of the Obstetrics and Prenatal Medicine Working Group of the DGGG.

The incidence of chronic inflammatory bowel disease (chronic IBD) in persons of reproductive age is high. Chronic IBD does not typically lead to impaired fertility. Nevertheless, the percentage of women suffering from chronic IBD who have children is lower than that of the general population, due to self-imposed childlessness. Providing women with open, unbiased information and, if necessary, helping them to overcome baseless fears should therefore be an essential part of preconception counseling. With the exception of methotrexate, most standard drugs can and should be continued during pregnancy. If the pregnancy occurs during an inactive phase of disease, the rate of complications in pregnancy should, in principle, not be higher than normal. Nevertheless, pregnant women with chronic IBD are classed as high-risk pregnancies. Organ screening in accordance with DEGUM II criteria should be carried out in every case, and women must be monitored for the potential development of placental insufficiency. Any flare-ups which occur during pregnancy should be treated in full. Vaginal delivery can be considered if there is no perianal manifestation of disease; however, the individual risk must be carefully weighed up.

Colitis ulcerosa: a propósito de un caso pediátrico / Ulcerative colitis: about a pediatric case / Colite ulcerativa: sobre um caso pediátrico

RESUMEN Se presentó el caso de un paciente masculino de 8 años de edad con antecedentes de salud anterior, referido a la consulta externa de Gastroenterología del Hospital Nacional Guido Valadares, de Timor Oriental, por episodios recurrentes de diarreas mucosanguinolentas acompañadas de dolor abdominal en hipogastrio de cuatro meses de evolución. Se realizaron exámenes de laboratorio, ultrasonido abdominal y videocolonoscopia con citología y biopsia de la mucosa del colon. El estudio endoscópico informó una colitis ulcerativa extensa y la histología arrojó el diagnóstico de una enfermedad inflamatoria crónica intestinal del tipo colitis ulcerosa. La colitis ulcerosa es un proceso inflamatorio intestinal de origen desconocido que causa inflamación crónica, difusa y continua, en la mucosa y submucosa. Su incidencia en los niños está aumentando y afecta, incluso, a los lactantes. Se indicó tratamiento dietético y medicamentoso. Actualmente se encuentra asintomático y lleva seguimiento mensual en la consulta de Digestivo.

ABSTRACT The case of an 8-year-old male patient with a previous health history was presented, referred to the Gastroenterology outpatient clinic of the Guido Valadares National Hospital, East Timor, for recurrent episodes of mucosanguineous diarrhea accompanied by abdominal pain in the hypogastrium with four months of evolution. Laboratory tests, abdominal ultrasound and video colonoscopy with cytology and biopsy of the colon mucosa were performed. The endoscopic study reported extensive ulcerative colitis and the histology gave the diagnosis of a chronic inflammatory bowel disease of the ulcerative colitis type. Ulcerative colitis is an inflammatory intestinal process of unknown origin that causes chronic, diffuse and continuous inflammation in the mucosa and submucosa. Its incidence in children is increasing and affects even infants. Dietary and drug treatment was indicated. He is currently asymptomatic and undergoes monthly follow-up in the Digestive Clinic.

RESUMO Foi apresentado o caso de um paciente do sexo masculino, 8 anos, com antecedentes de saúde, encaminhado ao ambulatório de Gastroenterologia do Hospital Nacional Guido Valadares, Timor Leste, por episódios recorrentes de diarreia mucosanguínea acompanhada de dor abdominal em hipogástrio de quatro meses de evolução. Foram realizados exames laboratoriais, ultrassonografia abdominal e videocolonoscopia com citologia e biópsia da mucosa do cólon. O estudo endoscópico relatou colite ulcerativa extensa e a histologia deu o diagnóstico de doença inflamatória intestinal crônica do tipo colite ulcerativa. A colite ulcerosa é um processo inflamatório intestinal de origem desconhecida que causa inflamação crônica, difusa e contínua na mucosa e na submucosa. Sua incidência em crianças está aumentando e afeta até mesmo bebês. Foi indicado tratamento dietético e medicamentoso. Ele atualmente é assintomático e tem acompanhamento mensal na consulta Digestiva.

[Update: enterogenic spondylarthritis]. / Update: enteropathische Spondyloarthritis.

Spondylarthritis (SpA) is one of the most frequent extraintestinal manifestations of chronic inflammatory bowel disease (IBD). Several arthritogenic enterobacterial infections can induce sequelae such as reactive SpA. Studies on the gut-synovium axis in view of genetic, immunological, clinical and therapeutic aspects has made enterogenic SpA a model disease of all forms of SpA. The same applies for investigating IBD, as subclinical gut inflammation seen in SpA patients has provided significant evidence for a better understanding of mucosa-associated early immune events in Crohn's disease (CD). This article summarizes the pathognomonic clinical features, diagnostic steps, differential diagnosis and current pathogenetic models of enterogenic SpA. Knowledge of pathogenetic contexts leads to concrete treatment recommendations. These vary individually depending on the underlying IBD, on the inflammatory intestinal or rheumatic activity and on the rheumatological manifestation pattern.

Activation of Resolution Pathways to Prevent and Fight Chronic Inflammation: Lessons From Asthma and Inflammatory Bowel Disease.

Formerly considered as a passive process, the resolution of acute inflammation is now recognized as an active host response, with a cascade of coordinated cellular and molecular events that promotes termination of the inflammatory response and initiates tissue repair and healing. In a state of immune fitness, the resolution of inflammation is contained in time and space enabling the restoration of tissue homeostasis. There is increasing evidence that poor and/or inappropriate resolution of inflammation participates in the pathogenesis of chronic inflammatory diseases, extending in time the actions of pro-inflammatory mechanisms, and responsible in the long run for excessive tissue damage and pathology. In this review, we will focus on how resolution can be the target for therapy in "Th1/Th17 cell-driven" immune diseases and "Th2 cell-driven" immune diseases, with inflammatory bowel diseases (IBD) and asthma, as relevant examples. We describe the main cells and mediators stimulating the resolution of inflammation and discuss how pharmacological and dietary interventions but also life style factors, physical and psychological conditions, might influence the resolution phase. A better understanding of the impact of endogenous and exogenous factors on the resolution of inflammation might open a whole area in the development of personalized therapies in non-resolving chronic inflammatory diseases.

["Decoratively figured blisters" on the whole integument in initially diagnosed ulcerative colitis]. / "Schmuckvoll konfigurierte Blasen" am gesamten Integument bei erstdiagnostizierter Colitis ulcerosa.

The rare case of a 61-year-old patient suffering from linear IgA dermatosis is presented. The patient was previously hospitalized with chronic inflammatory bowel disease. The correct diagnosis of the disease was based on clinical and histological findings. Serological methods, such as indirect immunofluorescence, ELISA and immunoblotting are suitable for identification of the autoantibodies. In this case the detection of IgA antibodies along the basal membrane was achieved by direct immunofluorescence. Other bullous dermatoses with similar symptoms, such as an IgG-mediated bullous pemphigoid have to be excluded. The therapy of linear IgA dermatosis is ensured by steroid-containing topical agents, alongside antiseptic measures as well as systemic dapsone p.o.

The intestinal complement system in inflammatory bowel disease: Shaping intestinal barrier function.

The complement system is part of innate sensor and effector systems such as the Toll-like receptors (TLRs). It recognizes and quickly systemically and/or locally respond to microbial-associated molecular patterns (MAMPs) with a tailored defense reaction. MAMP recognition by intestinal epithelial cells (IECs) and appropriate immune responses are of major importance for the maintenance of intestinal barrier function. Enterocytes highly express various complement components that are suggested to be pivotal for proper IEC function. Appropriate activation of the intestinal complement system seems to play an important role in the resolution of chronic intestinal inflammation, while over-activation and/or dysregulation may worsen intestinal inflammation. Mice deficient for single complement components suffer from enhanced intestinal inflammation mimicking the phenotype of patients with chronic inflammatory bowel disease (IBD) such as Crohn's disease (CD) or ulcerative colitis (UC). However, the mechanisms leading to complement expression in IECs seem to differ markedly between UC and CD patients. Hence, how IECs, intestinal bacteria and epithelial cell expressed complement components interact in the course of IBD still remains to be mostly elucidated to define potential unique patterns contributing to the distinct subtypes of intestinal inflammation observed in CD and UC.

Berberine inhibits macrophage M1 polarization via AKT1/SOCS1/NF-κB signaling pathway to protect against DSS-induced colitis.

Berberine has been reported to have protective effects in colitis treatment. However, the detailed mechanisms remain unclear. Herein, we demonstrated that berberine could protect against dextran sulfate sodium (DSS)-induced colitis in mice by regulating macrophage polarization. In the colitis mouse model, berberine ameliorated DSS-induced colon shortening and colon tissue injury. Moreover, berberine-treated mice showed significant reduction in the disease activity index (DAI), pro-inflammatory cytokines expression and macrophages infiltration compared with the DSS-treated mice. Notably, berberine significantly reduced the percentage of M1 macrophages. In vitro analysis also confirmed the inhibitory effects of berberine on macrophages M1 polarization in RAW267.4 cells. Further investigation showed that berberine promoted AKT1 expression in mRNA and protein level. Silence of AKT1 abolished the inhibitory effect of berberine on macrophages M1 polarization. The berberine-induced AKT1 expression promoted suppressers of cytokine signaling (SOCS1) activation, which inhibited nuclear factor-kappa B (NF-κB) phosphorylation. In addition, we also found that berberine activated AKT1/SOCS1 signaling pathway but inhibited p65 phosphorylation in macrophages in vivo. Therefore, we concluded that berberine played a regulatory role in macrophages M1 polarization in DSS-induced colitis via AKT1/SOCS1/NF-κB signaling pathway. This unexpected property of berberine may provide a potential explanation for its protective effects in colitis treatment.

[NOD2 gene mutation in Moroccan patients with Crohn's disease: prevalence, genotypic study and correlation of NOD2 gene mutation with the phenotype of Crohn's disease]. / Mutation du gène NOD2 chez les patients marocains atteints de la maladie de Crohn: prévalence, étude génotypique et corrélation au phénotype de la maladie.

The aim of this study was to determine the prevalence of NOD2/CARD15 gene mutations in a group of Moroccan patients with Crohn's disease and to study its correlation with genotype-phenotypic expression. We conducted a cross-sectional case-control study over a period of 16 months. 101 patients with Crohn's disease were enrolled between January 2012 and April 2013 as well as a control group of 107 patients. We performed a genetic analysis to identify 3 NOD2 gene variants: p.Arg702Trp, p.Gly908Arg and p.Leu1007fsins. Then we conducted a study of the correlation between genotype and phenotypic expression. The genetic analysis of patients with Crohn's disease highlighted the presence of NOD2 mutation in 14 patients (13.77%) versus 7 patients (6.53%) in the control group. The study of the frequency of different alleles showed p.Gly908Arg mutation in 6.43%, p.Leu1007fsins in 0.99% and p.Arg702Trp in 0.49% versus 2.80%, 0% and 0.46% in the control group respectively. The study of the correlation between genotype and phenotypic expression showed that CARD15 mutation is associated with ileocecal Crohn's disease, with fistulizing and stenosing behavior in Crohn's disease as well as with severe evolution and frequent recourse to surgery and immunosuppressants. The prevalence of NOD2/ CARD15 mutation in our case series is low. This mutation is correlated with severe Crohn's disease.

[A case of idiopathic myointimal hyperplasia of mesenteric veins]. / Un cas d'hyperplasie myointimale idiopathique des veines mésentériques du côlon.

The idiopathic myointimal hyperplasia of mesenteric veins is a rare pathology, affecting recto-sigmoid and mimicking clinically an inflammatory chronic disease of the bowel. Only about fifteen cases have been reported in the literature. This lesion is characterized by a myointimal thickening of the mesenteric veins, without inflammatory infiltrate of the vascular wall, differentiating it from vasculitis. We present here the case of a 48-year-old man, in whom the diagnosis of ulcerative colitis then digestive vasculitis had first been raised.

Immunohistochemistry in the diagnosis of dysplasia in chronic inflammatory bowel disease colorectal polyps.

BACKGROUND AND STUDY AIMS: Development of cancer is the most significant complication in inflammatory bowel disease (IBD). Distinguishing true dysplasia from reactive atypia in polyps is difficult, leading sometimes to the unsatisfactory diagnosis of "indefinite for dysplasia". Therefore, there is a need for the development of markers that can help improve diagnosis. We evaluated the diagnostic value of the expression of AMACR, Ki67 and p53 by immunohistochemistry in the diagnosis of dysplasia in polyps developed on IBD. PATIENTS AND METHODS: Forty colorectal polyps in IBD were studied. These had been diagnosed over a period of 11years. Dysplasia was classified according to the Vienna Classification (version 2000). Immunohistochemistry was performed using anti-AMACR, anti-Ki67 and anti-p53 antibodies. RESULTS: Polyps were classified as follows: 21 negative for dysplasia (ND), 10 indefinite for dysplasia (IFD), 6 low-grade dysplasia (LGD), 1 high-grade dysplasia (HGD) and 2 adenocarcinomas (ACA). AMACR positivity was observed in all polyps with HGD and ACA, 5 of the 6 LGD polyps and 3 of the 10 IFD (p=0.007). p53 immunostaining showed nuclear staining in the basal part of the crypts in 8 of the 10 IFD lesions. In ACA and HGD polyps, p53 positivity was typically observed in all epithelial cell layers (p=0.004). ACA and HGD showed diffuse and scattered staining of Ki67 along the full length of the crypts. Five lesions with LGD had extension of Ki-67 positive cells up to and into the surface epithelium. Ki67 staining in all IFD lesions was restricted to the basal third of the crypt (p<0.001). By combining the three markers, a relationship with dysplasia was statistically significant (p<0.001). Sensitivity ranged from 66.7% to 88.9% and specificity from 71.4% to 100%. The positive predictive value (PPV) for detecting dysplasia using these different antibodies ranged from 66.7% to 100% and the negative predictive value (NPV) for excluding dysplasia ranged from 85.7% to 93.3%. CONCLUSIONS: The high degree of sensitivity and specificity of AMACR, p53 and Ki67 for dysplasia in IBD suggests that these antibodies, when combined, may be useful to detect neoplastic epithelium in this condition.

The gut in spondyloarthritis.

The links between the bowel and spondyloarthritis, although demonstrated many years ago, have been placed under the spotlight by recent findings. Thus, studies have established that bowel inflammation is associated with the joint disease activity, sacroiliac joint inflammation by magnetic resonance imaging, and elevated levels of biomarkers for bowel inflammation (S100 proteins) or antimicrobial antibodies (anti-flagellin). IL-23/Th17 pathway activation originating in the bowel has been documented in studies demonstrating that lymphoid cells expressing the IL-23 receptor can migrate to the bloodstream, bone marrow, and joints, via a mechanism involving adhesion molecules. Bacteria present in the bowel are increasingly emerging as major players. Thus, dysbiosis of the bowel microbiota can induce IL-23 production and local inflammatory responses. These new data suggest avenues of research for future treatments.