Orally Deliverable Iron-Ceria Nanotablets for Treatment of Inflammatory Bowel Disease.

Ceria-based nanoparticles are versatile in treating various inflammatory diseases, but their feasibility in clinical translation is undermined by safety concerns and a limited delivery system. Meanwhile, the idiopathic nature of inflammatory bowel disease (IBD) calls for a wider variety of therapeutics via moderation of the intestinal immune system. In this regard, the synthesis and oral formulation of iron-ceria nanoparticles (CF NPs) with enhanced nanozymic activity and lower toxicity risk than conventional ceria-based nanoparticles are reported. CF NPs are clustered in calcium phosphate (CaP) and coated with a pH-responsive polymer to provide the enteric formulation of iron-ceria nanotablets (CFNT). CFNT exhibits a marked alleviative efficacy in the dextran sodium sulfate (DSS)-induced enterocolitis model in vivo by modulating the pro-inflammatory behavior of innate immune cells including macrophages and neutrophils, promoting anti-inflammatory cytokine profiles, and downregulating key transcription factors of inflammatory pathways.

Mouse adaptation of human inflammatory bowel diseases microbiota enhances colonization efficiency and alters microbiome aggressiveness depending on the recipient colonic inflammatory environment.

BACKGROUND: Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. RESULTS: Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. CONCLUSIONS: Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract.

Imaging findings of thoracic manifestations of Crohn's disease and ulcerative colitis.

Thoracic manifestations of inflammatory bowel disease (IBD) are rare, occurring in less than 1% of patients. Unlike most other extra-intestinal manifestations, they predominate in patients with ulcerative colitis rather than in Crohn's disease. In most patients, thoracic involvement follows the onset of IBD by several years. However, thoracic involvement may also occur synchronously or even precede the onset of digestive symptoms. The thoracic manifestations of IBD include airway involvement and parenchymal lung abnormalities. Airways are the most frequent anatomical site for thoracic involvement in IBD. Airway manifestations usually develop several years after the onset of intestinal manifestations, preferentially when the latter are stable or in remission. Airway manifestations include bronchial wall thickening, bronchiectasis, small airway disease, and tracheal wall thickening. Parenchymal lung abnormalities are less prevalent in IBD and include organizing pneumonia, necrobiotic nodules, noncaseating granulomatous nodules, drug-induced pneumonia, and rarely interstitial lung diseases. The differential diagnosis between organizing pneumonia, necrobiotic nodules, and noncaseating granulomatous nodules is difficult and usually requires histopathological analysis for a definite diagnosis. Radiologists play a key role in the detection of thoracic manifestations of Crohn's disease and ulcerative colitis and, therefore, need to be familiar with their imaging findings. This article aims to offer an overview of the imaging findings of thoracic manifestations in patients with Crohn's disease or ulcerative colitis. CRITICAL RELEVANCE STATEMENT: Thoracic manifestations of Crohn's disease and ulcerative colitis include tracheal involvement, bronchiectasis, small airway disease, and parenchymal lung abnormalities such as organizing pneumonia and necrobiotic nodules. These rare manifestations (< 1% of patients) more often affect patients with ulcerative colitis. KEY POINTS: Thoracic manifestations of inflammatory bowel disease are rare, occurring in less than 1% of patients. Thoracic manifestations are more frequent in patients with ulcerative colitis than Crohn's disease. Bronchial disease is the most frequent thoracic manifestation of Crohn's disease and ulcerative colitis.

Mucocutaneous manifestations of inflammatory bowel disease.

Mucocutaneous manifestations can be indicative of a variety of gastrointestinal diseases, and the dermatologist needs to know how to recognize them to refer the right patients to the gastroenterologist. Conversely, the gastroenterologist is often confronted with mucocutaneous lesions that raise the question of a possible association with a known digestive disease. Among the extra-intestinal manifestations of inflammatory bowel disease (IBD), mucocutaneous manifestations are the most common. This review will provide a breakdown by classifying them into 4 groups: 1) reactive manifestations, which include neutrophilic dermatoses, aphthous stomatitis, erythema nodosum, and vasculitis; 2) Crohn's disease-specific granulomatous skin lesions, which are histologically characterized by tuberculoid granulomas similar to those found in the gastrointestinal tract; 3) nutritional deficiency manifestations secondary to anorexia, malabsorption, loss, and drug interactions; and 3) a variety of autonomous autoimmune or inflammatory skin diseases. Dermatologists may also be involved in the management of the adverse effects of IBD treatments, especially the so-called "paradoxical" psoriatic eruptions.

Peripheral Blood Eosinophilia at Diagnosis of Inflammatory Bowel Disease Is Associated with Severe Disease Course; A Nationwide Study From the epi-IIRN Cohort.

BACKGROUND & AIMS: We conducted this nationwide study to evaluate the association between peripheral blood eosinophilia (PBE) and long-term outcomes in children and adults with inflammatory bowel diseases (IBD). METHODS: Data from the epi-IIRN cohort, a validated population-based IBD database, included patients diagnosed between 2005-2020 who had an eosinophil count at diagnosis, and those of non-IBD controls. PBE was defined as an eosinophil count of >0.5 X109/L Severe disease course was defined as corticosteroid dependency, use of ≥2 biologics from different classes, or surgery. Time-to-outcomes, including severe disease course, was determined by Cox proportional hazard models. RESULTS: Included were 28,133 patients (15,943 Crohn's disease [CD] and 12,190 ulcerative colitis [UC]), and 28,724 non-IBD controls. The prevalence of PBE was 13% in the IBD group and 5% in controls (P < .001). PBE was more prevalent in UC (16.1%) compared to CD (10.6%, OR=1.52 (95%CI 1.42-1.63); P < .001) and in pediatric-onset (23.5%) compared to adult-onset (11%) IBD (OR=2.14 (1.97-2.31); P <.001). In a multivariate analysis, PBE was a predictor of severe disease course in IBD (hazard ratio [HR]=1.49, 95%CI 1.38-1.62, P < .001). PBE also predicted time-to-hospitalization (HR=1.24, 95%CI 1.19-1.30), use of corticosteroids (HR=1.32, 95%CI 1.28-1.36), corticosteroid dependency (HR=1.37, 95%CI 1.31-1.43), and need of biologics (HR=1.27, 95%CI 1.21-1.33). CONCLUSION: In this largest nationwide study, PBE predicted severe IBD course. These findings support the use of PBE as a marker of adverse outcome of IBD and as a potential target for future therapies.

SUMOylation at the crossroads of gut health: insights into physiology and pathology.

SUMOylation, a post-translational modification involving the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target substrates, plays a pivotal role at the intersection of gut health and disease, influencing various aspects of intestinal physiology and pathology. This review provides a comprehensive examination of SUMOylation's diverse roles within the gut microenvironment. We examine its critical roles in maintaining epithelial barrier integrity, regulating immune responses, and mediating host-microbe interactions, thereby highlighting the complex molecular mechanisms that underpin gut homeostasis. Furthermore, we explore the impact of SUMOylation dysregulation in various intestinal disorders, including inflammatory bowel diseases and colorectal cancer, highlighting its implications as a potential diagnostic biomarker and therapeutic target. By integrating current research findings, this review offers valuable insights into the dynamic interplay between SUMOylation and gut health, paving the way for novel therapeutic strategies aimed at restoring intestinal equilibrium and combating associated pathologies.

Post-operative Crohn's Disease Recurrence and Infectious Complications: A Transcriptomic Analysis.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory condition affecting the gastrointestinal tract, characterized by complications such as strictures, fistulas, and neoplasia. Despite medical advancements, a significant number of patients with Crohn's disease require surgery, and many experience post-operative complications and recurrence. Previous studies have analyzed gene expression to study recurrence and post-operative complications independently. This study aims to identify overlapping differentially expressed genes and pathways for recurrence and post-operative complications. METHODS: A dataset including 45 patients with Crohn's disease, including gene expression from ileum and colon tissue, endoscopic recurrence, and intra-abdominal septic complications was analyzed. Gene set enrichment analysis was used to identify gene pathways associated with the outcomes. Finally, a multi-variable logistic regression model was created to assess whether gene pathways were independently associated with both outcomes. RESULTS: In ileum tissue, several inflammatory pathways, including interferon alpha and gamma response were upregulated in patients with endoscopic recurrence and intra-abdominal septic complications. In addition, there was upregulation of the epithelial mesenchymal transition pathway. In colon tissue, metabolic processes, such as myogenesis and oxidative phosphorylation were downregulated in both outcomes. In a multivariate model, downregulation of myogenesis in colon tissue was significantly associated with both endoscopic recurrence and intra-abdominal septic complications. CONCLUSION: These findings shed light on the underlying biology of these outcomes and suggest potential biomarkers or therapeutic targets to reduce their occurrence. Further validation and multi-institutional studies are warranted to confirm these results and improve post-operative outcomes for patients with Crohn's disease.

Epidemiology of Elderly-Onset IBD: A Nationwide Population-based Cohort Study.

BACKGROUND AND AIMS: We examined the incidence and natural history of patients with very elderly-onset (herein, referred to as very late-onset) inflammatory bowel diseases (IBD) (age ≥70y at diagnosis), compared with patients diagnosed between ages 60-69y in Denmark. METHODS: In the Danish National Patient Register, between 1980-2018, we identified all individuals ≥60y with newly diagnosed Crohn's disease (CD) and ulcerative colitis (UC) and examined trends in incidence, cumulative risk of hospitalization, treatment patterns, IBD-related surgery, serious infection, cancer and cardiovascular and venous thromboembolic risks among very late-onset (70-79y or 80+ years) vs. late-onset (60-69y) IBD, using non-parametric competing risk analysis treating death as competing risk. RESULTS: We identified 3,459 patients with onset of CD at age ≥60y (47% ≥70y) and 10,774 patients with onset of UC aged ≥60y (51% ≥70y). Over the last three decades, incidence changes for very late-onset and late-onset IBD have followed the same patterns. Also, both for CD and UC, cumulative incidence of IBD-related hospitalization and corticosteroid use was comparable in very late-onset vs. late-onset patients. However, the burden of disease-modifying therapy, either immunomodulator or TNF antagonist use, and major IBD-related surgery was significantly lower in patients with very late-onset than in late-onset IBD. On the other hand, 5-year risk of serious infections and cardiovascular events was higher in patients with very late-onset IBD. CONCLUSION: This nationwide cohort study shows that patients diagnosed with very late-onset (≥70y) IBD have a higher relative burden of disease- and aging-related complications, with limited use of steroid-sparing strategies and surgery, compared with late-onset IBD.

[Small Molecule Therapy for Inflammatory Bowel Disease: JAK Inhibitors and S1PR Modulators].

Small molecules, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor modulators (S1PRMs), are promising new treatments for inflammatory bowel disease (IBD). Small molecules exhibit more predictable pharmacokinetics than biologics, are less likely to induce immune responses, and can be administered orally. JAK inhibitors function by blocking the activity of JAK enzymes, which prevents the subsequent phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins. Tofacitinib and filgotinib are approved for treating ulcerative colitis (UC), while upadacitinib is approved for UC and Crohn's disease. Nevertheless, JAK inhibitors can increase the risk of herpes zoster, cancer, major adverse cardiovascular events, and venous thromboembolism. S1PRMs bind to S1PRs, particularly S1PR1, on lymphocytes. This interaction inhibits lymphocytes from exiting the lymph nodes and migrating to the gut, thereby reducing inflammation and the immune response in the intestinal mucosa. Ozanimod and etrasimod are S1PRMs approved for the treatment of UC, but they can cause side effects such as bradycardia, conduction disorder, and macular edema. Overall, JAK inhibitors and S1PRMs offer significant benefits in managing IBD, although their potential side effects require careful monitoring.

Intestinal biofilms: pathophysiological relevance, host defense, and therapeutic opportunities.

SUMMARYThe human intestinal tract harbors a profound variety of microorganisms that live in symbiosis with the host and each other. It is a complex and highly dynamic environment whose homeostasis directly relates to human health. Dysbiosis of the gut microbiota and polymicrobial biofilms have been associated with gastrointestinal diseases, including irritable bowel syndrome, inflammatory bowel diseases, and colorectal cancers. This review covers the molecular composition and organization of intestinal biofilms, mechanistic aspects of biofilm signaling networks for bacterial communication and behavior, and synergistic effects in polymicrobial biofilms. It further describes the clinical relevance and diseases associated with gut biofilms, the role of biofilms in antimicrobial resistance, and the intestinal host defense system and therapeutic strategies counteracting biofilms. Taken together, this review summarizes the latest knowledge and research on intestinal biofilms and their role in gut disorders and provides directions toward the development of biofilm-specific treatments.

Analysis of the effect of hypusination in myeloid cells on colitis and colitis-associated cancer.

Hypusine is an amino acid synthesized by the enzyme deoxyhypusine synthase (DHPS). It is critical for the activity of eukaryotic translation initiation factor 5A (EIF5A). We reported that hypusination i) in macrophages supports the innate response towards pathogenic bacteria and ii) in epithelial cells maintains intestinal homeostasis. Herein, we investigated the effect of myeloid hypusination on the outcome of colitis and colitis-associated cancer. We found that patients with Crohn's disease exhibit increased levels of DHPS and EIF5AHyp in cells infiltrating the colon lamina propria. However, the specific deletion of Dhps in myeloid cells had no impact on clinical, histological, or inflammatory parameters in mice treated with dextran sulfate sodium (DSS). Further, tumorigenesis and level of dysplasia were not affected by myeloid deletion of Dhps in the azoxymethane-DSS model. The composition of the fecal and the mucosa-associated microbiome was similar in animals lacking or not DHPS in myeloid cells. Thus, hypusination in myeloid cells does not regulate colitis associated with epithelial injury and colitis-associated cancer. Enhancement of the DHPS/hypusine pathway in patients with inflammatory bowel disease could have therapeutic impact through epithelial effects, but modulation of hypusination in myeloid cells will be unlikely to affect the disease.

Importance of Gut Microbiota in Patients with Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBDs), such as Crohn's disease (CD) and ulcerative colitis (UC), are chronic diseases of the digestive system with a multifactorial and not fully understood etiology. There is research suggesting that they may be initiated by genetic, immunological, and lifestyle factors. In turn, all of these factors play an important role in the modulation of intestinal microflora, and a significant proportion of IBD patients struggle with intestinal dysbiosis, which leads to the conclusion that intestinal microflora disorders may significantly increase the risk of developing IBD. Additionally, in IBD patients, Toll-like receptors (TLRs) produced by intestinal epithelial cells and dendritic cells treat intestinal bacterial antigens as pathogens, which causes a disruption of the immune response, resulting in the development of an inflammatory process. This may result in the occurrence of intestinal dysbiosis, which IBD patients are significantly vulnerable to. In this study, we reviewed scientific studies (in particular, systematic reviews with meta-analyses, being studies with the highest level of evidence) regarding the microflora of patients with IBD vs. the microflora in healthy people, and the use of various strains in IBD therapy.

Hydroalcoholic extract of Araucaria sp. brown propolis alleviates ulcerative colitis induced by TNBS in rats by reducing inflammatory cell infiltration and oxidative damage.

OBJECTIVE: To investigate the effects of Araucaria sp. brown propolis (ABP) against trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. METHODS: Animals received vehicle (1% DMSO, 1 ml/kg) or hydroalcoholic extract of ABP (hydroalcoholic extract of Araucaria sp. brown propolis (HEABP), 30, 100, and 300 mg/kg) orally, or dexamethasone (25 mg/kg, s.c.) for 5 days. On day 4, the animals received intracolonic TNBS (150 mg/kg), on day 6 they were euthanized. The weight of the animals, the macroscopic and microscopic colonic damage, reduced glutathione (GSH) and malondialdehyde (MDA) levels, and the activity of glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and myeloperoxidase (MPO) were measured in colon homogenate. The action of HEABP and two isolated compounds in neutrophil migration was recorded. KEY FINDINGS: HEABP (100 and 300 mg/kg), but not dexamethasone, decreased colonic lesion, and increased colonic mucin staining. In parallel, HEABP decreased MDA and restored GSH levels and the activity of SOD, CAT, and GST in the colon. A dose-dependent inhibition of MPO activity was observed (LogIC50 = 1.9). Moreover, HEBPA and the junicedric and abietic acids inhibited the neutrophil chemotaxis in vitro and HEBPA reduced neutrophil migration in vivo. CONCLUSION: HEABP may be promising in the therapies for inflammatory bowel diseases, reducing oxidative and inflammatory damage, especially mediated by neutrophils.

Causal Effects of Inflammatory Bowel Diseases on the Risk of Kidney Stone Disease.

BACKGROUND: Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, have been increasingly associated with kidney stone disease, posing significant health challenges globally. OBJECTIVE: This research sought to determine the causal relationship between kidney stone disease risk and inflammatory bowel disorders. METHODOLOGY: This retrospective cohort study included patients with IBDs, such as ulcerative colitis or Crohn's disease, who were diagnosed at least 18 years of age. Information was gathered with an emphasis on patients having comprehensive medical histories and confirmed cases of kidney stone disease from January to December 2022. Medical records were retrospectively evaluated by trained staff to extract treatment information and clinical, radiological, and demographic data. To evaluate relationships, statistical analysis was carried out in SPSS software version 23 using Chi-square tests and descriptive statistics. RESULTS: The study included 320 patients diagnosed with IBDs, among which 198 (61.87%) had Crohn's disease, and 122 (38.13%) were diagnosed with ulcerative colitis. The cohort consisted of 140 females (43.75%) and 180 men (56.25%), with a mean age of 45.5 years. Regarding smoking, 113 people (35.31%) reported being smokers, whereas 207 people (64.69%) did not smoke. Additionally, 18 (5.62%) of the population had an underweight BMI, 136 (42.50%) had a normal BMI, 119 (37.19%) had an overweight BMI, and 47 (14.69%) had an obese BMI. Of the patients, 86 (26.88%) had a prior history of kidney stone disease, while 194 (60.62%) did not. Aminosalicylates were the most often used therapy modality for IBD in 189 (58.97%) of cases, followed by corticosteroids in 117 (36.56%) and immunomodulators in 93 (28.94%). Radiological examinations showed that renal calculi were present in 60 (18.75%) of patients, and kidney stones occurred in 40 (12.50%) of patients throughout the research period. The smoking status (p=0.006) and prior history of kidney stones (p<0.001) were the corresponding p-values for the significant results. CONCLUSION: The study highlights an increased risk of kidney stone disease in IBD patients, particularly among smokers and those with a recurrent history of kidney stones. Of the 320 patients, 198 (61.87%) had Crohn's disease and 122 (38.13%) had ulcerative colitis, with a significant relationship found between kidney stones and both smoking (113 patients, 35.31%, p=0.006) and a prior history of kidney stones (86 patients, 26.88%, p<0.001). The findings emphasize the need for targeted preventive measures and close monitoring of these high-risk groups.

Cardiac magnetic resonance in a rare case of recurrent mesalazine-induced myocarditis.

Mesalazine represents a key treatment for intestinal bowel diseases and only in rare cases produces cardiac toxicity, with a not completely known mechanism. We report a case of a 25-year-old man with a first episode of myocarditis after 2 weeks from the first mesalazine intake, documented also by a characteristic cardiac magnetic resonance pattern. Then, after less than 1 month, he suffered myocarditis recurrence and so, guided by a multidisciplinary team evaluation, in the suspicion of mesalazine-induced myocarditis, the drug was promptly stopped, with consequent recovery of cardiac damage. In our patient, the recurrence of myocarditis because of the non-interruption of the drug is very peculiar (only three cases described in literature) and definitively confirms the diagnosis.

This paper reports an exemplary case of cardiac toxicity induced by mesalazine, a key treatment for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. In rare cases, this drug can lead to cardiac impairment, with a mechanism not yet clarified. The young patient described experiencing a first episode of myocarditis (inflammation of the heart muscle cells) after 2 weeks of starting mesalazine. The diagnosis was possible thanks to cardiac magnetic resonance, a noninvasive exam providing high-definition images associated with tissue characterization. Mesalazine was not discontinued because drug-induced etiology was not suspected, due to its rarity. Consequently, the patient suffered a second episode of myocarditis, diagnosed by endomyocardial biopsy, an invasive technique that can accurately assess the etiology of myocardial damage, leading to prompt cessation of treatment. Since myocarditis can have various causes, diagnosis was also facilitated through a multidisciplinary team, which ruled out other possible causes for this condition. This case report is highly educational and underscores the importance of clinicians being vigilant about this side effect and considering it in patients taking mesalazine who present with myocarditis, to promptly discontinue the treatment. Mesalazine interruption is otherwise the only effective therapy for this condition, in addition to anti-inflammatory and analgesic drugs. Furthermore, this paper highlights the increasing importance of multidisciplinary teams, comprising various specialists, for accurate diagnosis and therapeutic decisions. The authors also propose an algorithm for diagnosing mesalazine-induced myocarditis, with certainty derived from recurrence after drug rechallenge, either voluntarily or accidentally, as demonstrated in this case.

Fecal calprotectin and endoscopic scores: The cornerstones in clinical practice for evaluating mucosal healing in inflammatory bowel disease.

Managing inflammatory bowel disease (IBD) is becoming increasingly complex and personalized, considering the advent of new advanced therapies with distinct mechanisms of action. Achieving mucosal healing (MH) is a pivotal therapeutic goal in IBD management and can prevent IBD progression and reduce flares, hospitalization, surgery, intestinal damage, and colorectal cancer. Employing proactive disease and therapy assessment is essential to achieve better control of intestinal inflammation, even if subclinical, to alter the natural course of IBD. Periodic monitoring of fecal calprotectin (FC) levels and interval endoscopic evaluations are cornerstones for evaluating response/remission to advanced therapies targeting IBD, assessing MH, and detecting subclinical recurrence. Here, we comment on the article by Ishida et al Moreover, this editorial aimed to review the role of FC and endoscopic scores in predicting MH in patients with IBD. Furthermore, we intend to present some evidence on the role of these markers in future targets, such as histological and transmural healing. Additional prospective multicenter studies with a stricter MH criterion, standardized endoscopic and histopathological analyses, and virtual chromoscopy, potentially including artificial intelligence and other biomarkers, are desired.

Estrogen deprivation and estrogen receptor α antagonism decrease DSS colitis in female mice.

The association of hormonal contraception with increased risk of inflammatory bowel disease (IBD) observed in females suggests involvement of ovarian hormones, such as estradiol, and the estrogen receptors in the progression of intestinal inflammation. Here, we investigated the effects of prophylactic SERM2 and estradiol supplementation in dextran sulfate sodium-induced colitis using mice with intact ovaries and ovariectomized (OVX) female mice. We found that graded colitis score was threefold reduced in the OVX mice, compared to mice with intact ovaries. Estradiol supplementation, however, aggravated the colitis in OVX mice, increasing the colitis score to a similar level than what was observed in the intact mice. Further, we observed that immune infiltration and gene expression of inflammatory interleukins Il1b, Il6, and Il17a were up to 200-fold increased in estradiol supplemented OVX colitis mice, while a mild but consistent decrease was observed by SERM2 treatment in intact animals. Additionally, cyclo-oxygenase 2 induction was increased in the colon of colitis mice, in correlation with increased serum estradiol levels. Measured antagonist properties of SERM2, together with the other results presented here, indicates an exaggerating role of ERα signaling in colitis. Our results contribute to the knowledge of ovarian hormone effects in colitis and encourage further research on the potential use of ER antagonists in the colon, in order to alleviate inflammation.

The causal relationship between inflammatory bowel diseases and erythema nodosum: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Individuals with inflammatory bowel disease (IBD) exhibit a heightened likelihood of developing erythema nodosum (EN), but the presence of causal link is unknown. The purpose of the present research was to investigate this connection using a bidirectional two-sample Mendelian randomization (MR) analysis. METHODS: Summarized statistics for EN were sourced from the FinnGen consortium of European ancestry. The International Inflammatory Bowel Disease Genetic Consortium (IBDGC) was used to extract summary data for IBD. The inverse variance weighted (IVW) technique was the major method used to determine the causative link between them. RESULTS: The study evaluated the reciprocal causal link between IBD and EN. The IVW technique confirmed a positive causal link between IBD and EN (OR = 1.237, 95% CI: 1.109-1.37, p = 1.43 × 10- 8), as well as a strong causality connection between Crohn's disease (CD) and EN (OR = 1.248, 95% CI: 1.156-1.348, p = 1.00 × 10- 4). Nevertheless, a causal connection between ulcerative colitis (UC) and EN could not be established by the data. The reverse MR research findings indicated that analysis indicated that an increase in EN risks decreased the likelihood of UC (OR = 0.927, 95% CI: 0.861-0.997, p = 0.041), but the causal association of EN to IBD and CD could not be established. CONCLUSION: This investigation confirmed that IBD and CD had a causal connection with EN, whereas UC did not. In addition, EN may decrease the likelihood of UC. Further study must be performed to uncover the underlying pathophysiological mechanisms producing that connection.

Risk of Hematologic Malignancies in Patients with Inflammatory Bowel Disease: A Meta-Analysis of Cohort Studies.

Background/Aims: Inflammatory bowel disease (IBD) may contribute to the development of hematologic malignancies. In this study, the potential relationship between IBD and hematologic malignancies was investigated. Methods: We searched the PubMed, Web of Science, Embase, and Cochrane Library databases for all cohort studies comparing the incidence of hematologic malignancies in non-IBD populations with that in IBD patients, and we extracted relevant data from January 2000 to June 2023 for meta-analysis. Results: Twenty cohort studies involving 756,377 participants were included in this study. The results showed that compared with the non-IBD cohort, the incidence of hematologic malignancies in the IBD cohort was higher (standardized incidence ratio [SIR]=3.05, p<0.001). According to the specific types of IBD, compared with the non-IBD patients, the incidences of hematologic malignancies in ulcerative colitis patients (SIR=2.29, p=0.05) and Crohn's disease patients (SIR=3.56, p=0.005) were all higher. In the subgroup analysis of hematologic malignancy types, compared with the control group, the incidences of non-Hodgkin's lymphoma (SIR=1.70, p=0.01), Hodgkin's lymphoma (SIR=3.47, p=0.002), and leukemia (SIR=3.69, p<0.001) were all higher in the IBD cohort. Conclusions: The incidence of hematologic malignancies, including non-Hodgkin's lymphoma, Hodgkin's lymphoma, and leukemia is higher in patients with IBD (ulcerative colitis or Crohn's disease) than in non-IBD patients.

Taxonomic and phenotypic analysis of bifidobacteria isolated from IBD patients as potential probiotic strains.

BACKGROUND: Inflammatory Bowel Diseases (IBD) are a major public health issue with unclear aetiology. Changes in the composition and functionality of the intestinal microbiota are associated with these pathologies, including the depletion of strict anaerobes such as Feacalibacterium prausnitzii. Less evidence is observed for depletion in other anaerobes, among which bifidobacteria. This study characterized the taxonomic and functional diversity of bifidobacteria isolated from the human intestinal microbiota in active and non-active IBD patients by a culturomics approach and evaluated if these bifidobacteria might be used as probiotics for gut health. RESULTS: A total of 341 bifidobacteria were isolated from the intestinal microbiota of IBD patients (52 Crohn's disease and 26 ulcerative colitis patients), with a high proportion of Bifidobacterium dentium strains (28% of isolated bifidobacteria). In ulcerative colitis, the major species identified was B. dentium (39% of isolated bifidobacteria), in active and non-active ulcerative colitis. In Crohn's disease, B. adolescentis was the major species isolated from non-active patients (40%), while similar amounts of B. dentium and B. adolescentis were found in active Crohn's disease patients. The relative abundance of B. dentium was increased with age, both in Crohn's disease and ulcerative colitis and active and non-active IBD patients. Antibacterial capacities of bifidobacteria isolated from non-active ulcerative colitis against Escherichia coli LF82 and Salmonella enterica ATCC 14028 were observed more often compared to strains isolated from active ulcerative colitis. Finally, B. longum were retained as strains with the highest probiotic potential as they were the major strains presenting exopolysaccharide synthesis, antibacterial activity, and anti-inflammatory capacities. Antimicrobial activity and EPS synthesis were further correlated to the presence of antimicrobial and EPS gene clusters by in silico analysis. CONCLUSIONS: Different bifidobacterial taxonomic profiles were identified in the microbiota of IBD patients. The most abundant species were B. dentium, mainly associated to the microbiota of ulcerative colitis patients and B. adolescentis, in the intestinal microbiota of Crohn's disease patients. Additionally, the relative abundance of B. dentium significantly increased with age. Furthermore, this study evidenced that bifidobacteria with probiotic potential (antipathogenic activity, exopolysaccharide production and anti-inflammatory activity), especially B. longum strains, can be isolated from the intestinal microbiota of both active and non-active Crohn's disease and ulcerative colitis patients.