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The importance of the gut microbiota in human health is currently well established. It contributes to many vital functions such as development of the host immune system, digestion and metabolism, barrier against pathogens or brain–gut communication. Microbial colonization occurs during infancy in parallel with maturation of the host immune system; therefore, an adequate cross-talk between these processes is essential to generating tolerance to gut microbiota early in life, which is crucial to prevent allergic and immune-mediated diseases. Inflammatory bowel disease (IBD) is characterized by an exacerbated immune reaction against intestinal microbiota. Changes in abundance in the gut of certain microorganisms such as bacteria, fungi, viruses, and archaea have been associated with IBD. Microbes that are commonly found in high abundance in healthy gut microbiomes, such as F. prausnitzii or R. hominis, are reduced in IBD patients. E. coli, which is usually present in a healthy gut in very low concentrations, is increased in the gut of IBD patients. Microbial taxa influence the immune system, hence affecting the inflammatory status of the host. This review examines the IBD microbiome profile and presents IBD as a model of dysbiosis.

Background & aimsPregnancy can be a complex and risk filled event for women with inflammatory bowel disease (IBD). High-quality studies in this population are lacking, with limited data on medications approved to treat IBD during pregnancy. For patients, limited knowledge surrounding pregnancy impacts pregnancy rates, medication adherence, and outcomes. Limited provider knowledge leads to highly varied practices in care affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike. The Global Consensus Consortium is a group of 39 IBD and content experts and 7 patient advocates from 6 continents who convened to review and assess current data and come to an agreement on best practices based on these data.MethodsThe GRADE process was used when sufficient published data were available and the RAND process in those instances where expert opinion was needed to guide consistent practice. Recommendations were informed by the guiding principle that maternal health best supports infant health.ResultsThe topics were divided into ten categories with 34 GRADE recommendations and 35 Consensus statements.ConclusionsOverall, the goal of the group was to provide data-driven and practical guidance to improve the care of women with IBD around the globe based on the best available research.

Previous studies have shown the importance of self-perceptions of aging in predicting psychological distress throughout the life cycle. However, little is known about the processes through which self-perceptions of aging influence distress. The aim of the present study is to analyze the potential indirect effects of perceived control and pleasant activities in the association between self-perceptions of aging and depression and anxiety symptoms in middle-aged and older adults. A total of 315 people over 40 years of age (M age = 58.8; SD = 10.8; 67.9% women) participated. Two indirect effects analysis models were conducted in serial with the aim of analyzing the role of perceived control and pleasant activities in the relationship between the self-perceptions of aging and depressive (model 1) and anxiety (model 2) symptomatology. A direct effect was observed between self-perceptions of aging and depressive, and anxious symptomatology. In addition, indirect associations through the variables perceived control and pleasant activities were significant. The tested models explained 46.1% of the variance in depressive symptomatology and 34.8% of the variance in anxiety. The results of this study confirm the association between self-perceptions of aging and psychological distress. This association is exerted through lower perception of control and fewer pleasant activities. Interventions aimed at promoting effective coping strategies that favor perceived control, activity and emotional well-being should include a module on identifying and modifying of negative self-perceptions of aging in middle-aged and older adults.

Ustekinumab is a fully human monoclonal antibody against IL-12/23. Ustekinumab induced clinical response and maintained higher rate of response than placebo in patients with Crohn's disease (CD). This study aims to assess the effectiveness and safety of ustekinumab in refractory patients with CD in real-life practice.MethodsConsecutive patients with CD who were treated with subcutaneous ustekinumab between March 2010 and December 2014 were retrospectively included in a multicenter open-label study. Clinical response was defined by Harvey-Bradshaw index score and assessed after the loading doses, 6, 12 months, and last follow-up.ResultsOne hundred sixteen patients were included, with a median follow-up of 10 months (interquartile range: 5–21). Clinical response after loading ustekinumab was achieved in 97/116 (84%) patients. The clinical benefit at 6, 12 months, and at the end of the follow-up was 76%, 64%, and 58%, respectively. Dose escalation was effective in 8 of 11 (73%) patients. Perianal disease also improved in 11 of 18 (61%) patients with active perianal fistulae. The initial response to ustekinumab and previous use of more than 2 immunosuppressant drugs were associated with a clinical response to ustekinumab maintenance therapy. In contrast, previous bowel resection predicted a long-term failure with ustekinumab. Adverse events were reported in 11 (9.5%) patients, but none required ustekinumab withdrawal.ConclusionsSubcutaneous ustekinumab is effective and safe in a high proportion of patients with CD that were resistant to conventional immunosuppressant and antitumor necrosis factor drugs.

Background: Active disease during conception and pregnancy in women with inflammatory bowel disease (IBD) increases the risk of pregnancy complications and adverse neonatal outcomes. The use of IBD treatments during pregnancy should be weighed against their adverse effects on the neonate, but longer-term safety data and data on serious infection rates and malignancies postnatally are lacking, particularly for newer drugs, such as tofacitinib, vedolizumab and ustekinumab. Methods: This ongoing, prospective registry study being conducted at 70 centres in Spain is enrolling pregnant women who are ⩾18 years, are at any point in pregnancy up to the end of the second trimester and have a diagnosis of Crohn’s disease, ulcerative colitis or unclassified IBD. Patients will receive treatment decided independently by their IBD specialist. Each incident gestation will be followed up through pregnancy and the first 4 years postnatally. Three cohorts will be compared: biologicals exposed, immunomodulatory exposed and non-exposed. The primary endpoint is the risk of severe infection in newborns postnatally up to 4 years of age; other endpoints include serious adverse events (SAEs) such as pregnancy and delivery complications, neonatal SAEs, development [Ages and Stages Questionnaire-3 (ASQ3)], and malignancy incidence, up to 4 years of age. IBD specialists will collect maternal data (baseline/end of each trimester/1 month post-delivery), neonatal birth data, and the SAE and ASQ3 data in children exposed during pregnancy, reported every 3 months by the mother. Statistical analysis will include summary statistics for quantitative variables, comparisons of qualitative variables with significance set at p < 0.025 and a binary logistic regression model to determine the risk factors for severe infections. Results: Enrolment began in September 2019 and study completion is expected in September 2028. Conclusions: This prospective, controlled study will provide evidence on the long-term safety profile in children after intrauterine and lactation exposure to biological and immunomodulatory IBD treatments, including data on postnatal severe infections, development and malignancies. ClinicalTrials.gov identifier: NCT03894228

Pathological angiogenesis contributes to cancer progression and chronic inflammatory diseases. In inflammatory bowel disease, the microvasculature expands by intussusceptive angiogenesis (IA), a poorly characterized mechanism involving increased blood flow and splitting of pre‐existing capillaries. In this report, mice lacking the protease MT1‐MMP in endothelial cells (MT1 iΔ EC ) presented limited IA in the capillary plexus of the colon mucosa assessed by 3D imaging during 1% DSS‐induced colitis. This resulted in better tissue perfusion, preserved intestinal morphology, and milder disease activity index. Combined in vivo intravital microscopy and lentiviral rescue experiments with in vitro cell culture demonstrated that MT1‐MMP activity in endothelial cells is required for vasodilation and IA, as well as for nitric oxide production via binding of the C‐terminal fragment of MT1‐MMP substrate thrombospondin‐1 (TSP1) to CD47/αvβ3 integrin. Moreover, TSP1 levels were significantly higher in serum from IBD patients and in vivo administration of an anti‐MT1‐MMP inhibitory antibody or a nonamer peptide spanning the αvβ3 integrin binding site in TSP1 reduced IA during mouse colitis. Our results identify MT1‐MMP as a new actor in inflammatory IA and a promising therapeutic target for inflammatory bowel disease. Synopsis Inflammatory bowel disease comprising ulcerative colitis and Crohn's disease does not have a universal efficient therapy. This study identifies the molecular axis MT1‐MMP/thrombospondin‐1/αvβ3 integrin/nitric oxide as a target to reduce inflammatory intussusceptive angiogenesis and improve colitis. Early expansion of the capillaries in the intestinal mucosa during colitis was caused by intussusceptive/splitting angiogenesis (IA). Deletion of the protease MT1‐MMP from endothelial cells reduced IA and colitis severity. Thrombospondin‐1 (TSP1) processing by MT1‐MMP promoted nitric oxide production, vasodilation and IA. High levels of TSP1 were found in sera from patients suffering low active IBD. Targeting MT1‐MMP/TSP1/αvβ3 integrin/nitric oxide pathway by monoclonal antibodies or minipump‐delivered peptides decreased IA and ameliorates colitis. Graphical Abstract Inflammatory bowel disease comprising ulcerative colitis and Crohn's disease does not have a universal efficient therapy. This study identifies the molecular axis MT1‐MMP/thrombospondin‐1/αvβ3 integrin/nitric oxide as a target to reduce inflammatory intussusceptive angiogenesis and improve colitis.

Background: Tofacitinib is effective for refractory ulcerative colitis (UC), a chronic inflammatory disease of the colonic mucosa. However, its use has been associated with an increased risk of thromboembolic events, prompting regulatory restrictions. Understanding the pathophysiological mechanisms contributing to these potential risks is critical for patient safety. We aim to evaluate and compare ex vivo the effects of tofacitinib and anti-TNF on coagulation parameters and platelet function. Methods: Whole blood and platelet-rich plasma from 10 active UC (aUC) and 10 quiescent UC (qUC) patients and 10 healthy controls (HC) were spiked ex vivo with tofacitinib, anti-TNF (as comparator), or a sterile solution. Coagulation kinetics were measured by rotational thromboelastometry (ROTEM), platelet aggregation by aggregometry, and platelet activation by flow cytometry. The study was conducted at Hospital Universitario de La Princesa. Results: Flow cytometry showed increased expression of activation markers CD62P and CD63 and higher PAC-1 binding in platelets from both aUC and qUC patients incubated with either tofacitinib or anti-TNF versus no drug. No differences were found between the drugs. CD63 expression also increased in HC after drug exposure, with no differences between anti-TNF or tofacitinib. Platelet aggregation and coagulation parameters did not differ between tofacitinib, anti-TNF, and no drug in aUC, qUC, and HC. Conclusions: Tofacitinib does not alter platelet function or coagulation in UC patients under ex vivo conditions compared to anti-TNF. The increased thromboembolic risk observed in some populations treated with tofacitinib cannot be attributed to these factors in UC patients.

INTRODUCTION:Real-world data on the effectiveness of upadacitinib for inflammatory bowel disease (IBD) are limited. To assess upadacitinib persistence, effectiveness, and safety in a real-world scenario.METHODS:Retrospective multicenter study of patients with IBD who received upadacitinib before 31st December 2022 and at least 12 weeks before the recruitment date. Clinical effectiveness was assessed based on partial Mayo score for ulcerative colitis (UC) and Harvey-Bradshaw index for Crohn's disease (CD).RESULTS:We included 100 patients (68 with CD, and 32 with UC). Patients had previously received a median of 4 advanced therapies. Twenty-three discontinued the treatment (median follow-up 7.6 months). CD (vs UC) (hazard ratio 3.7; 95% confidence interval [CI]: 1.04-12.9) and age below 40 years at upadacitinib initiation (hazard ratio 2.4; 95% CI: 1.0-5.8) were associated with treatment discontinuation in multivariable analysis. Clinical remission for IBD was achieved in 59% of patients at week 8, 64% at week 12, and 42% at week 52. The proportion of patients with UC previously exposed to tofacitinib (n = 25) who achieved clinical remission was 78% at week 12, and 50% at week 52. Factors associated with clinical remission at week 12 were UC diagnosis (odds ratio [OR] 4.6; 95% CI: 1.3-17), mild or moderate activity at baseline (OR 8; 95% CI: 1.1-56), and not smoking (OR 4.4; 95% CI: 1.5-13). Dose escalation recaptured remission in 60% of patients with relapse. Eighty percent of patients with active immune-mediated diseases or extraintestinal manifestations improved with upadacitinib. Forty-three patients reported adverse events, 11 of them serious.DISCUSSION:Upadacitinib is effective and safe for treating patients with highly refractory IBD, even in previously treated with Janus kinase inhibitors.

Rapid symptom relief is an important consideration for patients with ulcerative colitis (UC) experiencing a flare. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active UC. We evaluated patient-reported symptomatic improvement from patients in the ELEVATE UC program. This study was a post-hoc analysis of pooled daily e-diary data from patients with moderately to severely active UC receiving etrasimod or placebo in the phase III ELEVATE UC 52 and ELEVATE UC 12 trials. During the 12-week induction periods, patients self-reported stool frequency and rectal bleeding on days 1-28. Daily symptomatic response and symptomatic remission were calculated (partial modified Mayo Score). Overall, 787 patients (527 receiving etrasimod, 260 placebo) were included in the analysis. Etrasimod-treated patients had statistically significantly higher rates of symptomatic response and symptomatic remission during the first 28 days of therapy, with adjusted differences (95% CIs) reaching statistical significance from day 2 (5.6% [0.8-10.3], P = .022) to day 11 (4.7% [0.4-9.0], P = .034), respectively. In patients naïve to biologic/Janus kinase inhibitor therapy, symptomatic response was statistically significantly improved with etrasimod vs placebo from day 3 (8.9% [2.3-15.5], P = .008). Symptomatic improvement rates were similar with and without concomitant corticosteroid use. In this post-hoc analysis, improvements in UC symptoms occurred in patients receiving etrasimod vs placebo from as early as day 2. These findings indicate a rapid onset of symptomatic effect with etrasimod treatment for moderately to severely active UC. NCT03945188, NCT03996369.

Mercury (Hg), particularly as methylmercury (MeHg), is a nonessential, persistent, and bioaccumulative toxic element with high biomagnification capacity and is considered a threat to marine environments. We evaluated total Hg concentrations in liver, kidney, and brain in 62 individuals of 9 bird species linked to marine ecosystems from western Mediterranean admitted in a Wildlife Rehabilitation Center (WRC) (Alicante, Spain, 2005–2020). Age- and sex-related differences in Hg levels, as well as the cause of admission to the WRC, were also evaluated in certain species. The species studied were: northern gannet (Morus bassanus), European shag (Phalacrocorax aristotelis), great cormorant (Phalacrocorax carbo), osprey (Pandion haliaetus), Balearic shearwater (Puffinus mauretanicus), yellow-legged gull (Larus michahellis), razorbill (Alca torda), common tern (Sterna hirundo), and black-headed gull (Chroicocephalus ridibundus). Concentrations in feathers of 27 individuals, and concentrations in internal tissues in 7 other individuals of 7 different species were also reported but not statistically evaluated due to the limited number of samples. Results suggest that individuals were chronically exposed to Hg through diet. The differences in Hg concentrations among species may be explained by their diet habits. Mercury concentrations strongly correlated between tissues (r = 0.78–0.94, p < 0.001, n = 61–62). Some individuals of certain species (i.e., European shag, northern gannet, and great cormorant) showed Hg concentrations close to or above those described in the literature as causing reproductive alterations in other avian species. Consequently, certain individuals inhabiting western Mediterranean could be at risk of suffering long-term, Hg-related effects. Some of the species evaluated are listed within different categories of threat according to the International Union for Conservation of Nature (IUCN) and are endangered at a national level, so this study will provide valuable information for assessors and authorities in charge of the management of the environment and pollution.