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Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-α modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-α induction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-α expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-α expression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression.

The long-term goal of our ongoing studies is to determine if, and to what extent, a multi-mineral product (Aquamin) could benefit individuals with ulcerative colitis (UC). As a step toward achieving that goal, we carried out a pilot 180-day biomarker trial (clinicaltrials.gov ID: NCT03869905) in patients with UC in remission or with mild disease. A total of 28 subjects participated in the study. Each subject was randomly assigned to receive either Aquamin for 180 days or placebo for 90 days. At Day-90, placebo subjects crossed over to Aquamin for the final 90 days. At Day-0, -90 and -180, serum samples were analyzed for C-reactive protein (CRP), alkaline phosphatase (ALP), intestine-specific ALP (ALPI), and for biomarkers of bone turnover (osteocalcin, TRAP5b and bone-specific ALP [BALP]). Stool specimens were assessed for fecal calprotectin (fCAL) and colon biopsies were examined histologically by Geboes scoring at the same time points. Each subject underwent DEXA scanning (at Day-0 and Day-180 only). In addition, mass spectrometry-based proteomic assessment was performed using colon biopsies obtained at each time point. Subjects who received Aquamin for the complete 180-day period (a total of 12) demonstrated improvements in all biomarkers (CRP, fCAL, ALP, ALPI, and Geboes scoring); this was not observed in the placebo group (16 subjects). When cumulative pre-post differences were compared between the Aquamin and placebo groups, Aquamin treatment significantly decreased these differences (a 24% decrease as compared to a 38% increase with placebo, p = 0.0284). Subjects who received Aquamin for 90-days showed intermediary responses. Subjects receiving Aquamin for 180 days also demonstrated increases in bone mineral density (BMD) and bone mineral content (BMC), resulting in a statistically significant increase (7.3%, p = 0.0324) in the hip strength index over the treatment period. This was accompanied by increases in osteocalcin and TRAP5b and a decrease in BALP. The proteomic screen demonstrated upregulation of multiple gut barrier proteins, cell surface transporter molecules and certain proteins with anti-inflammatory potential in response to Aquamin. Aquamin treatment also led to downregulation of several proteins associated with the pro-inflammatory state. The results presented here suggest that the use of a multi-mineral intervention improves disease-related biomarkers in patients with UC. These studies suggest the potential value of the mineral intervention as a low-cost, non-toxic adjuvant therapy for mild UC or for individuals with UC in remission.

There is an unmet need for novel blood-based biomarkers that offer timely and accurate diagnostic and prognostic testing in inflammatory bowel diseases (IBD). We aimed to investigate the diagnostic and prognostic utility of serum calprotectin (SC) in IBD. A total of 171 patients (n=96 IBD, n=75 non-IBD) were prospectively recruited. A multi-biomarker model was derived using multivariable logistic regression analysis. Cox proportional hazards model was derived to assess the contribution of each variable to disease outcomes. SC correlated strongly with current biomarkers, including fecal calprotectin (FC) (n=50, ρ=0.50, P=1.6 × 10 ). SC was the strongest individual predictor of IBD diagnosis (odds ratio (OR): 9.37 (95% confidence interval (CI): 2.82-34.68), P=4.00 × 10 ) compared with other markers (C-reactive protein (CRP): OR 8.52 (95% CI: 2.75-28.63), P=2.80 × 10 ); albumin: OR 6.12 (95% CI: 1.82-22.16), P=0.004). In a subset of 50 patients with paired SC and FC, the area under receiver operating characteristic discriminating IBD from controls was better for FC than for SC (0.99, (95% CI 0.87-1.00) and 0.87 (95% CI:0.78-0.97), respectively; P=0.01). At follow-up (median 342 days; interquartile range: 88-563), SC predicted treatment escalation and/or surgery in IBD (hazard ratio (HR) 2.7, 95% CI: 1.1-4.9), in particular Crohn's disease (CD) (HR 4.2, 95% CI 1.2-15.3). A model incorporating SC and either CRP or albumin has a positive likelihood ratio of 24.14 for IBD. At 1 year, our prognostic model can predict treatment escalation in IBD in 65% of cases (95% CI: 43-79%) and 80% (95% CI: 31-94%) in CD if ≥2 blood marker criteria are met. A diagnostic and prognostic model that combines SC and other blood-based biomarkers accurately predicts the inflammatory burden in IBD and has the potential to predict disease and its outcomes. Our data warrant further detailed exploration and validation in large multicenter cohorts.

Background/objectivesUlcerative colitis (UC) is an immune-mediated disease that causes inflammation in the gastrointestinal tract. Diet has an important role in the treatment of UC. This study aimed to compare the effects of extra virgin olive oil (EVOO), as a functional food, with canola oil in the treatment of UC.Subjects/methodsForty patients were participating in this crossover clinical trial. Thirty two patients completed two intervention rounds. Blood samples were taken before and after 20 days intervention. Disease activity score and gastrointestinal symptoms were evaluated using the Mayo score and gastrointestinal symptom rating scale (GSRS) respectively.ResultsErythrocyte sedimentation rate (p = 0.03) and high-sensitivity C-reactive protein (p < 0.001) were decreased significantly after EVOO consumption. Bloating, constipation, fecal urgency, incomplete defecation, and final GSRS were reduced significantly after EVOO consumption (p < 0.05).ConclusionsIntake of EVOO decreased the inflammatory markers and improved gastrointestinal symptoms in UC patients. It seems this functional food can be beneficial in the treatment of UC as a complementary medicine.

Objective Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC. Design In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels. Results The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups. Conclusions A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13. Trial registration number ClinicalTrials.gov number NCT01284062.

INTRODUCTION:Patients with inflammatory bowel disease (IBD) are predisposed to the reactivation of viral infections such as cytomegalovirus (CMV). Clinical discrimination of disease flares and colonic CMV reactivation is difficult in patients with established diagnosis of IBD, and there are no reliable noninvasive diagnostic tools yet. Furthermore, the influence of novel therapeutics including biologicals and Janus kinase inhibitors on the risk of CMV colitis is unclear. The goal of this study was to identify risk factors and clinical determinants of CMV colitis that could serve as minimally invasive markers both for active CMV colitis and relapse.METHODS:To this end, a retrospective analysis of 376 patients with suspected or confirmed CMV colitis 2016-2023 was performed.RESULTS:Previous administration of systemic steroids increased the odds of CMV colitis to OR 4.6. Biologicals did not change the incidence of CMV colitis but decreased the OR of a relapse to 0.13. Clinical parameters such as severely bloody diarrhea, intense microscopic ulcerative damage, and decreased serum tryptophan correlated with detection of CMV. Importantly, persistent decrease of tryptophan was observed in patients with CMV relapse. Furthermore, tryptophan degradation through the kynurenine pathway was increased in CMV-positive patients.DISCUSSION:Taken together, we identify decreased serum tryptophan as a novel potential minimally invasive marker to aid identification of IBD patients with active CMV colitis and at high risk for relapse.

Introduction Vitamin D deficiency is common in Paediatric Inflammatory Bowel Disease (PIBD) and has been implicated in disease pathogenesis and disease exacerbation. Current guidelines recommend oral vitamin D supplementation when 25OHD levels are below 50 nmol/L. Supplementation comes in two forms: either a daily supplement of a low dose of vitamin D3 (2000 IU) for several months or a single high dose of oral vitamin D3-termed ‘stoss’ therapy, with no consensus regarding optimum treatment. Methods A randomised controlled trial was conducted in children with a prior diagnosis of PIBD with 25OHD deficiency (< 50 nmol/L), comparing 2000 IU oral D3 daily to a stoss protocol (oral D3 dosage 400,000 IU for 3–12 years of age or 800,000 IU for > 12 years). Children were followed for 12 months, with biochemistry (25OHD, calcium, magnesium, phosphate, parathyroid hormone, haemoglobin, haematocrit, platelets, albumin), stool markers (calprotectin, S100A12), anthropometrics (weight, height, body mass index) as well as clinical disease indices (Paediatric Crohn’s Disease Activity Index, Paediatric Ulcerative Colitis Activity Index) and medication use collected at 3, 6, 9 and 12 months. Results 74 children aged 5–18 years completed the study. Both 2000 IU daily and stoss protocol significantly increased 25OHD from baseline values at 3, 6, 9 and 12 months. One patient randomised to stoss protocol had a 25OHD level of 263 nmol/L with normal serum calcium. There was no difference in biochemical, stool or clinical markers between groups at any time point, nor was there any correlation between 25OHD level and calprotectin or 25OHD level and clinical disease activity scores. Conclusion Stoss protocol was non-inferior to 2000 IU daily vitamin D3 in raising 25OHD levels at 12 months. There was also no difference between 25OHD levels at 3, 6 and 9 months between groups.

Background The optimum dosage for vitamin D supplementation has not yet been elucidated in patients with Ulcerative colitis (UC). The aim of this study was to investigate the effects of two vitamin D regimens in UC patients with vitamin D deficiency. Methods In this double blind randomized clinical trial, 50 patients with mild to moderate UC, who met inclusion criteria, received either 1000 or 2000 IU/day of vitamin D (as low dose or high dose group, respectively) for 12 weeks. Serum 25-hydroxy vitamin D (25-OHD) level, total antioxidant capacity (TAC), and Total Oxidant Status (TOS), the inflammatory bowel disease questionnaire − 9 (IBDQ-9) score and the Simple Clinical Colitis Activity Index Questionnaire (SCCAI) score were assessed before and after intervention. Results At the end of study, serum 25-OHD levels significantly increased in the high dose group ( P  < 0.001) and the increase was significantly more than low dose group (6.7 ± 3.8 ng/mL in the high dose group versus 0.2 ± 0.5 ng/mL in the low dose group) ( P  < 0.001). Serum TOS concentration decreased significantly (− 0.37 ± 0.26) only in the high dose group ( P value = 0.023). There was no statistically significant change in serum TAC between two groups during the study. IBDQ-9 mean score significantly increased in high dose group compared to the low dose group ( P value = 0.001) and SCCAI score in both groups reduced (− 2.58 ± 2.16 and − 0.9 ± 0.3 in high dose and low dose respectively), while this reduction was significant only in the high dose group ( P value ≥0.001). Conclusion Our results indicate that 2000 IU daily dose of vitamin D can increase serum 25-OHD concentration, and quality of life, while it reduces disease activity in UC patients with vitamin D deficiency. We recommend assessment of the vitamin D status in all patients with UC because they may benefit from vitamin D therapy.

Abstract Background We utilized patient samples from the large, phase 2b/3 SELECTION trial to identify circulating biomarkers of ulcerative colitis (UC) and potential early mediators of filgotinib treatment effects. Methods Samples were collected at baseline and during the induction phase of the SELECTION trial. Evaluated biomarkers comprised serum and stool proteins (measured by enzyme-linked immunosorbent assay), whole-blood cell counts, and whole-blood RNA-seq-derived gene-expression factors identified via exploratory factor analysis. Biomarker levels were assessed by baseline disease severity (endoscopy/bleeding/stool and Mayo Clinic Score) and biologic status (naive vs experienced). Effects of filgotinib on biomarker levels, including week 4 biomarker changes that may mediate week 10 clinical improvements, were assessed. Results The biomarker analysis set included 598 biologic-naive patients and 592 biologic-experienced patients. Systemic inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], serum amyloid A [SAA], and platelet cell counts) had the strongest positive correlations with baseline UC disease severity. CRP, IL-6, SAA, and neutrophil activation biomarkers (including neutrophil gelatinase-associated lipocalin [NGAL], tumor necrosis factor ɑ, and oncostatin M [OSM]), as well as platelet, neutrophil, and monocyte cell counts were increased in biologic-experienced versus biologic-naive patients. Gene-expression-derived plasmablast and cell proliferation factors were positively correlated with disease severity; B cell, T-cell activation, and plasmacytoid dendritic cell factors were negatively correlated. Filgotinib reduced nearly all proinflammatory biomarkers correlated with baseline UC disease activity; reduced SAA, CRP, IL-6, NGAL, and OSM at week 4 were identified as mediators of improved week 10 clinical scores. Conclusions Filgotinib significantly impacted circulating biomarkers related to UC pathology. Several proinflammatory and neutrophil activation biomarkers may be early mediators of filgotinib treatment effects. ClinicalTrials.gov identifier NCT02914522 Lay Summary Patient samples from the phase 2b/3 SELECTION trial were utilized to identify circulating biomarkers of ulcerative colitis and potential early mediators of filgotinib treatment effects. Proinflammatory and neutrophil activation biomarkers may be early mediators of clinical improvement with filgotinib treatment.

Hematological parameters were evaluated, proinflammatory immune response indices lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR) were calculated, and iron was detected in tumor tissues by Perls’ staining of histological sections in high (HR) and low resistant (LR) to hypoxia male C57BL/6 mice with colitis-associated colorectal cancer (CAC) induced by intraperitoneal injection of azoxymethane and three cycles of consumption of dextran sulfate sodium. The animals were euthanized on day 141 after azoxymethane administration. The relative number of monocytes in the blood increased in HR mice of the experimental group in comparison with the control group, and was higher than in LR animals. In LR mice with CAC, the relative number of lymphocytes and monocytes, absolute number of monocytes in the blood decreased and the NLR increased in comparison with the control; the LMR was higher than in HR animals. Regardless of hypoxia resistance, the mice developed normocytic hypochromic anemia; iron accumulation in the tumor was observed only in LR animals. The obtained data on more pronounced changes in hematological parameters in LR animals should be taken into account in the development of new approaches to the inflammatory and tumor diseases therapy, including CAC.