Lactobacillus rhamnosus GG Administration Is Associated with Stimulation of Vitamin D/VDR Pathway and Mucosal Microbiota Modulation in Ulcerative Colitis Patients: A Pilot Study

The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases

As it is known, colon carcinogenesis is associated with the inflammatory bowel disease (IBD). Colorectal cancer (CRC) being observed in 5.5-13.5 % of patients with ulcerative colitis (UC) and in 0.4-0.8 % of patients with Crohn disease (CD). The gut mucosa of patients with CD, but not with UC, as well as the stroma of CRC have elevated numbers of CD68(+) macrophages. It is known also that the expression of Fas Ligand (FasL), representing another branch of immunoreactivity, in the lesions of CRC and UC but not of CD is upregulated. The fact that enterocyte apoptosis is increased in lesions of CD and lymphocytes in UC are resistant to Fas-mediated apoptosis can be the keypoint for understanding the hypothesis [17], suggesting that cells express FasL and are able to kill Fas-expressing activated lymphocytes and escape rejection by the immune system, which can be the basis for differences in association of UC and CD with CRC. The aim of this study was to evaluate the number of CD68(+) macrophages and to analyze FasL expression in colon mucosa of patients with UC, CD and CRC in order to assess its value for prognosis of CRC. Expression of CD68 and FasL was analyzed immunohistochemically in the samples of colon mucosa taken from the affected areas of 4 patients with UC, 6 patients with CD and 10 patients with CRC. In addition in 7 CRC patients the samples taken from unaffected areas were analyzed. We find average expression of FasL in both unaffected and affected areas of CRC patients was higher than in CD patients (p = 0.04, p = 0.00). Average expression of FasL in affected areas of CRC patients was higher (p = 0.02) than in UC patients and the same (p = 0.23) as in unaffected areas of CRC patients. The revealed associations support the possibility to use expression of CD68 and FasL as prognostic markers for transformation of IBD to CRC.

BackgroundPatients with inflammatory bowel disease (IBD) who receive biologicals frequently experience lack or loss of response. Our aim was to describe the use and efficacy of biological therapy in a tertiary IBD center.MethodsWe included all bio-naive IBD patients who initiated biological therapy between 2010 and 2020 at our centre. Their medical records were reviewed.ResultsThe population consisted of 327 Crohn’s disease (CD) patients, 291 ulcerative colitis (UC) patients, and 3 patients with IBD unclassified (IBDU). The median follow-up was 3 years (interquartile range = 2–5) after initiating therapy. The annual number of patients initiating biological therapy rose from 29 (2010) to 85 (2019). Most patients (457, 73.6%) received 1 biological drug; 164 (26.4%) patients received 2 or more biologicals. Primary lack of response was observed in 36.4% (106/291) and 17.4% (57/327) of UC and CD patients; loss of response was observed in 27.1% (79/291) and 31.5% (103/327) of UC and CD patients, respectively. The 5-year surgery rates were 26.6% and 20.4% in UC and CD patients, respectively. Multivariate Cox regression showed that treatment with thiopurine reduced the likelihood of needing to switch biological therapy, requiring surgery or corticosteroids in UC patients (HR: 0.745, 95% CI: 0.559–0.993), but not in CD patients (HR: 0.996, 95% CI: 0.736–1.349).ConclusionsThe annual number of IBD patients initiated on biological therapy increased considerably between 2010 and 2020. One-quarter of these patients required surgery after 5 years. Our findings suggest a beneficial effect of concurrent thiopurines for UC patients receiving biologicals, but this was not found for CD patients. This effect in UC patients was not observed when we included patients initiating thiopurines up to 6 months after the introduction of biological therapy.

P-056: Buccal epithelial cell chemokine release as a biomarker for clinical response to therapy in inflammatory bowel disease

Background Due to the increasing prevalence of inflammatory bowel diseases (IBD), an ageing population and the increased risk of cancer associated with IBD, the number of patients diagnosed before or while having their IBD is increasing. We aimed to describe the treatment of IBD patients with a prior malignant diagnosis relative to IBD patients without. Methods Danish national registers were used to identify all incident Crohn’s disease (CD) and Ulcerative Colitis (UC) patients in Denmark, their exposure to drugs and surgeries, and cancer status, between 1996-2022. Cox regressions compared the risk of exposure to medications and the risk of surgery for patients with malignant comorbidity. Results 58,402 incident IBD patients (18,383 CD (31.5%), 40,019 UC (68.5%)) were included and followed for a median of 10 years (IQR: 5, 17 yrs). 2,370 (4.1%) had cancer prior to IBD. Of the remaining 56,032 IBD patients, 4,445 (7.9%) had their first cancer diagnosis after their IBD diagnosis. Anti-TNF therapy was used in 16% (n = 92) of CD patients with cancer prior to IBD and in 41% (n = 6,857) of CD patients without cancer. Anti-TNF was used in 9.0% (n = 161) of UC patients with cancer prior to IBD and in 20% (n = 7,159) of UC patients without cancer. Immunomodulators were used in 27% (n = 159) of CD patients with cancer prior to IBD and in 52% (n = 8,594) of CD patients without cancer. Immunomodulators were used in 12% (n = 220) of UC patients with cancer prior to IBD and in 27% (n = 9,555) UC patients without cancer. Exposure to medical therapy was visualised in Figure 1 Being diagnosed with cancer prior to CD diagnosis was negatively associated with exposure to immunomodulators (p = 0.005), while it increased the risk of receiving no medical treatment compared to CD patients without prior cancer (p < 0.001). The need for surgery was not associated with having cancer prior to CD diagnosis (p = 0.705). In UC patients, a negative association was found for both immunomodulators (p = 0.001) and for receiving no treatment (p < 0.001), while a positive association was found for both anti-TNF (p = 0.027) and anti-integrin therapy (p < 0.001) for UC patients with prior cancer. Prior cancer increased the risk of requiring surgery for UC patients (p < 0.001) Conclusion Patients with cancer prior to IBD were treated differently than patients without prior cancer as they received less immunomodulator therapy and more often received no medical therapy at all. UC patients more often required surgery, while this was not the case for CD patients. This supports the need for an individualised approach to immunosuppressive treatment for IBD patients with cancer.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by persistent inflammation and tissue remodeling. Matrix metalloproteinases (MMPs) play a key role in extracellular matrix degradation, and their dysregulation is implicated in IBD. However, the specific role of membrane-type MMPs (MT-MMPs) in UC remains underexplored. This study investigates the expression of MT-MMPs in UC patients, including new cases and treatment-resistant patients, and evaluates their expression patterns compared to healthy people. Colon biopsy samples were collected from three groups: healthy controls (n = 20), newly diagnosed UC patients (n = 20), and UC patients resistant to standard treatments (n = 20). The mRNA expression levels of MT-MMPs were assessed using quantitative real-time PCR. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic utility of these MT-MMPs. Correlation analysis was also conducted to explore the relationship between MT-MMPs and inflammatory markers (CRP, ESR) and vitamin D levels. Out of 6 members of MT-MMPs, MT2-MMP, and MT5-MMP were significantly downregulated in new cases and resistant UC patients compared to controls (P < 0.0001). ROC analysis demonstrated high sensitivity and specificity for MT2-MMP and MT5-MMP in differentiating UC patients from healthy individuals. Additionally, MT2,5-MMP expression was negatively correlated with CRP, ESR, and vitamin D levels, indicating their possible modulation of systematic inflammation. MT2-MMP and MT5-MMP are downregulated in UC and may serve as diagnostic biomarkers for disease severity. The findings highlight the need for further investigation into their therapeutic potential in modulating inflammation and tissue remodeling in UC.

Ulcerative colitis with low-grade dysplasia

Introduction: Resolvin molecules have anti-inflammatory activity in inflammatory bowel diseases (IBDs). We aimed to evaluate whether serum resolvin D1 (RvD1) and resolvin E1 (RvE1) values can correlate to clinical and laboratory traits of IBDs. Methods: This case-control study included 62 patients with IBDs (32 ulcerative colitis (UC) patients, 30 Crohn’s disease (CD) patients) and 28 healthy controls. The Mayo Clinical scoring system (MCS) was used for the clinical and endoscopic features for UC, and the Crohn's disease activity index was used to assess the disease activity in CD patients. Human RvD1 and RvE1 kits were used for the serum enzyme-linked immunosorbent assay. Results: RvD1 concentrations were significantly lower in UC and CD patients compared to the control group [182.69 (118.24-450.80) ng/L and 342.07 (203.57-989.04) ng/L vs. 353.65 (216.14-1125.40) ng/L respectively, p=0.002]. RvD1 and RvE1 concentrations were higher in UC patients who were in the clinically remission phase than the patients in the activation phase [602.18 (176.13-1181.60) ng/L and 170.37 (113.21-216.21) ng/L, p=0.005 vs. 302.10 (122.18-527.37) ng/L and 74.17 (67.38-122.66) ng/L, p=0.004, respectively]. RvD1 values were higher in UC patients who had inactive endoscopic findings than the patients having active disease [426.11(175.94-891.03 ng/L and 169.62(109.97-202.80) ng/L, p=0.009, respectively]. The ROC (receiver operating characteristic curve) analysis revealed RvD1 and RvE1 levels had considerable diagnostic significances for the increased MCS in UC (AUC=0.809, 95%CI: 0.630-0.988, p&lt;0.001 vs AUC=0.814, 95%CI: 0.637-0.991, p&lt;0.001). Conclusion: Decreased serum RvD1 values might be used as an auxiliary biomarker for the diagnosis and the activity of UC.

BACKGROUND Diverticulitis is a frequent and often serious condition of the colon, with its complexity increasing in the presence of inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC). This study aims to evaluate the impact of IBD on diverticulitis outcomes, focusing on hospitalization rates, surgical interventions, and mortality. METHODS We conducted a retrospective analysis of deidentified, aggregate patient data from the TriNetX research network. We used 122,511 diverticulitis patients, identifying those with concurrent CD or UC. Propensity score matching was employed to ensure balanced baseline characteristics between IBD and non-IBD patients, adjusting for variables such as age, gender, comorbidities (e.g., diabetes, chronic kidney disease), and lifestyle factors (e.g., tobacco and alcohol use). Hospitalization rates were calculated based on admissions directly linked to diverticulitis, as tracked in the dataset without distinguishing specific complications. Colectomy rates (both elective and emergency surgeries) and mortality were also assessed. Kaplan-Meier survival curves and Cox proportional hazards models were used to evaluate time-to-event outcomes, including overall survival. RESULTS Out of the 122,511 patients, 1.4% had UC and 1.1% had CD. Compared to non-IBD patients, who had a hospitalization incidence of 9.2%, IBD patients had a substantially higher rate of 15.4% for UC patients and 12.1% for CD patients (p&amp;lt; 0.001). Additionally, IBD patients had higher rates of colectomy (UC: 3.8%, CD: 4.5%) than non-IBD patients (1.7%; p&amp;lt; 0.001). IBD patients had a significantly higher mortality rate than non-IBD patients, with 5.7% of UC patients and 4.9% of CD patients dying from their illness (p&amp;lt; 0.001). According to Kaplan-Meier analysis, IBD patients had a considerably decreased survival rate (p&amp;lt; 0.001), whereas UC patients had the lowest survival results. CONCLUSION Compared to individuals without IBD, those who have diverticulitis with concomitant IBD—especially UC and CD—had far worse clinical outcomes, including greater rates of hospitalization, colectomy, and death. These findings imply that customized care strategies may be necessary to improve outcomes for diverticulitis in IBD patients, highlighting the need for more monitoring and perhaps more aggressive treatment regimens. This table summarizes baseline characteristics of patients diagnosed with diverticulitis, highlighting differences among those with Crohn’s disease, ulcerative colitis, and non-IBD patients. This forest plot presents hospitalization, colectomy, and mortality rates among patients with inflammatory bowel disease (IBD) with concomitant diverticulitis.

Inflammatory bowel disease, a dysregulated host‐microbiota interaction: Are probiotics a new therapeutic option?

Although psychiatric disturbances and personality features are possibly involved in inflammatory bowel disease, little attention has been given to the potential role of defense mechanisms in the formation, course, or prognosis of the disease. The purpose of the present study was to determine whether certain defense styles and ego mechanisms of defense are associated with inflammatory bowel disease, including both ulcerative colitis and Crohn's disease. Seventy-six consecutive unselected outpatients participated in the study. The sample consisted of 39 patients with Crohn's disease, 33 with ulcerative colitis, and 4 with an intermediate form of inflammatory bowel disease. The Symptom Distress Checklist (SCL-90-R), Defense Style Questionnaire (DSQ), and Hostility and Direction of Hostility Questionnaire (HDHQ) were used. Crohn's disease patients presented a more immature defensive profile than ulcerative colitis patients, using a "maladaptive action" style, as well as "consumption" and "pseudo-altruism" defense mechanisms more often. These differences were statistically significant and they were independent of age, sex, educational level, disease extension, and pharmacologic treatment. A significant positive correlation was also found between disease activity and defensive profiles in both ulcerative colitis and Crohn's disease patients. In contrast, there was no statistically significant difference between ulcerative colitis and Crohn's disease patients in terms of psychiatric symptoms. Crohn's disease patients presented a different and more immature defensive profile than patients with ulcerative colitis. In addition, the more psychologically mature inflammatory bowel disease patients had lower rates of relapses and surgical operations, providing evidence that these aspects of personality are likely to influence the patients' adaptation to the disease.

An imbalance in gut microbiota seems to contribute to the development of chronic inflammatory disorders of the gastrointestinal tract, such as ulcerative colitis (UC). Although it has been suggested that probiotic supplementation is an effective approach to colitis, its effects on intestinal flora and on mucosal cytokine balance have never been explored. To evaluate the effect of Lactobacillus casei (L.casei) DG, a probiotic strain, on colonic-associated microbiota, mucosal cytokine balance, and toll-like receptor (TLR) expression. Twenty-six patients with mild left-sided UC were randomly allocated to one of three groups for an 8-week treatment period: the first group of 7 patients received oral 5-aminosalicylic acid (5-ASA) alone, the second group of 8 patients received oral 5-ASA plus oral L.casei DG, and the third group of 11 patients received oral 5-ASA and rectal L.casei DG. Biopsies were collected from the sigmoid region to culture mucosal-associated microbes and to assess cytokine and TLR messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (RT-PCR). 5-ASA alone or together with oral L.casei DG failed to affect colonic flora and TLR expression in a significant manner, but when coupled with rectally administered L.casei DG, it modified colonic microbiota by increasing Lactobacillus spp. and reducing Enterobacteriaceae. It also significantly reduced TLR-4 and interleukin (IL)-1β mRNA levels and significantly increased mucosal IL-10. Manipulation of mucosal microbiota by L.casei DG and its effects on the mucosal immune system seem to be required to mediate the beneficial activities of probiotics in UC patients.

The aim of the study was to determine the differences in terms of ghrelin presence in the colon between the patients with ulcerative colitis (UC) and control patients. Sixty-one UC and 15 control patients were included in the study. Immunohistochemical staining for ghrelin was investigated in colonic biopsy samples of UC and control patients. UC patients were subdivided into Group A (absence of ghrelin staining) and Group B (presence of staining for ghrelin in biopsy samples). Disease activity scores, laboratory parameters and quantitative ghrelin staining were compared in both groups of UC patients, as well as with the observations in control patients. Cells in colonic mucosa stained for ghrelin were identified in twenty-three (37.7%) UC patients, while this proportion in control patients was 6/15(40%). A significant difference was found between Groups A and B for serum albumin concentration but not for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin concentration or leucocyte count. Mayo score/disease activity index (DAI) for UC were significantly higher in Group A than in Group B (p = 0.03). There were no differences in the amount of colonic ghrelin staining between healthy individuals and UC patients. Colonic ghrelin staining in UC patients seems to be associated with the increased activity of this disease.

We read with great interest the article by Taghavi et al. (1) presenting data on epidemiological factors of inflammatory bowel disease (IBD) in the southern region of Iran. The study included a great number of patients and the data was analyzed retrospectively. First of all, the article demonstrated an overall increase in the incidence rates of both Ulcerative Colitis (UC) and Crohn’s Disease (CD). The study raises several important issues about the presentation of IBD epidemiology and provided some interesting data. First, Taghavi et al. mentioned the female predominance in both UC and CD. In our study, we found male predominance in UC (2) with a rate of 1.4:1 and this finding was compatible with the results of a multicenter IBD epidemiologic survey from Turkey (3). In the mentioned study, male to female ratio was 1.3:1 in both UC and CD groups (3). Secondly, in Taghavi et al. study the mean age was 34.68 ± 1.44 years (range: 8 79 years) in UC patients and 32.97 ± 1.34 years (range: 9 – 80 years) in CD patients. The peak age range was 20 to 29 years for IBD and no second peak was detected (1). In our multicenter study, the mean age was 42.6 ± 14.6 years in UC patients and 37.4 ± 12.8 years in CD patients (3) and two peaks were detected for IBD between 20 to 30 and 50 to 70 years (3). Third, in Iranian population, the frequency of smoking was 5.2% in UC patients and 7.4% in CD patients and no significant correlation was detected between smoking and the type of the disease (1). In Turkish population, the frequency of smoking was 15.5% in UC patients and 49.3% in CD patients, and smoking was obviously more frequent in CD than UC (P < 0.001) (3). In conclusion, IBD is frequently encountered in Turkey and Iran but less seen in North and West Europe. In our region, IBD incidence is gradually increasing by two decades because of the community and physicians’ increased knowledge about IBD, using new diagnostic techniques and also a real increase in the IBD incidence rate. So, health authorities and the researches should properly and professionally focus IBD.

Objective To investigate the role and significance of miRNA-21 in the pathogenesis and development of inflammatory bowel disease (IBD). Methods The expressions of microRNA-21 (miRNA-21) in colonic mucosa and peripheral blood CD4+ T cells were analyzed by fluorescence quantitative polymerase chain reaction (PCR) in 26 patients with active Crohn's disease (CD), 23 patients with active ulcerative colitis (UC) and 19 healthy controls. The relative expression amount of miRNA-21 in colonic mucosal and peripheral blood CD4+ T cells in 11 patients with CD was compared before and after infliximab (IFX) treatment, and its correlation with tumor necrosis factor(TNF)-α was analyzed. t-test was performed for comparison between groups. The correlation between miRNA-21 expression in peripheral blood CD4+ T cells and serum TNF-α was analyzed by Spearman correlation analysis. Results The expression of miRNA-21 in colonic mucosa of CD patients and UC patients was 4.720±0.397 and 4.993±0.415, respectively, which were both higher than that of healthy control group (1.101±0.284), and the differences were statistically significant (t=7.657 and 8.356, both P<0.01). The expression of miRNA-21 in peripheral blood CD4+ T cells of CD patients and UC patients was 3.254±0.323 and 3.450±0.311, which were both higher than that of healthy control group (0.891±0.220), and the differences were statistically significant (t=6.007 and 7.098, both P<0.01). After 12 weeks of IFX treatment, simple endoscopic score for Crohn's disease (SES-CD) of CD patients was 8.019±0.349, which was lower than that before treatment (21.502±1.185), and the difference was statistically significant (t=10.910, P<0.01). The serum TNF-α level was 61.570±6.252, which was lower than that before treatment (173.500±12.670), and the difference was statistically significant (t=7.926, P<0.01). The results of correlation analysis indicated that serum TNF-α level was positively correlated with miRNA-21 expression in peripheral blood CD4+ T cells (r=0.780 4, P<0.01). Conclusions The increasing of miRNA-21 expression in IBD was closely correlated with the serum TNF-α level and severity of inflammation. miRNA-21 might be a new target for IBD treatment. Key words: miRNA-21; Inflammatory bowel diseases; Crohn disease; Colitis, ulcerative