Gastroenterology and Hepatology from Bed to Bench

Aim: To evaluate the efficacy and safety of sphingosine-1-phosphate (S1P) receptor modulators in treating ulcerative colitis (UC) and Crohn’s disease (CD).

Background: Inflammatory Bowel Disease (IBD) is a chronic immune-mediated condition that remains challenging to manage. S1P receptor modulators offer a novel therapeutic approach by targeting immune cell trafficking, potentially improving disease outcomes.

Methods: A systematic review and meta-analysis were conducted by searching PubMed, Scopus, and Cochrane Library major electronic databases for randomized controlled trials (RCTs) investigating S1P receptor modulators in IBD. Clinical outcomes assessed included clinical remission, clinical response, endoscopic improvement, histologic remission, and serious adverse events. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using a fixed-effects model.

Results: Seven RCTs with a total of 2,597 patients were included. S1P receptor modulators significantly improved clinical remission (OR = 1.49, 95% CI: 1.21–1.84, p < 0.001), histologic remission (OR = 1.74, 95% CI: 1.31–2.31, p < 0.001), endoscopic improvement (OR = 1.58, 95% CI: 1.23–2.04, p < 0.001), and clinical response (OR = 1.27, 95% CI: 1.05–1.54, p = 0.01). The risk of serious adverse events did not significantly differ between treatment and placebo groups (OR = 1.28, 95% CI: 0.92–1.80, p = 0.14), suggesting a favorable safety profile.

Conclusion: This meta-analysis supports S1P receptor modulators, particularly ozanimod and etrasimod, as effective and safe treatments for UC. Further studies are needed to assess long-term safety and direct comparisons with existing biologic therapies.

Aim: The aim of this study was to systematically review the global epidemiology of Inflammatory Bowel Disease (IBD).

Background: IBD is a global concern, and its incidence is rising worldwide.

Methods: We searched PubMed, Scopus, and Web of Science from 1 January 2000 to 14 July 2022 using MeSH keywords. All population-based studies that reported the incidence or prevalence of IBD, Crohn's disease (CD), or ulcerative colitis (UC) were included. Random effect models were applied to combine the prevalence and incidence.

Results: Findings from 215 studies were analyzed. The global prevalence rates of IBD, CD, and UC were 229.7 per 100,000 (95% confidence interval: 212.4 to 247.0), 84.2 (78.5 to 89.9), and 120.4 (110.5 to 130.3), and the incidence was 9.7 per 100,000 person-years (9.2 to 10.2), 4.0 (3.8 to 4.2), and 5.0 (4.6 to 5.3), respectively. The highest IBD and CD incidence were seen in Oceania (21.3 [12.9 to 29.7] and 12.2 [8.5 to 15.9], respectively), while the highest incidence of UC was reported in North America (9.8 [6.7 to 12.8]). According to the pooled prevalence, Europe had the highest prevalence rates of IBD and UC (348.4 [315.2 to 381.5] and 198.6 [181.6 to 215.6], respectively), whereas Oceania was the continent with the highest CD prevalence (173.6 [151.8 to 195.4]).

Conclusion: Our findings showed that the incidence and prevalence of IBD in both developed and developing nations are mounting. Special focus should be placed on understanding and managing pediatric CD cases, necessitating targeted research and early interventions.

Aim: This review aims to summarize the characteristics of gut microbiota in celiac patients and assess its composition compared to healthy controls.

Background: The gut microbiota influences the regulation of host immunity. Accordingly, alterations in the intestinal microbiota, also known as dysbiosis, have been studied in various gastrointestinal disorders, including celiac disease.

Methods: We conducted a systematic review of available studies over the last decade (2013-2023). The comprehensive search was performed using various academic databases. The selected studies focused on the analysis of gut microbiota from duodenal and/or fecal samples and included both pediatric and adult populations.

Results: Twenty-two articles were included following PRISMA guidelines: nine on fecal microbiota, six on duodenal microbiota, and seven on both. The findings revealed significant differences in bacterial prevalence associated with celiac disease across 17 studies, with celiac patients showing altered microbial diversity characterized by an increase in pathogenic bacteria and a decrease in beneficial bacteria such as Bifidobacterium and Lactobacillus, compared to healthy controls. However, other studies showed no significant distinction between groups of children affected by celiac disease and control groups. Some articles also highlight the effect of a gluten-free diet on the composition of the gut microbiota.

Conclusion: Current data on the composition of the gut microbiome in patients with celiac disease is characterized by considerable heterogeneity and inconsistency. This highlights the need for a thorough and holistic approach to understand better these variations and their impact on the health of people with celiac disease.

Functional gastrointestinal disorders (FGID) are prevalent illnesses associated with diminished quality of life and increased healthcare utilization. These conditions influence gut sensitivity, motility, microbiota, immunological function, and nervous processing in the brain. Chronic symptoms, including pain and dyspepsia, are exacerbated by maladaptive patient behaviors, stress, and co-morbidity. Studies of functional neuroimaging reveal increased brain responses in regions associated with gut sensory processing and salient cues, altered central regulation of endocrine and autonomic nerve responses, and aberrant connections in pain processing and the default mode network. This neuroimaging helps us understand the pathophysiology and outcomes of patients better.  From the standpoint of brain connection, research in this area can further our understanding of the central pathophysiology of FGID and pave the way for the objective diagnosis and development of novel therapeutics for FGID. Prospective Neuroimaging research may change from brain mapping to clinical prognosis prediction due to technological advances in machine learning algorithms used in imaging. The usefulness and revelations of functional brain imaging are highlighted in this review, along with the areas that require development and, lastly, recommendations for future research.

Aim: In this study, global and regional trends between 1990 and 2021 were examined by sex, level of development, and geography, and projected to 2025.

Background: Diarrheal disease continues to be a leading cause of morbidity and mortality in children under the age of five (U5).

Methods: We assessed GBD 2021 data for U5 children in 204 countries, 21 regions, and 7 super-regions with joinpoint regression to analyze time trends, a hybrid ARIMA-ETS-ANN model to project prevalence and mortality until 2025, and longitudinal multilevel modeling to determine the effect of development level. Spatial clustering in 1990 and 2021 was assessed with Local Moran's I.

Results: In 2021, the global prevalence and mortality rates of diarrheal disease among children under five were 885.07 and 51.72 per 100,000 population, respectively. Between 1990 and 2021, global U5 mortality decreased by 80.4%, and prevalence by 71.8%. The heaviest burden remained in Sub-Saharan Africa (SSA) and South Asia (SA), though all super-regions experienced statistically significant decreases. Joinpoint regression across the entire interval (1990–2021) revealed significant overall reductions in mortality (AAPC −5.15; 95% CI: −5.19, −5.10) and prevalence (AAPC −3.98; 95% CI: −4.03, −3.94). Hybrid forecasts predict ongoing decreases through 2025, with prevalence reaching 631.3 and mortality 36.6 per 100,000 population worldwide. Multilevel models revealed steeper annual reductions in low- and medium-Human Development Index (HDI) nations, corroborated by significant time–HDI interaction terms (β=79.76 for prevalence; β=7.50 for mortality; both p<0.001), although such countries had a persisting higher absolute burden. Spatial analysis revealed enduring hotspots in SSA and SA in both 1990 and 2021, and the formation of new clusters in several high-income countries. Coldspots occurred primarily in high-income and island nations.

Conclusion: Significant global advancements have lessened the burden of diarrheal disease in U5 children; yet, ongoing disparities attributed to unsafe water, poor sanitation and hygiene, undernutrition, and low maternal education underscore the necessity for combined water, sanitation, and hygiene interventions, rotavirus immunization, and community-based health education in high-risk areas.

Aim: This study evaluated and compared the success rates of intussusception reduction in children younger under three years of age using colonoscopy versus ultrasound-guided saline enema.

Background: Intussusception involves telescoping one segment of the intestine into another.

Methods: This experimental study included 41 children under three years old who were diagnosed with intussusception via ultrasound and admitted for reduction treatment. Participants were randomly assigned to either the saline enema or colonoscopy intervention. Data analysis was conducted using Chi-square tests and independent T-tests, utilizing SPSS 23.

Results: Among the 41 children, 16 underwent reduction via colonoscopy, achieving a success rate of 81.25% (13 out of 16). In contrast, the saline enema method demonstrated a success rate of 84% (21 out of 25). The difference in success rates between the two methods was not statistically significant. Factors such as gender, age, the location of intussusception (ileocolic vs. colocolic), and the size of the intussusception did not significantly influence the success rates for either approach. Notably, intra-abdominal free fluid was significantly associated with reduced success rates for the saline enema method (P = 0.044). At the same time, no such association was found for the colonoscopy method (P = 0.142). Additionally, the presence of lymphadenopathy between the invaginated segments significantly impacted the success of the saline enema method (P = 0.036) but did not affect colonoscopy outcomes (P = 0.375).

Conclusion: The study concluded that there was no significant difference in the success rates of intussusception reductions between the colonoscopy and saline enema methods. Lymph nodes between invaginated loops and intraperitoneal fluid significantly decrease the success rate of saline enema reductions, suggesting that colonoscopy may be preferable in such cases.  

Aim: This study assessed the prevalence of anti-Hepatitis E Virus (HEV) IgG and IgM antibodies in Solid Organ Transplant (SOT) recipients in Fars Province, southern Iran.

Background: HEV is a common cause of viral hepatitis worldwide. Immunocompromised individuals, particularly SOT recipients, are at risk of chronic HEV infection.

Methods: In this cross-sectional study, 150 serum samples were collected from SOT recipients, including those with liver, kidney, intestinal, or simultaneous pancreas-kidney transplantation. The sera were stored at –20°C and analyzed for anti-HEV IgG and IgM, using a commercial ELISA kit. Data were analyzed, using SPSS.

Results: The mean age of participants was 46.24 ± 15.14 years; with 96 (64%) being male. Anti-HEV IgG antibodies were detected in 53 (35.3%) patients. The prevalence among liver and kidney recipient recipients was 33.3% and 39.2%, respectively (p = 0.63). Anti-HEV IgG seropositivity was significantly associated with older age (p < 0.001) and elevated blood urea nitrogen levels (p = 0.008). No significant associations were observed with other demographic or clinical variables (p > 0.05). All patients tested negative for anti-HEV IgM antibodies.

Conclusion: HEV exposure is relatively common among SOT recipients in southern Iran. The significant association with elevated blood urea nitrogen levels highlights the importance of renal function monitoring in this population.

Aim: This study aimed to assess the impact of a six-week gluten-free diet (GFD) on the iron profiles of patients with non-celiac gluten sensitivity (NCGS) and CD.

Background: Iron-deficiency anaemia (IDA) is a significant clinical feature of gluten-related disorders, especially Celiac disease (CD).

Methods: The study included 29 CD patients (mean age 40.28 ± 15.57 years) and 29 NCGS patients (mean age 30.31 ± 7.78 years) presenting with IDA who were enrolled in the study during 2023-2024. Haemoglobin, serum iron, serum ferritin, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) levels were assessed at the beginning and after six weeks of GFD. HLA typing was conducted using the Real-time PCR-based SYBR Green method.

Results: Ferritin levels significantly increased in both CD and NCGS groups after the GFD, from 43.7807 to 50.5279 ng/mL and 23.0862 to 42.9910 ng/mL, respectively. Moreover, serum iron and TSAT levels significantly increased in the NCGS group, from 64.8034 to 81.3466 μg/dL and 19.29 ± 11.70 to 23.99 ± 9.05, respectively (p = 0.003).

Conclusion: The most frequent symptoms in CD and NCGS patients were bloating/bone disease (62.1%) and bone disease (37.9%), respectively. GFD was effective in improving IDA in both CD and NCGS patients. Further research is necessary to assess the therapeutic effect of GFD in patients with gastrointestinal symptoms and IDA.

Aim: This study reports differential expression of Antisense RNAs (asRNAs) by analyzing transcriptomic profiles in gallbladder cancer (GBC).

Background: asRNAs play crucial roles in developing various tumors. However, the presence and biological mechanism of asRNAs in GBC development are still unknown.

Methods: Differentially expressed asRNAs (DE-asRNAs) were systematically identified from RNA sequencing data \ from ten GBC patients. Functional enrichment analysis was performed, followed by the identification of mRNAs targeted by asRNAs and the construction of a gene regulatory network of asRNAs targeting mRNAs.

Results: Of the 891 asRNAs identified, 17 DE-asRNAs were statistically significant. Out of 17, 12 asRNAs were upregulated, and five asRNAs were downregulated. Functional enrichment analysis showed their role in methylation and developmental processes. Of the 17 asRNAs, 14 are novel (UNC5B-AS1, SLC2A1-AS1, BBOX1-AS1, SOX21-AS1, ELFN1-AS1, TRPM2-AS, DNAH17-AS1, DCST1-AS1, VPS9D1-AS1, MIR1-1HG-AS1, HAND2-AS1, PGM5P4-AS1, PGM5P3-AS1, and MAGI2-AS). Enrichment analysis of asRNAs with target mRNAs showed enrichment in biological regulation and developmental processes involved in the PI3K, p53, apoptosis, and VEGF signaling pathways.

Conclusion: This study identified 14 asRNAs for the first time and showed that asRNAs targeting mRNAs strongly associated with tumor development in GBC through the PI3KCA and TP53 pathways.

Aim: This study investigates drug repurposing as a viable approach identifying existing pharmacological agents that could be applied to NAFLD management.

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent and complex liver condition affecting approximately 25% of the global population, with significant links to metabolic disorders such as obesity and type 2 diabetes. Despite its high burden, no approved therapies currently exist for NAFLD, underscoring the need for effective treatments.

Methods: We utilized two publicly available datasets (GSE126848 and GSE130970) to identify differentially expressed genes (DEGs) and constructed a protein-protein interaction (PPI) network using Cytoscape. Hub and bottleneck (H&B) genes were identified and further analyzed for pathway enrichment using DAVID and KEGG. Drug candidates were identified through the Connectivity Map (CMap) platform, focusing on compounds with counter-gene signatures.

Results: Pathway analysis highlighted critical pathways involved in NAFLD pathogenesis, including the AGE-RAGE and Rap1 signaling pathways. Several promising repurposed drugs, such as WYE-354 and Triciribine, were identified, targeting key mechanisms like lipid metabolism and inflammation.

Conclusion: This study suggests that drug repurposing may accelerate the development of effective NAFLD therapies, although further clinical validation is needed to confirm the therapeutic potential of these findings.

Aim: Given the positive results of some research, this study aimed to explore the relationship between the presence of Helicobacter pylori (HP) in gastric histopathology and the location and grade of tumors in an institutional sample of patients diagnosed with colorectal cancer (CRC).

Background: Epidemiological studies have been conducted to investigate the association between HP infection and CRC.

Methods: This cross-sectional study retrieved data from the hospital database, considering inclusion criteria and medical record availability for patients who underwent both endoscopy and colonoscopy and were diagnosed with CRC. Patients were grouped based on tumor grade and location and compared regarding the presence or absence of HP pathogen in endoscopic biopsy direct smears.

Results: Data from 241 patients were available, 220 of whom had adenocarcinoma. A statistically significant relationship between tumor differentiation grade and HP positivity was observed (P= 0.001). Each 1-level increase in grade was associated with 2.2 times higher odds of HP positivity. No significant relationships existed in the analysis of tumor location related to HP positivity.

Conclusion: In colorectal cancer patients, the presence of the HP pathogen may be linked to a higher likelihood of high-grade colorectal cancers. This finding needs to be explored in screening cohorts.

Aim: Based on studies, E. coli strains producing colibactin are selectively enriched in patients with IBD and CRC. This finding raises the possibility that the mentioned compounds may affect this organism and prompted us to conduct this study.

Background: Currently, vitamin D3 is highly recommended in the therapeutic management of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Similar to 5-Aminosalicylic acid (5-ASA) which is a mainstay in treatment of IBD and prevention of CRC related inflammation, the importance of vitamin D3 is also mainly attributed to a series of known protective effects of this compound, particularly regulation of immune response and gut microbiota.

Methods: The antimicrobial effects of vitamin D3 and 5-ASA against E. coli isolated from patients with CRC, IBD, and healthy individuals were assessed by microdilution broth. The expression of virulence-associated genes (clbN, ompC, chuA and yfgL) in isolates treated with these compounds was tested by real-time PCR.

Results: Neither vitamin D3 nor 5-ASAinhibited bacterial growth at the investigated concentrations. The expression of clbN and ompC significantly decreased in vitamin D3-treated isolates (p= 0.01, p= 0.02, respectively). This downregulation was also significant in isolates from the CRC group in comparison with those from IBD patients and healthy individuals.

Conclusion: Vitamin D3's effect on downregulating colibactin, one of the proposed factors in colon carcinogenesis, highlights another unknown aspect of this multifaceted drug. The inability of both studied compounds to inhibit the growth of E. coli may show their benefit in not disturbing the balance of the microbiota.