MicroRNAs in inflammatory bowel disease: What do we know and what can we expect?

MicroRNAs (miRNAs), small non-coding RNAs composed of 18-24 nucleotides, are potent regulators of gene expression, contributing to the regulation of more than 30% of protein-coding genes. Considering that miRNAs are regulators of inflammatory pathways and the differentiation of intestinal epithelial cells, there is an interest in exploring their importance in inflammatory bowel disease (IBD). IBD is a chronic and multifactorial disease of the gastrointestinal tract; the main forms are Crohn's disease and ulcerative colitis. Several studies have investigated the dysregulated expression of miRNAs in IBD, demonstrating their important roles as regulators and potential biomarkers of this disease. This editorial presents what is known and what is expected regarding miRNAs in IBD. Although the important regulatory roles of miRNAs in IBD are clearly established, biomarkers for IBD that can be applied in clinical practice are lacking, emphasizing the importance of further studies. Discoveries regarding the influence of miRNAs on the inflammatory process and the exploration of their role in gene regulation are expected to provide a basis for the use of miRNAs not only as potent biomarkers in IBD but also as therapeutic targets for the control of inflammatory processes in personalized medicine.

Acute heart failure as an adverse event of tumor necrosis factor inhibitor therapy in inflammatory bowel disease: A review of the literature.

Tumor necrosis factor inhibitors (anti-TNFs) are widely used therapies for the treatment of inflammatory bowel diseases (IBD); however, their administration is not risk-free. Heart failure (HF), although rare, is a potential adverse event related to administration of these medications. However, the exact mechanism of development of HF remains obscure. TNFα is found in both healthy and damaged hearts. Its effects are concentration- and receptor-dependent, promoting either cardio-protection or cardiomyocyte apoptosis. Experimental rat models with TNFα receptor knockout showed increased survival rates, less reactive oxygen species formation, and improved diastolic left ventricle pressure. However, clinical trials employing anti-TNF therapy to treat HF had disappointing results, suggesting abolishment of the cardioprotective properties of TNFα, making cardiomyocytes susceptible to apoptosis and oxidation. Thus, patients with IBD who have risk factors should be screened for HF before initiating anti-TNF therapy. This review aims to discuss adverse events associated with the administration of anti-TNF therapy, with a focus on HF, and propose some approaches to avoid cardiac adverse events in patients with IBD.

Intestinal Microbiota and miRNA in IBD: A Narrative Review about Discoveries and Perspectives for the Future.

Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC) and comprises a chronic gastrointestinal tract disorder characterized by hyperactive and dysregulated immune responses to environmental factors, including gut microbiota and dietary components. An imbalance of the intestinal microbiota may contribute to the development and/or worsening of the inflammatory process. MicroRNAs (miRNAs) have been associated with various physiological processes, such as cell development and proliferation, apoptosis, and cancer. In addition, they play an important role in inflammatory processes, acting in the regulation of pro- and anti-inflammatory pathways. Differences in the profiles of miRNAs may represent a useful tool in the diagnosis of UC and CD and as a prognostic marker in both diseases. The relationship between miRNAs and the intestinal microbiota is not completely elucidated, but recently this topic has gained prominence and has become the target of several studies that demonstrate the role of miRNAs in the modulation of the intestinal microbiota and induction of dysbiosis; the microbiota, in turn, can regulate the expression of miRNAs and, consequently, alter the intestinal homeostasis. Therefore, this review aims to describe the interaction between the intestinal microbiota and miRNAs in IBD, recent discoveries, and perspectives for the future.

Gut microbiota, inflammatory bowel disease and colorectal cancer.

The gut microbiota is a complex community of microorganisms that inhabit the digestive tracts of humans, living in symbiosis with the host. Dysbiosis, characterized by an imbalance between the beneficial and opportunistic gut microbiota, is associated with several gastrointestinal disorders, such as irritable bowel syndrome (IBS); inflammatory bowel disease (IBD), represented by ulcerative colitis and Crohn's disease; and colorectal cancer (CRC). Dysbiosis can disrupt the mucosal barrier, resulting in perpetuation of inflammation and carcinogenesis. The increase in some specific groups of harmful bacteria, such as Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF), has been associated with chronic tissue inflammation and the release of pro-inflammatory and carcinogenic mediators, increasing the chance of developing CRC, following the inflammation-dysplasia-cancer sequence in IBD patients. Therefore, the aim of the present review was to analyze the correlation between changes in the gut microbiota and the development and maintenance of IBD, CRC, and IBD-associated CRC. Patients with IBD and CRC have shown reduced bacterial diversity and abundance compared to healthy individuals, with enrichment of Firmicute sand Bacteroidetes. Specific bacteria are also associated with the onset and progression of CRC, such as Fusobacterium nucleatum, E. coli, Enterococcus faecalis, Streptococcus gallolyticus, and ETBF. Future research can evaluate the advantages of modulating the gut microbiota as preventive measures in CRC high-risk patients, directly affecting the prognosis of the disease and the quality of life of patients.

MicroRNAs expression influence in ulcerative colitis and Crohn's disease: A pilot study for the identification of diagnostic biomarkers.

BACKGROUND: Inflammatory bowel disease (IBD) comprises two distinct diseases, Crohn's disease (CD) and ulcerative colitis (UC), both of which are chronic, relapsing inflammatory disorders of the gastrointestinal tract with a mostly unknown etiology. The incidence and prevalence of IBD are continually increasing, indicating the need for further studies to investigate the genetic determinants of these diseases. Since microRNAs (miRNAs) regulate protein translation via complementary binding to mRNA, discovering differentially expressed miRNAs (DE) in UC or CD patients could be important for diagnostic biomarker identification, assisting in the appropriate disease differentiation progressing the understanding of IBD pathogenesis. AIM: To determine the miRNA expression profile in UC and CD patients and the potential pathophysiological contributions of differentially expressed miRNA. METHODS: A total of 20 formalin-fixed paraffin-embedded colonic samples were collected from the Pathology Department of Botucatu Medical School at São Paulo State University (Unesp). The diagnosis of UC or CD was based on clinical, endoscopic, radiologic, and histological criteria and confirmed by histopathological analysis at the time of selection. The TaqMan™ Array Human MicroRNA A+B Cards Set v3.0 (Applied Biosystems™) platform was used to analyze 754 miRNAs. Targets of DE-miRNAs were predicted using miRNA Data Integration Portal (mirDIP) and the miRNA Target Interaction database (MiRTarBase). All statistical analyses were conducted using GraphPad Prism software. Parametric and nonparametric data were analyzed using t-tests and Mann-Whitney U tests, respectively. RESULTS: The results showed that of the 754 miRNAs that were initially evaluated, 643 miRNAs were found to be expressed in at least five of the patients who were diagnosed with either CD or UC; the remaining 111 miRNAs were not considered to be expressed in these patients. The expression levels of 28 miRNAs were significantly different between the CD and UC patients (P ≤ 0.05); 13 miRNAs demonstrated a fold-change in expression level greater than 1. Five miRNAs with a downregulated expression were selected for enrichment analysis. The miRNAs whose expression levels were significantly lower in UC patients than in CD patients were enriched in certain signaling pathways that were mostly correlated with cancer-related processes and respective biomarkers. CONCLUSION: MiRNAs could be used to differentiate UC from CD, and differently expressed miRNAs could help explain the distinct pathophysiology of each disease.

MicroRNA expression in inflammatory bowel disease-associated colorectal cancer.

MicroRNAs (miRNAs) are non-coding RNA molecules composed of 19-25 nucleotides that regulate gene expression and play a central role in the regulation of several immune-mediated disorders, including inflammatory bowel diseases (IBD). IBD, represented by ulcerative colitis and Crohn's disease, is characterized by chronic intestinal inflammation associated with an increased risk of colorectal cancer (CRC). CRC is one of the most prevalent tumors in the world, and its main risk factors are obesity, physical inactivity, smoking, alcoholism, advanced age, and some eating habits, in addition to chronic intestinal inflammatory processes and the use of immunosuppressants administered to IBD patients. Recent studies have identified miRNAs associated with an increased risk of developing CRC in this population. The identification of miRNAs involved in this tumorigenic process could be useful to stratify cancer risk development for patients with IBD and to monitor and assess prognosis. Thus, the present review aimed to summarize the role of miRNAs as biomarkers for the diagnosis and prognosis of IBD-associated CRC. In the future, therapies based on miRNA modulation could be used both in clinical practice to achieve remission of the disease and restore the quality of life for patients with IBD, and to identify the patients with IBD at high risk for tumor development.

Intestinal anti-inflammatory activity of Ground Cherry (Physalis angulata L.) standardized CO2 phytopharmaceutical preparation.

AIM: To investigate the effects of Ground Cherry (Physalis angulata L.) standardized supercritical CO2 extract in trinitrobenzenesulphonic acid (TNBS) model of rat intestinal inflammation. METHODS: The animals were divided into groups that received vehicle or P. angulata extract (PACO2) orally at the doses 25, 50 and 100 mg/kg daily by 5 d before TNBS damage. Protective effects of PACO2 were assessed by macroscopic analysis, biochemical determinations of the levels of myeloperoxidase (MPO), alkaline phosphatase (ALP), glutathione and cytokines (such as INF-γ, IL-1ß, IL-6, IL-10 and TNF-α), gene expression evaluation (including Hsp70, heparanase, NF-κB, mitogen-activated protein kinases (Mapk) 1, 3, 6 and 9, and the mucins genes Muc 1, 2, 3 and 4) and histopathological studies using optical, and electronic (transmission and scanning) microscopy. RESULTS: PACO2 extract promoted a significant reduction in MPO and ALP activities, reducing oxidative stress and neutrophil infiltration. These effects were accompanied by significant reduction of colonic levels of IFN-γ and IL-6 and down-regulation of heparanase, Hsp70, Mapk3, Mapk9, Muc1 and Muc2 genes expression when compared with TNBS-control animals. In addition, protective effects were also evidenced by reduced neutrophil infiltration, recovery of cell architecture and replacement of mucin by histopathological and ultrastructural analysis. CONCLUSION: Physalis angulata supercritical CO2 extract is an intestinal anti-inflammatory product that modulates oxidative stress, immune response and expression of inflammatory mediators, with potentially utility for treating inflammatory bowel disease.

Experimental evidence of MAP kinase gene expression on the response of intestinal anti-inflammatory drugs.

AIM: The etiopathogenesis of inflammatory bowel disease (IBD) is unclear and further understanding of the mechanisms that regulate intestinal barrier integrity and function could give insight into its pathophysiology and mode of action of current drugs used to treat human IBD. Therefore, we investigated how intestinal inflammation affects Map kinase gene expression in rats, and if current intestinal anti-inflammatory drugs (sulphasalazine, prednisolone and azathioprine) act on these expressions. MATERIAL AND METHODS: Macroscopic parameters of lesion, biochemical markers (myeloperoxidase, alkaline phosphatase and glutathione), gene expression of 13Map kinases, and histologic evaluations (optic, electronic scanning and transmission microscopy) were performed in rats with colonic inflammation induced by trinitrobenzenesulphonic (TNBS) acid. KEY FINDINGS: The colonic inflammation was characterized by a significant increase in the expression of Mapk1, Mapk3 and Mapk9 accompanied by a significant reduction in the expression ofMapk6. Alterations inMapk expression induced by TNBS were differentially counteracted after treatment with sulphasalazine, prednisolone and azathioprine. Protective effects were also related to the significant reduction of oxidative stress, which was related to increase Mapk1/3 expressions, which were reduced after pharmacological treatment. SIGNIFICANCE: Mapk1, Mapk3,Mapk6 and Mapk9 gene expressionswere affected by colonic inflammation induced by TNBS in rats and counteracted by sulphasalazine, prednisolone and azathioprine treatments, suggesting that these genes participate in the pharmacological response produced for these drugs.