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.

Evaluation of a Standardized Extract Obtained from Cashew Apple (Anacardium occidentale L.) Bagasse in DSS-Induced Mouse Colitis.

Inflammatory bowel diseases (IBD) include Crohn's disease and ulcerative colitis. Several studies relate eating habits to different aspects of IBD, such as progression and worsening of the clinical condition. Therefore, many natural products (NPs) such as polyphenols and carotenoids have been identified as promising agents in supporting IBD. An interesting source for obtaining bioactive NPs is the by-products of the food industry. The present study evaluated the potential beneficial effect of a standardized extract (CAE) obtained from cashew apple bagasse in the dextran sulfate sodium (DSS)-induced ulcerative colitis model in mice. This was the first time that CAE had been evaluated in this experimental model. Chemical evaluation of CAE identified carotenoids (96.28 ± 0.15 mg/100 g), phenolic compounds (37.49 ± 0.64 mg/100 g), and a mixture of anacardic acids (C15:3 = 94.2 ± 0.6 mg/100 g; C15:2 = 108.4 ± 0.1 mg/100 g; C15:1 = 214.8 ± 0.2 mg/100 g). Administration of CAE (500 mg/kg, 4 days, p.o.) after DSS challenge was more effective in delaying disease progression compared with prior treatment (500 mg/kg, 30 days, p.o.), according to the disease activity index. However, no treatment strategy with CAE was able to prevent or inhibit disease progression, since all parameters evaluated (macroscopic, biochemical, and histopathological) in CAE-treated animals were similar to those observed in DSS-challenged animals. Despite the high dose (500 mg/kg), the standardized extract (CAE) did not result in an effective concentration of carotenoids. Furthermore, as some anacardic acids have been reported as histone acetyltransferases inhibitors, there could be a possible antagonistic relationship between carotenoids and anacardic acids. Complementary research will be necessary to test the hypothesis of antagonism. Thus, an optimized extract, with an even higher concentration of carotenoids, obtained from cashew apple bagasse, can be developed as a possible adjuvant food supplement for inflammatory bowel diseases.

Dietary intervention with avocado (Persea americana Mill.) ameliorates intestinal inflammation induced by TNBS in rats.

Nutritional interventions have been shown to be an interesting approach for the treatment of chronic diseases, including inflammatory bowel disease (IBD). Persea americana Mill. (avocado), is a potential food to be used for the prevention or treatment of intestinal inflammation, due to its nutritional value and pharmacological effects. In this study we evaluated if the dietary intervention with avocado fruit pulp could as an intestinal anti-inflammatory diet using a trinitrobenzenesulfonic acid (TNBS) model of intestinal inflammation in rats. For this purpose, 5, 10 or 20% of avocado fruit pulp was incorporated in the diet of rats, for 21 days before and 7 days after TNBS-induced intestinal inflammation. Dietary intervention with avocado fruit pulp (20%) decreased the extension of colonic lesions (1.38 ± 0.99 vs. 2.67 ± 0.76 cm), weight/length colon ratio (151.03 ± 31.45 vs. 197.39 ± 49.48 cm), inhibited myeloperoxidase activity (891.2 ± 243.2 vs 1603 ± 158.2 U/g), reduced tumor necrosis factor-α (53.94 ± 6.45 vs. 114.9 ± 6.21 pg/mg), interleukin-1ß (583.6 ± 106.2 vs. 1259 ± 81.68 pg/mg) and interferon gamma (27.95 ± 2.97 vs. 47.79 ± 3.51 pg/mg) levels and prevented colonic glutathione depletion (2585 ± 77.2 vs 1778 ± 167.2 nmol/g). The consumption of enriched diet with 20% avocado pulp by 28 days did not promote any alterations in the biochemical or behavioral parameters evaluated. Avocado showed intestinal anti-inflammatory activity, modulating immune response, and acting as antioxidant. The dietary intervention with avocado was safe, suggesting its potential as a complementary treatment in intestinal inflammation.

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.

Gastrointestinal effects of Mentha aquatica L. essential oil.

Found in humid regions and waterways and popularly used to treat gastrointestinal problems among other applications, the present study evaluated the M. aquatica essential oil (OEMa) as a therapeutic alternative to treat gastrointestinal disorders. Produced by steam distillation, chemical composition of OEMa was determined by GC-MS analysis. The ethanol-induced ulcer and the dose-repeated acetylsalicylic acid (ASA)-induced gastrointestinal lesions models in rats evaluated, respectively, the prophylactic and curative effects of EOMa on peptic ulcers. The EOMa's effect on gastric secretion, gastric mucus and gastrointestinal motility were evaluated in in vivo models. The curative effect of EOMa on acute colitis was evaluated using the DSS-induced colitis model in mice. Obtained in 0.17% yield (w/w), with carvone (54.82 ± 1.39 g/100 g oil) as the main constituent, EOMa (at 75 mg/kg) showed potent gastroprotective effect (> 90%) mediated by non-protein sulfhydryl compounds (NPSH) and nitric oxide (NO) modulation alongside reduction in gastric secretion volume and total acidity. EOMa did not affect gastric mucus production and gastrointestinal motility. In dose-repeated ASA-induced gastrointestinal lesions model, EOMa (at 25 mg/kg) promoted the inflammatory process resolution both in gastric and duodenal walls by modulating NPSH, NO and myeloperoxidase levels. Despite delaying in 2 days the clinical symptoms worsening, EOMa (at 25 mg/kg) was not able to protect colon tissues from DSS-induced acute colitis as evidenced by macroscopic, biochemical, and histopathological parameters. This is the first report of Mentha aquatica essential oil as a promising herbal medicine for peptic ulcers treatment together with an adjuvant effect in IBD.

Spilanthol, the Principal Alkylamide from Acmella oleracea, Attenuates 5-Fluorouracil-Induced Intestinal Mucositis in Mice.

Mucositis is one of the commonest side effects in cancer patients undergoing treatment with radiotherapy and/or chemotherapy, and it currently lacks appropriate and effective treatment. Acmella oleracea, a species of flowering herb from South America, contains spilanthol, an alkylamide that has several pharmacological properties, including anesthetic, analgesic, and anti-inflammatory activities. Therefore, the purpose of this work was to evaluate the effect of spilanthol in intestinal mucositis in Swiss mice induced by 5-fluorouracil (5-FU), an antineoplastic agent administered systemically for the treatment of many different cancers. The repeated administration of 5-FU resulted in intestinal mucositis and consequent decreased food intake, together with weight loss, in all the animals. Daily administration of spilanthol significantly lowered the severity of intestinal mucositis, reducing histopathological changes and increasing the villus height in the animals treated with spilanthol at a dosage of 30 mg/kg (p < 0.0044) compared to a group exposed only to 5-FU. A decrease of myeloperoxidase activity was also observed in the animals treated with 30 mg/kg of spilanthol (p < 0.05), although several pro-inflammatory cytokines were not quantifiable in any group. In conclusion, the data demonstrated that spilanthol effectively reduced inflammation in a mouse model of intestinal mucositis induced by 5-FU, and that the compound might be a promising therapeutic candidate for the prevention and treatment of this condition.

4-methylesculetin, a coumarin derivative, ameliorates dextran sulfate sodium-induced intestinal inflammation.

4-methylesculetin is one of the coumarin derivatives with great anti-oxidant and anti-inflammatory activities. Recent studies have shown that 4-methylesculetin has a promising potentiality to treat inflammatory diseases, especially those related to reactive oxygen species, as inflammatory bowel disease. Based on this, the present study aims to investigate the intestinal anti-inflammatory activity of 4-methylesculetin in dextran sulfate sodium (DSS) model. For this purpose, mice received DSS 5% for 5 days followed by 2 days of filtered tap water. Treated groups received orally 5 or 25 mg/kg of 4-methylesculetin daily since the first day. Macroscopic, microscopic and biochemical parameters were evaluated. 4-methylesculetin (25 mg/kg) improved microscopic parameters, decreased MPO activity, reduced the colonic levels of IL-6 and counteracted GSH depletion when compared with DSS-control group. Our results show the intestinal anti-inflammatory activity of 4-methylesculetin in DSS model, which is related to its antioxidant and anti-inflammatory properties. This way, 4-methylesculetin, is a new potential compound for treatment of both types of IBD.