Treatment Of Intestinal Inflammatory Diseases Research Articles

Effects of Kalimeris indica (L.) Sch Bip on colitis-associated colorectal cancer.

Kalimeris indica (L.) Sch Bip (K. indica) is a plant of the genus Kalimeris in Asteraceae, and its whole herb can be used as medicine for the treatment of intestinal inflammatory diseases. But the mechanism is not clear. Therefore, this study was designed to explore the mechanism of K. indica (KI) in colitis-associated colorectal cancer. The expression levels of miR-31-5p and proinflammatory factors were detected using THP-1 and Caco2 cells in vitro. KI could rescue the upregulation of miR-31-5p induced by IL-6 and TNF-α in Caco2 and THP-1 cells. In LPS-stimulated PMA-differentiated THP-1 cells, KI restored miR-31-5p expression by downregulating the expression of IL-6 and TNF-α. C57BL/6 mice were used to construct CAC model through the induction of azoxymethane/dextran sulfate sodium. The successfully established CAC mice were treated with water extract of KI through intragastric administration for 5weeks. The result showed that KI could significantly reduce the atypical hyperplasia in colon tissue, and inhibit the expression of proinflammatory factors such as IL-6, TNF, IL-11, IL-7, etc. At the same time, KI could restore the level of miR-31-5p in mice, and therefore the downstream LATS2 to inhibit the development of CAC. These above results indicate that KI is a potentially effective herb medicine to prevent CAC.

Pectic polysaccharides from Aconitum carmichaelii leaves protects against DSS-induced ulcerative colitis in mice through modulations of metabolism and microbiota composition

The industrial processing of Aconitum carmichaelii roots for use in Traditional Chinese Medicine generates a high amount of waste material, especially leaves. An acidic polysaccharide fraction isolated from these unutilized leaves, AL-I, was in our previous work shown to contain pectic polysaccharides. This study aimed to investigate the protective effect of AL-I on ulcerative colitis for the possible application of A. carmichaelii leaves in the treatment of intestinal inflammatory diseases. AL-I was found to alleviate symptoms and colonic pathological injury in colitis mice, and ameliorate the levels of inflammatory indices in serum and colon. The production of short- and branched-chain fatty acids was also restored by AL-I. The observed protective effect could be due to the inhibition of NOD1 and TLR4 activation, the promotion of gene transcription of tight-junction proteins, and the modulation of gut microbiota composition like Bacteroides, Dubosiella, Alistipes and Prevotella,. A regulation of serum metabolomic profiles being relevant to the bacterial change, such as D-mannose 6-phosphate, D-erythrose 4-phosphate and uric acid, was also observed.

Regulation of intestinal immunity by dietary fatty acids.

Dietary fatty acids are absorbed through the intestine and are fundamental for cellular energy provision and structural formation. Dietary fatty acids profoundly affect intestinal immunity and influence the development and progression of inflammatory bowel disease, intestinal infections and tumors. Although different types of fatty acids exert differential roles in intestinal immunity, a western diet, rich in saturated fatty acids with abundant carbohydrates and studied as high-fat diet (HFD) in animal experiments, disturbs intestinal homeostasis and plays a pathogenic role in intestinal inflammatory diseases. Here, we review recent findings on the regulation of intestinal immunity by dietary fatty acids, focusing on HFD. We summarize HFD-altered immune responses leading to susceptibility to intestinal pathology and dissect the mechanisms involving the impact of HFD on immune cells, intestinal epithelial cells and the microbiota. Understanding the perturbation of intestinal immunity by HFD will provide new strategies for prevention and treatment of intestinal inflammatory diseases.

Dietary supplements for intestinal inflammation.

Intestinal inflammation leads to various chronic diseases, collectively known as inflammatory bowel disease (IBD). IBD mainly affects the large intestine, but it can also affect the gastrointestinal tract as a whole. Its major symptoms are pain, diarrhea, and weight loss, and it is usually associated with deficiencies of both macro- and micronutrients. Unluckily, after some time the body develops resistance against the already available drugs: thus, many patients fail to maintain remission, which is achieved in less than 50% of cases. Diet is a major determinant of gut inflammation. An unbalanced diet can affect the gut microbiota and cause dysbiosis, which is related to a dysregulated host immune response. The Mediterranean Diet its renowned for its anti-inflammatory effects and for preventing dysbiosis. In order to improve management and treatment of intestinal inflammatory diseases, it should become common practice to integrate the patient's diet with dietary supplements with anti-inflammatory effects (probiotics, butyrate, phosphatidylcholine, lactoferrin, palmitoylethanolamide, silymarin, and omega 3), which maintain the stability of the intestinal microbial cohort and strengthen the mucosal barrier, thus preventing or soothing IBD symptoms. Dietary supplements may help fight the high costs, the adverse side effects, and the recurrent relapses typical of drug use.

Regulation of ILC3/Th17-Mediated Intestinal Immune Response by Circadian Rhythm

The circadian rhythm is a widely-recognized phenomenon, according to which the life activities of organisms change periodically, synchronizing with the day and night cycles. The activities of the immune system are also regulated by the circadian rhythm. Group 3 innate lymphoid cells (ILC3s) and T helper 17 (Th17) cells (ILC3/Th17) are the innate and adaptive subsets of immune cells mediating type 17 immune response, which is featured by the expression of transcription factor retinoid orphan receptor gamma t (RORγt) and the production of interleukin (IL)-17 and IL-22. The processes of type 17 immune response are completed mainly through the participation of ILC3/Th17 and are closely associated with the intestinal immune response. Recent studies have found that the immune response mediated by ILC3/Th17 is intricately regulated by the circadian rhythm through molecular mechanisms controlling the circadian rhythm, or through other external factors that change according to the light-darkness cycle, for example the food intake rhythm. The secretion of cytokines changes along with the regulatory effect of circadian rhythm on ILC3/Th17, which in turn impacts, to a certain degree, on the onset and development of intestinal inflammatory diseases, including bacterial infection and autoimmune diseases. The understanding of mechanisms regulating ILC3/Th17 responses by the circadian rhythm may promote better understanding of the course of action of the immune system and facilitate the development and discovery of potential targets for treatment of intestinal inflammatory diseases.

The potential of Akkermansia muciniphila in inflammatory bowel disease.

Akkermansia muciniphila is a next-generation probiotic with significant application prospects. The role of A. muciniphila in metabolic diseases and tumor immunotherapy has been widely recognized. Recent clinical trials further confirmed its safety and therapeutic value in human metabolic diseases. A. muciniphila also shows potential in the treatment of intestinal inflammatory diseases, especially for inflammatory bowel disease (IBD). The improvement in the efficacy of washed microbiota transplantation (WMT) in treating IBD is closely related to the increase in the abundance of A. muciniphila in patients' gut. However, there is still controversy regarding the pro-inflammatory or anti-inflammatory effect of A. muciniphila on IBD. Currently, several studies targeting the correlation between A. muciniphila and IBD have demonstrated opposite conclusions. Similarly, the interventional studies exploring causality between them also come to conflicting results. This article therefore aims to review the relationship between A. muciniphila and IBD, the effect of intervention of A. muciniphila on IBD, and the possible reasons for the contradictory role of A. muciniphila in the treatment of IBD. KEY POINTS: The effect of A. muciniphila on inflammatory bowel disease is controversy. A. muciniphila shows anti-inflammatory potential in IBD. The colitogenicity of A. muciniphila is context dependent.

Roles of Macrophages in the Development and Treatment of Gut Inflammation.

Macrophages, which are functional plasticity cells, have the ability to phagocytize and digest foreign substances and acquire pro-(M1-like) or anti-inflammatory (M2-like) phenotypes according to their microenvironment. The large number of macrophages in the intestinal tract, play a significant role in maintaining the homeostasis of microorganisms on the surface of the intestinal mucosa and in the continuous renewal of intestinal epithelial cells. They are not only responsible for innate immunity, but also participate in the development of intestinal inflammation. A clear understanding of the function of macrophages, as well as their role in pathogens and inflammatory response, will delineate the next steps in the treatment of intestinal inflammatory diseases. In this review, we discuss the origin and development of macrophages and their role in the intestinal inflammatory response or infection. In addition, the effects of macrophages in the occurrence and development of inflammatory bowel disease (IBD), and their role in inducing fibrosis, activating T cells, reducing colitis, and treating intestinal inflammation were also reviewed in this paper.

Probiotic Escherichia coli Nissle 1917-derived outer membrane vesicles enhance immunomodulation and antimicrobial activity in RAW264.7 macrophages

BackgroundProbiotic Escherichia coli Nissle 1917 (EcN) has been widely studied for the treatment of intestinal inflammatory diseases and infectious diarrhea, but the mechanisms by which they communicate with the host are not well-known. Outer membrane vesicles (OMVs) are produced by Gram-negative bacteria and deliver microbial molecules to distant target cells in the host, which play a very important role in mediating bacteria-host communication. Here, we aimed to investigate whether EcN-derived OMVs (EcN_OMVs) could mediate immune regulation in macrophages.ResultsIn this study, after the characterization of EcN_OMVs using electron microscopy, nanoparticle tracking and proteomic analyses, we demonstrated by confocal fluorescence microscopy that EcN_OMVs could be internalized by RAW 264.7 macrophages. Stimulation with EcN_OMVs at appropriate concentrations promoted proliferation, immune-related enzymatic activities and phagocytic functions of RAW264.7 cells. Moreover, EcN_OMVs induced more anti-inflammatory responses (IL-10) than pro-inflammatory responses (IL-6 and TNF-α) in vitro, and also modulated the production of Th1-polarizing cytokine (IL-12) and Th2-polarizing cytokine (IL-4). Treatments with EcN_OMVs effectively improved the antibacterial activity of RAW 264.7 macrophages.ConclusionsThese findings indicated that EcN_OMVs could modulate the functions of the host immune cells, which will enrich the existing body of knowledge of EVs as an important mechanism for the communication of probiotics with their hosts.

Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway.

Alpha-ketoglutarate (AKG) is a critical nutritional factor in the maintenance of intestinal homeostasis. However, the relative mechanism of AKG has not been well understood. It was recently shown that the interaction between nuclear factor kappa B (NF-κB)-mediated inflammatory pathway and pregnane X receptor (PXR)-regulated detoxification pathway is a check and balance mechanism for keeping the homeostatic state of the intestine, preventing the onset of intestinal inflammation which may lead to cancer. In the current study we used lipopolysaccharide (LPS)-challenged piglet and intestinal porcine epithelial cells-J2 models to investigate the effects of dietary AKG supplementation on the intestinal immune system and PXR regulated target expression. We found that LPS induced significant activation of the NF-κB-mediated inflammatory pathway with concomitant impairment of intestinal nutrient absorption. AKG administration increased intracellular AKG and its metabolite concentrations and enhanced the mRNA expression of alpha-ketoglutarate dehydrogenase in vivo and in vitro. Thus dietary AKG supplementation reversed the adverse effects induced by LPS. We also found a strong inhibitory effects on the NF-κB-mediated inflammatory pathway, especially, in the AKG-treated intestinal tissues, LPS-induced NF-κB phosphorylation was inhibited and TNF-α was suppressed. Interestingly, AKG has potent effects in regulating the PXR and its downstream targets such as CYP3As and CYP2Bs in vivo and in vitro, although AKG is not a known PXR ligand. One potential mechanism for the up-regulation of the PXR pathway is through the down-regulation of NF-κB pathway which in turn de-represses the PXR-regulated target expression. Taken together, our results suggest that AKG improves intestinal immune system through modulating the interaction between PXR and NF-κB. Our findings have important implications for the prevention and treatment of intestinal inflammatory diseases in neonates.

Comparative evaluation of the course, diagnostics and treatment of intestinal inflammatory diseases in Nizhny Novgorod Region in 2014–2015 and 2009-2010

Comparative evaluation of the course, diagnostics and treatment of intestinal inflammatory diseases in Nizhny Novgorod Region in 2014–2015 and 2009-2010

Abnormal cannabidiol attenuates experimental colitis in mice, promotes wound healing and inhibits neutrophil recruitment.

BackgroundNon-psychotropic atypical cannabinoids have therapeutic potential in a variety of inflammatory conditions including those of the gastrointestinal tract. Here we examined the effects of the atypical cannabinoid abnormal cannabidiol (Abn-CBD) on wound healing, inflammatory cell recruitment and colitis in mice.MethodsColitis was induced in CD1 mice by a single intrarectal administration of trinitrobenzene sulfonic acid (TNBS, 4 mg/100 μl in 30 % ethanol) and Abn-CBD and/or the antagonists O-1918 (Abd-CBD), AM251 (CB1 receptor) and AM630 (CB2 receptor), were administered intraperitoneally (all 5 mg/kg, twice daily for 3 days). The degree of colitis was assessed macro- and microscopically and tissue myeloperoxidase activity was determined. The effects of Abn-CBD on wound healing of endothelial and epithelial cells (LoVo) were assessed in a scratch injury assay. Human neutrophils were employed in Transwell assays or perfused over human umbilical vein endothelial cells (HUVEC) to study the effect of Abn-CBD on neutrophil accumulation and transmigration.ResultsTNBS-induced colitis was attenuated by treatment with Abn-CBD. Histological, macroscopic colitis scores and tissue myeloperoxidase activity were significantly reduced. These effects were inhibited by O-1918, but not by AM630, and only in part by AM251. Wound healing of both HUVEC and LoVo cells was enhanced by Abn-CBD. Abn-CBD inhibited neutrophil migration towards IL-8, and dose-dependently inhibited accumulation of neutrophils on HUVEC.ConclusionsAbn-CBD is protective against TNBS-induced colitis, promotes wound healing of endothelial and epithelial cells and inhibits neutrophil accumulation on HUVEC monolayers. Thus, the atypical cannabinoid Abn-CBD represents a novel potential therapeutic in the treatment of intestinal inflammatory diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12950-016-0129-0) contains supplementary material, which is available to authorized users.

Red bean extracts protect rats against intestinal inflammatory damage.

Red beans comprise part of the diet in Korean culture. Anti-inflammatory and anti-septic activities of the butanol fraction of red bean ethanol extracts (BF-RBEE) are known. The intestinal antiinflammatory activity of BF-RBEE and related mechanisms were studied using a rat model of acetic acid-induced colitis. Oral treatment with BF-RBEE (100 mg/kg of body weight) suppressed body weight loss and intestinal inflammatory damage in colitic rats. BF-RBEE treatment reduced the myeloperoxidase activity and the malondialdehyde level that were increased in colitic rats, and restored the reduced level of glutathione. BF-RBEE also inhibited acetic acid-mediated increases in mRNA levels of nitric oxide synthase, interleukin-1β, and tumor necrosis factor-α. Similarly, treatment with 1mg/kg of prednisolone protected rats against intestinal colitic damage with corresponding decreases in levels of these inflammatory indicators. Red beans can be useful for treatment of intestinal inflammatory diseases.

Palmitoylethanolamide ameliorates development of colitis caused by injection of dinitrobenzene sulfonic acid in mice (840.3)

Dinitrobenzene sulfonic acid (DNBS) induced colitis has proven to be a useful experimental model of intestinal bowel disease (IBD). N‐palmitoylethanolamide (PEA) is an endogenous fatty acid amide with important analgesic, anti‐inflammatory and neuroprotective effects.The aim of the study was to examine the effects of a new formulation of PEA (PEA ultramicronized) in mice subjected to experimental colitis. PEA was administered daily i.p, (10 mg/kg, 10% ethanol). Four days after DNBS, colon nuclear factor NF‐ kB was increased as well as TNF‐a and IL‐1b production, neutrophil infiltration and adhesion molecules expression. Immunohistochemistry for inducible nitric oxide synthase (iNOS), nitrotyrosine and poly (ADP‐ribose) polymerase (PARP) showed an intense staining in the inflamed colon. PEA significantly reduced the appearance of diarrhea and body weight loss. This was associated with a significant reduction of MPO activity, NF‐kB, pro‐inflammatory cytokines release, iNOS, nitrotyrosine and PARP and reduced up‐regulation of ICAM‐1, P‐selectin and metalloproteinases. Thus, the results of this study suggested that administration of PEA may be beneficial for treatment of intestinal inflammatory diseases.

Lactobacillus fermentum attenuates the proinflammatory effect of Yersinia enterocolitica on human epithelial cells

Lactobacilli represent a major component of the human microbiota. In this study we investigated whether and how Lactobacillus fermentum inhibits the proinflammatory responses of human epithelial cells on Yersinia enterocolitica infection. Human epithelial cells were exposed to Y. enterocolitica pYV(-) or L. fermentum or to both strains, combinations of heat-killed L. fermentum or supernatant of L. fermentum cultures and Y. enterocolitica. The modulation of Y. enterocolitica induced IL-8 levels in the culture supernatants was determined and activation of Rac, p38, and NF-kappaB was investigated. Exposure of human epithelial cells to L. fermentum does not induce NF-kappaB activation and subsequent IL-8 secretion in HeLa cells, whereas Y. enterocolitica induces NF-kappaB activation and high levels of IL-8. Viable L. fermentum, supernatant of L. fermentum cultures, but not heat-killed L. fermentum, inhibited IL-8 secretion of HeLa cells triggered by Y. enterocolitica. Lactobacillus fermentum-exposed HeLa cells showed decreased Rac, p38, and NF-kappaB activation after Y. enterocolitica infection. Treatment of L. fermentum supernatants with phospholipase C abolished the inhibitory effect, indicating that a secreted phospholipid mediates the antiinflammatory properties of L. fermentum. Adhesion to or invasion of Y. enterocolitica into epithelial cells was not altered by coincubation with L. fermentum. Our results lead to the conclusion that L. fermentum inhibits the Y. enterocolitica-induced IL-8 production by a possibly secreted phospholipid of <10 kDa molecular weight. These data suggest that L. fermentum may have probiotic properties modulating intestinal inflammatory responses and might offer new therapeutic strategies in the treatment of intestinal inflammatory diseases.

Immunology of the intestinal tract

The last half century has witnessed the birth, infancy, and early adolescence of a new field, intestinal immunology, with an explosion of knowledge about the role of the intestinal immune system in normal intestinal physiology and disease. This field is still in its rapid growth phase. A major spin-off of such growth will be the development of new approaches for the diagnosis and treatment of disease. For example, studies of oral tolerance have led to new insights into possible mechanisms of autoimmunity and ultimately could lead to new treatments for autoimmune disease. The discovery that Peyer's patches are a major inductive site for initiation of the mucosal immune response, and IgA responses in particular, and that antigen enters these sites via the M cell, forms one current basis for the development of new mucosal vaccines and vaccine delivery systems. Studies of immunogenetics are leading to new insights into the molecular basis of diseases such as celiac disease, IBD, and hepatic disorders. Studies of cytokines and the role they play in acute and chronic inflammation are leading to new approaches for the treatment of intestinal inflammatory diseases. The field of intestinal immunology is now well on its way through the turbulent "teenage" years. It is true maturation over the next several decades will test and witness the evolution and validity of concepts formed over the past 50 years. Certainly, tremendous growth and change will come with the increasing application of molecular tools, and the enthusiasm and the fresh insights brought by the next generation of young investigators, as they begin to further unravel the intricacies of the intestinal immune system and its role in health and disease.