Attenuation Of Intestinal Inflammation Research Articles

The Possible Synergistic Pharmacological Effect of an Oral Berberine (BBR) and Curcumin (CUR) Complementary Therapy Alleviates Symptoms of Irritable Bowel Syndrome (IBS): Results from a Real-Life, Routine Clinical Practice Settings-Based Study.

Irritable bowel syndrome (IBS) is a prevalent chronic functional gastrointestinal disorder, characterised by recurrent abdominal discomfort and altered bowel movements. IBS cause a significantly negative impact on quality of life (QoL). Growing pharmacological evidence suggests that berberine (BBR) and curcumin (CUR) may mitigate IBS symptoms through multiple complementary synergistic mechanisms, resulting in the attenuation of intestinal inflammation and regulation of bowel motility and gut functions. In the present observational study conducted under real-life routine clinical practice settings, 146 patients diagnosed with IBS were enrolled by general practitioner clinics and pharmacies in Belgium. For the first time, this study assessed the potential synergistic pharmacological effect of a combined oral BBR/CUR supplement (Enterofytol® PLUS, containing 200 mg BBR and 49 mg CUR) (two tablets daily for 2 months), serving as complementary therapy in the management of IBS. Following the 2-month supplementation, significant improvements were observed in the patients' IBS severity index (IBSSI) (47.5%) and all the primary IBS symptoms, such as abdominal discomfort (47.2%), distension (48.0%), intestinal transit (46.8%), and QoL (48.1%) (all p < 0.0001). The improvement in the patients' IBSSI was independent of age, sex, and IBS sub-types. The patients' weekly maximum stool passage frequency decreased significantly (p < 0.0001), and the stool status normalized (p < 0.0001). The patients' need for concomitant conventional IBS treatment decreased notably: antispasmodics by 64.0% and antidiarrhoeals by 64.6%. Minor adverse effects were reported by a small proportion (7.1%) of patients, mostly gastrointestinal. The majority (93.1%) experienced symptom improvement or resolution, with a high satisfaction rate (82.6%) and willingness to continue the supplementation (79.0%). These findings support the potential synergistic pharmacological role of BBR and CUR in IBS, and their co-supplementation may alleviate IBS symptoms and improve QoL.

The Impact of Tributyrin on Performance and Intestinal Health of Broiler Chickens Post Coccidiosis Vaccination

Coccidiosis is a major intestinal disease affecting broiler chickens. Tributyrin (TB) is a valid alternative to butyrate acid, which was associated with the improvement of performance and attenuation of intestinal inflammation in animal production. However, there are few reports on TB as a prophylactic treatment against coccidiosis in broilers. The aim of the study was to investigate the effects of TB supplementation on performance and intestinal health of broiler chickens post coccidiosis vaccination with a mixed-species Eimeria. In the first experiment, 612 broiler chicks were randomly assigned to two treatments with six replicates. Treatments included no TB supplementation and coccidiosis vaccination (CV1), or TB supplementation (400 mg/kg) and coccidiosis vaccination (TBCV1). On day 5, all broilers received a single vaccine dose. Performance, intestinal histopathology, clinical severity, and fecal oocyst counts were evaluated from day 1 to day 63. TB supplementation resulted in a nonsignificant effect on body weight gain (BWG), feed intake (FI), and mortality-corrected feed conversion ratio (FCR), except in increased FI on days 22-42 (P < 0.05). The TBCV1 group had increased (P < 0.05) villi heights in the duodenum and increased (P < 0.05) villi widths in the ileum on day 63 of age and reduced oocyst shedding on days 19-26 compared to CV1(P < 0.05). The route of administration in the second experiment was different from the first experiment in which the seeder birds (half of birds from each pen) received a tenfold dose on day 5. TB supplementation in broilers resulted in increased (P < 0.05) BWG and reduced (P < 0.05) FCR on days 22-42, and increased (P < 0.05) villi heights in the duodenum and increased (P < 0.05) villi widths in the ileum on day 63 of age, as well as a lower frequency (P < 0.05) of intestinal hemorrhage on days 13-62 and reduced (P < 0.001) oocyst shedding on day 5 post-Eimeria challenge. In conclusion, the study demonstrated that TB can be considered as a feed additive for protecting broilers from coccidiosis on days 22-42.

Microbiota attenuates chicken transmission-exacerbated campylobacteriosis in Il10\u2212/\u2212 mice

Campylobacter jejuni is a prevalent foodborne pathogen mainly transmitting through poultry. It remains unknown how chicken-transmitted C. jejuni and microbiota impact on human campylobacteriosis. Campylobacter jejuni AR101 (Cj-P0) was introduced to chickens and isolated as passage 1 (Cj-P1). Campylobacter jejuni Cj-P1-DCA-Anaero was isolated from Cj-P0-infected birds transplanted with DCA-modulated anaerobic microbiota. Specific pathogen free Il10−/− mice were gavaged with antibiotic clindamycin and then infected with Cj-P0, Cj-P1, or Cj-P1-DCA-Anaero, respectively. After 8 days post infection, Il10−/− mice infected with Cj-P1 demonstrated severe morbidity and bloody diarrhea and the experiment had to be terminated. Cj-P1 induced more severe histopathology compared to Cj-P0, suggesting that chicken transmission increased C. jejuni virulence. Importantly, mice infected with Cj-P1-DCA-Anaero showed attenuation of intestinal inflammation compared to Cj-P1. At the cellular level, Cj-P1 induced more C. jejuni invasion and neutrophil infiltration into the Il10−/− mouse colon tissue compared to Cj-P0, which was attenuated with Cj-P1-DCA-Anaero. At the molecular level, Cj-P1 induced elevated inflammatory mediator mRNA accumulation of Il17a, Il1β, and Cxcl1 in the colon compared to Cj-P0, while Cj-P1-DCA-Anaero showed reduction of the inflammatory gene expression. In conclusion, our data suggest that DCA-modulated anaerobes attenuate chicken-transmitted campylobacteriosis in mice and it is important to control the elevation of C. jejuni virulence during chicken transmission process.

Attenuation of intestinal inflammation in IL-10 deficient mice by a plasmid carrying Lactococcus lactis strain

BackgroundInflammatory bowel diseases (IBD) are intestinal disorders characterized by inflammation in the gastrointestinal tract (GIT) and to date, no efficient treatments exist. Interleukin-10 (IL-10), one of the most important anti-inflammatory cytokines of the immune response, has been under study due to its potential for IBD therapy; however, systemic treatments lead to undesirable side effects and oral administration is limited due to its quick degradation. To avoid these bottlenecks, we previously engineered an invasive Lactococcus lactis (L. lactis) strain capable of delivering, directly to host cells, a eukaryotic DNA expression vector coding for IL-10 of Mus musculus (pValac:il-10) that diminished inflammation in two induced mouse models of intestinal inflammation. Thus, the aim of this study was to analyze its therapeutic effect in the IL-10-deficient mouse model (IL-10−/−) that spontaneously and gradually develops an inflammation that modifies the immune system and resembles Crohn’s disease (CD) in humans, and evaluate if it would also diminish and/or prevent the onset of this disease.ResultsOral administration of L. lactis MG1363 FnBPA+ (pValac:il-10) to IL-10−/− mice not only led to IL-10 production by these, but consequently also diminished the severe development of the disease, with animals showing lower macroscopic scores and histological damages, increased IL-10 levels and tendency to lower pro-inflammatory cytokine levels.ConclusionsThe results of this study, together with the previously published ones using this DNA delivery-based strategy, show that it is capable of creating and maintaining an anti-inflammatory environment in the GIT and thus effectively diminish the onset of inflammation in various mouse models.

Exploring the Molecular Mechanisms Underlying the Protective Effects of Microbial SCFAs on Intestinal Tolerance and Food Allergy.

A body of evidence suggests that food allergy (FA) has increased in prevalence over the past few decades. Novel findings support the hypothesis that some commensal bacteria and particularly microbial metabolites might contribute to development of oral tolerance and prevention from FA. Recently, beneficial effects of short-chain fatty acids (SCFAs), the main class of gut microbiota-derived metabolites, on FA have been proposed. The intestinal SCFAs are major end products during bacterial fermentation of complex and non-digestible carbohydrates such as dietary fiber. The multifaceted mechanisms underlying beneficial effects of SCFAs on the mucosal immune system comprise the regulation of diverse cellular pathways in epithelial, dendritic, and T cells, as well as the impact on the immunometabolism and epigenetic status of regulatory lymphocytes. Of note, SCFAs are effective inhibitors of histone deacetylases (HDACs). As a consequence, SCFAs appear to be implicated in attenuation of intestinal inflammation and autoimmune diseases. In this review, we will discuss the recent development in this research area by highlighting the role of the individual SCFAs acetate, propionate, butyrate, and pentanoate in promoting the differentiation of regulatory T and B cells and their potential beneficial effects on the prevention of FA. In this context, targeted alterations in the gut microbiota in favor of SCFA producers or supplementation of medicinal food enriched in SCFAs could be a novel therapeutic concept for FA.

Mechanistic insights into the attenuation of intestinal inflammation and modulation of the gut microbiome by krill oil using in vitro and in vivo models

BackgroundThe anti-inflammatory property of ω-3 polyunsaturated fatty acids (PUFA) has been exploited in the management of inflammatory bowel disease (IBD) with promising results. However, it remains unclear if PUFA play a significant role in the resolution of inflammation and promotion of mucosal healing. Krill oil (KO) is a natural product rich in PUFA and the potent antioxidant, astaxanthin. In this study, we attempted to understand the mechanisms through which KO modulates the gut microbiome and metabolome using in vitro and in vivo colitis models and a multi-omics based approach.ResultsKO significantly decreased LPS-induced IL1β and TNFα expression in human macrophages in vitro in a dose-dependent manner by regulating a broad spectrum of signaling pathways, including NF-κB and NOD-like receptor signaling, and displayed a synergistic effect with COX2 and IKK2 inhibitors in attenuating inflammatory pathways. Moreover, KO was involved in the resolution of inflammation by promoting M2 polarization and enhancing macrophage-mediated intracellular bacterial killing. Parasite-dependent intestinal mucosal damage and microbial dysbiosis induced by Trichuris suis infection in pigs were partially restored by feeding KO. KO supplementation reduced the abundance of Rickettsiales and several species of Lactobacillus, which were among the important features identified by random forests analysis contributing to classification accuracy for KO supplementation. Several microbial signatures with strong predictive power for the status of both infection and supplementation were identified. The inhibitory effect of KO on histidine metabolism was identified using untargeted metabolomics. KO supplementation reduced several key metabolites related to histamine metabolism by suppressing the expression of a gene encoding l-histidine decarboxylase in the colon mucosa and reducing histamine biosynthesis of microbial origin. Moreover, the pro-resolving properties of KO were validated using a Citrobacter rodentium-induced Th1-dependent colitis murine model. Further, microbial signatures with high prediction accuracy for colitis-related pathophysiological traits were identified in mice.ConclusionThe findings from this study provided a mechanistic basis for optimizing microbiome-inspired alternative therapeutics in the management of IBD. The microbial signatures identified, particularly those with strong predictive accuracy for colitis phenotypes, will facilitate the development of biomarkers associated with appropriate dietary intervention to manage intestinal inflammation.2RJFJL_x6c2huo5Y76Q5vsVideo abstract.

Changes in intestinal immunity, gut microbiota, and expression of energy metabolism–related genes explain adenoma growth in bilberry and cloudberry-fed ApcMin mice

We showed previously that ellagitannin-rich cloudberries and anthocyanin-rich bilberries reduce the number of intestinal adenomas in multiple intestinal neoplasia/+ (ApcMin) mice. We also found that cloudberries decreased the size of adenomas, whereas bilberries increased it. Here we hypothesized that the difference in adenoma growth could be explained by dissimilar effects of the berries on intestinal immune responses and gut microbiota, potentially driven by the distinct polyphenol compositions of the 2 berries. Our objectives were to investigate lymphocyte subtypes and the predominant cecal bacterial diversity in mice fed with bilberries and cloudberries, and to analyze global gene expression profiles in the intestinal mucosa. Immunostainings of CD3+ T lymphocytes, FoxP3+ regulatory T lymphocytes, and CD45R+ B lymphocytes revealed a smaller ratio of intraepithelial to all mucosal CD3+ T lymphocytes in the cloudberry-fed mice compared with controls, suggesting an attenuation of inflammation. Bilberry feeding induced no changes in the density of any of the lymphocyte subtypes. The predominant bacterial diversity in cecal contents, analyzed using polymerase chain reaction–denaturating gradient gel electrophoresis, was higher in the bilberry group than in the control or cloudberry groups. The microbial profiles of cloudberry-fed mice clustered together and were associated with small adenoma size. Pathway analyses of gene expression data showed that cloudberry down-regulated and bilberry up-regulated the expression of energy metabolism–related genes in the intestinal mucosa. In conclusion, attenuation of intestinal inflammation, changes in microbial profiles, and down-regulation of mucosal energy metabolism may account for the smaller adenoma size in cloudberry-fed mice in comparison to bilberry-fed mice.

Traditional Chinese medicine formulas for irritable bowel syndrome: from ancient wisdoms to scientific understandings.

Traditional Chinese Medicine (TCM) serves as the most common alternative therapeutic approach for Western medicine and benefits IBS patients globally. Due to the lack of scientific evidence in the past, TCM formulas were not internationally well recognized as promising IBS remedies. In this review, firstly, we present the etiology and therapy of IBS in terms of traditional Chinese medical theory. Secondly, we summarize the clinical randomized controlled trials (RCTs) of TCM formulas for IBS patients that are available in the literature (from 1998 to September 2013), in which 14 RCTs conducted of high quality were discussed in detail. Of the 14 selected trials, 12 of those concluded that TCM formulas provided superior improvement in the global symptoms of IBS patients over the placebo or conventional medicines. As well, all 14 RCTs suggested that TCM formulas have good safety and tolerability. Last but not least, we explore the pharmacological mechanisms of the anti-IBS TCM formulas available in the literature (from 1994 to September, 2013). Collectively, in combating IBS symptoms, most TCM formulas exert multi-targeting actions including the regulation of neurotransmitters and hormones in the enteric nervous system (ENS), modulation of smooth muscle motility in the gastrointestinal (GI) tract, modulation of the hypothalamic-pituitary-adrenal (HPA) axis, attenuation of intestinal inflammation and restoration of intestinal flora, etc. In conclusion, TCM formulas appear to be promising for IBS treatment. This review provides a useful reference for the public in furthering a better understanding and acceptance of TCM formulas as IBS remedies.

Intestinal alkaline phosphatase: novel functions and protective effects

Important protective roles of intestinal alkaline phosphatase (IAP)--including regulation of intestinal surface pH, absorption of lipids, detoxification of free nucleotides and bacterial lipopolysaccharide, attenuation of intestinal inflammation, and possible modulation of the gut microbiota--have been reviewed recently. IAP is modulated by numerous nutritional factors. The present review highlights new findings on the properties of IAP and extends the list of its protective functions. Critical assessment of data suggests that some IAP properties are a direct result of dephosphorylation of proinflammatory moieties, while others (e.g., gut barrier protection and microbiota shaping) may be secondary to IAP-mediated downregulation of inflammation. IAP and tissue-nonspecific alkaline phosphatase isoforms characterize the small intestine and the colon, respectively. Gastrointestinal administration of exogenous IAP ameliorates gut inflammation and favors gut tissue regeneration, whereas enteral and systemic IAP administration attenuates systemic inflammation only. Finally, the IAP gene family has a strong evolutionary link to food-driven changes in gastrointestinal tract anatomy and microbiota composition. Therefore, stimulation of IAP activity by dietary intervention is a goal for preserving gut homeostasis and health by minimizing low-grade inflammation.

Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation

Retinoic acid (RA), a vitamin A metabolite, modulates mucosal T helper cell responses. Here we examined the role of RA in regulating IL-22 production by γδ T cells and innate lymphoid cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1β or IL-18 and IL-23. In vivo RA attenuated colon inflammation induced by dextran sodium sulfate treatment or Citrobacter rodentium infection. This was associated with a significant increase in IL-22 secretion by γδ T cells and innate lymphoid cells. In addition, RA treatment enhanced production of the IL-22-responsive antimicrobial peptides Reg3β and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed by treatment with an anti-IL-22 neutralizing antibody, demonstrating that RA mediates protection by enhancing IL-22 production. To define the molecular events involved, we used chromatin immunoprecipitation assays and found that RA promoted binding of RA receptor to the IL-22 promoter in γδ T cells. Our findings provide novel insights into the molecular events controlling IL-22 transcription and suggest that one key outcome of RA signaling may be to shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells and innate lymphoid cells.

The beneficial effect of Rheum tanguticum polysaccharide on protecting against diarrhea, colonic inflammation and ulceration in rats with TNBS-induced colitis: The role of macrophage mannose receptor in inflammation and immune response

Rhubarb has been used as a folk remedy for gastrointestinal disease in China for over two thousand years. In the present study, we evaluated the effect of Rheum tanguticum polysaccharide (RTP), a water soluble fraction extracted from rhubarb, on protection from inflammation and colonic damage in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. RTP protected against diarrhea, colon weight increase, and ulceration induced by TNBS. It was at least as effective as dexamethasone (DEX). RTP significantly decreased myeloperoxidase (MPO) activity in the colonic mucosa. Oral administration of RTP was as effective as intraperitoneal (i.p.) injection on toxicity protection and MPO activity. To further investigate the possible underlying mechanism, we studied the role of mannose receptor (MR) in cytokine secretion, ligand binding and endocytosis of macrophages. The secretion of IFN-γ was dramatically increased while IL-4 decreased in colitis compared to the control (normal rats), and RTP restored the condition similar to the control in vivo. The secretion of IFN-γ by macrophages was induced by RTP and lipoarabinomannan (LAM) but not mannose in vitro. Mannose completely inhibited the effect of RTP, while RTP and LAM affected each other on IFN-γ secretion. The MR-mediated ligand binding and endocytosis of macrophages were markedly decreased in colitis and RTP restored their function to near normal condition. The results indicated that RTP targeted MR and down-regulation of Th1-polarized immune response may be the possible mechanism for its attenuation of intestinal inflammation and damage. RTP may be useful for treatment of patients with inflammatory bowel disease.

Salmonella entericaSerovar Typhimurium Pathogenicity Island 2 Is Necessary for Complete Virulence in a Mouse Model of Infectious Enterocolitis

Salmonella species cause a wide range of disease in multiple hosts. Salmonella enterica serovar Typhimurium causes self-limited intestinal disease in humans and systemic typhoid-like illness in susceptible mice. The prevailing dogma in murine S. enterica serovar Typhimurium pathogenesis is that distinct virulence mechanisms-Salmonella pathogenicity islands 1 and 2 (SPI1 and SPI2)-perform distinct roles in pathogenesis, the former being important for invasion and intestinal disease and the latter important for intracellular survival and systemic persistence and disease. Although evidence from bovine infections has suggested that SPI2 has a role in ileal disease, there is no evidence that SPI2 is important for inflammation in a disease that more closely recapitulates human colitis. Using S. enterica serovar Typhimurium strains that lack functional type III secretion systems, we demonstrate that SPI2 is essential for complete virulence in murine infectious enterocolitis. Using a recently characterized murine model (M. Barthel,S. Hapfelmeier, L. Quintanilla-Martinez, M. Kremer, M. Rohde, M. Hogardt, K. Pfeffer, H. Russmann, and W. D. Hardt, Infect. Immun. 71:2839-2858, 2003), we demonstrate that SPI1 mutants are unable to cause intestinal disease 48 h after infection and that SPI2-deficient bacteria also cause significantly attenuated typhlitis. We show that at the peak of inflammation in the cecum, SPI2 mutants induce diminished intercellular adhesion molecule 1 expression and neutrophil recruitment but that wild-type and mutant Salmonella are similarly distributed in the lumen of the infected organ. Finally, we demonstrate that attenuation of intestinal inflammation is accompanied by resolution of typhlitis in the mutant, but not wild-type, infections. Collectively, these results indicate that SPI2 is needed for enterocolitis, as well as for systemic disease.