Development Of Gut Inflammation Research Articles

TRAIL suppresses gut inflammation and inhibits colitogeic T-cell activation in experimental colitis via an apoptosis-independent pathway

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals. Recently, accumulating evidence demonstrated that TRAIL regulates autoimmune inflammation and immune cell homeostasis in several autoimmune animal models, suggesting a novel immunoregulatory role of TRAIL in autoimmune diseases. However, the impact of TRAIL in inflammatory bowel disease is yet undefined. This study is to address the therapeutic effects and immunoregulatory role of TRAIL in autoimmune gut inflammation. We demonstrated herein that TRAIL significantly suppressed gut inflammation and reduced the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis model. Suppression of gut inflammation was not due to induction of apoptosis in colonic T cells, dendritic cells, or epithelium cells by TRAIL. In contrast, TRAIL directly inhibited activation of colitogenic T cells and development of gut inflammation in an adoptive transfer-induced colitis model. The anti-inflammatory effects of TRAIL on colitis were abolished when T cells from TRAIL receptor (TRAIL-R) knockout mice were adoptively transferred, suggesting that TRAIL regulates autoreactive colitogenic T-cell activation in the development of gut inflammation. Our results demonstrate that TRAIL effectively inhibited colonic T-cell activation and suppressed autoimmune colitis, suggesting a potential therapeutic application of TRAIL in human inflammatory bowel disease.

Analysis of Physiological Parameters of Desulfovibrio Strains from Individuals with Colitis.

Intestinal sulfate-reducing bacteria are often isolated from patients with inflammatory bowel disease, including ulcerative colitis, and can be involved in the development of gut inflammation. A comparison of the metabolism of intestinal sulfate-reducing bacteria isolated from individuals with colitis and healthy controls using statistical analysis has never been studied and described before. The aim of our research was to evaluate the parameters of dissimilatory sulfate reduction in Desulfovibrio species that were isolated from the feces of healthy objects and individuals with colitis. Principal component analysis indicates that the strains that were isolated from individuals with colitis grouped in the same cluster by biomass accumulation and sulfide production, same as the strains isolated from healthy individuals. Sulfate and lactate consumption measured over time showed negative correlation (Pearson correlations, p<0.01), healthy: -0.760; colitis: -0.770; healthy: -0.828; colitis: -0.847, respectively. The calculated linear regression (R2) was lower in biomass accumulation and hydrogen sulfide production, 0.531; 0.625 respectively. Thus, biomass accumulation and sulfide production, together with measured kinetic parameters play an important factor in bowel inflammation, including ulcerative colitis. Additionally, acetate production can also synergize with H2S, while sulfate consumption and lactate oxidation likely represent minor factors in bowel disease.

The Role of Microbiota and Intestinal Permeability in the Pathophysiology of Autoimmune and Neuroimmune Processes with an Emphasis on Inflammatory Bowel Disease Type 1 Diabetes and Chronic Fatigue Syndrome.

In steady state conditions intestinal immune homeostasis is maintained by a sophisticated bidirectional dialogue between the microbiota and the intestinal immune system. This "cross talk" is enabled by the presence of highly adapted secretory cells, sampling cells and pattern recognition receptors in the gastric epithelium. Herein we discuss the mechanisms involved in the breakdown of intestinal homeostasis and the development of systemic immune activation and neuroinflammation with a view to discussing the importance of these processes, in tandem with genetic and environmental factors, in the pathophysiology of (auto)immune diseases.Data is presented explaining how immune tolerance is maintained and how it may breakdown. The breakdown of immune homeostasis following the development of gut inflammation, caused for example by gut dysbiosis, and the consequent increased intestinal permeability, is increasingly considered to be the ultimate source of the systemic immune activation and T helper 17/T regulatory cell imbalances, and maybe neurological disturbances, seen in autoimmune diseases such as Type 1 diabetes and inflammatory bowel disease. Increased intestinal permeability and translocation of commensal antigens into the systemic circulation is also a likely cause of the severe fatigue and an almost bewildering range of neurocognitive, neuroimaging and overall symptom presentations seen in patients with a diagnosis of Chronic Fatigue Syndrome.

Development of gut inflammation in mice colonized with mucosa-associated bacteria from patients with ulcerative colitis.

BackgroundDisturbances in the intestinal microbial community (i.e. dysbiosis) or presence of the microbes with deleterious effects on colonic mucosa has been linked to the pathogenesis of inflammatory bowel diseases. However the role of microbiota in induction and progression of ulcerative colitis (UC) has not yet been fully elucidated.MethodsThree lines of human microbiota-associated (HMA) mice were established by gavage of colon biopsy from three patients with active UC. The shift in microbial community during its transferring from humans to mice was analyzed by next-generation sequencing using Illumina MiSeq sequencer. Spontaneous or dextran sulfate sodium (DSS)-induced colitis and microbiota composition profiling in germ-free mice and HMA mice over 3–4 generations were assessed to decipher the features of the distinctive and crucial events occurring during microbial colonization and animal reproduction.ResultsNone of the HMA mice developed colitis spontaneously. When treated with DSS, mice in F4 generation of one line of colonized mice (aHMA) developed colitis. Compared to the DSS-resistant earlier generations of aHMA mice, the F4 generation have increased abundance of Clostridium difficile and decrease abundance of C. symbiosum in their cecum contents measured by denaturing gradient gel electrophoresis and DNA sequencing.ConclusionIn our study, mucosa-associated microbes of UC patients were not able to induce spontaneous colitis in gnotobiotic BALB/c mice but they were able to increase the susceptibility to DSS-induced colitis, once the potentially deleterious microbes found a suitable niche.Electronic supplementary materialThe online version of this article (doi:10.1186/s13099-015-0080-2) contains supplementary material, which is available to authorized users.

Contributions of dendritic cells and macrophages to intestinal homeostasis and immune defense

Intestinal mononuclear phagocytes have collectively emerged as key players in the maintenance of gut homeostasis, the development of gut inflammation and its resolution. Moreover, recent intense research efforts of many laboratories have revealed evidence for critical labor division between lamina propria-resident CD103(+) dendritic cells and CX3CR1(+) macrophages. In depth understanding of the respective activities of these cells in the mucosal landscape might pave the way for novel treatments of inflammatory bowel disorders (IBD).

M1757 Impact of Luminal and Systemic Iron on the Development of Chronic Ileitis Targeting the Gut Microbial Composition and Stress Response in Intestinal Epithelial Cells

activity, but also MMP-9 activity in DSS-treated mice. Chymase activity was significantly lower in the NK3201-treated group than in the placebo-treated group. MMP-9 level was also significantly lower in the NK3201-treated group than in the placebo-treated group. In NSAID-induced small intestinal enteritis, MMP-9 level was significantly increased to 5.6 and 9.2 times of control intestinal. Chymase inhibitor significantly decreased to 13.9% the ulcer index compared with placebo. Conclusion: These findings suggest that chymase plays an important role in the development of gut inflammation via MMP-9 activation.

Immunity, Inflammation, and Allergy in the Gut

The gut immune system has the challenge of responding to pathogens while remaining relatively unresponsive to food antigens and the commensal microflora. In the developed world, this ability appears to be breaking down, with chronic inflammatory diseases of the gut commonplace in the apparent absence of overt infections. In both mouse and man, mutations in genes that control innate immune recognition, adaptive immunity, and epithelial permeability are all associated with gut inflammation. This suggests that perturbing homeostasis between gut antigens and host immunity represents a critical determinant in the development of gut inflammation and allergy.

New insights into the pathogenesis of inflammatory bowel disease

Several important advances have been made over the past few years that have expanded our knowledge of the immunology of the gut and its complex interactions with commensal organisms. Critical developments in our understanding of the pathogenesis of inflammatory bowel diseases include the discovery of Toll-like receptors and the identification of not one but two susceptibility genes for Crohn's disease. We have furthered our understanding significantly concerning the role of dendritic cells in the development of gut inflammation. In addition, a novel hypothesis suggesting a protective role for helminthic infections is gaining experimental evidence and direct clinical applicability. In this review we summarize these key developments in the pathophysiology of inflammatory bowel disease and attempt to ascribe clinical relevance where applicable.

Prevention of gut inflammation by Bifidobacterium in dextran sulfate-treated gnotobiotic mice associated with Bacteroides strains isolated from ulcerative colitis patients

Indigenous Bacteroides strains are closely associated with the occurrence and exacerbation of ulcerative colitis (UC). In this study, we aimed to clarify the effect of Bifidobacterium strains, another major member of colonic bacteria, on the development of gut inflammation using gnotobiotic mouse models associated with Bacteroides strains isolated from UC patients. Dextran sulfate (DSS) administration induced inflammation in the large intestine, in particular of the cecum, in the gnotobiotic mice associated with three strains of Bacteroides vulgatus, judging from the myeloperoxidase activity, occult blood score, and IgG leakage into the intestinal contents. However, the severity of the inflammation was greatly reduced in the gnotobiotic mice associated with both B. vulgatus and Bifidobacterium strains. The severity of the cecal inflammation was well correlated with the concentration of succinic acid in the cecum. Bacteriologically, the density of B. vulgatus strain A (BV-A) greatly decreased and the predominant strain changed from BV-A to BV-B on additional association with Bifidobacterium strains. Among gnotobiotic mice associated with a single B. vulgatus strain, the severity of cecal inflammation in BV-A-associated mice was greater than that in BV-B-associated mice. Each Bifidobacterium strain produced compound(s) more effectively inhibiting the growth of BV-A than BV-B in in vitro culture. Taken together, these results suggest that the severity of DSS-induced gut inflammation is closely associated with a particular B. vulgatus strain, and that Bifidobacterium strains may repress exacerbation of intestinal inflammation through growth inhibition of the B. vulgatus strain.

Resistant starch and “the butyrate revolution”

Early epidemiological studies indicated that populations that consume a high proportion of non-starch polysaccharide (NSP) dietary fibre (DF) in their daily diet suffer less from gastrointestinal diseases, in particular colorectal cancers, than populations that consume diets that are high in fat and protein but low in NSP fibre. In this respect, diet, by increasing the amount of vegetables and NSP DF's, has been suggested to contribute as much as 25–35% to risk reduction for colorectal cancer. A reduction of fat intake may further reduce the risk by 15–25%. Based on these observations, DF's and substances that are part of the fibre complex such as antioxidants, flavonoids, sulphur containing compounds and folate have been proposed as potentially protective agents against colon cancer. However, results from controlled prospective studies in which beta-carotene and vitamin E or isolated dietary fibres were given to high risk groups showed disappointing results. There are recent indications that the regular consumption of certain subclasses of highly fermentable dietary fibre sources result in gut associated immune and flora modulation as well as a significant production of short chain fatty acids. In vitro studies as well as animal studies indicate that in particular propionate and butyrate have the potential to support the maintenance of a healthy gut and to reduce risk factors that are involved in the development of gut inflammation as well as colorectal cancer. A suggestion put forward is that beneficial effects may be obtained in particular by the consumption of resistant starch (RS) because of the high yield of butyrate and propionate when fermented. These SCFA are the prime substrates for the energy metabolism in the colonocyte and they act as growth factors to the healthy epithelium. In normal cells butyrate has been shown to induce proliferation at the crypt base, enhancing a healthy tissue turnover and maintenance. In inflamed mucosa butyrate stimulates the regeneration of the diseased lining of the gut. In neoplastic cells butyrate inhibits proliferation at the crypt surface, the site of potential tumour development. Moreover, models of experimental carcinogenesis in animals have shown the potential to modify a number of metabolic actions and steps in the cell cycle in a way that early events in the cascade of cancer development may be counteracted while stages of progression may be slowed down. The present review highlights a number of these aspects and describes the metabolic and functional properties of RS and butyrate.