Onset Of Intestinal Inflammation Research Articles

Systematic Review: The Gut Microbiome and Its Potential Clinical Application in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic relapsing–remitting systemic disease of the gastrointestinal tract. It is well established that the gut microbiome has a profound impact on IBD pathogenesis. Our aim was to systematically review the literature on the IBD gut microbiome and its usefulness to provide microbiome-based biomarkers. A systematic search of the online bibliographic database PubMed from inception to August 2020 with screening in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. One-hundred and forty-four papers were eligible for inclusion. There was a wide heterogeneity in microbiome analysis methods or experimental design. The IBD intestinal microbiome was generally characterized by reduced species richness and diversity, and lower temporal stability, while changes in the gut microbiome seemed to play a pivotal role in determining the onset of IBD. Multiple studies have identified certain microbial taxa that are enriched or depleted in IBD, including bacteria, fungi, viruses, and archaea. The two main features in this sense are the decrease in beneficial bacteria and the increase in pathogenic bacteria. Significant differences were also present between remission and relapse IBD status. Shifts in gut microbial community composition and abundance have proven to be valuable as diagnostic biomarkers. The gut microbiome plays a major role in IBD, yet studies need to go from casualty to causality. Longitudinal designs including newly diagnosed treatment-naïve patients are needed to provide insights into the role of microbes in the onset of intestinal inflammation. A better understanding of the human gut microbiome could provide innovative targets for diagnosis, prognosis, treatment and even cure of this relevant disease.

Lithocholic acid regulates colonic epithelial barrier function and apoptosis: Implications for inflammatory bowel disease

BackgroundIncreased apoptosis and loss of epithelial barrier function are hallmark features in the pathogenesis of inflammatory bowel disease. While bile acids are classically known for their roles in facilitating digestion and absorption of fats, they have more recently become appreciated as a family of enterocrine hormones that regulate many aspects of intestinal function. However, even though changes in luminal bile acids are closely associated with IBD pathogenesis, their roles in regulating epithelial barrier function are still largely unknown. Lithocholic acid (LCA) is a secondary colonic bile acid whose luminal levels are decreased and which we have recently shown to be protective against the onset of intestinal inflammation. The aim of the current study was to investigate the effects of LCA on colonic epithelial barrier function and apoptosis.MethodsC57BL/6 mice were administered dextran sodium sulphate (DSS, 2.5%) in drinking water for 5 days to induce epithelial damage and intestinal inflammation and disease severity was measured as disease activity index (DAI). Mice received PBS or Na+‐lithocholate (LCA) via IP injection each day. Epithelial permeability was assessed by measuring the flux of orally‐gavaged FITC‐dextran from the lumen into the blood. Levels of cleaved PARP, measured by Western blotting, were used as a marker of apoptosis. To examine the effects of LCA on cytokine‐induced barrier dysfunction in vitro, monolayers of T84 colonic epithelial cells, treated INF‐ɣ and TNF‐α, were employed.ResultsAfter 5 days, animals treated with LCA had a significantly lower DAI score (5.12 ± 1.0) than those of mice treated with DSS alone (9.0 ± 0.5) (n = 12; p ≤ 0.001). DSS treatment increased the flux of FITC‐dextran from the lumen into the blood by 2.3 ± 0.7 fold and this was reduced to 1.3 ± 0.2 fold in LCA‐treated animals (n = 12). The apoptotic marker, cleaved‐PARP, was increased 19.9 ± 10.9 fold in mucosal tissues isolated from DSS treated mice and this was also reduced to 3.9 ± 1.1 fold by LCA treatment (n = 3 – 4; p ≤ 0.01). In monolayers of cultured T84 colonic epithelial cells, treatment with a combination of the proinflammatory cytokines, INF‐ɣ (40 ng/ml) and TNF‐α (20 ng/ml) increased FITC‐dextran flux from the apical to basolateral domain by 4.9 ± 0.7 fold of that in control cells, while treatment with LCA (10 μM) practically abolished this response to 1.3 ± 0.5 fold (n = 8; p ≤ 0.001). Levels of cleaved‐PARP were increased by 4.4 ± 1.8 fold in IFN/TNF treated cells but this was reduced to 1.9 ±0.1 fold in LCA treated cells (n = 4). Similarly, GW4064 (5 μM), an agonist of the nuclear bile acid receptor, FXR, also prevented IFN/TNF‐induced FITC‐dextran flux and PARP cleavage in cultured epithelial cells.ConclusionsBy virtue of its capacity to prevent cytokine‐induced epithelial apoptosis and disruption of barrier function, these data imply a protective role for LCA in conditions of colonic inflammation. Thus, LCA and its associated signalling pathways present promising targets for the development of new approaches to promote colonic barrier function in the treatment of IBD.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cell-specific Activation of the Nrf2 Antioxidant Pathway Increases Mucosal Inflammation in Acute but Not in Chronic Colitis.

The transcription factor Nrf2 is a major modulator of the cellular antioxidant response. Oxidative burst of infiltrating macrophages leads to a massive production of reactive oxygen species in inflamed tissue of inflammatory bowel disease patients. This oxidative burst contributes to tissue destruction and epithelial permeability, but it is also an essential part of the antibacterial defence. We therefore investigated the impact of the Nrf2 orchestrated antioxidant response in both acute and chronic intestinal inflammation. To study the role of Nrf2 overexpression in mucosal inflammation, we used transgenic mice conditionally expressing a constitutively active form of Nrf2 [caNrf2] either in epithelial cells or in the myeloid cell lineage. Acute colitis was induced by dextran sulphate sodium [DSS] in transgenic and control animals, and changes in gene expression were evaluated by genome-wide expression studies. Long-term effects of Nrf2 activation were studied in mice with an IL-10-/- background. Expression of caNrf2 either in epithelial cells or myeloid cells resulted in aggravation of DSS-induced acute colitis. Aggravation of inflammation by caNrf2 was not observed in the IL-10-/- model of spontaneous chronic colitis, where even a trend towards reduced prolapse rate was observed. Our findings show that a well-balanced redox homeostasis is as important in epithelial cells as in myeloid cells during induction of colitis. Aggravation of acute DSS colitis in response to constitutive Nrf2 expression emphasises the importance of tight regulation of Nrf2 during the onset of intestinal inflammation.

P037. Remodelling events preceding clinical onset of intestinal inflammation reveal the predictive power of the extracellular matrix

P037. Remodelling events preceding clinical onset of intestinal inflammation reveal the predictive power of the extracellular matrix

Initiation of an inflammatory response in resident intestinal lamina propria cells -use of a human organ culture model.

Resident human lamina propria immune cells serve as powerful effectors in host defense. Molecular events associated with the initiation of an intestinal inflammatory response in these cells are largely unknown. Here, we aimed to characterize phenotypic and functional changes induced in these cells at the onset of intestinal inflammation using a human intestinal organ culture model. In this model, healthy human colonic mucosa was depleted of epithelial cells by EDTA treatment. Following loss of the epithelial layer, expression of the inflammatory mediators IL1B, IL6, IL8, IL23A, TNFA, CXCL2, and the surface receptors CD14, TLR2, CD86, CD54 was rapidly induced in resident lamina propria cells in situ as determined by qRT-PCR and immunohistology. Gene microarray analysis of lamina propria cells obtained by laser-capture microdissection provided an overview of global changes in gene expression occurring during the initiation of an intestinal inflammatory response in these cells. Bioinformatic analysis gave insight into signalling pathways mediating this inflammatory response. Furthermore, comparison with published microarray datasets of inflamed mucosa in vivo (ulcerative colitis) revealed a significant overlap of differentially regulated genes underlining the in vivo relevance of the organ culture model. Furthermore, genes never been previously associated with intestinal inflammation were identified using this model. The organ culture model characterized may be useful to study molecular mechanisms underlying the initiation of an intestinal inflammatory response in normal mucosa as well as potential alterations of this response in inflammatory bowel disease.

The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases

Intestinal inflammation arises from abnormal host-microbe interactions. The perturbations of homeostatic coexistence involve host genetic factors, barrier function, innate and adaptive immunity, as well as qualitative and quantitative changes in the composition of the microbiota. Dysbiosis toward selected micro-organisms and decreased complexity of commensal bacteria have been observed in patients with Crohn's disease and ulcerative colitis, but it is not clear whether the dysbiosis contributes to development of inflammatory bowel disease or is instead a consequence of the disease. Pathogens with virulence factors that allow them to breach the intestinal barrier and induce chronic inflammation might mediate the pathogenesis of these diseases. To identify new therapeutic approaches for inflammatory bowel disease, it is important to identify host susceptibility factors involved in the control of microbial infection, characterize potential pathogens, and eliminate them or block the expression of their virulence factors.

The role of pro-inflammatory peptides in the onset of intestinal inflammation

The role of pro-inflammatory peptides in the onset of intestinal inflammation

Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor.

The cause of Crohn's disease is unknown, although alterations in intestinal permeability may play a primary role. Because we were interested in permeability changes that occur before the onset of intestinal inflammation, we took advantage of the known genetic predisposition to this disease and studied not only patients with Crohn's disease, but their clinically unaffected relatives as well. Intestinal permeability was assessed using the marker polyethylene glycol-400 ingested with a standard meal. We found that 17 normal volunteers absorbed 215 +/- 29.6 mg (mean +/- SE), whereas 11 patients with Crohn's disease absorbed 514 +/- 94.7 mg and their 32 healthy relatives absorbed 566 +/- 62.4 mg. The twofold increase in permeability of patients and their relatives (p less than 0.005 compared with controls) indicates that the intestinal defect in the ability to exclude larger sized molecules is not secondary to clinically recognized intestinal inflammation, but is a primary defect that may be an etiologic factor in this disease.