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Background: Inflammatory bowel disease (IBD) is a multifactorial condition influenced by the immune system, the intestinal microbiota, environmental factors, genetic and epigenetic factors. Genetic- and environment- induced dysregulation of the Nuclear Factor-kappa B (NF-κB) transcription factor pathway has been linked to IBD pathogenesis., Objective: To assess the current evidence in relation to the contribution of the classical and alternative NF-κB pathways in IBD and to discuss the epigenetic mechanisms that impact on NF-κB function., Methods: A Medline search for 'NF-kappaB/NF-κB', in combination with terms including 'inflammatory bowel disease/IBD', 'intestinal inflammation', 'Crohn's disease', 'ulcerative colitis', 'colitis'; 'epigenetics', 'DNA methylation', 'histones', 'microRNAs/miRNAs' and 'short non-coding/long non-coding RNAs' was performed., Results: Both NF-κB pathways contribute to the chronic inflammation underlying IBD by regulating the inflammatory immune responses and homeostasis of the intestinal epithelium (classical pathway) or regulating bowel inflammation and epithelial microfold (M) cell function (alternative pathway). DNA methylation is a common epigenetic modification in intestinal inflammation, including NFKB1 and RELA loci. Conversely, little is understood regarding epigenetic effects on genes encoding other NF-κB subunits, particularly those of the alternative pathway, and in the context of IBD. However, NF-κB interaction with chromatin modifiers is also seen to be an essential mechanism of regulation of downstream target genes relevant to NF-κB-mediated inflammatory responses., Conclusion: Further research is clearly warranted in this area, as understanding the cell-specific regulation of the NF-κB pathways will bring researchers into a position to achieve more efficient stratification of IBD patients, and more targeted and effective choice of treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Inflammatory bowel diseases (IBDs) cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs that alter NF-κB signalling and could be repositioned for use in IBD. The SysmedIBD Consortium established a novel drug-repurposing pipeline based on a combination of in silico drug discovery and biological assays targeted at demonstrating an impact on NF-κB signalling, and a murine model of IBD. The drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. The effects of clarithromycin effects were validated in several experiments: it influenced NF-κB-mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to lipopolysaccharide; and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids. These findings demonstrate that in silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of IBD, and that further clinical assessment of clarithromycin in the management of IBD is required.This article has an associated First Person interview with the joint first authors of the paper., Competing Interests: Competing interestsV.A.P.M.d.S. is a shareholder and director of GeneXplain GmbH. A.K. is a shareholder and director of LifeGlimmer GmbH., (© 2020. Published by The Company of Biologists Ltd.)

Inflammatory bowel disease (IBD) is associated with anaemia and oral iron replacement to correct this can be problematic, intensifying inflammation and tissue damage. The intestinal microbiota also plays a key role in the pathogenesis of IBD, and iron supplementation likely influences gut bacterial diversity in patients with IBD. Here, we assessed the impact of dietary iron, using chow diets containing either 100, 200 or 400 ppm, fed ad libitum to adult female C57BL/6 mice in the presence or absence of colitis induced using dextran sulfate sodium (DSS), on (i) clinical and histological severity of acute DSS-induced colitis, and (ii) faecal microbial diversity, as assessed by sequencing the V4 region of 16S rRNA. Increasing or decreasing dietary iron concentration from the standard 200 ppm exacerbated both clinical and histological severity of DSS-induced colitis. DSS-treated mice provided only half the standard levels of iron ad libitum (i.e. chow containing 100 ppm iron) lost more body weight than those receiving double the amount of standard iron (i.e. 400 ppm); p<0.01. Faecal calprotectin levels were significantly increased in the presence of colitis in those consuming 100 ppm iron at day 8 (5.94-fold) versus day-10 group (4.14-fold) (p<0.05), and for the 400 ppm day-8 group (8.17-fold) versus day-10 group (4.44-fold) (p<0.001). In the presence of colitis, dietary iron at 400 ppm resulted in a significant reduction in faecal abundance of Firmicutes and Bacteroidetes, and increase of Proteobacteria, changes which were not observed with lower dietary intake of iron at 100 ppm. Overall, altering dietary iron intake exacerbated DSS-induced colitis; increasing the iron content of the diet also led to changes in intestinal bacteria diversity and composition after colitis was induced with DSS., Competing Interests: The authors have declared that no competing interests exist.

Chronic inflammation is a common factor in the development of many gastrointestinal malignancies. Examples include inflammatory bowel disease predisposing to colorectal cancer, Barrett's esophagus as a precursor of esophageal adenocarcinoma, and Helicobacter pylori-induced gastric cancer. The classical activation pathway of NF-κB signaling has been identified as regulating several sporadic and inflammation-associated gastrointestinal tract malignancies. Emerging evidence suggests that the alternative NF-κB signaling pathway also exerts a distinct influence on these processes. This review brings together current knowledge of the role of the alternative NF-κB signaling pathway in the gastrointestinal tract, with a particular emphasis on inflammation-associated cancer development., (Copyright © 2016 the American Physiological Society.)

Objective: Colonic mucosa-associated Escherichia coli are increased in Crohn's disease (CD) and colorectal cancer (CRC). They variously haemagglutinate, invade epithelial cell lines, replicate within macrophages, translocate across M (microfold) cells and damage DNA. We investigated genes responsible for these effects and their co-association in colonic mucosal isolates., Design: A fosmid library yielding 968 clones was prepared in E coli EPI300-T1 using DNA from a haemagglutinating CRC isolate, and resulting haemagglutinating clones were 454-pyrosequenced. PCR screening was performed on 281 colonic E coli isolates from inflammatory bowel disease (IBD) (35 patients), CRC (21) and controls (24; sporadic polyps or irritable bowel syndrome)., Results: 454-Pyrosequencing of fosmids from the haemagglutinating clones (n=8) identified the afimbrial adhesin afa-1 operon. Transfection of afa-1 into E coli K-12 predictably conferred diffuse adherence plus invasion of HEp-2 and I-407 epithelial cells, and upregulation of vascular endothelial growth factor. E coli expressing afaC were common in CRC (14/21, p=0.0009) and CD (9/14, p=0.005) but not ulcerative colitis (UC; 8/21) compared with controls (4/24). E coli expressing both afaC and lpfA (relevant to M-cell translocation) were common in CD (8/14, p=0.0019) and CRC (14/21, p=0.0001), but not UC (6/21) compared with controls (2/24). E coli expressing both afaC and pks (genotoxic) were common in CRC (11/21, p=0.0015) and UC (8/21, p=0.022), but not CD (4/14) compared with controls (2/24). All isolates expressed dsbA and htrA relevant to intra-macrophage replication, and 242/281 expressed fimH encoding type-1 fimbrial adhesin., Conclusions: IBD and CRC commonly have colonic mucosal E coli that express genes that confer properties relevant to pathogenesis including M-cell translocation, angiogenesis and genotoxicity.

The mucosal barrier has three major components, the mucus layer, the epithelial glycocalyx and the surface epithelium itself, whose integrity largely depends on tight junction function. In health, there is relatively little direct interaction between the luminal microbiota and the epithelium - the continuous mucus layer in the colon keeps the surface epithelium out of contact with bacteria and the ileo-caecal valve ensures that the distal small intestine is relatively microbe free. Most interaction takes place at the Peyer's patches in the distal ileum and their smaller colonic equivalents, the lymphoid follicles. Peyer's patches are overlain by a 'dome' epithelium, 5% of whose cells are specialised M (microfold) epithelial cells, which act as the major portal of entry for bacteria. There are no goblet cells in the dome epithelium and M cells have a very sparse glycocalyx allowing easy microbial interaction. It is intriguing that the typical age range for the onset of Crohn's disease (CD) is similar to the age at which the number of Peyer's patches is greatest. Peyer's patches are commonly the sites of the initial lesions in CD and the 'anti-pancreatic' antibody associated with CD has been shown to have as its epitope the glycoprotein 2 that is the receptor for type-1 bacterial fimbrial protein (fimH) on M cells. There are many reasons to believe that the mucosal barrier is critically important in the pathogenesis of inflammatory bowel disease (IBD). These include (i) associations between both CD and ulcerative colitis (UC) with genes that are relevant to the mucosal barrier; (ii) increased intestinal permeability in unaffected relatives of CD patients; (iii) increased immune reactivity against bacterial antigens, and (iv) animal models in which altered mucosal barrier, e.g. denudation of the mucus layer associated with oral dextran sulphate in rodents, induces colitis. Whilst some IBD patients may have genetic factors leading to weakening of the mucosal barrier, it is likely that environmental factors may be even more important. Some may be subtle and indirect, e.g. the effects of stress on the mucosa barrier, whilst others may be more obvious, e.g. the effect of pathogen-related gastroenteritis, known often to act as trigger for IBD relapse. We have also been very interested in the potentially harmful effects of ingested detergents - either by contamination of cutlery by inadequate rinsing or via ingestion of processed foods containing permitted emulsifiers. In vitro and ex vivo studies show that even very small trace amounts of these surfactants can greatly increase bacterial translocation. Implications for therapy are not yet so obvious. We advise our IBD patients to avoid processed foods containing emulsifiers and to rinse their dishes well - whilst accepting that there is no direct evidence yet to support this. Therapies that aim to enhance the mucosal barrier have yet to come to market, but trials of enteric-delivered phosphatidylcholine in UC are promising. The faecal concentration of mucus-degrading bacterial enzymes (particularly proteases, sulphatases and sialidases) correlates with disease activity in UC, and these represent good targets for therapy., (© 2014 S. Karger AG, Basel.)

Background/aims: Crohn's disease (CD) and ulcerative colitis (UC) are both typified by an altered intestinal microbiota, and gene associations imply various defects in the mucosal barrier and in the innate immune response to bacteria. This review aims to assess how alterations in diet or use of modified bacteria could have therapeutic effects in CD or UC., Methods: A MEDLINE search using the terms 'prebiotic', 'genetically modified bacteria', 'mucosal barrier in association with ulcerative colitis', 'Crohn's disease' or 'microbiota'., Results: A large body of data from in vitro and animal studies shows promise for therapeutic approaches that target the microbiota. Approaches include dietary supplementation with fermentable fibres (prebiotics) and soluble fibres that block bacterial-epithelial adherence (contrabiotics), enhancement of the mucosal barrier with phosphatidylcholine, and use of genetically modified bacteria that express IL-10 or protease inhibitors. Vitamin D supplementation also shows promise, acting via enhancement of innate immunity. Clinical trials have shown benefit with enterically delivered phosphatidylcholine supplementation in UC and near-significant benefit with vitamin D supplementation in CD., Conclusion: Strategies that target the microbiota or the host defence against it appear to be good prospects for therapy and deserve greater investment., (© 2014 S. Karger AG, Basel.)

If bacteria cause IBD, then it should be possible to target the bacteria with therapies and cure or at least treat the disease. Discovery of a successful intervention, unless found by chance, will depend on knowing more about which bacteria are involved, where they are and how to remove them. Some evidence for the possible role of bacteria has come from in vivo studies of the effects of diverting the faecal stream away from sites of IBD. Alternative hypotheses arise from the diversion studies that could incriminate other components of the faecal stream that include bile acids and dietary components. Antibiotics will only really be adequately tested when we know what the target bacteria are and where they are, e.g. whether in the lumen or mucosa and whether intracellular or extracellular. Some encouraging responses have been observed, however, with empirical antibiotic therapy., (Copyright © 2012 S. Karger AG, Basel.)

Twin studies have demonstrated the importance of environmental factors in the pathogenesis of inflammatory bowel disease, but progress has been relatively slow in identifying these, with the exception of smoking, which is positively associated with Crohn's disease and negatively associated with ulcerative colitis. Genetic studies have identified risk alleles which are involved in host-bacterial interactions and the mucosal barrier, and evidence is building for a likely pathogenic role for changes in the gut microbiome, with respect to both faecal and mucosa-associated microbiota. Some of these changes may be secondary to inflammation, nevertheless promising new therapeutic targets are beginning to emerge.

Background: Mucosally adherent E. coli are found in inflammatory bowel disease (IBD) and colon cancer. They promote release of the proinflammatory cytokine interleukin-8 (IL-8). We explored mechanisms for this release and its inhibition by drugs., Methods: IL-8 release from colon epithelial cells in response to mucosal E. coli isolates from IBD, colon cancer, and controls was characterized at the cellular and molecular level., Results: IL-8 response of HT29 cells was greater with Crohn's disease (689 +/- 298 [mean +/- SD] pg IL-8/mL at 4 hours, n = 7) and colon cancer isolates (532 +/- 415 pg/mL, n = 14) than with ulcerative colitis (236 +/- 58 pg/mL, n = 6) or control isolates (236 +/- 100 pg/mL, n = 6, P < 0.0001). Bacterial supernatants contained shed flagellin that triggered IL-8 release. For whole bacteria the IL-8 response to E. coli that agglutinate red blood cells (548 +/- 428 pg IL-8/mL, n = 16), a function that correlates with epithelial invasion, was greater than for nonhemagglutinators (281 +/- 253 pg/mL, n = 17; P < 0.0001). This was particularly marked among E. coli that, although flagellate, could not release IL-8 from TLR5-transfected HEK293 cells. IL-8 release was mediated by extracellular-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) and inhibited by mesalamine, but not hydrocortisone, at therapeutic concentrations., Conclusions: Mucosa-associated E. coli shed flagellin that elicits epithelial IL-8 release but this may only become relevant when the mucosal barrier is weakened to expose basolateral TLR5. Adherent and invasive IBD and colon cancer E. coli isolates also elicit a flagellin-independent IL-8 response that may be relevant when the mucosal barrier is intact. The IL-8 release is MAPK-dependent and inhibited by mesalamine.

Introduction/background: Inflammatory bowel disease (IBD) results from complex interactions between: host genome, immune system, mucosa, bacteria, and environment., Sources of Data: Review of PubMed database using search terms 'bacteria and inflammatory bowel disease' and 'genetics and inflammatory bowel disease'. PubMed 'related reference' feature and references from retrieved articles were examined., Areas of Agreement: IBD results from interaction between the microbiota of the gut and the immune system. Key gene defects associated with IBD are involved in bacterial recognition and processing. The environment at least modifies and may determine pathogenesis., Areas of Controversy: It has been disputed whether the primary defect in IBD is immunological or bacterial, and which bacteria are key. GROWING POINTS/AREAS FOR RESEARCH: 'M cells', the specialized epithelial cells that overlie Peyer's patches, are a major interface between gut bacteria and the immune system. Improved understanding is needed of the bacteria involved in IBD pathogenesis, their genotypes and phenotypes, their portal of entry and their mechanism for escaping attack from the immune system. Bacterial ligands involved in bacteria-epithelial adhesion are emerging, and molecular techniques are rapidly increasing our knowledge of the human intestinal microbiota.

Purpose of Review: Inflammatory bowel disease is thought to result from an abnormal response to the gut microbiota. This review discusses advances in knowledge of the changes in gut microbiota and host response in inflammatory bowel disease., Recent Findings: Approximately 15% of Crohn's disease cases in western populations result from mutations in NOD2/CARD15. This disease leads to defective intestinal defensin production and defective monocyte interleukin-8 response to bacterial peptidoglycan. A similar defective interleukin-8 response and consequent delayed neutrophil recruitment have also been shown in patients with Crohn's disease who do not have the NOD2 mutation. A consequence seems to be the accumulation in tissue of macrophages containing various bacteria, perhaps particularly Escherichia coli. In keeping with this patients with Crohn's disease have circulating antibodies against bacterial flagellar proteins of enterobacteria and clostridia. In ulcerative colitis, there is less evidence for invasion by or immune response to bacteria but changes in gut microbiota include a relative deficiency of bifidobacteria. There is considerable interest in probiotic or prebiotic therapies although so far little evidence for their efficacy., Summary: Molecular techniques are giving us better insight into the gut microbiota in inflammatory bowel disease that should translate into improved therapies.

Ulcerative colitis and colonic Crohn's disease (together known as inflammatory bowel disease or IBD) are both associated with increased risk for colorectal cancer. Although it is customary to emphasize differences in the biology of IBD-associated and sporadic colon cancer, we believe these are far outweighed by the similarities. These similarities suggest that they might have similar pathogenic mechanisms. Because the normal colon is arguably in a continual state of low-grade inflammation in response to its microbial flora, it is reasonable to speculate that both IBD-associated and sporadic colon cancer might be the consequence of bacteria-induced inflammation.

Ulcerative colitis and Crohn's disease (together known as Inflammatory Bowel Disease or IBD) are both associated with increased risk for colorectal cancer. Although it is conventional to emphasise differences between IBD-associated and sporadic colon cancer, such as a lower rate of Adenomatosis Polyposis Coli mutations and earlier p53 mutations, IBD-associated cancer has a similar dysplasia-cancer sequence to sporadic colon cancer, similar frequencies of major chromosomal abnormalities and of microsatellite instability and similar glycosylation changes. This suggests that IBD-associated colon cancer and sporadic colon cancer might have similar pathogenic mechanisms. Because the normal colon is arguably in a continual state of low-grade inflammation in response to its microbial flora, it is reasonable to suggest that both IBD-associated and sporadic colon cancer may be the consequence of bacteria-induced inflammation. We have speculated that the glycosylation changes might result in recruitment to the mucosa of bacterial and dietary lectins that might otherwise pass harmlessly though the gut lumen. These could then lead to increased inflammation and/or proliferation and thence to ulceration or cancer. The glycosylation changes include increased expression of onco-fetal carbohydrates, such as the galactose-terminated Thomsen-Friedenreich antigen (Gal beta1,3GalNAc alpha-), increased sialylation of terminal structures and reduced sulphation. These changes cannot readily be explained by alterations in glycosyltransferase activity but similar changes can be induced in vitro by alkalinisation of the Golgi lumen. Consequences of these changes may be relevant not only for cell-surface glycoconjugates but also for intracellular glycoconjugates.