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.

https://gut.bmj.com/content/gutjnl/63/5/761.full.pdf

Colonic mucosa-associated diffusely adherent afaC+ Escherichia coli expressing lpfA and pks are increased in inflammatory bowel disease and colon cancer

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.

Mucosal Barrier, Bacteria and Inflammatory Bowel Disease: Possibilities for Therapy

Microfold (M) cells are located in the epithelium covering mucosa-associated lymphoid tissues, such as the Peyer's patches (PPs) of the small intestine. M cells actively transport luminal antigens to the underlying lymphoid follicles to initiate an immune response. The molecular machinery of M-cell differentiation and function has been vigorously investigated over the last decade. Studies have shed light on the role of M cells in the mucosal immune system and have revealed that antigen uptake by M cells contributes to not only mucosal but also systemic immune responses. However, M-cell studies usually focus on infectious diseases; the contribution of M cells to autoimmune diseases has remained largely unexplored. Accumulating evidence suggests that dysbiosis of the intestinal microbiota is implicated in multiple systemic diseases, including autoimmune diseases. This implies that the uptake of microorganisms by M cells in PPs may play a role in the pathogenesis of autoimmune diseases. We provide an outline of the current understanding of M-cell biology and subsequently discuss the potential contribution of M cells and PPs to the induction of systemic autoimmunity, beyond the mucosal immune response.

/pdf/the-roles-of-peyer-s-patches-and-microfold-cells-in-the-gut-3bh4wp6mhs.pdf

The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases.

Inflammatory Bowel Disease (IBD) includes a set of pathologies that result from a deregulated immune response that may affect any portion of the gastrointestinal tract. The most prevalent and defined forms of IBD are Crohn’s disease and ulcerative colitis. Although the etiology of IBD is not well defined, it has been suggested that environmental and genetic factors contribute to disease development, and that the interaction between these two factors can trigger the pathology. Diet, medication use, vitamin D status, smoking and bacterial infections have been proposed to influence or contribute to the onset or development of the disease in susceptible individuals. The infection with pathogenic bacteria is a key factor that can influence the development and severity of this disease. Here, we present a comprehensive review of studies performed in human and mice susceptible to IBD, which support the notion that infection with bacterial pathogens, such as Salmonella, could promote the onset of IBD due to permanent changes in the intestinal microbiota, disruption of the epithelial barrier and alterations of the intestinal immune response after infection.

/pdf/a-potential-role-of-salmonella-infection-in-the-onset-of-3acyfyaoy0.pdf

A Potential Role of Salmonella Infection in the Onset of Inflammatory Bowel Diseases

Background: Inflammatory bowel disease (IBD) is characterized by excessive immune responses to altered intestinal microbiota in genetically susceptible individuals. The diagnosis of IBD depends on clinical, endoscopic, histological, radiological and biochemical criteria, which may be invasive, time consuming and usually not accepted by patients with IBD. Key Messages: Serological biomarkers have been demonstrated to be a series of rapid, non-invasive approaches for assessments of early diagnosis, disease activity and prognosis for IBD. Importantly, serum antibodies against microbial antigens or auto-antigens have been used as biomarkers in predicting disease course, complications and responses to medications and surgery. Moreover, they have been demonstrated to be useful in distinguishing patients with Crohn's disease (CD) from those with ulcerative colitis (UC). Recently, a great number of new serum biomarkers (e.g., anti-glycoprotein 2, anti-granulocyte macrophage colony-stimulating factor, anti-neutrophil cytoplasmic antibody, anti-Saccharomyces cerevisiae antibody, anti-laminaribioside carbohydrate IgG antibody, anti-mannobioside carbohydrate IgG antibody, antibody to the outer membrane protein of Escherichia coli, anti-CBir1) have been found to be present in patients with IBD and are potentially used in the diagnosis and prediction. The presence of these antibodies in the sera is due to the disruption of intestinal mucosa barrier and they may reflect a possibly genetic loss of immunological tolerance toward microbiota-derived antigens. Due to their non-invasive, easily accessible, repetitive and economical characteristics, these biomarkers have been found to serve as precious supplementary means in the diagnosis and disease evaluation of IBD. Conclusions: Currently, the most important utility of serological biomarkers is to evaluate the aggressive risks of disease phenotype, complications or surgery requirement, predict prognosis of the disease and distinguish CD from UC. However, they have limited values in making initially definite diagnosis for IBD. Therefore, more effective biomarkers with high sensitivity and specificity need to be further explored in the future.

ASCA, ANCA, ALCA and Many More: Are They Useful in the Diagnosis of Inflammatory Bowel Disease?

Backround and aims: The aetiopathogenesis of Crohn’s disease, an inflammatory bowel disease (IBD), is not yet fully understood. Autoimmune mechanisms are thought to play a role in the development of Crohn’s disease, but the target antigens and the underlying pathways have not been sufficiently identified. Methods: Based on data from immunoblotting and matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry, the major antigenic target of pancreatic autoantibodies (PABs), which are specific for Crohn’s disease, was identified. Specificity of autoantibody reactivity was confirmed by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IIF) using purified rat and human recombinant GP2 synthesised in transiently transfected mammalian HEK 293 cells. Real-time polymerase chain reaction (rt-PCR) and IIF were used to detect mRNA and antigen localisation in human colon biopsies. Results: The major zymogen granule membrane glycoprotein 2 (GP2) was identified as the autoantigen of PABs in Crohn’s disease. PAB-positive sera from patients with Crohn’s disease (n = 42) displayed significantly higher IgG reactivity to rat GP2 in ELISA than either PAB-negative sera (n = 31), or sera from patients with ulcerative colitis (n = 49), or sera from blood donors (n = 69) (p Conclusion: Anti-GP2 autoantibodies constitute novel Crohn’s disease-specific markers, the quantification of which could significantly improve the serological diagnosis of IBD. The expression of GP2 in human enterocytes suggests an important role for anti-GP2 response in the pathogenesis of Crohn’s disease.

https://gut.bmj.com/content/gutjnl/58/12/1620.full.pdf

Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn's disease

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Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn's disease