From a case-control survey to a diagnostic viral gastroenteritis panel for testing of general practitioners' patients.

OBJECTIVE: To evaluate the pathogenicity of a broad range of 11 possible gastroenteritis viruses, by means of statistical relationships with cases vs. controls, or Ct-values, in order to establish the most appropriate diagnostic panel for our general practitioner (GP) patients in the Netherlands (2010-2012). METHODS: Archived stool samples from 1340 cases and 1100 controls were retested using internally controlled multiplex real-time PCRs for putative pathogenic gastroenteritis viruses: adenovirus, astrovirus, bocavirus, enterovirus, norovirus GI and GII, human parechovirus, rotavirus, salivirus, sapovirus, and torovirus. RESULTS: The prevalence of any virus in symptomatic cases and asymptomatic controls was 16.6% (223/1340) and 10.2% (112/1100), respectively. Prevalence of astrovirus (adjusted odds ratio (aOR) 10.37; 95% confidence interval (CI) 1.34-80.06) and norovirus GII (aOR 3.10; CI 1.62-5.92) was significantly higher in cases versus controls. Rotavirus was encountered only in cases. We did not find torovirus and there was no statistically significant relationship with cases for salivirus (aOR 1,67; (CI) 0.43-6.54)), adenovirus non-group F (aOR 1.20; CI 0.75-1.91), bocavirus (aOR 0.85; CI 0.05-13.64), enterovirus (aOR 0.83; CI 0.50-1.37), human parechovirus (aOR 1.61; CI 0.54-4.77) and sapovirus (aOR 1.15; CI 0.67-1.98). Though adenovirus group F (aOR 6.37; CI 0.80-50.92) and norovirus GI (aOR 2.22, CI: 0.79-6.23) are known enteropathogenic viruses and were more prevalent in cases than in controls, this did not reach significance in this study. The Ct value did not discriminate between carriage and disease in PCR-positive subjects. CONCLUSIONS: In our population, diagnostic gastroenteritis tests should screen for adenovirus group F, astrovirus, noroviruses GI and GII, and rotavirus. Case-control studies as ours are lacking and should also be carried out in populations from other epidemiological backgrounds.

Epidemiology of enteric virus infections in children living in the Amazon region.

OBJECTIVES: To verify the frequency of viruses causing acute gastroenteritis (AGE) in association with the histo-blood group antigen (HBGA) and Rotarix™ vaccination coverage in children from the Amazon region. DESIGN: Fecal and saliva samples were collected from children with AGE (n = 485) and acute respiratory infection (ARI) (n = 249) clinical symptoms. Rotavirus A (RVA), norovirus, human adenovirus (HAdV), and sapovirus (SaV) were verified in feces by molecular detection. Saliva samples were used for HBGA phenotyping/FUT3 genotyping. Blood group types, clinical aspects and Rotarix™ RVA vaccination data were recorded. RESULTS: Norovirus remained the most prevalently detected cause of AGE (38%, 184/485 and ARI 21.3%, 53/249). High HAdV frequencies were observed in AGE children (28.6%, 139/485) and ARI children (37.3%, 93/249). RVA was the third most prevalent virus causing AGE (22.7%, 110/485 and ARI 19.3%, 48/249) and a low RV1 coverage (61%, 448/734) was verified. The SaV frequencies were lower (7.2%, 35/485 for AGE and 6.8%, 17/249 for ARI). Secretor children were HBGA susceptible to HAdV infection (OR 1.5, 95% CI 1.0-2.3; P = 0.04) but not to RVA, norovirus or SaV infection. CONCLUSIONS: Norovirus could be considered the main etiological agent of AGE. No association was verified for HBGA susceptibility to RVA, norovirus and SaV. Secretor children showed a slight susceptibility to HAdV infection and the Le (a-b-) heterogeneous SNPs on the FUT3 gene.

Virus-Host Interactions Between Nonsecretors and Human Norovirus.

BACKGROUND & AIMS: Human norovirus infection is the leading cause of acute gastroenteritis. Genetic polymorphisms, mediated by the FUT2 gene (secretor enzyme), define strain susceptibility. Secretors express a diverse set of fucosylated histoblood group antigen carbohydrates (HBGA) on mucosal cells; nonsecretors (FUT2-/-) express a limited array of HBGAs. Thus, nonsecretors have less diverse norovirus strain infections, including resistance to the epidemiologically dominant GII.4 strains. Because future human norovirus vaccines will comprise GII.4 antigen and because secretor phenotype impacts GII.4 infection and immunity, nonsecretors may mimic young children immunologically in response to GII.4 vaccination, providing a needed model to study cross-protection in the context of limited pre-exposure. METHODS: By using specimens collected from the first characterized nonsecretor cohort naturally infected with GII.2 human norovirus, we evaluated the breadth of serologic immunity by surrogate neutralization assays, and cellular activation and cytokine production by flow cytometry. RESULTS: GII.2 infection resulted in broad antibody and cellular immunity activation that persisted for at least 30 days for T cells, monocytes, and dendritic cells, and for 180 days for blocking antibody. Multiple cellular lineages expressing interferon-γ and tumor necrosis factor-α dominated the response. Both T-cell and B-cell responses were cross-reactive with other GII strains, but not GI strains. To promote entry mechanisms, inclusion of bile acids was essential for GII.2 binding to nonsecretor HBGAs. CONCLUSIONS: These data support development of within-genogroup, cross-reactive antibody and T-cell immunity, key outcomes that may provide the foundation for eliciting broad immune responses after GII.4 vaccination in individuals with limited GII.4 immunity, including young children.

Cytokine response after stimulation of culture cells by zinc and probiotic strain.

Intestinal porcine epithelial cells were used for an in vitro analysis of mRNA expression levels of inflammatory cytokines (IL-8, IL-18) and transcriptional factors (MyD88 and NF-κß). Cells were exposed to inorganic and organic zinc sources (in two different concentrations-50 µmol/L and 100 µmol/L) alone or combined with Lactobacillus reuteri B6/1, which was also applied individually. The total exposure time was 4 h. Quantitative reverse transcriptase PCR was used to determine expression levels of the aforementioned parameters. In general, upregulation was observed; however, a decrease of some mRNA's abundance was also determined. Differences in expression were analysed statistically using ANOVA and Tukey analyses. High relative expression was shown for IL-8, IL-18 and MyD88 in groups treated with 100 µmol/L of inorganic sources of zinc (ZnSO4) (p < 0.05), while groups treated with the organic form did not exhibit significant changes in expression. Also, 50 µmol/L of either zinc source did not significantly modify the transcriptional profile of the cytokines and transcription factors, showing that even inorganic sources, at lower concentrations, do not elicit a significant inflammatory reaction. In summary, supplementation of organic zinc source (Gly-Zn chelate) ensures that IL-8, IL-18, MyD88 and NF-κß expression levels are not positively regulated. In contrast, inorganic sources of zinc (ZnSO4) could induce an inflammatory reaction. However, this response could be dampened if L. reuteri B6/1 is administered, showing the helpful aspect of using probiotics to modulate an inflammatory response. Conclusively, the use Gly-Zn chelate appears as an optimal alternative for Zn administration that does not compromise normal intestinal homeostasis.

Children Attending Day Care Centers are a Year-round Reservoir of Gastrointestinal Viruses.

Viral gastroenteritis causes high morbidity worldwide. In this study, stool samples from 179 children aged 0-6 years attending Danish day care centers were investigated for gastrointestinal viruses. Each child was observed for one year with submission of samples and questionnaires every two months. Adenovirus, norovirus, rotavirus, and sapovirus were detected in samples using real-time PCR. A total of 229 (33%) of the 688 samples collected tested positive for at least one virus. At the first sampling point, adenovirus was shed by 6%, norovirus genotype I by 3% and genotype II by 12%, rotavirus A by 9%, and sapovirus by 21% of the 142 children included in the risk factor analyses. Increasing age was identified as a protective factor against testing positive for gastrointestinal virus, whereas nausea during the previous two months was positively associated with testing positive. Odds of shedding adenovirus were 9.6 times higher among children treated with antibiotics within the previous two months than among children who were not. Gastrointestinal viruses were shed year-round and high viral loads were observed in samples from both symptomatic and asymptomatic children, suggesting children in day care as a reservoir and a possible source of spreading of viruses into the community.

Identification of novel adenovirus genotype 90 in children from Bangladesh.

Novel adenovirus genotypes are associated with outbreaks of disease, such as acute gastroenteritis, renal disease, upper respiratory tract infection and keratoconjunctivitis. Here, we identify novel and variant adenovirus genotypes in children coinfected with enterotoxigenic Escherichia coli, in Bangladesh. Metagenomic sequencing of stool was performed and whole adenovirus genomes were extracted. A novel species D virus, designated genotype 90 (P33H27F67) was identified, and the partial genome of a putative recombinant species B virus was recovered. Furthermore, the enteric types HAdV-A61 and HAdV-A40 were found in stool specimens. Knowledge of the diversity of adenovirus genomes circulating worldwide, especially in low-income countries where the burden of disease is high, will be required to ensure that future vaccination strategies cover the diversity of adenovirus strains associated with disease.

How are the expression patterns of gut antimicrobial peptides modulated by human gastrointestinal diseases? A bridge between infectious, inflammatory, and malignant diseases.

The human gut barrier is the tissue exposed to the highest load of microorganisms, harbouring 100 trillion bacteria. In addition, the gut's renewal rate outruns that of any other human tissue. Antimicrobial peptides (AMPs) are highly optimized defense molecules in the intestinal barrier optimized to maintain gastrointestinal homeostasis. Alterations in AMPs activity can lead to or result from human gastrointestinal diseases. In this review, unique, conserved, or otherwise regular alterations in the expression patterns of human AMPs across gastrointestinal inflammatory and infectious diseases were analyzed for pattern elucidation. Human gastrointestinal diseases are associated with alterations in gut AMPs' expression patterns in a peptide-specific, disease-specific, and pathogen-specific way, modulating human gastrointestinal functioning. Across diseases, there is a (i) marked reduction in otherwise constitutively expressed AMPs, leading to increased disease susceptibility, and a (ii) significant increase in the expression of inducible AMPs, leading to tissue damage and disease severity. Infections and inflammatory conditions are associated with altered gene expression in the gut, whose patterns may favour cellular metaplasia, mucosal dysfunction, and disease states. Altered expression of AMPs can thus thrive disease severity and evolution since its early stages. Nevertheless, the modulation of AMP expression patterns unveils promising therapeutic targets.

Giardia secretome highlights secreted tenascins as a key component of pathogenesis.

Background: Giardia is a protozoan parasite of public health relevance that causes gastroenteritis in a wide range of hosts. Two genetically distinct lineages (assemblages A and B) are responsible for the human disease. Although it is clear that differences in virulence occur, the pathogenesis and virulence of Giardia remain poorly understood. Results: The genome of Giardia is believed to contain open reading frames that could encode as many as 6000 proteins. By successfully applying quantitative proteomic analyses to the whole parasite and to the supernatants derived from parasite culture of assemblages A and B, we confirm expression of ∼1600 proteins from each assemblage, the vast majority of which are common to both lineages. To look for signature enrichment of secreted proteins, we considered the ratio of proteins in the supernatant compared with the pellet, which defined a small group of enriched proteins, putatively secreted at a steady state by cultured growing trophozoites of both assemblages. This secretome is enriched with proteins annotated to have N-terminal signal peptide. The most abundant secreted proteins include known virulence factors such as cathepsin B cysteine proteases and members of a Giardia superfamily of cysteine-rich proteins that comprise variant surface proteins, high-cysteine membrane proteins, and a new class of virulence factors, the Giardia tenascins. We demonstrate that physiological function of human enteric epithelial cells is disrupted by such soluble factors even in the absence of the trophozoites. Conclusions: We are able to propose a straightforward model of Giardia pathogenesis incorporating key roles for the major Giardia-derived soluble mediators.

Enzymatic cleavage promotes disassembly of GII.3 norovirus virus like particles and its binding to salivary histo-blood group antigens.

In this study, we found that addition of fecal extract significantly promoted the binding of GII.3 NoV VLPs to salivary HBGAs. SDS-PAGE analysis indicated that major capsid proteins (VP1) were cleaved into two major bands with molecular weights of 26 and 31kD, respectively. Pretreatment of fecal extract by boiling or addition of protease inhibitor cocktail or type specific protease inhibitor (leupeptin and aprotinin) during incubation all decreased VP1 cleavage and its binding to salivary HBGAs. Trypsin digestion led to cleavage of VP1 and promoted its binding to HBGAs, suggesting that the active enzyme(s) might be trypsin or trypsin-like enzymes. Trypsin and fecal extract pretreatment all led to loss of morphological intact VLPs, indicating enhanced signal was possible due to increased binding of fragmented subunits. N-terminal sequencing was performed to characterize the cleavage sites with indecisive results. In vitro VLP-salivary HBGAs binding blockade assay using VLPs derived from VP1 of different GII.3 strains and rabbit anti-genotype specific hyperimmune serum indicated that GII.3 NoVs might have conservative HBGA binding sites. In summary, our results provide evidence about the widespread presence of active enzyme in fecal samples that can cleave GII.3 NoV VLPs and demonstrate that GII.3 NoVs have conservative HBGA binding sites which might have implications in the design of multivalent NoV vaccines.

Nutrient Deprivation Affects Salmonella Invasion and Its Interaction with the Gastrointestinal Microbiota.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a foodborne enteric pathogen and a major cause of gastroenteritis in humans. It is known that molecules derived from the human fecal microbiota downregulate S. Typhimurium virulence gene expression and induce a starvation-like response. In this study, S. Typhimurium was cultured in minimal media to mimic starvation conditions such as that experienced by S. Typhimurium in the human intestinal tract, and the pathogen's virulence in vitro and in vivo was measured. S. Typhimurium cultured in minimal media displayed a reduced ability to invade human epithelial cells in a manner that was at least partially independent of the Salmonella Pathogenicity Island 1 (SPI-1) type III secretion system. Nutrient deprivation did not, however, alter the ability of S. Typhimurium to replicate and survive inside epithelial cells. In a murine model of S. Typhimurium-induced gastroenteritis, prior cultivation in minimal media did not alter the pathogen's ability to colonize mice, nor did it affect levels of gastrointestinal inflammation. Upon examining the post-infection fecal gastrointestinal microbiota, we found that specifically in the 129Sv/ImJ murine strain S. Typhimurium cultured in minimal media induced differential microbiota compositional shifts compared to that of S. Typhimurium cultured in rich media. Together these findings demonstrate that S. Typhimurium remains a potent pathogen even in the face of nutritional deprivation, but nevertheless that nutrient deprivation encountered in this environment elicits significant changes in the bacterium genetic programme, as well as its capacity to alter host microbiota composition.

Fluorescence-based gene reporter plasmid to track canonical Wnt signaling in ENS inflammation.

In several gut inflammatory or cancer diseases, cell-cell interactions are compromised, and an increased cytoplasmic expression of ß-catenin is observed. Over the last decade, numerous studies provided compelling experimental evidence that the loss of cadherin-mediated cell adhesion can promote ß-catenin release and signaling without any specific activation of the canonical Wnt pathway. In the present work, we took advantage of the ability of lipofectamine-like reagent to cause a synchronous dissociation of adherent junctions in cells isolated from the rat enteric nervous system (ENS) for obtaining an in vitro model of deregulated ß-catenin signaling. Under these experimental conditions, a green fluorescent protein Wnt reporter plasmid called ΔTop_EGFP3a was successfully tested to screen ß-catenin stabilization at resting and primed conditions with exogenous Wnt3a or lipopolysaccharide (LPS). ΔTop_EGFP3a provided a reliable and strong fluorescent signal that was easily measurable and at the same time highly sensitive to modulations of Wnt signaling following Wnt3a and LPS stimulation. The reporter gene was useful to demonstrate that Wnt3a exerts a protective activity in the ENS from overstimulated Wnt signaling by promoting a downregulation of the total ß-catenin level. Based on this evidence, the use of ΔTop_EGFP3a reporter plasmid could represent a more reliable tool for the investigation of Wnt and cross-talking pathways in ENS inflammation.

Genetic Diversity of Human Adenovirus in Children with Acute Gastroenteritis, Albania, 2013-2015.

The objectives of the present study were to assess the occurrence of human adenoviruses (HAdVs) in paediatric patients with gastroenteritis in Albania and to characterize HAdV strains. Faecal specimens from children admitted with acute gastroenteritis to the Paediatric Hospital in Tirana were screened for HAdV, using broad-range primers targeting the hexon gene, in combination with species-specific primers targeting the fiber gene. Phylogenetic analysis was then performed to assess the genetic relationships among the different sequences and between the sequences of the samples and those of the prototype strains. Adenovirus DNA was detected in 33/142 samples (23.2%); 14 belonged to species F (13 HAdV-41 and 1 HAdV-40), 13 to species C (1 HAdV-1, 8 HAdV-2, and 4 HAdV-5), 5 to species B (HAdV-3), and 1 to species A (HAdV-12). Rotavirus coinfection was present in 9/33 (27.2%) positive samples. In the remaining 24 positive samples (12 enteric--F species; 12 nonenteric--A, B, or C species), HAdVs were detected as unique viral pathogens, suggesting that HAdV may be an important cause of diarrhoea in children requiring hospitalization. This is the first study investigating the presence of human adenoviruses (species A-G) as etiologic agents of viral gastroenteritis in children in Albania.

Increased Expression of DUOX2 Is an Epithelial Response to Mucosal Dysbiosis Required for Immune Homeostasis in Mouse Intestine.

BACKGROUND & AIMS: Dual oxidase 2 (DUOX2), a hydrogen-peroxide generator at the apical membrane of gastrointestinal epithelia, is up-regulated in patients with inflammatory bowel disease (IBD) before the onset of inflammation, but little is known about its effects. We investigated the role of DUOX2 in maintaining mucosal immune homeostasis in mice. METHODS: We analyzed the regulation of DUOX2 in intestinal tissues of germ-free vs conventional mice, mice given antibiotics or colonized with only segmented filamentous bacteria, mice associated with human microbiota, and mice with deficiencies in interleukin (IL) 23 and IL22 signaling. We performed 16S ribosomal RNA gene quantitative polymerase chain reaction of intestinal mucosa and mesenteric lymph nodes of Duoxa(-/-) mice that lack functional DUOX enzymes. Genes differentially expressed in Duoxa(-/-) mice compared with co-housed wild-type littermates were correlated with gene expression changes in early-stage IBD using gene set enrichment analysis. RESULTS: Colonization of mice with segmented filamentous bacteria up-regulated intestinal expression of DUOX2. DUOX2 regulated redox signaling within mucosa-associated microbes and restricted bacterial access to lymphatic tissues of the mice, thereby reducing microbiota-induced immune responses. Induction of Duox2 transcription by microbial colonization did not require the mucosal cytokines IL17 or IL22, although IL22 increased expression of Duox2. Dysbiotic, but not healthy human microbiota, activated a DUOX2 response in recipient germ-free mice that corresponded to abnormal colonization of the mucosa with distinct populations of microbes. In Duoxa(-/-) mice, abnormalities in ileal mucosal gene expression at homeostasis recapitulated those in patients with mucosal dysbiosis. CONCLUSIONS: DUOX2 regulates interactions between the intestinal microbiota and the mucosa to maintain immune homeostasis in mice. Mucosal dysbiosis leads to increased expression of DUOX2, which might be a marker of perturbed mucosal homeostasis in patients with early-stage IBD.

Eosinophilic Esophagitis and Gastroenteritis.

Eosinophilic gastrointestinal disease (EGID) can be classified as eosinophilic esophagitis (EoE) when the eosinophilia is limited to the esophagus or as eosinophilic gastritis (EG) if it is limited to the gastric tract, eosinophilic colitis (EC) if it is limited to the colon, and eosinophilic gastroenteritis (EGE) if the eosinophilia involves one or more parts of the gastrointestinal tract. EoE is by far the most common EGID. It is a well-defined chronic atopic disease due to a T helper type 2 (Th2) inflammation triggered often by food allergens. EoE diagnosis is done if an esophageal biopsy shows at least 15 eosinophils per high power field (eos/hpf). Globally accepted long-term therapies for EoE are the use of swallowed inhaled steroids or food antigen avoidance. The treatment of EoE is done not only to control symptoms but also to prevent complications such as esophageal stricture and food impaction. EGE cause non-specific gastrointestinal (GI) symptoms and are diagnosed if esophagogastroduodenoscopy (EGD)/colonoscopy show eosinophilia in one or more parts of the GI tract. They are rare diseases with an unclear pathogenesis, and they are poorly defined in terms of diagnostic criteria and treatment. Before initiating treatment of any EGE, it is imperative to conduct a differential diagnosis to exclude other causes of hypereosinophilia with GI localization. EGE are often poorly responsive to therapy and there is no commonly accepted long-term treatment. EG has many characteristics similar to EoE, including the fact that it is often due to a food allergen-driven Th2 inflammation; transcriptome analysis however shows that it is more a systemic disease and has a different gene signature than EoE. EC is a benign form of delayed food allergy in infant and is instead a difficult-to-treat severe inflammatory condition in older children and adults. EC in the latter groups can be a manifestation of drug allergy or autoimmune disease. Overall EGE, EC, and EG are rare and are a diagnosis of exclusion until more common causes of eosinophilia have been excluded.

Overexpression of HMGB1 A-box reduced lipopolysaccharide-induced intestinal inflammation via HMGB1/TLR4 signaling in vitro.

AIM: To investigate the inhibitory effects and mechanism of high mobility group box (HMGB)1 A-box in lipopolysaccharide (LPS)-induced intestinal inflammation. METHODS: Overexpression of HMGB1 A-box in human intestinal epithelial cell lines (SW480 cells) was achieved using the plasmid pEGFP-N1. HMGB1 A-box-overexpressing SW480 cells were stimulated with LPS and co-culturing with human monocyte-like cell lines (THP-1 cells) using a Transwell system, compared with another HMGB1 inhibitor ethyl pyruvate (EP). The mRNA and protein levels of HMGB1/toll-like receptor (TLR) 4 signaling pathways [including HMGB1, TLR4, myeloid differentiation factor88 (MYD88), Phosphorylated Nuclear Factor κB (pNF-κB) p65] in the stimulated cells were determined by real-time polymerase chain reaction and Western blotting. The levels of the proinflammatory mediators [including HMGB1, interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α] in the supernatants of the stimulated cells were determined by ELISA. RESULTS: EP downregulated the mRNA and protein levels of HMGB1, inhibited the TLR4 signaling pathways (TLR4, MYD88 and pNF-κB p65) and reduced the secretion of proinflammatory mediators (HMGB1, IL-1ß, IL-6 and TNF-α) in the SW480 and THP-1 cells activated by LPS but not in the unstimulated cells. Activated by LPS, the overexpression of HMGB1 A-box in the SW480 cells also inhibited the HMGB1/TLR4 signaling pathways and reduced the secretion of these proinflammatory mediators in the THP-1 cells but not in the transfected and unstimulated cells. CONCLUSION: HMGB1 A-box, not only EP, can reduce LPS-induced intestinal inflammation through inhibition of the HMGB1/TLR4 signaling pathways.

Proteases and their receptors as mediators of inflammation-associated colon cancer.

Chronic inflammation increases the risk of developing cancer. For example, patients with severe and prolonged inflammatory bowel disease, particularly ulcerative colitis, have a significantly higher risk of developing colorectal cancer. Serine proteases coordinating the coagulation cascade and immune cell proteases play important roles in regulating the inflammatory response through their actions on protease-activated receptors (PAR). PARs and their activating proteases have also been implicated in many cancers, including CRC. Importantly, the actions of proteases could be important for mediating the transition from chronic inflammation to cancer. PAR activation has been shown to have pro-tumourigenic effects including the production of matrix metalloproteinases that can promote tumour cell growth and metastasis, and transactivation of the epidermal growth factor receptor, which is a main target for cancer treatment. Additionally, PAR activation can also result in increased expression of cyclooxygenase (COX)-2, an important enzyme mediating inflammation, resolution, and cancer progression. In this review, we will highlight our current knowledge about the effects of proteases and their receptors on intestinal inflammation and cancer, and explore the potential role of PAR-induced COX-2 on colitis-associated cancer.

Inflammatory and non-inflammatory roles for Toll-like receptors in gastrointestinal cancer.

Collectively, cancers of the gastrointestinal (GI) tract (including the esophagus, stomach, duodenum, colon, rectum, liver, gall bladder and bile ducts) are the most prevalent and deadly worldwide. A common denominator in the pathogenesis of these GI tract cancers is chronic inflammation, as evidenced by the fact that sufferers of inflammatory bowel disease (IBD) are significantly more susceptible to colon cancer than healthy individuals. However, since only a relatively small proportion of individuals with chronic inflammatory conditions such as IBD go on to develop cancer, research has focused on identifying discrepancies in the host immune system that may be responsible for promoting carcinogenesis in inflamed tissue. To this end, molecular pathways linking inflammation and cancer are emerging, with one series of candidates being members of the Toll-like receptor family.

Chronic inflammation and colorectal cancer: the role of vascular endothelial growth factor.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer in males and the second in females worldwide. Accumulating evidence has demonstrated that patients with chronic inflammation in bowels have an increased risk to develop CRC. Various inflammatory cells and mediators produced during chronic inflammation are orchestrated through different molecular signaling pathways and lead to the formation of a microenvironment in favor of tumorigenesis. Vascular endothelial growth factor (VEGF), which can be induced by chronic inflammation, plays a pivotal role in tumor angiogenesis as well as tumor growth and metastasis. Antiangiogenic therapy targeting VEGF and its signaling pathways represents a promising strategy to inhibit colorectal tumorigenesis. Indeed, anti-angiogenic agents modulating VEGF ligands and their receptors have already exhibited great potential in treating patients with CRC, especially when combined with conventional chemotherapeutic agents. This review discusses the promoting role of chronic inflammation in colorectal tumorigenesis at different stages including tumor initiation, promotion, progression and metastasis, highlighting the contributory role of VEGF in angiogenesis during the development from chronic inflammation to CRC. It also describes the clinical significance of anti- VEGF therapy in the treatment of such disease.

The genetic landscapes of inflammation-driven gastrointestinal tract cancers.

Gastrointestinal (GI) tract cancers account for a significant proportion of human malignancies. While classical multistep carcinogenesis is characterized by the stochastic accumulation of genetic mutations, additional extrinsic factors can also contribute to tumor promotion. Inflammation plays a critical role in cancers of the GI tract, for which the two major etiological factors are tissue injuries and altered microbiota. Together with infiltrating immune cells, all of these components generate a dynamic tumor microenvironment that inevitably induces malignant progression and metastatic growth. Crosstalk between tumor and immune cells is mediated by a multitude of pro- and anti- inflammatory cytokines. Their biological actions are propagated in both tumor and immune cells through an intricate network of intracellular signaling pathways that ultimately modulate essential cellular functions such as tumorigenic properties and lineage specification. Using the vast amount of information stored in the database on genetic changes associated with human cancers that has been collected over the past decades, this book chapter will first profile the genomic and transcriptomic landscapes of some of the major GI tract cancers. Critical driver genes and pro-inflammatory cytokines will be discussed in detail. The mechanisms by which genetic mutations in cancer cells can provoke inflammation and vice versa will be explored. The way in which the symbiotic relationship between cancer cells and chronic inflammation can modulate tumor cell behavior will be examined. We will present some of the most recent advancements in the targeting of inflammation for the treatment of GI tract cancers.