Investigating the causal relationship between inflammatory bowel disease and simple appendicitis using Mendelian randomization.

The relationship between simple appendicitis and inflammatory bowel disease (IBD) is not clear. In this study, we approach the issue from a genetic perspective, using Mendelian randomization (MR) tools to explore the potential causal connection between the two. We used GWAS data from 12,882 IBD patients (21,770 controls), 5956 crohn's disease (CD) patients (14,927 controls), 6968 ulcerative colitis (UC) patients (20,464 controls), and 4604 simple appendicitis patients (481,880 controls). These statistical data were derived from a large-scale whole-genome association study of individuals with European ancestry. The primary analytical method for inferring the causal relationship between the conditions involved the use of the Inverse Variance Weighting (IVW) method as the main approach for bidirectional MR analysis. The MR analysis results predicted IBD was associated with a lower risk of simple appendicitis (OR: 0.947 (0.911, 0.984), p = 0.005). The results for CD (OR: 0.948 (0.916, 0.981), p = 0.002) and UC (OR: 0.954 (0.917, 0.992), p = 0.020) are consistent with this finding. In the reverse MR analysis, there is no significant association between simple appendicitis and the occurrence of IBD (p > 0.05), and the same holds true for CD and UC (p > 0.05). Our MR study results suggest a potential negative causal effect of IBD on the occurrence of simple appendicitis. Conversely, there does not appear to be a significant causal relationship between simple appendicitis and the risk of developing IBD.

Gene Expression Profiling in Pediatric Appendicitis.

Importance: Appendicitis is the most common indication for urgent surgery in the pediatric population, presenting across a range of severity and with variable complications. Differentiating simple appendicitis (SA) and perforated appendicitis (PA) on presentation may help direct further diagnostic workup and appropriate therapy selection, including antibiotic choice and timing of surgery. Objective: To provide a mechanistic understanding of the differences in disease severity of appendicitis with the objective of developing improved diagnostics and treatments, specifically for the pediatric population. Design, Setting, and Participants: The Gene Expression Profiling of Pediatric Appendicitis (GEPPA) study was a single-center prospective exploratory diagnostic study with transcriptomic profiling of peripheral blood collected from a cohort of children aged 5 to 17 years with abdominal pain and suspected appendicitis between November 2016 and April 2017 at the Alberta Children's Hospital in Calgary, Alberta, Canada, with data analysis reported in August 2023. There was no patient follow-up in this study. Exposure: SA, PA, or nonappendicitis abdominal pain. Main Outcomes and Measures: Blood transcriptomics was used to develop a hypothesis of underlying mechanistic differences between SA and PA to build mechanistic hypotheses and blood-based diagnostics. Results: Seventy-one children (mean [SD] age, 11.8 [3.0] years; 48 [67.6%] male) presenting to the emergency department with abdominal pain and suspected appendicitis were investigated using whole-blood transcriptomics. A central role for immune system pathways was revealed in PA, including a dampening of major innate interferon responses. Gene expression changes in patients with PA were consistent with downregulation of immune response and inflammation pathways and shared similarities with gene expression signatures derived from patients with sepsis, including the most severe sepsis endotypes. Despite the challenges in identifying early biomarkers of severe appendicitis, a 4-gene signature that was predictive of PA compared to SA, with an accuracy of 85.7% (95% CI, 72.8-94.1) was identified. Conclusions: This study found that PA was complicated by a dysregulated immune response. This finding should inform improved diagnostics of severity, early management strategies, and prevention of further postsurgical complications.

Investigation of VGLL3 and sub-target genes in the aetiology of paediatric acute appendicitis: a prospective case-control study.

PURPOSE: Vestigial like family member 3 (VGLL3) and its sub-target genes show considerable transcriptomic overlap in terms of several autoimmune and inflammatory diseases. Herein, we investigated the role of VGLL3 rs13074432 polymorphism and its sub-target genes in the aetiology of acute appendicitis (AA). METHODS: In this prospective case-control study, we included 250 patients (age, 0-18 years) who underwent appendectomy with the diagnosis of AA (patient group; blood and appendix tissue samples) and 200 healthy children (control group; only blood samples) without appendectomy. ELISA method was used for protein-level detection of VGLL3 and sub-target genes expression change in obtained tissue samples, and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used for mRNA level detection. Genotyping analyses were performed on DNA samples isolated from blood using TaqMan SNP genotyping test. RESULTS: The frequency of TT variant genotype (p < 0.001) and T allele (p = 0.002) showed a significant decrease in the patient group compared with the control group. No significant correlation was observed between the expression of VGLL3 in the appendiceal tissue and patient clinical and demographic data (p > 0.050). CONCLUSION: This study revealed that the VGLL3 gene and its sub-target genes are associated with AA aetiology.

Detection of Enterobius vermicularis in archived formalin-fixed paraffin-embedded (FFPE) appendectomy blocks: It's potential to compare genetic variations based on mitochondrial DNA (cox1) gene.

Acute appendicitis represents one of the most common causes of emergency abdominal surgery worldwide. Meanwhile, Enterobius vermicularis has been suggested as one of the probable causes of appendicitis. In this study, the morphological characteristics of the remnant pinworms and pathologic changes were explored in old-archived FFPE tissues of appendectomies. Moreover, we provide the first molecular identification, genetic, and haplotype variation of this nematode from the old-archived FFPE tissue section of appendectomy using the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. Seventeen FFPE appendectomies with E. vermicularis infection, stored over 12-22 years, were collected from two different geographical areas of Iran. In the histopathological examination, tissue changes were observed in thirteen cases (76.4%) and inflammation in four blocks (23.5%). After DNA extraction, the cox1 gene was amplified in twelve (70.6%) cases using the nested polymerase chain reaction (PCR). Phylogenetic analysis and a median-joining network of 78 available cox1 sequences of E. vermicularis revealed 59 haplotypes. We identified five haplotypes that fell into type B. All Haplotypes are novel except for two haplotypes, Hap32 and Hap37, identical to E. vermicularis sequences from Iran, Greece, and Germany. The ranges of diversity distance and haplotype diversity within the isolates were 0-1.9% and HD:0.643-0.667, subsequently. Overall, the absence of inflammation or even tissue changes in some sections can suggest the possible non-inflammatory role of E. vermicularis in appendicitis. Although FFPE material suffers from PCR inhibition, we could successfully use nested PCR to characterize E. vermicularis in old-archived appendectomy blocks and suggest this method as a complementary diagnosis technique in pathology. While the predominant type was B in the Middle East and Europe, further studies on a larger sample size from different geographical regions could probably confirm the results obtained in the present study.

Differential expression of Chitinase 3-Like 1 protein in appendicitis and appendix carcinomas.

BACKGROUND: Chitinase 3-Like 1 (CHI3L1) has been used as an inflammatory biomarker for a variety of diseases, but its expression in acute appendicitis and appendix carcinomas remains unclear. METHODS: Sixty cases of patients were studied, including 46 acute appendicitis and 14 appendix carcinomas. We divided the acute appendicitis group into acute uncomplicated appendicitis (AUA), suppurative appendicitis (SA), and gangrenous appendicitis (GA). The appendix carcinoma group was divided into appendiceal neuroendocrine neoplasms (ANENs) and appendiceal mucinous neoplasms (AMN). Controls were 32 healthy donors. Blood neutrophil to lymphocyte ratio (NLR), CHI3L1, C-reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A (SAA) were measured in the patients. Meanwhile, immunohistochemistry and immunofluorescence were used to identify the expression level and location of CHI3L1 in different cell types in appendix tissues. RESULTS: Compared with the controls, CHI3L1 serum levels were up-regulated in SA, GA, and AMN groups, while no significant difference was observed in the AUA and ANEN groups. Immunofluorescence revealed that CHI3L1 expression was high in macrophages and adenocarcinoma cells of appendix tissues but not in the neuroendocrine carcinoma tissues. Moreover, levels of NLR and CRP in the SA and GA groups were considerably higher than in the control group. IL-6 and SAA in SA, GA, ANENs, and AMN groups were also increased compared with the control group. In addition, CHI3L1 displayed good performance in predicting appendicitis, with an AUC of 0.862. CONCLUSION: CHI3L1 was highly expressed in acute appendicitis and appendiceal mucinous neoplasms, which can be used as a novel biomarker predicting appendicitis.

Distribution of RET proto-oncogene variants in children with appendicitis.

BACKGROUND: In addition to patient-related systemic factors directing the immune response, the pathomechanisms of appendicitis (AP) might also include insufficient drainage leading to inflammation caused by decreased peristalsis. Genetic predisposition accounts for 30%-50% of AP. M. Hirschsprung (HSCR), also characterized by disturbed peristalsis, is associated with variants in the RET proto-oncogene. We thus hypothesized that RET variants contribute to the etiology of AP. METHODS: DNA from paraffin-embedded appendices and clinical data of 264 children were analyzed for the RET c.135A>G variant (rs1800858, NC_000010.11:g.43100520A>G). In 46 patients with gangrenous or perforated AP (GAP), peripheral blood DNA was used for RET sequencing. RESULTS: Germline mutations were found in 13% of GAP, whereas no RET mutations were found in controls besides the benign variant p.Tyr791Phe (NC_000010.11:g.43118460A>T). In GAP, the polymorphic G-allele in rs2435352 (NC_000010.11:g.43105241A>G) in intron 4 was underrepresented (p = 0.0317). CONCLUSION: Our results suggest an impact of the RET proto-oncogene in the etiology of AP. Mutations were similar to patients with HSCR but no clinical features of HSCR were observed. The pathological phenotypes in both populations might thus represent a multigenic etiology including RET germline mutations with phenotypic heterogeneity and incomplete penetrance.

Association Between NEDD4L Variation and the Genetic Risk of Acute Appendicitis: A Multi-institutional Genome-Wide Association Study.

Importance: The familial aspect of acute appendicitis (AA) has been proposed, but its hereditary basis remains undetermined. Objective: To identify genomic variants associated with AA. Design, Setting, and Participants: This genome-wide association study, conducted from June 21, 2019, to February 4, 2020, used a multi-institutional biobank to retrospectively identify patients with AA across 8 single-nucleotide variation (SNV) genotyping batches. The study also examined differential gene expression in appendiceal tissue samples between patients with AA and controls using the GSE9579 data set in the National Institutes of Health's Gene Expression Omnibus repository. Statistical analysis was conducted from October 1, 2019, to February 4, 2020. Main Outcomes and Measures: Single-nucleotide variations with a minor allele frequency of 5% or higher were tested for association with AA using a linear mixed model. The significance threshold was set at P = 5 × 10-8. Results: A total of 29 706 patients (15 088 women [50.8%]; mean [SD] age at enrollment, 60.1 [17.0] years) were included, 1743 of whom had a history of AA. The genomic inflation factor for the cohort was 1.003. A previously unknown SNV at chromosome 18q was found to be associated with AA (rs9953918: odds ratio, 0.99; 95% CI, 0.98-1.00; P = 4.48 × 10-8). This SNV is located in an intron of the NEDD4L gene. The heritability of appendicitis was estimated at 30.1%. Gene expression data from appendiceal tissue donors identified NEDD4L to be among the most differentially expressed genes (14 of 22 216 genes; ß [SE] = -2.71 [0.44]; log fold change = -1.69; adjusted P = .04). Conclusions and Relevance: This study identified SNVs within the NEDD4L gene as being associated with AA. Nedd4l is involved in the ubiquitination of intestinal ion channels and decreased Nedd4l activity may be implicated in the pathogenesis of AA. These findings can improve the understanding of the genetic predisposition to and pathogenesis of AA.

Stromal Cells Covering Omental Fat-Associated Lymphoid Clusters Trigger Formation of Neutrophil Aggregates to Capture Peritoneal Contaminants.

The omentum is a visceral adipose tissue rich in fat-associated lymphoid clusters (FALCs) that collects peritoneal contaminants and provides a first layer of immunological defense within the abdomen. Here, we investigated the mechanisms that mediate the capture of peritoneal contaminants during peritonitis. Single-cell RNA sequencing and spatial analysis of omental stromal cells revealed that the surface of FALCs were covered by CXCL1+ mesothelial cells, which we termed FALC cover cells. Blockade of CXCL1 inhibited the recruitment and aggregation of neutrophils at FALCs during zymosan-induced peritonitis. Inhibition of protein arginine deiminase 4, an enzyme important for the release of neutrophil extracellular traps, abolished neutrophil aggregation and the capture of peritoneal contaminants by omental FALCs. Analysis of omental samples from patients with acute appendicitis confirmed neutrophil recruitment and bacterial capture at FALCs. Thus, specialized omental mesothelial cells coordinate the recruitment and aggregation of neutrophils to capture peritoneal contaminants.

Simultaneous acute appendicitis in identical twin boys.

Acute appendicitis is one of the most common causes of abdominal pain in children but remains a diagnostic challenge, and insight into the aetiology of the condition is lacking. A case of simultaneous acute appendicitis in monozygotic twin boys is reported here. Familial aggregation in acute appendicitis has been described, but the underlying causes for this are not well understood. The patients reported here were both genetically identical and lived a mostly identical lifestyle. Their simultaneous presentation would be exceedingly rare if explained entirely by chance, suggesting a role for both genetic and environmental influences. Increased knowledge of this occurrence may assist in prompt diagnosis and reporting on the incidence and timing of appendicitis in monozygotic twins could better elucidate the genetic and environmental factors that predispose to this disease.

Low mitochondrial DNA copy number of resected cecum appendix correlates with high severity of acute appendicitis.

BACKGROUND/PURPOSE: The roles of mitochondrial DNA alterations in acute appendicitis (AA) remain unclear. We evaluated the alterations of mtDNA copy number and mtDNA integrity [proportion of mtDNA templates without 8-hydroxyl-2'-deoxyguanosine (8-OHdG)] of the resected cecum appendixes in clinically suspected acute appendicitis (CSAA). METHODS: A total of 228 CSAA patients, including 50 harbored negative AA (NAA), 155 true AA (TAA) without rupture and 23 TAA with rupture, who underwent appendectomies were enrolled. Tissues of resected cecum appendixes from the paraffin-embedded pathological blocks were subjected to DNA extraction, and their mtDNA copy number and mtDNA integrity were determined by quantitative real-time polymerase chain reaction (Q-PCR). RESULTS: During the progression of disease severity from NAA to TAA without rupture and further TAA with rupture, increases of white blood cell (WBC) counts (p = 0.001), positive bacterial culture rates in turbid ascites (p = 0.016) and area (p < 0.001)/or volume (p < 0.001) indices of resected cecum appendixes were noted among CSAA patients. On the contrary, decrease of mtDNA copy number (p = 0.003) was observed during disease progression of CSAA patients, especially in female patients (p = 0.007). Furthermore, lower mtDNA copy numbers were correlated with higher WBC counts (p = 0.001) and larger area (p = 0.003) or volume (p < 0.001) indices of the resected cecum appendixes. However, such an alteration was not observed in mtDNA integrity of resected cecum appendixes. CONCLUSION: We conclude that a low mtDNA copy number of the resected cecum appendix may reflect high severity of acute appendicitis.

The Role of Specific Chemokines in the Amelioration of Colitis by Appendicitis and Appendectomy.

The appendix contains abundant lymphoid tissue and is constantly exposed to gut flora. When completed at a young age, appendicitis followed by appendectomy (AA) prevents or significantly ameliorates Inflammatory Bowel Diseases (IBDs) in later life. Inflammatory bowel disease comprises Crohn's disease and ulcerative colitis. Our murine AA model is the only existing experimental model of AA. In our unique model, AA performed in the most proximal colon limits colitis pathology in the most distal colon by curbing T-helper 17 cell activity, diminishing autophagy, modulating interferon activity-associated molecules, and suppressing endothelin vaso-activity-mediated immunopathology. In the research presented in this paper, we have examined the role of chemokines in colitis pathology with our murine AA model. Chemokines are a family of small cytokines with four conserved cysteine residues. Chemokines induce chemotaxis in adjacent cells with corresponding receptors. All 40 known chemokine genes and 24 chemokine receptor genes were examined for gene expression levels in distal colons three days post-AA and 28 days post-AA. At 28 days post-AA, the chemokine gene CCL5 was significantly upregulated. Furthermore, Gene Set Enrichment Analysis (GSEA) showed upregulation of seven CCL5-associated gene-sets 28 days post-AA in contrast to just one gene-set downregulated at the same time-point. The chemokine gene CXCL11 was significantly upregulated three days post-AA and 28 days post-AA. Evaluation using GSEA showed upregulation of six CXCL11-associated gene sets but no downregulation of any gene set. At 28 days post-AA, CCL17 gene expression was significantly downregulated. There was no expression of any chemokine receptor gene three days post-AA, but CCR10 was the only chemokine receptor gene that displayed differential gene expression (upregulation) 28 days post-AA. No CCR10-associated gene set was upregulated in GSEA in contrast to one downregulated gene set. Our analysis resulted in identifying three new therapeutic targets towards ameliorating colitis: CCL5, CXCL11, and CCL17. While CCL5 and CXCL11 are good therapeutic chemokine candidates to be exogenously administered, CCL17 is a good candidate chemokine to competitively inhibit or limit colitis pathology.

Familial history aggregation on acute appendicitis.

Appendectomy is the most commonly performed surgical procedure, affecting 1%-8% of the paediatric population, with a total 7% lifetime risk, most likely in adolescents and young adults.A case of familial aggregation was reported in our hospital in a family composed of nine siblings from which six of them (66.6%) had been treated of acute appendicitis, five of them in our centre.Many factors have been described as predisposing to appendicitis. Several studies have highlighted the influence of genes in the evolution of this disease and its severity, demonstrating a relative risk increase by three when family history is present.Family history of acute appendicitis is an important factor to be taken into consideration during the medical interview. Clinicians attempting to fine-tune their diagnostic accuracy when patients present with acute abdominal pain should inquire about family history of appendicitis.

Sequence variant at 4q25 near PITX2 associates with appendicitis.

Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10-11). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk.

Role of endothelial nitric oxide synthases system on acute appendicitis.

BACKGROUND: Obstruction and inflammation of the appendix lumen is the leading physiopathological process during acute appendicitis (AA). Although the relationship between inflammation and endothelial nitric oxide synthases (eNOS) has been well described, no recent data describing the relationship between inflammation during AA and polymorphism of the eNOS gene has been reported. Given the limited data available, we believed that defining the relationship between AA and eNOS would be a beneficial contribution. METHODS: A total of 201 patients admitted to the emergency department with AA and 201 healthy volunteers selected from among the relatives of patients were included. Polymorphism of the eNOS was assessed. RESULTS: Intron 4a/4a was positive in 119 participants, genotype G894T GT was positive in 71 patients with AA, and 786-1 was positive in 71 patients with AA. These results suggest that no statistically significant correlation exists between genotypes of AA patients and control subjects regarding 4a/b, G894-GT, and 786-1 eNOS polymorphisms. CONCLUSION: Though the present results suggest that no statistically significant correlation exists between AA and eNOS gene polymorphism, to claim otherwise is also impractical. We believe that the present results will lay the groundwork for future, larger studies.

Polymorphisms in the IL-6 and IL-6R receptor genes as new diagnostic biomarkers of acute appendicitis: a study on two candidate genes in pediatric patients with acute appendicitis.

BACKGROUND: Acute appendicitis (AA) (OMIM: 107700) is an inflammatory disease which is characterized by appendiceal inflammation. Genetic and environmental factors contribute to the development of AA. Especially, multiple genetic factors appear to be promising in the explanation of etiopathogenesis of AA. IL-6 (Interleukin-6) is an inflammatory cytokine and IL-6 receptor (IL-6R) plays an important role in the immune response. IL-6 (-572G/C rs1800796) and IL-6R (1:G.154448302 T > C rs7529229) gene polymorphisms may have an impact on cytokine production, immune response and these gene polymorphisms may be used as inflammatory markers in the diagnosis of appendicitis. METHOD: A total of 75 children with appendicitis, and 75 healthy children were included in the study. DNA extracts were obtained from peripheral lymphocytes. Single-nucleotide polymorphisms (SNPs) were analysed using an automated SYBR® Green RT-PCR system in pediatric patients with appendicitis (n = 75) and healthy controls (n = 75). RESULTS: The allele and genotype frequencies for IL-6 rs1800796 and IL-6R rs7529229 polymorphisms were not different between the study groups (p > 0.05). Any statistically significant differences as for age, sex and other laboratory factors were not detected between the patients with appendicitis for genotype-allele frequencies (p > 0.05). Still in analyses performed to determine correlations among age, and gender of the patients, routine laboratory parameters and allele-genotype frequencies, a statistically significant intergroup difference was not detected. Genotype and allele frequencies were consistent with Hardy-Weinberg equilibrium (HWE) in all groups. DISCUSSION: This is the first study to investigate the effects of functional two polymorphisms on IL-6 and IL-6R genes in a pediatric patient group with AA risk. With this study we investigated the contribution of IL-6 (-572G/C rs1800796) and IL-6R (1:G.154448302 T > C rs7529229) polymorphisms on pathogenesis, and severity of AA in pediatric patients with AA: These results will guide further genetic researches to be performed on the role of IL-6 and IL-6R in AA. CONCLUSIONS: Given the putative biological importance of this SNPs, these emerging data can provide a new foundation to stimulate future debate and genetic investigations of AA, focusing on new molecular mechanisms such as other IL gene polymorphisms, particularly in accessible peripheral tissues for novel molecular diagnostics for appendicitis.

Endothelial Fas-Ligand in Inflammatory Bowel Diseases and in Acute Appendicitis.

Fas-mediated induction of apoptosis is a major factor in the selection of lymphocytes and downregulation of immunological processes. In the present study, we have assessed endothelial Fas-ligand (FasL) expression in normal human ileum, appendix, and colon, and compared the expression levels with that in inflammatory bowel disease and in acute appendicitis. In a normal appendix, endothelial FasL levels were constant in almost half of the mucosal vessels; but, in the normal ileum and colon, endothelial FasL was practically restricted to areas in close proximity to lymphatic follicles, and was expressed mainly in the submucosal aspect of the follicles in the vessels with high endothelium. In samples from subjects with either Crohn's disease or ulcerative colitis, the extent of endothelial FasL expression was elevated in the submucosa and associated with an elevated number of lymphoid follicles. In inflammatory bowel disease, ulcers and areas with a high density of mononuclear cells expressing FasL also showed an elevated density of blood vessels with endothelial FasL expression. Although the function of endothelial FasL remains unclear, such a specific expression pattern suggests that endothelial FasL expression has a role in the regulation of lymphocyte access to the peripheral lymphoid tissues, including the intestinal mucosa.

Characteristic changes in microbial community composition and expression of innate immune genes in acute appendicitis.

Appendicitis represents a common and severe gastrointestinal illness in younger individuals worldwide. The disease is characterized by an excessive inflammatory response and it is believed that bacterial overgrowth due to blockage of the appendix lumen might be involved. Despite the high incidence, only limited data on the pathophysiological changes exist; in particular, the innate immune responses involved are largely unknown. Real-time PCR analysis of tissue samples from inflamed and normal appendices demonstrated differentially regulated expression patterns of epithelial-derived antimicrobial peptides (AMP). The α-defensins human neutrophil peptides 1-3, HD5 and HD6, as well as the two ß-defensins, human ß-defensins (hBD)-2 and hBD-3, were up-regulated, whereas hBD-1 was down-regulated in acute appendicitis. Expression of upstream regulators of AMP expression, NOD-2 and TLRs 1, 2, 4, 5, 7, 8 and 10 was significantly increased as detected by real-time PCR. Finally, we confirmed the involvement of the pro-inflammatory cytokines IL-1ß and IL-8, and detected characteristic changes in microbial community composition in appendicitis tissue specimens by 16S rDNA based detection techniques. In this study, we demonstrate a differential regulation of the innate immune system along with an altered bacterial diversity in acute appendicitis.

Increased levels of deleted in malignant brain tumours 1 (DMBT1) in active bacteria-related appendicitis.

AIMS: Deleted in malignant brain tumours 1 (DMBT1; gp340) is a secreted glycoprotein which is found in the surface lining epithelia of human small and large intestine. DMBT1 is suggested to play a role in enterocyte differentiation and surface protection from intestinal bacteria. The aim of this study was to elucidate DMBT1 expression in bacteria-related active intestinal inflammation such as appendicitis. METHODS AND RESULTS: mRNA and protein levels of DMBT1 were analysed in surgical resections of 50 appendices (active inflammation: n = 25). In non-actively inflamed appendices, inter-individual differences in basal DMBT1 levels of enterocytes and some non-epithelial cells were found. In active appendicitis, enterocytic DMBT1 mRNA expression was increased approximately fivefold, which was paralleled by a corresponding increase of cytoplasmic and secreted DMBT1 protein levels. Increased DMBT1 expression was predominant in enterocytes adjacent to erosive lesions or ulcers. CONCLUSIONS: Our data demonstrate that bacteria-related active inflammation results in a sharp increase of DMBT1 levels in enterocytes. These findings substantiate the view that DMBT1 is of functional relevance for host defence and modulation of the course of intestinal bacteria-related inflammatory responses.