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Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions of the intestinal tract. IBD are believed to result from an inappropriate immune response against the intestinal flora in genetically predisposed patients. The precise etiology of these diseases is not fully understood, therefore treatments rely on the dampening of symptoms, essentially inflammation, rather than on the cure of the disease. Despite the availability of biologics, such as anti-TNF antibodies, some patients remain in therapeutic failure and new treatments are thus needed. The multiligand receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in inflammatory reactions and immune system activation. Here, we investigated the role of RAGE in intestinal inflammation and its potential as a therapeutic target in IBD. We showed that RAGE was upregulated in inflamed tissues from IBD patients compared to controls. Rage−/−mice were less susceptible to intestinal and colonic inflammation development than WT mice. WT mice treated with the RAGE-specific inhibitor FPS-ZM1 experienced less severe enteritis and colitis. We demonstrated that RAGE could induce intestinal inflammation by promoting oxidative stress and endothelial activation which were diminished by FPS-ZM1 treatment. Our results revealed the RAGE signaling pathway as a promising therapeutic target for IBD patients.

Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions of the intestinal tract. IBD are believed to result from an inappropriate immune response against the intestinal flora in genetically predisposed patients. The precise etiology of these diseases is not fully understood, therefore treatments rely on the dampening of symptoms, essentially inflammation, rather than on the cure of the disease. Despite the availability of biologics, such as anti-TNF antibodies, some patients remain in therapeutic failure and new treatments are thus needed. The multiligand receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in inflammatory reactions and immune system activation. Here, we investigated the role of RAGE in intestinal inflammation and its potential as a therapeutic target in IBD. We showed that RAGE was upregulated in inflamed tissues from IBD patients compared to controls. Rage−/−mice were less susceptible to intestinal and colonic inflammation development than WT mice. WT mice treated with the RAGE-specific inhibitor FPS-ZM1 experienced less severe enteritis and colitis. We demonstrated that RAGE could induce intestinal inflammation by promoting oxidative stress and endothelial activation which were diminished by FPS-ZM1 treatment. Our results revealed the RAGE signaling pathway as a promising therapeutic target for IBD patients.

ObjectiveNatural history of paediatric-onset ulcerative proctitis (UP) is poorly described. Our aim was to describe the phenotype and disease course of incident UP in a population-based study of paediatric-onset UC.Patients and methodsAll patients with UC diagnosed <17 years from 1988 to 2004, and followed during >2 years have been extracted from a population-based registry. UC location was defined according to the Paris classification. Cumulative risks for use of immunosuppressants (IS), anti-tumour necrosis factor alpha (TNF-α) therapy, colonic extension and colectomy were described using Kaplan-Meier method. Risk factors for colonic extension were assessed using Cox proportional hazards models.Results158 patients with paediatric-onset UC (91 females) with a median age at diagnosis of 14.5 years (Q1: 11.4–Q3: 16.1) have been identified and followed during a median of 11.4 years (8.2–15.8). Among them, 25% had UP (E1) at diagnosis and 49% of them presented a colonic extension at maximal follow-up. In these children, the cumulative risk for colonic extension was 10% at 1 year, 45% at 5 years and 52% at 10 years. No parameter at diagnosis was associated with colonic extension in the UP (E1 group). IS use was significantly lower in patients with UP than in those with E2, E3 or E4 location (p=0.049). For the UP cohort, the cumulative risk for colectomy was 3% at 1 year, 10% at 5 years, 13% at 10 years and 13% at 15 years. Risks for colonic extension, treatment with anti-TNF-α and colectomy did not differ between the E1 group and the E2–E3–E4 group.ConclusionsUP is frequent in paediatric-onset UC and should not be considered as a minor disease. Compared with more extensive UC locations, risks for colonic extension, anti-TNF-α therapy and colectomy were similar in UP, whereas the risk for use of IM was lower.

BACKGROUND & AIMS: Familial aggregation argues for genetic susceptibility to Crohn's disease. The aim of this study was to compare the age of onset and the clinical features of Crohn's disease between patients with familial disease and those with sporadic disease and investigate the concordance for disease location and type among relatives with Crohn's disease. METHODS: Seventy-two families with 2 (n = 55), 3 (n = 8), 4 (n = 6), and 5 or more (n = 3) affected first- degree relatives were selected for the study. A population of 1377 patients with sporadic nonfamilial Crohn's disease was used for comparison. RESULTS: Clinical data were obtained from 176 patients with familial Crohn's disease (79 men and 97 women). Median age at onset was younger in familial Crohn's disease than in sporadic cases: 22 vs. 26.5 years (P < 0.01). In familial cases, fewer patients had exclusively colonic involvement and more patients had both small bowel and colonic involvement. Among relatives of families with 2 affected members, 56% were concordant for disease location and 49% for disease type. These percentages reached 83% and 76%, respectively, within families with more than 2 affected members. CONCLUSIONS: Patients with familial Crohn's disease are characterized by an early age at onset with more extensive disease and may represent a homogeneous clinical subgroup with a particularly strong genetic influence. (Gastroenterology 1996 Sep;111(3):604-7)

ABSTRACTCrohn’s disease (CD) results from a complex interplay between host genetic factors and endogenous microbial communities. In the current study, we used Ion Torrent sequencing to characterize the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in patients with CD and their nondiseased first-degree relatives (NCDR) in 9 familial clusters living in northern France-Belgium and in healthy individuals from 4 families living in the same area (non-CD unrelated [NCDU]). Principal component, diversity, and abundance analyses were conducted, and CD-associated inter- and intrakingdom microbial correlations were determined. Significant microbial interactions were identified and validated using single- and mixed-species biofilms. CD and NCDR groups clustered together in the mycobiome but not in the bacteriome. Microbiotas of familial (CD and NCDR) samples were distinct from those of nonfamilial (NCDU) samples. The abundance of Serratia marcescensand Escherichia coliwas elevated in CD patients, while that of beneficial bacteria was decreased. The abundance of the fungus Candida tropicaliswas significantly higher in CD than in NCDR (P= 0.003) samples and positively correlated with levels of anti-Saccharomyces cerevisiaeantibodies (ASCA). The abundance of C. tropicaliswas positively correlated with S. marcescensand E. coli, suggesting that these organisms interact in the gut. The mass and thickness of triple-species (C. tropicalisplus S. marcescensplus E. coli) biofilm were significantly greater than those of single- and double-species biofilms. C. tropicalisbiofilms comprised blastospores, while double- and triple-species biofilms were enriched in hyphae. S. marcescensused fimbriae to coaggregate or attach with C. tropicalis/E. coli, while E. coliwas closely apposed with C. tropicalis. Specific interkingdom microbial interactions may be key determinants in CD.IMPORTANCEHere, we characterized the gut bacterial microbiota (bacteriome) and fungal community (mycobiome) in multiplex families with CD and healthy relatives and defined the microbial interactions leading to dysbiosis in CD. We identified fungal (Candida tropicalis) and bacterial (Serratia marcescensand Escherichia coli) species that are associated with CD dysbiosis. Additionally, we found that the level of anti-Saccharomyces cerevisiaeantibodies (ASCA; a known CD biomarker) was associated with the abundance of C. tropicalis. We also identified positive interkingdom correlations between C. tropicalis, E. coli, and S. marcescensin CD patients and validated these correlations using in vitrobiofilms. These results provide insight into the roles of bacteria and fungi in CD and may lead to the development of novel treatment approaches and diagnostic assays.