Match!

A New Look at Crohn's Disease

Published on Aug 1, 2006in Annals of the New York Academy of Sciences4.295
· DOI :10.1196/annals.1326.030
Jan Wehkamp43
Estimated H-index: 43
(Robert Bosch Hospital),
Eduard F. Stange40
Estimated H-index: 40
(Robert Bosch Hospital)
Abstract
: Crohn's disease (CD), a chronic inflammatory disease of the intestinal mucosa is usually located in the small intestine (ileum) and or in the colon. Ileal CD has been linked to a mutation in the NOD2 gene, a bacterial recognition protein. A disturbed antimicrobial defense as provided by an arsenal of different epithelial defensins seems to be a critical factor in disease pathogenesis. Defensins are antimicrobial peptides and in the ileum are mainly expressed in Paneth cells (PCs), epithelial cells that also express NOD2. In the colon, defensins are expressed by enterocytes or metaplastic PCs. Ileal CD patients are characterized by a reduced antibacterial activity and a specific reduction of ileal PC defensins. In ileal Crohn's patients displaying a NOD2 mutation, this decrease is even more pronounced. In contrast, CD of the colon is characterized by an impaired induction of beta defensins in enterocytes. In conclusion, the regional localizations of CD, either ileal or colonic disease, can be linked to different defects in defensin expression. In line with these new findings, we predict that future therapeutic strategies aimed at restoring the host–microbe balance at the intestinal mucosa may prove superior to those that broadly suppress inflammation and adaptive immunity.
  • References (41)
  • Citations (56)
📖 Papers frequently viewed together
200143.07Nature
20 Authors (Jean-Pierre Hugot, ..., Gilles Thomas)
4,542 Citations
758 Citations
200143.07Nature
17 Authors (Yasunori Ogura, ..., Judy H. Cho)
4,083 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References41
Newest
#1Jan Wehkamp (UC Davis: University of California, Davis)H-Index: 43
#2Nita H. Salzman (MCW: Medical College of Wisconsin)H-Index: 32
Last. Charles L. BevinsH-Index: 62
view all 17 authors...
758 CitationsSource
#1Jan Wehkamp (UC Davis: University of California, Davis)H-Index: 43
#2Michael Schmid (Robert Bosch Hospital)H-Index: 1
Last. Eduard F. Stange (Robert Bosch Hospital)H-Index: 40
view all 4 authors...
Crohn's disease is a chronic, inflamma- tory disease of the intestinal mucosa. Although in- testinal bacteria are implicated in disease patho- genesis, the etiology is still unclear. The main lo- cation of disease is the small intestine (ileum) and the colon. Ileal disease has been linked to a muta- tion in the NOD2 gene. Defensins are antimicro- bial peptides and in the ileum, are mainly ex- pressed in Paneth cells, epithelial cells that also express NOD2. In the colon, defensins are ex- presse...
127 CitationsSource
#1Koichi S. Kobayashi (Harvard University)H-Index: 40
#2Mathias Chamaillard (UM: University of Michigan)H-Index: 40
Last. Richard A. Flavell (Yale University)H-Index: 208
view all 7 authors...
1,432 CitationsSource
#1Elizabeth Furrie (Dund.: University of Dundee)H-Index: 19
#2Sandra MacfarlaneH-Index: 33
Last. G.T. MacfarlaneH-Index: 34
view all 7 authors...
Background and aims: Ulcerative colitis (UC) is an acute and chronic inflammatory disease of the large bowel with unknown aetiology. The immune response against normal commensal microorganisms is believed to drive inflammatory processes associated with UC. Therefore, modulation of bacterial communities on the gut mucosa, through the use of probiotics and prebiotics, may be used to modify the disease state. Methods: A synbiotic was developed for use in UC patients combining a probiotic, Bifidobac...
498 CitationsSource
Rather than a unique disorder, Crohn’s disease is regarded as a common denominator for various immune mediated inflammatory diseases of the gastrointestinal tract. These various subforms of Crohn’s disease are characterised by T cell mediated tissue destruction in the gut. In contrast with autoimmune diseases where autoantibodies react with self antigens, inflammation in Crohn’s disease is directed against antigens that are mainly derived from the environment.1 Although it may sound trivial, thi...
53 CitationsSource
Purpose of review Innate immune defense of the small intestine is mediated in part by antimicrobial peptides and proteins secreted by Paneth cells, epithelial cells positioned at the base of the crypts of Lieberkuhn. Recent studies have yielded better understanding of the role that Paneth cells may play in host defense. Emerging data suggest that these cells may contribute to the pathophysiology of several human diseases. A wealth of data has also emerged on the regulatory pathways of Paneth cel...
79 CitationsSource
#1Jan Wehkamp (Bosch)H-Index: 43
#2Jürgen Harder (CAU: University of Kiel)H-Index: 43
Last. Eduard F. Stange (Bosch)H-Index: 42
view all 14 authors...
Background: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn’s disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human α defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we comp...
657 CitationsSource
#1Puja VoraH-Index: 5
#2Adrienne YoudimH-Index: 2
Last. Maria T. Abreu (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 50
view all 11 authors...
The intestinal epithelium serves as a barrier to the intestinal flora. In response to pathogens, intestinal epithelial cells (IEC) secrete proinflammatory cytokines. To aid in defense against bacteria, IEC also secrete antimicrobial peptides, termed defensins. The aim of our studies was to understand the role of TLR signaling in regulation of β-defensin expression by IEC. The effect of LPS and peptidoglycan on β-defensin-2 expression was examined in IEC lines constitutively or transgenically exp...
284 CitationsSource
#1Jan Wehkamp (Robert Bosch Hospital)H-Index: 43
#2Jürgen HarderH-Index: 43
Last. Eduard F. Stange (Robert Bosch Hospital)H-Index: 40
view all 12 authors...
Little is known about the defensive mechanisms induced in epithelial cells by pathogenic versus probiotic bacteria. The aim of our study was to compare probiotic bacterial strains such as Escherichia coli Nissle 1917 with nonprobiotic, pathogenic and nonpathogenic bacteria with respect to innate defense mechanisms in the intestinal mucosal cell. Here we report that E. coli strain Nissle 1917 and a variety of other probiotic bacteria, including lactobacilli—in contrast to more than 40 different E...
370 CitationsSource
#2Jerome BoudeauH-Index: 7
Last. Jean-Frederic Colombel (French Institute of Health and Medical Research)H-Index: 129
view all 10 authors...
Abstract Background & Aims: Adherent-invasive Escherichia coli (AIEC) pathovar has been identified in the intestinal mucosa of patients with Crohn's disease (CD). AIEC reference strain LF82 is able to adhere to intestinal epithelial cells, to invade epithelial cells via a mechanism involving actin polymerization and microtubules, and to survive and replicate within macrophages. This study was performed to assess the prevalence of AIEC associated with intestinal mucosa of patients with CD, ulcera...
975 CitationsSource
Cited By56
Newest
#1Xiaolei Pei (PKU: Peking University)H-Index: 3
#2Danfeng Zheng (PKU: Peking University)H-Index: 2
Last. Ying Wang (PKU: Peking University)H-Index: 13
view all 11 authors...
Monocytes/macrophages have been found to be an important component of colitis. However, the key chemokine that initiates the CCR2+ monocytes migration from circulation to colitis tissue remains to be undiscovered. PC3-secreted microprotein (PSMP) is a novel chemokine whose receptor is CCR2. The physiological and pathological functions of PSMP have not yet been reported. In this study, PSMP was found to be expressed in colitis and colonic tumor tissues from patients and significantly up-regulated...
3 CitationsSource
#1David B. Alexander (Nagoya City University)H-Index: 18
#2Masaaki Iigo (Nagoya City University)H-Index: 29
Last. Hiroyuki Tsuda (Nagoya City University)H-Index: 53
view all 8 authors...
A 22-year-old male suffering from abdominal pain, repeated diarrhea, and weight loss visited the Digestive Disease Department of Nagoya City University Hospital on 19 December 2011. He was hospitalized and diagnosed with Crohn’s colitis. His Crohn’s Disease Activity Index (CDAI) was 415. Treatment by granulocyte apheresis, mesalazine, and adalimumab was started. His CDAI was 314 on 30 December and 215 on 5 January. A colonoscopic examination on 19 January showed almost complete remission in the ...
1 CitationsSource
#1Lorena Coretti (University of Naples Federico II)H-Index: 8
#2Alessandro Natale (University of Naples Federico II)H-Index: 2
Last. Raffaela Pero (University of Naples Federico II)H-Index: 18
view all 8 authors...
Crohn’s disease (CD) is a chronic inflammation of the intestinal mucosa, characterized by periods of acute recurrence and remission. Depending on the specific region affected, CD is classified as ileal CD or colonic CD. It is largely accepted that the intestinal microbiota is involved in the onset of the pathology. Indeed, a reduced immune tolerance to components of the intestinal commensal microbiota and inflammation of the intestinal barrier typifies patients with CD. Several studies have show...
8 CitationsSource
#1Nobuhiko KamadaH-Index: 1
#2Gerhard RoglerH-Index: 1
Background: Mononuclear phagocytes, such as monocytes, macrophages, and dendritic cells, are important cellular components of the innate immune system that contri
3 CitationsSource
#1Moritz LeppkesH-Index: 6
#2Markus F. NeurathH-Index: 99
Last. Christoph BeckerH-Index: 38
view all 4 authors...
Abstract Genome-wide association studies have provided many genetic alterations, conferring susceptibility to multifactorial polygenic diseases, such as inflammatory bowel diseases. Yet, how specific genetic alterations functionally affect intestinal inflammation often remains elusive. It is noteworthy that a large overlap of genes involved in immune deficiencies with those conferring inflammatory bowel disease risk has been noted. This has provided new arguments for the debate on whether inflam...
2 CitationsSource
#1Genaro G. OrtizH-Index: 32
view all 9 authors...
Obsevation: Endotoxic shock is a life-threatening condition and its sequelae represent an array of clinical symptoms that encompass systemic inflammation, coagulopathy, and abnormalities of the renal, hepatic, pulmonary and hematologic systems, followed by multi-organ failure. Furthermore, systemic failure leads to an unfavorable environment in the gut that causes an imbalance in the homeostasis of intestinal microbiota. In the present study, the effect of symbiotics as adjuvant therapy in endot...
Source
#1Bärbel Stecher (LMU: Ludwig Maximilian University of Munich)H-Index: 38
Genetic susceptibility, the mucosal immune system, and environmental factors such as the microbiota, stress, and diet, contribute to the pathogenesis of inflammatory bowel disease (IBD) ( 15 ). Involvement of the microbiota has been proposed early on, as microbiota manipulation by antibiotics or probiotics can treat or alleviate IBD symptoms in humans. In experimental animal models, the gut luminal microbiota is required for the induction of chronic inflammation ( 16 ). Different theories about ...
55 CitationsSource
#1Luc Biedermann (UZH: University of Zurich)H-Index: 19
#2GerhardRogler (UZH: University of Zurich)H-Index: 63
The intestinal microbiota (previously referred to as “intestinal flora”) has entered the focus of research interest not only in microbiology but also in medicine. Huge progress has been made with respect to the analysis of composition and functions of the human microbiota. An “imbalance” of the microbiota, frequently also called a “dysbiosis,” has been associated with different diseases in recent years. Crohn’s disease and ulcerative colitis as two major forms of inflammatory bowel disease, irri...
61 CitationsSource
#1Mani P Grover (Deakin University)H-Index: 3
#2Sara Ballouz (CSHL: Cold Spring Harbor Laboratory)H-Index: 10
Last. Merridee A. Wouters (Deakin University)H-Index: 24
view all 7 authors...
Human genome sequencing has enabled the association of phenotypes with genetic loci, but our ability to effectively translate this data to the clinic has not kept pace. Over the past 60 years, pharmaceutical companies have successfully demonstrated the safety and efficacy of over 1,200 novel therapeutic drugs via costly clinical studies. While this process must continue, better use can be made of the existing valuable data. In silico tools such as candidate gene prediction systems allow rapid id...
26 CitationsSource
#1Adam A. Strömstedt (Uppsala University)H-Index: 11
#2Jenny Felth (Uppsala University)H-Index: 8
Last. Lars Bohlin (Uppsala University)H-Index: 40
view all 3 authors...
Introduction: Identifying bioactive molecules from complex biomasses requires careful selection and execution of relevant bioassays in the various stages of the discovery process of potential leads ...
9 CitationsSource