Germ-free and Colonized Mice Generate the Same Products from Enteric Prodefensins

Pütsep, Katrin; Axelsson, Lars-Göran; Boman, Anita; Midtvedt, Tore; Normark, Staffan; Boman, Hans G.; Andersson, Mats

doi:10.1074/jbc.m007816200

Cited by 126 publications

(110 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, the expression of defensins 3 and 5 synthesized predominantly by Paneth cells or neutrophils (5) was specifically reduced by the antibiotic treatment, whereas the defensins predominantly found in epithelial cells (5), ␤-defensins, were not significantly affected. Contrary to our results, Putsep et al (45) did not find any differences in the qualitative profile of prodefensin peptides present in germ-free or conventional mice. They concluded that the intestinal microbiota did not affect the production of defensins by the Paneth cells.…”

Section: Discussioncontrasting

confidence: 56%

Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome

Schumann

Nutten²,

Donnicola³

et al. 2005

Physiological Genomics

139

View full text Add to dashboard Cite

The postnatal maturation of the gut, partially modulated by bacterial colonization, ends up in the establishment of an efficient barrier to luminal antigens and bacteria. The use of broad-spectrum antibiotics in pediatric practices alters the gut bacterial colonization and, consequently, may impair the maturation of the gut barrier function. To test this hypothesis, suckling Sprague-Dawley rats received a daily intragastric gavage of antibiotic (Clamoxyl; an amoxicillin-based commercial preparation) or saline solution from postnatal day 7 (d7) until d17 or d21. Luminal microbiota composition and global gene expression profile were analyzed on samples from small intestine and colon of each group. The treatment with Clamoxyl resulted in the almost-complete eradication of Lactobacillus in the whole intestine and in a drastic reduction of colonic total aerobic and anaerobic bacteria, in particular Enterobacteriacae and Enterococcus. The global gene expression analysis revealed that Clamoxyl affects the maturation process of 249 and 149 Affymetrix probe sets in the proximal and distal small intestine, respectively, and 163 probe sets in the colon. The expression of genes coding for Paneth cell products (defensins, matrilysin, and phospholipase A2) was significantly downregulated by the Clamoxyl treatment. A significant downregulation of major histocompatibility complex (MHC) class Ib and II genes, involved in antigen presentation, was also observed. Conversely, mast cell proteases expression was upregulated. These results suggest that early treatment with a largespectrum antibiotic deeply affects the gut barrier function at the suckling-weaning interface, a period during which the gut is challenged by an array of novel food-borne antigens. innate immunity; antigen presentation; mast cell THE GASTROINTESTINAL (GI) mucosa is in constant contact with a luminal environment that contains not only nutrients but also a huge array of potentially harmful microorganisms and toxins. A healthy GI mucosa is able to handle this massive collection of antigens and modulate the immune response according to the level of hazard related to each antigen. This capacity of the GI tract is defined as gut barrier function. In infants, the intestine remains immature and relatively permeable to antigens during the first weeks of life (3,18,50). Subsequently, the postnatal maturation of the mucosal barrier reduces drastically such transfer, so that in healthy adults, only small amounts of dietary antigens can reach the circulation (22). The maturation of the intestinal barrier is the consequence of morphological and functional changes of the mucosa, which occur under genetic and endocrine control (6). However, the onset of weaning and the impact of bacterial colonization have been shown to modulate this process (11, 28). The comparison of germ-free vs. conventional microbiota animals has brought interesting clues to further our understanding of the impact of the gut microbiota on the different mechanisms involved in the gut barrier function. In...

show abstract

Section: Discussioncontrasting

confidence: 56%

Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome

Schumann

Nutten²,

Donnicola³

et al. 2005

Physiological Genomics

139

View full text Add to dashboard Cite

show abstract

“…However, in this model, lysozyme levels were also similarly decreased (47). It should also be noted that the levels of PC ␣-defensins in mice are unchanged under germ-free vs. bacterially colonized conditions (48). Therefore, although it is possible that adherent or luminal bacteria (16,18,19) that are part of the commensal microbiota in the small intestine may cause reduction in PC ␣-defensin expression, we favor the alternative hypothesis that host factors are likely the main contributors to our findings.…”

Section: Discussionmentioning

confidence: 97%

Reduced Paneth cell α-defensins in ileal Crohn's disease

Wehkamp

Salzman

Porter

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

898

809

View full text Add to dashboard Cite

The pathogenesis of Crohn s disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human ␣-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC ␣-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC ␣-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of ␣-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of ␣-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and͞or perpetuate this disease.innate immunity ͉ intestine ͉ bacteria ͉ inflammatory bowel disease

show abstract

“…PC differentiation occurs independent of microbial stimuli, as does expression of several PC products including lysozyme, sPLA2 and defensins. 19,23 However several PC products, including RegIIIγ and Angiogenins are induced by bacterial colonization via TLR stimulation.…”

Section: Pc Defensins Influence the Composition Of The Bacterial Micrmentioning

confidence: 99%

Paneth cell defensins and the regulation of the microbiome

Salzman

2010

Gut Microbes

111

View full text Add to dashboard Cite

r ecently, our laboratory demonstrated that paneth cell defensins, innate antimicrobial peptides that contribute to mucosal host defense, are able to regulate the composition of the intestinal bacterial microbiome. using complementary mouse models of defensin deficiency (mmp7 -/-) and surplus (hd5 +/+ ), we noted defensin-dependent reciprocal shifts in the dominant bacterial species of the small intestine, without changes in total bacterial numbers. in addition, mice that expressed hd5 showed a significant loss of segemented filamentous bacteria (sfB), resulting in reduced numbers of Th17 cells in the lamina propria. This data showed a novel role for pc defensins in intestinal homeostasis, by regulation of the small intestinal microbiome. The microbiome plays an essential role in mediating host physiology, metabolism and immune response. The ability of pc defensins to regulate the composition of the biome suggests a much broader importance of these innate immune effectors than previously considered. in this addendum, the role of pc defensins in the regulation of the intestinal microbiome is reviewed, and discussed in the context of recent evidence that highlights the important role of pcs and defensins in the pathophysiology of inflammatory bowel disease.

show abstract

Germ-free and Colonized Mice Generate the Same Products from Enteric Prodefensins

Cited by 126 publications

References 26 publications

Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome

Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome

Reduced Paneth cell α-defensins in ileal Crohn's disease

Paneth cell defensins and the regulation of the microbiome

Contact Info

Product

Resources

About