Microbial host interactions in IBD: Implications for pathogenesis and therapy

Sartor, R. Balfour; Muehlbauer, Marcus

doi:10.1007/s11894-007-0066-4

Cited by 97 publications

(20 citation statements)

References 131 publications

(117 reference statements)

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“…Once this balance is shifted a dysbiosis in microbiome dynamics occurs that contributes to IBD pathogenesis [1–3]. The importance of a well balanced gastrointestinal microbiota is underlined by the findings in animals such as chickens, mice and rabbits that, when raised in germ-free (GF) or sterile conditions, have underdeveloped GI associated lymphoid tissue (GALT) and concomitant decreases in antibody profiles [2–5].…”

Section: The Microbiomementioning

confidence: 99%

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Novel Players in Inflammatory Bowel Disease Pathogenesis

Murphy

Kwon

Boone

2012

Curr Gastroenterol Rep

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Technological and conceptual advances in inflammatory bowel disease research have uncovered new mechanisms that contribute to the pathogenesis of these disorders. It is becoming increasingly clear that the microbiota of the gut and the response of intestinal cells to that microbiota can initiate or contribute to intestinal inflammation. Evidence from genetic studies have identified IBD-associated genes implicated in autophagy and innate sensing of microbes. These genes also play key roles in the homeostasis of a cell type that stands at the interface of host-microbial interaction – the Paneth cell. Here we discuss recent findings that underscore the importance of the microbiome, Paneth cells and autophagy in inflammatory bowel disease.

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Section: The Microbiomementioning

confidence: 99%

“…However there is significant evidence that the microbiome can drive intestinal inflammation [1]. In patients, intestinal diversion, and resultant reduction in lumenal flora has been successful in amelioration of symptoms of CD.…”

Section: The Microbiomementioning

confidence: 99%

Novel Players in Inflammatory Bowel Disease Pathogenesis

Murphy

Kwon

Boone

2012

Curr Gastroenterol Rep

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“…The etiopathogenesis of IBD remains unknown but is thought to involve a combination of genetic and non-genetic risk factors that regulate mucosal immune response, mucosal barrier function, and response to microbial factors [7]. Multiple epithelial molecules have been identified as mediators of IBD pathogenesis including those that control epithelial homeostasis [8].…”

Section: Introductionmentioning

confidence: 99%

Prohibitin 1 Modulates Mitochondrial Stress-Related Autophagy in Human Colonic Epithelial Cells

et al. 2012

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IntroductionAutophagy is an adaptive response to extracellular and intracellular stress by which cytoplasmic components and organelles, including damaged mitochondria, are degraded to promote cell survival and restore cell homeostasis. Certain genes involved in autophagy confer susceptibility to Crohn's disease. Reactive oxygen species and pro-inflammatory cytokines such as tumor necrosis factor α (TNFα), both of which are increased during active inflammatory bowel disease, promote cellular injury and autophagy via mitochondrial damage. Prohibitin (PHB), which plays a role in maintaining normal mitochondrial respiratory function, is decreased during active inflammatory bowel disease. Restoration of colonic epithelial PHB expression protects mice from experimental colitis and combats oxidative stress. In this study, we investigated the potential role of PHB in modulating mitochondrial stress-related autophagy in intestinal epithelial cells.MethodsWe measured autophagy activation in response to knockdown of PHB expression by RNA interference in Caco2-BBE and HCT116 WT and p53 null cells. The effect of exogenous PHB expression on TNFα- and IFNγ-induced autophagy was assessed. Autophagy was inhibited using Bafilomycin A1 or siATG16L1 during PHB knockdown and the affect on intracellular oxidative stress, mitochondrial membrane potential, and cell viability were determined. The requirement of intracellular ROS in siPHB-induced autophagy was assessed using the ROS scavenger N-acetyl-L-cysteine.ResultsTNFα and IFNγ-induced autophagy inversely correlated with PHB protein expression. Exogenous PHB expression reduced basal autophagy and TNFα-induced autophagy. Gene silencing of PHB in epithelial cells induces mitochondrial autophagy via increased intracellular ROS. Inhibition of autophagy during PHB knockdown exacerbates mitochondrial depolarization and reduces cell viability.ConclusionsDecreased PHB levels coupled with dysfunctional autophagy renders intestinal epithelial cells susceptible to mitochondrial damage and cytotoxicity. Repletion of PHB may represent a therapeutic approach to combat oxidant and cytokine-induced mitochondrial damage in diseases such as inflammatory bowel disease.

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“…In the IBD-susceptible host, aberrant TLR signaling may contribute to destructive host responses and chronic inflammation, disturbing mucosal and commensal homeostasis and leading to many different clinical phenotypes [25]. Hyperactivation of the adaptive immune system, secondary to TLR deficiency, may drive tissue damage and progressive inflammation in IBD [26,27]. Characterization of different IBD-associated gene defects have highlighted fundamental, defining variability in TLR regulation and function, dependent on disease processes and predominant cell type involvement in the intestinal mucosa [28,29].…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor activation by helminths or helminth products to alleviate inflammatory bowel disease

Sun

Wang

et al. 2011

Parasites Vectors

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Helminth infection may modulate the expression of Toll like receptors (TLR) in dendritic cells (DCs) and modify the responsiveness of DCs to TLR ligands. This may regulate aberrant intestinal inflammation in humans with helminthes and may thus help alleviate inflammation associated with human inflammatory bowel disease (IBD). Epidemiological and experimental data provide further evidence that reducing helminth infections increases the incidence rate of such autoimmune diseases. Fine control of inflammation in the TLR pathway is highly desirable for effective host defense. Thus, the use of antagonists of TLR-signaling and agonists of their negative regulators from helminths or helminth products should be considered for the treatment of IBD.

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Microbial host interactions in IBD: Implications for pathogenesis and therapy

Cited by 97 publications

References 131 publications

Novel Players in Inflammatory Bowel Disease Pathogenesis

Novel Players in Inflammatory Bowel Disease Pathogenesis

Prohibitin 1 Modulates Mitochondrial Stress-Related Autophagy in Human Colonic Epithelial Cells

Toll-like receptor activation by helminths or helminth products to alleviate inflammatory bowel disease

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