scholarly journals A specific gene-microbe interaction drives the development of Crohn’s disease–like colitis in mice

2019 ◽  
Vol 4 (34) ◽  
pp. eaaw4341 ◽  
Author(s):  
R. Caruso ◽  
T. Mathes ◽  
E. C. Martens ◽  
N. Kamada ◽  
A. Nusrat ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Inflammation ◽  
Intestinal Bacteria ◽  
Specific Gene ◽  
Inflammatory Disorder ◽  
Phagocyte Nadph Oxidase ◽  
Abnormal Immune Response ◽  
Marked Accumulation ◽  
Combined Deficiency

Bacterial dysbiosis is associated with Crohn’s disease (CD), a chronic intestinal inflammatory disorder thought to result from an abnormal immune response against intestinal bacteria in genetically susceptible individuals. However, it is unclear whether dysbiosis is a cause or consequence of intestinal inflammation and whether overall dysbiosis or specific bacteria trigger the disease. Here, we show that the combined deficiency of NOD2 and phagocyte NADPH oxidase, two CD susceptibility genes, triggers early-onset spontaneous TH1-type intestinal inflammation in mice with the pathological hallmarks of CD. Disease was induced byMucispirillum schaedleri, a Gram-negative mucus-dwelling anaerobe. NOD2 and CYBB deficiencies led to marked accumulation ofMucispirillum, which was associated with impaired neutrophil recruitment and killing of the bacterium by luminal neutrophils. Maternal immunoglobulins againstMucispirillumprotected mutant mice from disease during breastfeeding. Our results indicate that a specific intestinal microbe triggers CD-like disease in the presence of impaired clearance of the bacterium by innate immunity.

scholarly journals Oral Manifestations of Crohn’s Disease: A Case Report and Review of the Literature

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Victoria L. Woo
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Failure To Thrive ◽  
Intestinal Bacteria ◽  
Inflammatory Disorder ◽  
Oral Manifestations ◽  
Initial Manifestation ◽  
Presenting Symptoms ◽  
Early Markers ◽  
Delayed Growth

Crohn’s disease (CD) is an inflammatory disorder of the gastrointestinal tract that is likely caused by an inappropriate mucosal inflammatory response to intestinal bacteria in a genetically predisposed host. The lesions of CD can involve any region of the GI tract as well as extraintestinal sites such as the skin, joints, and eyes. The most common presenting symptoms are abdominal pain and prolonged diarrhea associated with fevers, fatigue, and malaise. Delayed growth and failure to thrive may also be observed in pediatric patients. Oral manifestations of CD are known as oral CD and may precede GI involvement, thus serving as early markers of this condition. We describe a 6-year-old male who presented with oral lesions as his initial manifestation of disease and review the current literature pertaining to oral CD.

scholarly journals Irgm1-deficiency leads to myeloid dysfunction in colon lamina propria and susceptibility to the intestinal pathogenCitrobacter rodentium

2019 ◽  
Author(s):  
Gregory A. Taylor ◽  
Hsin-I Huang ◽  
Brian E. Fee ◽  
Nourhan Yousssef ◽  
Viviana Cantillana ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Lamina Propria ◽  
Host Defense ◽  
Intestinal Inflammation ◽  
Myeloid Cells ◽  
Intestinal Bacteria ◽  
Citrobacter Rodentium ◽  
Intracellular Killing ◽  
Host Mortality

AbstractIRGMand its mouse orthologueIrgm1are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity.IRGMdysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility toCitrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to controlC. rodentiumoutgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing ofC. rodentiumor exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response toC. rodentiuminfection and are essential forC. rodentiumimmunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced byC. rodentiuminfection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction.Author SummaryIntestinal macrophages are seeded by peripheral monocytes that enter the intestine and mature into an essential component of immune defense. While this process is shaped by intestinal bacteria, the mechanisms that regulate the process, and their roles in host defense to enteric pathogens are poorly defined. We find thatIrgm1– the orthologue of the human Crohn’s disease resistance gene,IRGM– is required for monocyte/macrophage remodeling in response to the gram-negative enteric pathogenCitrobacter rodentium, with absence of Irgm1 leading to systemic spread of the bacterium and host mortality. Failure to remodel colonic monocytes/macrophages was due to a key requirement for Irgm1 in colon-infiltrating monocytes, which underwent dramatically high rates of cell death, specifically during the setting of enteric bacterial infection. While Irgm1/IRGM proteins are well appreciated for their role in regulating intracellular bacterial killing, our results expand the paradigm for Irgm1/IRGM-mediated host defense by demonstrating an essential function for Irgm1/IRGM to control the survival and population remodeling of monocytes and macrophages that expand during enteric infection and defend against pathogenic bacteria. These findings have significant implications for the genesis of Crohn’s disease in individuals that carryIRGMvariants.

XI. Novel mouse models to study pathogenic mechanisms of Crohn's disease

2000 ◽  
Vol 278 (5) ◽  
pp. G665-G669 ◽  
Author(s):  
Theresa T. Pizarro ◽  
Kristen O. Arseneau ◽  
Fabio Cominelli
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mouse Models ◽  
Intestinal Inflammation ◽  
The United States ◽  
Inflammatory Disorder ◽  
Chronic Inflammatory Disorder ◽  
Therapeutic Modalities ◽  
Genetically Manipulated ◽  
Chronic Intestinal Inflammation

Crohn's Disease (CD) affects more than 500,000 individuals in the United States and represents the second most common chronic inflammatory disorder after rheumatoid arthritis. Although major advances have been made in defining the basic mechanisms underlying chronic intestinal inflammation, the precise etiopathogenesis of CD remains unknown. We have recently characterized two novel mouse models of enteritis that express a CD-like phenotype, namely the TNF ΔARE model of tumor necrosis factor (TNF) overexpression and the SAMP1/Yit model of spontaneous ileitis. The unique feature of these models is that they closely resemble CD for location and histopathology. These genetically manipulated new models of intestinal inflammation offer a powerful tool to investigate potential causes of human disease and may allow the development of novel disease-modifying therapeutic modalities for the treatment of CD.

scholarly journals P087 The role of bile acids in mediating fibrosis in inflammatory bowel disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S187-S187
Author(s):  
K Hazel ◽  
N McGinley ◽  
A O’Toole ◽  
S Keely
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Bile Acids ◽  
Intestinal Inflammation ◽  
Smooth Muscle Actin ◽  
Significant Inhibition ◽  
Inflammatory Disorder ◽  
Protective Effects ◽  
Alpha Smooth Muscle Actin ◽  
Naturally Occurring

Abstract Background Crohn’s disease is a chronic inflammatory disorder of the gastrointestinal tract that affects approximately 15,000 people in Ireland. 10% of these patients will develop fibrostenosing disease, usually requiring surgery. There are currently no antifibrotic medications in use for the treatment of fibrostenosing CD. Bile acids (BAs), produced in the liver and classically known for their roles in facilitating fat absorption from the diet, have previously been shown to have the capacity to regulate fibroblast activation and to exert protective effects against both hepatic fibrosis and intestinal inflammation. Therefore, altered mucosal fibroblast function in response to luminal BAs may be an important factor in the pathogenesis of fibrostenosing Crohn’s disease. Our aim is to determine if treatment of fibroblasts under pro-fibrotic conditions with naturally occurring BAs decreases markers associated with fibrosis. Methods NIH/3T3, a murine fibroblast cell line, were treated with TGF-ß (5 ng/ml) to induce their activation and transition to myofibroblasts in the absence or presence of varying concentrations of the naturally-occurring BAs, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) over 24 hours. qPCR was employed to determine expression of alpha-smooth muscle actin (aSMA), an important marker for ECM deposition and fibrosis. Results Treatment of fibroblasts with DCA within the range of normal physiological concentrations (50 to 200 µM) induced a significant inhibition of TGF-ß-induced aSMA expression. At a concentration of 100 µM, DCA reduced TGF-ß-induced responses by 50%, compared to cells treated with TGF-ß-alone (RQ=2.17; RQ=4.58, respectively) (n=6) (p=0.0031) (Figure 1). Similarly, treatment with UDCA at supraphysiological concentrations (500 µM) decreased aSMA expression following TGF-ß stimulation (RQ=1.75; RQ=3.69, respectively) (n=5) (Figure 2). Treatment with conjugated BAs TDCA and TUDCA suggest an intracellular mechanism of action by DCA and UDCA. INT-777, the specific agonist of the TGR5 bile acid receptor, also reduced TGF-ß-induced aSMA expression, suggesting this receptor may be involved in mediating the effects of naturally-occurring BAs. Figure 1: Figure 2: Conclusion We have shown that treatment of fibroblasts under pro-fibrotic conditions with the BAs, DCA and UDCA, results in a significant decrease in aSMA expression. These data suggest that BAs represent a promising target for the development of new anti-fibrotic agents to treat/prevent fibrostenosing CD.

scholarly journals Bacterial Characteristics of Intestinal Tissues From Patients With Crohn’s Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Desen Sun ◽  
Xiaolong Ge ◽  
Shasha Tang ◽  
Yaxin Liu ◽  
Jun Sun ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Species Diversity ◽  
Crohn's Disease ◽  
Intestinal Inflammation ◽  
Bacterial Load ◽  
Intestinal Bacteria ◽  
Associated Bacteria ◽  
Microbiological Methods ◽  
Highly Correlated ◽  
Specific Species

Background and AimsIt is believed that intestinal bacteria play an indispensable role in promoting intestinal inflammation. However, the characteristics of these tissue-associated bacteria remain elusive. The aim of this study is to explore the bacterial loads, compositions, and structures in the noninflamed mucosa, inflamed mucosa, and creeping fat taken from patients with Crohn’s disease (CD).MethodsNoninflamed mucosa, inflamed mucosa, and creeping fat samples were obtained from 10 surgical patients suffering from CD. Total bacterial DNA was extracted in a sterile environment using aseptic techniques. The V3–V4 regions of bacterial 16S rDNA were amplified and analysed using standard microbiological methods. qPCR was used to confirm the change in abundance of specific species in additional 30 independent samples.ResultsInflamed mucosa exhibited the highest bacterial load (3.8 and 12 times more than that of non-inflamed mucosa and creeping fat) and species diversity. The relative abundance of Proteobacteria was dominant in most samples and was negatively associated with Firmicutes. Moreover, the relative abundances of Methylobacterium and Leifsonia in creeping fat significantly increased more than twice as much as other tissue types. The bacterial community structure analysis showed that the bacterial samples from the same individual clustered more closely.ConclusionThis study reveals the significant differences in bacterial load, species diversity, and composition among different intestinal tissue types of CD patients and confirms that the bacterial samples from the same individual are highly correlated. Our findings will shed light on fully revealing the characteristics of tissue-associated bacteria and their roles in CD pathogenesis.

scholarly journals DIETARY FIBER DEPRIVATION QUELLS COLONIC INFLAMMATION BY TARGETING GUT PATHOBIONTS IN A NEW MODEL OF CROHN’S DISEASE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S39-S39
Author(s):  
Roberta Caruso ◽  
Peter Kuffa ◽  
Naohiro Inohara ◽  
Gabriel Nunez
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Gut Microbiota ◽  
Dietary Intervention ◽  
Intestinal Inflammation ◽  
Mucosal Immune Response ◽  
Inflammatory Disorder ◽  
Mucus Layer ◽  
Experimental Conditions ◽  
Chronic Intestinal Inflammation

Abstract Crohn’s disease (CD) is a chronic intestinal inflammatory disorder that results from a dysregulated mucosal immune response to symbiotic bacteria in genetically susceptible individuals. While genetic predispositions to CD have been well documented, the overall contribution of genetic factors to disease development remains unclear. Indeed, abnormal interactions between microbes and the immune system have been identified as the core defect leading to chronic intestinal inflammation. We used a “multi-hit” genetic approach to study the complex interplay between host immunity and microbes in the context of CD. We have found that the combined deficiency of NOD2 and phagocyte NADPH oxidase (i.e. CYBB), two CD susceptibility genes, triggers microbiota-dependent and spontaneous TH1-type colitis in mice that is accompanied by the pathological hallmarks seen in CD patients. Disease was induced by Mucispirillum schaedleri, a gram-negative mucus-dwelling anaerobe. The absence of the two anti-microbial genes (i.e. NOD2 and CYBB) resulted in a marked accumulation of M. schaedleri in the gut lumen, the colonic mucus layer and ultimately a focal penetration of the intestinal wall. Accumulation of M. schaedleri was associated with impaired recruitment of neutrophils in the intestine and subsequently inefficient elimination of the bacterium. Among the environmental factors associated with CD, diet shapes the composition of the gut microbiota and can be used to manage disease symptoms. Our experiments have shown that consumption of a fiber-free diet leads to a depletion of the colonic mucus layer and increased proximity between microbes and the gut epithelium. Interestingly, these experimental conditions are effective at inhibiting intestinal inflammation observed in our model of CD-like colitis when used both as a preventive and as a therapeutic approach. In addition to shaping the overall gut microbiota composition, this dietary intervention specifically alters the abundance and/or localization of the disease-causing M. schaedleri in the double mutant mice. Our results provide direct evidence that a specific intestinal microbe can, in conjunction with impaired bacterial clearance, trigger CD-like disease. Our results also indicate that dietary approaches can be successfully used to target microbial-driven intestinal pathology.

Experimental Intestinal Stenosis Alters Crohn’s Disease-Like Intestinal Inflammation in Ileitis-Prone Mice

2021 ◽  
Author(s):  
Ioannis Georgopoulos ◽  
Eleftheria Mavrigiannaki ◽  
Sotiria Stasinopoulou ◽  
Georgios Renieris ◽  
Georgios Nikolakis ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Inflammation ◽  
Intestinal Stenosis

scholarly journals Extracellular vesicles package dsDNA to aggravate Crohn’s disease by activating the STING pathway

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Fan Zhao ◽  
Tao Zheng ◽  
Wenbin Gong ◽  
Jie Wu ◽  
Haohao Xie ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Extracellular Vesicles ◽  
Intestinal Inflammation ◽  
Therapeutic Effects ◽  
Murine Colitis ◽  
Sting Pathway ◽  
Deficient Mice

AbstractCrohn’s disease (CD) is an intestinal immune-dysfunctional disease. Extracellular vesicles (EVs) are membrane-enclosed particles full of functional molecules, e.g., nuclear acids. Recently, EVs have been shown to participate in the development of CD by realizing intercellular communication among intestinal cells. However, the role of EVs carrying double-strand DNA (dsDNA) shed from sites of intestinal inflammation in CD has not been investigated. Here we isolated EVs from the plasma or colon lavage of murine colitis and CD patients. The level of exosomal dsDNA, including mtDNA and nDNA, significantly increased in murine colitis and active human CD, and was positively correlated with the disease activity. Moreover, the activation of the STING pathway was verified in CD. EVs from the plasma of active human CD triggered STING activation in macrophages in vitro. EVs from LPS-damaged colon epithelial cells were also shown to raise inflammation in macrophages via activating the STING pathway, but the effect disappeared after the removal of exosomal dsDNA. These findings were further confirmed in STING-deficient mice and macrophages. STING deficiency significantly ameliorated colitis. Besides, potential therapeutic effects of GW4869, an inhibitor of EVs release were assessed. The application of GW4869 successfully ameliorated murine colitis by inhibiting STING activation. In conclusion, exosomal dsDNA was found to promote intestinal inflammation via activating the STING pathway in macrophages and act as a potential mechanistic biomarker and therapeutic target of CD.

scholarly journals Nutritional Therapy Strategies in Pediatric Crohn’s Disease

Nutrients ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 212
Author(s):  
Charlotte M. Verburgt ◽  
Mohammed Ghiboub ◽  
Marc A. Benninga ◽  
Wouter J. de Jonge ◽  
Johan E. Van Limbergen
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Enteral Nutrition ◽  
Intestinal Inflammation ◽  
Management Strategies ◽  
Nutritional Therapy ◽  
Nutritional Deficiencies ◽  
Intestinal Immunity ◽  
Exclusive Enteral Nutrition ◽  
Therapy Strategies

The increase in incidences of pediatric Crohn’s Disease (CD) worldwide has been strongly linked with dietary shifts towards a Westernized diet, ultimately leading to altered gut microbiota and disturbance in intestinal immunity and the metabolome. Multiple clinical studies in children with CD have demonstrated the high efficacy of nutritional therapy with exclusive enteral nutrition (EEN) to induce remission with an excellent safety profile. However, EEN is poorly tolerated, limiting its compliance and clinical application. This has spiked an interest in the development of alternative and better-tolerated nutritional therapy strategies. Several nutritional therapies have now been designed not only to treat the nutritional deficiencies seen in children with active CD but also to correct dysbiosis and reduce intestinal inflammation. In this review, we report the most recent insights regarding nutritional strategies in children with active CD: EEN, partial enteral nutrition (PEN), Crohn’s disease exclusion diet (CDED), and CD treatment-with-eating diet (CD-TREAT). We describe their setup, efficacy, safety, and (dis)advantages as well as some of their potential mechanisms of action and perspectives. A better understanding of different nutritional therapeutic options and their mechanisms will yield better and safer management strategies for children with CD and may address the barriers and limitations of current strategies in children.

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