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.

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.

Increased Th17-Inducing Activity of CD14+ CD163low Myeloid Cells in Intestinal Lamina Propria of Patients With Crohn’s Disease

2013 ◽  
Vol 145 (6) ◽  
pp. 1380-1391.e1 ◽  
Author(s):  
Takayuki Ogino ◽  
Junichi Nishimura ◽  
Soumik Barman ◽  
Hisako Kayama ◽  
Satoshi Uematsu ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Lamina Propria ◽  
Myeloid Cells ◽  
Intestinal Lamina Propria

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.

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.

Enteral nutrition for pediatric Crohn’s disease: significance and basic principles

2021 ◽  
Vol 19 (3) ◽  
pp. 70-82
Author(s):  
T.E.Borovik T.E.Borovik ◽  
◽  
A.S.Potapov A.S.Potapov ◽  
E.A.Roslavtseva E.A.Roslavtseva ◽  
A.I.Khavkin A.I.Khavkin ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Enteral Nutrition ◽  
Nutritional Support ◽  
Intestinal Inflammation ◽  
Bone Mineralization ◽  
Standard Diet ◽  
Newly Diagnosed ◽  
Basic Principles ◽  
Inflammatory Bowel

The characteristics of the diet traditionally recommended for Crohn’s disease often reduce patients’ consumption of essential nutrients. Therefore, an important role belongs to nutritional support with specialized formulas, the effectiveness of which has been proven both for inducing remission and optimizing the parameters of physical development and puberty, bone mineralization. Nutritional support should be provided for patients with newly diagnosed Crohn’s disease in the form of full enteral nutrition, and subsequently in remission, exacerbation, in the pre- and postoperative periods as an addition to the standard diet. Of particular interest is the CDED ModuLife program, which is based on a combination of enteral nutrition with specially selected foods aimed at reducing the activity of intestinal inflammation in Crohn’s disease. Key words: inflammatory bowel disease, Crohn’s disease, full enteral nutrition, partial enteral nutrition, enteral nutrition formulas

Physiological Basis for Novel Drug Therapies Used to Treat the Inflammatory Bowel Diseases I. Immunology and therapeutic potential of antiadhesion molecule therapy in inflammatory bowel disease

2005 ◽  
Vol 288 (2) ◽  
pp. G169-G174 ◽  
Author(s):  
Gert Van Assche ◽  
Paul Rutgeerts
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Adhesion Molecules ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Physiological Basis ◽  
Inflammatory Bowel

Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. They are also involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. In intestinal inflammation, many adhesion molecules are upregulated, but α4-integrins most likely hold a key position in directing leukocytes into the inflamed bowel wall. Therapeutic compounds directed against trafficking of leukocytes have been designed and are being developed as a novel class of drugs in the treatment of Crohn's disease and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Second, the changes in adhesion molecules and T cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered with respect to the therapeutic potential and the safety of antiadhesion molecule treatment. Antegren, or natalizumab, a humanized anti-α4 integrin IgG4 antibody, has been most extensively evaluated and may be close to registration. A more specific humanized α4β7-integrin MLN-02 has shown preliminary clinical efficacy in ulcerative colitis, and both antergren and MLN-02 appear to be very safe. Trials with the anti-ICAM-1 antisense oligonucleotide ISIS-2302 in steroid refractory Crohn's disease have provided conflicting efficacy data. In the near future, some of these novel biological agents may prove valuable therapeutic tools in the management of refractory inflammatory bowel disease, although it is too early to define the patient population that will benefit most from these agents.

scholarly journals Lamina propria macrophage phenotypes in relation to Escherichia coli in Crohn’s disease

2015 ◽  
Vol 15 (1) ◽  
Author(s):  
Timothy R. Elliott ◽  
Neil B. Rayment ◽  
Barry N. Hudspith ◽  
Rebecca E. Hands ◽  
Kirstin Taylor ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Lamina Propria ◽  
Macrophage Phenotypes
Sign in / Sign up

Export Citation Format

Share Document