Nickel particles are present in Crohn's disease tissue and exacerbate intestinal inflammation in IBD susceptible 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.

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Nutritional Therapy Strategies in Pediatric Crohn’s Disease

Nutrients ◽

10.3390/nu13010212 ◽

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

Voprosy detskoj dietologii ◽

10.20953/1727-5784-2021-3-70-82 ◽

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

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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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00423.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. G169-G174 ◽

Cited By ~ 56

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.

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Corrigendum to “Let-7b ameliorates Crohn’s disease-associated adherent-invasive E coli induced intestinal inflammation via modulating Toll-Like Receptor 4 expression in intestinal epithelial cells” [Biochem. Pharmacol. 15 (2018) 196–203]

Biochemical Pharmacology ◽

10.1016/j.bcp.2018.09.025 ◽

2018 ◽

Vol 158 ◽

pp. 35-36

Author(s):

Zhen Guo ◽

Xingchen Cai ◽

Xian Guo ◽

Yihan Xu ◽

Jianfeng Gong ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Epithelial Cells ◽

Intestinal Inflammation ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

E Coli

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Succinate Activates EMT in Intestinal Epithelial Cells through SUCNR1: A Novel Protagonist in Fistula Development

Cells ◽

10.3390/cells9051104 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1104 ◽

Cited By ~ 1

Author(s):

Dolores Ortiz-Masiá ◽

Laura Gisbert-Ferrándiz ◽

Cristina Bauset ◽

Sandra Coll ◽

Céline Mamie ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Epithelial Cells ◽

Wnt Signaling ◽

Intestinal Inflammation ◽

Intestinal Epithelial Cells ◽

Fistula Tract ◽

Intestinal Epithelial ◽

Mesenchymal Transition ◽

Ht29 Cells

The pathogenesis of Crohn’s disease-associated fibrostenosis and fistulas imply the epithelial-to-mesenchymal transition (EMT) process. As succinate and its receptor (SUCNR1) are involved in intestinal inflammation and fibrosis, we investigated their relevance in EMT and Crohn’s disease (CD) fistulas. Succinate levels and SUCNR1-expression were analyzed in intestinal resections from non-Inflammatory Bowel Disease (non-IBD) subjects and CD patients with stenosing-B2 or penetrating-B3 complications and in a murine heterotopic-transplant model of intestinal fibrosis. EMT, as increased expression of Snail1, Snail2 and vimentin and reduction in E-cadherin, was analyzed in tissues and succinate-treated HT29 cells. The role played by SUCNR1 was studied by silencing its gene. Succinate levels and SUCNR1 expression are increased in B3-CD patients and correlate with EMT markers. SUCNR1 is detected in transitional cells lining the fistula tract and in surrounding mesenchymal cells. Grafts from wild type (WT) mice present increased succinate levels, SUCNR1 up-regulation and EMT activation, effects not observed in SUCNR1−/− tissues. SUCNR1 activation induces the expression of Wnt ligands, activates WNT signaling and induces a WNT-mediated EMT in HT29 cells. In conclusion, succinate and its receptor are up-regulated around CD-fistulas and activate Wnt signaling and EMT in intestinal epithelial cells. These results point to SUCNR1 as a novel pharmacological target for fistula prevention.

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