Enteric Delivery of Regenerating Family Member 3 alpha Alters the Intestinal Microbiota and Controls Inflammation in Mice With Colitis

Darnaud, Marion; Santos, Alexandre Dos; Gonzalez, Patrick; Augui, Sandrine; Lacoste, Claire; Desterke, Christophe; Hertogh, Gert De; Valentino, Emma; Zheng, Jinzi; Boisgard, Raphaël; Neut, Christel; Dubuquoy, Laurent; Chiappini, Franck; Lepage, Patricia; Guerrieri, Francesca; Doré, Joël; Bréchot, Christian; Moniaux, Nicolas

doi:10.1053/j.gastro.2017.11.003

Cited by 121 publications

(106 citation statements)

References 47 publications

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“…OG1RF_12399-12402 increase survival of E. faecalis in macrophages in vitro and translocation to mesenteric lymph node cells in vivo. Invasion of resident intestinal bacteria through the intestinal epithelium and into the lamina propria is thought to contribute to the pathogenesis of inflammatory bowel diseases and experimental colitis (15)(16)(17)(18). Therefore, we hypothesized that OG1RF_12399-12402 accelerate colitis by enhancing intracellular survival in intestinal epithelial cells and macrophages.…”

Section: Resultsmentioning

confidence: 99%

Enterococcus faecalis Gluconate Phosphotransferase System Accelerates Experimental Colitis and Bacterial Killing by Macrophages

et al. 2019

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Enterococcus faecalis strains are resident intestinal bacteria associated with invasive infections, inflammatory bowel diseases, and colon cancer. Although factors promoting E. faecalis colonization of intestines are not fully known, one implicated pathway is a phosphotransferase system (PTS) in E. faecalis strain OG1RF that phosphorylates gluconate and contains the genes OG1RF_12399 to OG1RF_ 12402 (OG1RF_12399-12402). We hypothesize that this PTS permits growth in gluconate, facilitates E. faecalis intestinal colonization, and exacerbates colitis. We generated E. faecalis strains containing deletions/point mutations in this PTS and measured bacterial growth and PTS gene expression in minimal medium supplemented with selected carbohydrates. We show that E. faecalis upregulates OG1RF_ 12399 transcription specifically in the presence of gluconate and that E. faecalis strains lacking, or harboring a single point mutation in, OG1RF_12399-12402 are unable to grow in minimal medium containing gluconate. We colonized germfree wildtype and colitis-prone interleukin-10-deficient mice with defined bacterial consortia containing the E. faecalis strains and measured inflammation and bacterial abundance in the colon. We infected macrophage and intestinal epithelial cell lines with the E. faecalis strains and measured intracellular bacterial survival and proinflammatory cytokine secretion. The presence of OG1RF_12399-12402 is not required for E. faecalis colonization of the mouse intestine but is associated with an accelerated onset of experimental colitis in interleukin-10-deficient mice, altered bacterial composition in the colon, enhanced E. faecalis survival within macrophages, and increased proinflammatory cytokine secretion by colon tissue and macrophages. Further studies of bacterial carbohydrate metabolism in general, and E. faecalis PTS-gluconate in particular, during inflammation may identify new mechanisms of disease pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Enterococcus faecalis Gluconate Phosphotransferase System Accelerates Experimental Colitis and Bacterial Killing by Macrophages

et al. 2019

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“…17 RegIIIγ in epithelial cells acts as an antibacterial protein facilitating intestinal epithelial wound healing by preventing wound infection and inflammation. 18 In addition, Card9-null mice were also found to have fewer colonic T-helper (Th) 17 cells and exhibited impaired Th17 responses. As predicted, DSS-induced colitis in Card9 −/−mice inhibited intestinal epithelial restoration and impaired gut recovery by significantly increasing apoptosis and reducing proliferation of intestinal epithelial cells.…”

Section: Ard9 Deficien C Y Impaired Immune Re S P Ons E Smentioning

confidence: 99%

The multifaceted role of CARD9 in inflammatory bowel disease

Luo

Yang

Chen

et al. 2019

J Cellular Molecular Medi

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Inflammatory bowel disease (IBD) involves a dysregulated immune response to the gut microbiota. Emerging evidence has demonstrated that dysfunctions in caspase recruitment domain‐containing protein 9 (CARD9) may contribute to the pathogenesis of IBD. Interestingly, an allelic series of Card9 variants have both a common predisposing and rare protective function in IBD patients. In this review, we provide mechanistic insights into the role of the CARD9 adaptor molecule in intestinal inflammation and determine a potential CARD9‐targeting therapeutic approach against IBD.

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“…Oxidative stress plays an important role in the development and progression of IBD, and is associated with CRC pathogenesis [12][13][14] . In the gastrointestinal tract, oxidative stress leads to damages of the intestinal mucosal layer and epithelial cell apoptosis, which results in bacterial invasion in the gut and in turn stimulates the immune response [15][16][17] . Clinical studies show that the increase of ROS and biomarkers of oxidative injury contributes to tissue damage in IBD 17,18 .…”

Section: Introductionmentioning

confidence: 99%

“…In order to resist the oxidative damage, the intestinal epithelium contains an extensive system of antioxidants 20,21 . Colitis is usually associated with a decrease in the levels of antioxidants in colonic tissues 18 , whereas overexpression of antioxidant enzymes results in attenuation of colitis in mice 16 . Thus, a balance between oxidant and antioxidant mechanisms is necessary to maintain intestinal epithelial homeostasis.…”

Section: Introductionmentioning

confidence: 99%

The Histone Methyltransferase SETD2 Modulates Oxidative Stress to Attenuate Colonic Inflammation and Tumorigenesis in Mice

Liu

et al. 2020

Preprint

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BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory disease, and patients with IBD exhibit a higher risk of developing colorectal cancer (CRC). Epithelial barrier disruption is one of the major causes of IBD in which epigenetic modulation is pivotal. However, the epigenetic mechanisms underlying the epithelial barrier integrity regulation remain largely unexplored. Here, we investigated how SETD2, an epigenetic modifier, maintains intestinal epithelial homeostasis and attenuates colonic inflammation and tumorigenesis. METHODS: GEO public database and IBD tissues were used to investigate the clinical relevance of SETD2 in IBD. To define a role of SETD2 in the colitis, we generated mice with epithelium-specific deletion of Setd2 (Setd2Vil-KO mice). Acute colitis was induced by 2% dextran sodium sulfate (DSS), and colitis-associated CRC was induced by injecting azoxymethane (AOM), followed by three cycles of 2% DSS treatments. Colon tissues were collected from mice and analyzed by histology, immunohistochemistry and immunoblots. Organoids were generated from Setd2Vil-KO and control mice, and were stained with 7-AAD to detect apoptosis. A fluorescent probe, 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA), was used to detect the levels of ROS in intestinal epithelial cells (IECs) isolated from the two types of mice. RNA-seq and H3K36me3 ChIP-seq analyses were performed to identify the mis-regulated genes modulated by SETD2. Results were validated in functional rescue experiments by N-acetyl-l-cysteine (NAC) treatment and transgenes expression in IECs. RESULTS: SETD2 expression became decreased in IBD patients and DSS-treated colitis mice. Setd2Vil-KO mice displayed abnormal loss of mucus-producing goblet cells and antimicrobial peptide (AMP)-producing Paneth cells, and exhibited pre-mature intestinal inflammation development. Consistent with the reduced SETD2 expression in IBD patients, Setd2Vil-KO mice showed increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption and markedly increased intestinal permeability that subsequently facilitated inflammation-associated CRC. Mechanistically, deletion of Setd2 resulted in excess reactive oxygen species (ROS), which led to cellular apoptosis and defects in barrier integrity. NAC treatment in Setd2Vil-KO mice rescued epithelial barrier injury and apoptosis. Importantly, Setd2 depletion led to excess ROS by directly down-regulating antioxidant genes that inhibit ROS reaction. Moreover, overexpression of antioxidant PRDX6 in Setd2Vil-KO IECs largely alleviated the overproductions of ROS and improved the cellular survival. CONCLUSIONS: Deficiency of Setd2 specifically in the intestine aggravates epithelial barrier disruption and inflammatory response in colitis via a mechanism dependent on oxidative stress. Thus, our results highlight an epigenetic mechanism by which Setd2 modulates oxidative stress to regulate intestinal epithelial homeostasis. SETD2 might therefore be a pivotal regulator that maintains the homeostasis of the intestinal mucosal barrier.

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Enteric Delivery of Regenerating Family Member 3 alpha Alters the Intestinal Microbiota and Controls Inflammation in Mice With Colitis

Cited by 121 publications

References 47 publications

Enterococcus faecalis Gluconate Phosphotransferase System Accelerates Experimental Colitis and Bacterial Killing by Macrophages

Enterococcus faecalis Gluconate Phosphotransferase System Accelerates Experimental Colitis and Bacterial Killing by Macrophages

The multifaceted role of CARD9 in inflammatory bowel disease

The Histone Methyltransferase SETD2 Modulates Oxidative Stress to Attenuate Colonic Inflammation and Tumorigenesis in Mice

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