Tu1847 - Bacteroides Ovatus Monotherapy is Sufficient to Suppress Intestinal Inflammation in a Murine Colitis Model

Neoagarotetraose (NT), a hydrolytic product of agar by β-agarase, is known to possess bioactive properties. However, the mechanisms via which NT alleviates intestinal inflammation remain unknown. In this study, a dextran sulfate sodium (DSS)-induced murine model was developed to evaluate the effect of NT on gut microbiome and microbial metabolism using 16S rRNA gene sequencing and untargeted metabolomics. Our data demonstrate that NT ingestion improved gut integrity and inflammation scores. NT reversed the abundance of Proteobacteria from an elevated level induced by DSS and significantly increased the abundance of Verrucomicrobia. Further, NT significantly increased the abundance of Akkermansia and Lactobacillus and concomitantly decreased that of Sutterella, which were among the important features identified by random forests analysis contributing to classification accuracy for NT supplementation. A microbial signature consisting of Adlercreutzia (denominator) and Turicibacter (numerator) predicted the NT supplementation status. Moreover, NT significantly modulated multiple gut metabolites, particularly those related to histidine, polyamine and tocopherol metabolism. Together, our findings provided novel insights into the mechanisms by which NT modulated the gut microbiome and metabolome and should facilitate the development of NT as a potent prebiotic for colitis management.

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Bacteroides ovatus ATCC 8483 monotherapy is superior to traditional fecal transplant and multi-strain bacteriotherapy in a murine colitis model

Gut Microbes ◽

10.1080/19490976.2018.1560753 ◽

2019 ◽

Vol 10 (4) ◽

pp. 504-520 ◽

Cited By ~ 9

Author(s):

Faith D. Ihekweazu ◽

Tatiana Y. Fofanova ◽

Karen Queliza ◽

Dorottya Nagy-Szakal ◽

Christopher J. Stewart ◽

...

Keyword(s):

Fecal Transplant ◽

Murine Colitis ◽

Bacteroides Ovatus ◽

Colitis Model

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PWE-110 A Role For Peroxiredoxin-4 In A Murine Colitis Model Of Intestinal Inflammation

Gut ◽

10.1136/gutjnl-2014-307263.370 ◽

2014 ◽

Vol 63 (Suppl 1) ◽

pp. A172.2-A173 ◽

Cited By ~ 1

Author(s):

S Pfeuffer ◽

N Trost ◽

K Aden ◽

S Schreiber ◽

S Lipinski ◽

...

Keyword(s):

Intestinal Inflammation ◽

Murine Colitis ◽

Colitis Model

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

Cell Death and Disease ◽

10.1038/s41419-021-04101-z ◽

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.

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Targeting Human CD2 by the CB.219 Monoclonal Antibody Protects From Intestinal Inflammation in a Humanized Colitis Model

Gastroenterology ◽

10.1016/s0016-5085(11)62005-2 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-486

Author(s):

Anja A. Kuehl ◽

Nina N. Pawlowski ◽

Katja Grollich ◽

Ulrike Erben ◽

Martin Zeitz ◽

...

Keyword(s):

Monoclonal Antibody ◽

Intestinal Inflammation ◽

Colitis Model

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7 LACTOBACILLUS REUTERI SUPPRESSES PRO-INFLAMMATORY DRIVEN REACTIVE OXYGEN SPECIES IN VITRO IN HUMAN INTESTINAL EPITHELIAL CELLS AND IN VIVO IN A TNBS COLITIS MOUSE MODEL

Inflammatory Bowel Diseases ◽

10.1093/ibd/zaa010.106 ◽

2020 ◽

Vol 26 (Supplement_1) ◽

pp. S41-S41 ◽

Cited By ~ 1

Author(s):

Wenly Ruan ◽

Melinda Engevik ◽

Alexandra Chang-Graham ◽

Joseph Hyser ◽

James Versalovic

Keyword(s):

Reactive Oxygen Species ◽

Epithelial Cells ◽

Lactobacillus Reuteri ◽

Intestinal Inflammation ◽

Intestinal Epithelial Cells ◽

Oxygen Species ◽

Intestinal Epithelial ◽

Colitis Model

Abstract Background Reactive oxygen species (ROS) play a role in maintaining intestinal epithelial homeostasis and are normally kept at low levels via antioxidant compounds. Dysregulation of ROS can lead to intestinal inflammation and contribute to inflammatory bowel disease (IBD). Select gut microbes possess the enzymatic machinery to produce antioxidants whereas others can dysregulate levels of ROS. Our model microbe, Lactobacillus reuteri (ATCC PTA 6475), has been demonstrated to reduce intestinal inflammation in mice models. It contains the genes encoding two distinct GshA-like glutamylcysteine ligases. We hypothesize that L. reuteri can secrete γ-glutamylcysteine to suppress ROS, minimize NFκB activation and regulate secretion of e pithelial cytokines. Methods & Results Conditioned media from L. reuteri was analyzed via mass spectrometry to confirm the presence of γ-glutamylcysteine. All cysteine containing products including γ-glutamylcysteine were fluorescently tagged in the conditioned media and then incubated with HT29 cell monolayers as well as human jejunal enteroid (HJE) monolayers. γ-glutamylcysteine was demonstrated to enter intestinal epithelial cells based on microscopy. Next, a Thioltracker assay was used to show increased intracellular glutathione levels by L. reuteri secreted γ-glutamylcysteine. HT29 cells and HJEs were then treated with IL-1β or hydrogen peroxide, and L. reuteri metabolites as well as γ-glutamylcysteine significantly suppressed pro-inflammatory cytokine driven ROS and IL-8 production. L. reuteri secreted products also reduced activity of NFκB as determined by a luciferase reporter assay. γ-glutamylcysteine deficient mutants were generated by targeted mutagenesis of GshA genes, and these mutant L. reuteri strains had a diminished ability to suppress IL-8 production and ROS. To further test the role of L. reuteri secreted γ-glutamylcysteine in vivo, a 2,4,6-Trinitrobenzenesulfonic acid (TNBS)- induced mouse colitis model was used. Adolescent mice were orogavaged with PBS, L. reuteri, L. reuteri GshA2 mutant, or γ-glutamylcysteine for a week after which TNBS was rectally administered to induce colitis. We demonstrate that L. reuteri and γ-glutamylcysteine can suppress histologic inflammation compared to PBS control and L. reuteri GshA2 mutant groups. Conclusions Together these data indicate that L. reuteri secretes γ-glutamylcysteine which can enter the intestinal epithelial cells and modulate epithelial cytokine production. It acts via suppression of ROS and NFκB which then decreases IL-8 production. We are able to demonstrate this in vitro in both HT 29 cells and HJEs. We now also demonstrate this in vivo in a mouse colitis model. These experiments highlight a prominent role for ROS intermediates in microbiome-mammalian cell signaling processes involved in immune responses and intestinal inflammation.

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Local Treatment with Lactate Prevents Intestinal Inflammation in the TNBS-Induced Colitis Model

Frontiers in Immunology ◽

10.3389/fimmu.2016.00651 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 17

Author(s):

Carolina Iraporda ◽

David E. Romanin ◽

Ana A. Bengoa ◽

Agustina J. Errea ◽

Delphine Cayet ◽

...

Keyword(s):

Intestinal Inflammation ◽

Local Treatment ◽

Colitis Model

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Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor

eLife ◽

10.7554/elife.27652 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 8

Author(s):

Naresh S Redhu ◽

Vasudevan Bakthavatchalu ◽

Evan A Conaway ◽

Dror S Shouval ◽

Amy Tsou ◽

...

Keyword(s):

Infant Development ◽

Intestinal Inflammation ◽

Interleukin 10 ◽

Postnatal Period ◽

Macrophage Function ◽

Murine Colitis ◽

Macrophage Depletion ◽

Macrophage Dysfunction ◽

Inflammatory Bowel ◽

Deficient Mice

Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first two weeks of life, intestinal inflammation and macrophage dysfunction begin during the third week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota. However, IL10R did not directly regulate the microbial ecology during infant development. Interestingly, macrophage depletion with clodronate inhibited the development of colitis, while the absence of IL10R specifically on macrophages sensitized infant mice to the development of colitis. These results indicate that IL10R-mediated regulation of macrophage function during the early postnatal period is indispensable for preventing the development of murine colitis.

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