scholarly journals Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota

Science ◽  
2012 ◽  
Vol 338 (6103) ◽  
pp. 120-123 ◽  
Author(s):  
Janelle C. Arthur ◽  
Ernesto Perez-Chanona ◽  
Marcus Mühlbauer ◽  
Sarah Tomkovich ◽  
Joshua M. Uronis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
High Throughput Sequencing ◽  
Polyketide Synthase ◽  
Invasive Carcinoma ◽  
Intestinal Inflammation ◽  
Interleukin 10 ◽  
Microbial Composition ◽  
Tumor Multiplicity ◽  
E Coli ◽  
Inflammatory Bowel

Inflammation alters host physiology to promote cancer, as seen in colitis-associated colorectal cancer (CRC). Here, we identify the intestinal microbiota as a target of inflammation that affects the progression of CRC. High-throughput sequencing revealed that inflammation modifies gut microbial composition in colitis-susceptible interleukin-10–deficient (Il10−/−) mice. Monocolonization with the commensal Escherichia coli NC101 promoted invasive carcinoma in azoxymethane (AOM)–treated Il10−/− mice. Deletion of the polyketide synthase (pks) genotoxic island from E. coli NC101 decreased tumor multiplicity and invasion in AOM/Il10−/− mice, without altering intestinal inflammation. Mucosa-associated pks+E. coli were found in a significantly high percentage of inflammatory bowel disease and CRC patients. This suggests that in mice, colitis can promote tumorigenesis by altering microbial composition and inducing the expansion of microorganisms with genotoxic capabilities.

scholarly journals Replication Study: Intestinal inflammation targets cancer-inducing activity of the microbiota

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Kathryn Eaton ◽  
Ali Pirani ◽  
Evan S Snitkin ◽  
Elizabeth Iorns ◽  
Rachel Tsui ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Polyketide Synthase ◽  
Intestinal Inflammation ◽  
Meta Analysis ◽  
Experimental Studies ◽  
Early Death ◽  
Interleukin 10 ◽  
Original Study ◽  
E Coli ◽  
Clear Description

As part of the Reproducibility Project: Cancer Biology we published a Registered Report (Eaton et al., 2015) that described how we intended to replicate selected experiments from the paper “Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota” (Arthur et al., 2012). Here we report the results. We observed no impact on bacterial growth or colonization capacity when the polyketide synthase (pks) genotoxic island was deleted from E. coli NC101, similar to the original study (Supplementary Figure 7; Arthur et al., 2012). However, for the experiment that compared inflammation, invasion, and neoplasia in azoxymethane (AOM)-treated interleukin-10-deficient mice mono-associated with NC101 or NC101Δ pks the experimental timing of the replication attempt was longer than that of the original study. This difference was because in the original study the methodology was not clearly stated and likely led to the increased mortality and severity of inflammation observed in this replication attempt. Additionally, early death occurred during AOM treatment with higher mortality observed in NC101Δ pks mono-associated mice compared to NC101, which was in the same direction, but more severe than the original study (Suppleme1ntal Figure 10; Arthur et al., 2012). A meta-analysis suggests that mice mono-associated with NC101Δ pks have higher mortality compared to NC101. While these data were unable to address whether, under the conditions of the original study, NC101 and NC101Δ pks differ in inflammation, invasion, and neoplasia this replication attempt demonstrates that clear description of experimental methods is essential to ensure accurate reproduction of experimental studies.

scholarly journals Tackling the Threat of Cancer Due to Pathobionts Producing Colibactin: Is Mesalamine the Magic Bullet?

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 897
Author(s):  
Min Tang-Fichaux ◽  
Priscilla Branchu ◽  
Jean-Philippe Nougayrède ◽  
Eric Oswald
Keyword(s):  
Colorectal Cancer ◽  
Intestinal Inflammation ◽  
Gene Mutations ◽  
Magic Bullet ◽  
Induced Mutations ◽  
Human Colorectal Cancer ◽  
E Coli ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Colibactin is a genotoxin produced primarily by Escherichia coli harboring the genomic pks island (pks+ E. coli). Pks+ E. coli cause host cell DNA damage, leading to chromosomal instability and gene mutations. The signature of colibactin-induced mutations has been described and found in human colorectal cancer (CRC) genomes. An inflamed intestinal environment drives the expansion of pks+ E. coli and promotes tumorigenesis. Mesalamine (i.e., 5-aminosalycilic acid), an effective anti-inflammatory drug, is an inhibitor of the bacterial polyphosphate kinase (PPK). This drug not only inhibits the production of intestinal inflammatory mediators and the proliferation of CRC cells, but also limits the abundance of E. coli in the gut microbiota and diminishes the production of colibactin. Here, we describe the link between intestinal inflammation and colorectal cancer induced by pks+ E. coli. We discuss the potential mechanisms of the pleiotropic role of mesalamine in treating both inflammatory bowel diseases and reducing the risk of CRC due to pks+ E. coli.

scholarly journals Pretreatment with a Heat-Killed Probiotic Modulates the NLRP3 Inflammasome and Attenuates Colitis-Associated Colorectal Cancer in Mice

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 516 ◽  
Author(s):  
I-Che Chung ◽  
Chun-Nan OuYang ◽  
Sheng-Ning Yuan ◽  
Hsin-Chung Lin ◽  
Kuo-Yang Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Inflammasome Activation ◽  
E Coli ◽  
Nlrp3 Inflammasome Activation ◽  
Safe Strategy ◽  
Inflammatory Bowel ◽  
Fecal Content

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Inflammation contributes to cancer development and inflammatory bowel disease is an important risk factor for CRC. The aim of this study is to assess whether a widely used probiotic Enterococcus faecalis can modulate the NLRP3 inflammasome and protect against colitis and colitis-associated CRC. We studied the effect of heat-killed cells of E. faecalis on NLRP3 inflammasome activation in THP-1-derived macrophages. Pretreatment of E. faecalis or NLRP3 siRNA can inhibit NLRP3 inflammasome activation in macrophages in response to fecal content or commensal microbes, P. mirabilis or E. coli, according to the reduction of caspase-1 activation and IL-1β maturation. Mechanistically, E. faecalis attenuates the phagocytosis that is required for the full activation of the NLRP3 inflammasome. In in vivo mouse experiments, E. faecalis can ameliorate the severity of intestinal inflammation and thereby protect mice from dextran sodium sulfate (DSS)-induced colitis and the formation of CRC in wild type mice. On the other hand, E. faecalis cannot prevent DSS-induced colitis in NLRP3 knockout mice. Our findings indicate that application of the inactivated probiotic, E. faecalis, may be a useful and safe strategy for attenuation of NLRP3-mediated colitis and inflammation-associated colon carcinogenesis.

scholarly journals Cytotoxic Escherichia coli strains encoding colibactin, cytotoxic necrotizing factor, and cytolethal distending toxin colonize laboratory common marmosets (Callithrix jacchus)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Colleen S. McCoy ◽  
Anthony J. Mannion ◽  
Yan Feng ◽  
Carolyn M. Madden ◽  
Stephen C. Artim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cellular Differentiation ◽  
Gastrointestinal Disease ◽  
Phylogenetic Group ◽  
Cytolethal Distending Toxin ◽  
Whole Genome ◽  
Common Marmosets ◽  
E Coli ◽  
Cytotoxic Necrotizing Factor ◽  
Inflammatory Bowel

AbstractCyclomodulins are virulence factors that modulate cellular differentiation, apoptosis, and proliferation. These include colibactin (pks), cytotoxic necrotizing factor (cnf), and cytolethal distending toxin (cdt). Pathogenic pks+, cnf+, and cdt+ E. coli strains are associated with inflammatory bowel disease (IBD) and colorectal cancer in humans and animals. Captive marmosets are frequently afflicted with IBD-like disease, and its association with cyclomodulins is unknown. Cyclomodulin-encoding E. coli rectal isolates were characterized using PCR-based assays in healthy and clinically affected marmosets originating from three different captive sources. 139 E. coli isolates were cultured from 122 of 143 marmosets. The pks gene was detected in 56 isolates (40%), cnf in 47 isolates (34%), and cdt in 1 isolate (0.7%). The prevalences of pks+ and cnf+ E. coli isolates were significantly different between the three marmoset colonies. 98% of cyclomodulin-positive E. coli belonged to phylogenetic group B2. Representative isolates demonstrated cyclomodulin cytotoxicity, and serotyping and whole genome sequencing were consistent with pathogenic E. coli strains. However, the presence of pks+, cnf+, or cdt+ E. coli did not correlate with clinical gastrointestinal disease in marmosets. Cyclomodulin-encoding E. coli colonize laboratory common marmosets in a manner dependent on the source, potentially impacting reproducibility in marmoset models.

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

eLife ◽  
2017 ◽  
Vol 6 ◽  
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.

scholarly journals Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10

2019 ◽  
Vol 216 (2) ◽  
pp. 337-349 ◽  
Author(s):  
Peng Xiao ◽  
Huilun Zhang ◽  
Yu Zhang ◽  
Mingzhu Zheng ◽  
Rongbei Liu ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Interleukin 10 ◽  
Blood Monocytes ◽  
Stat3 Signaling ◽  
Tnf Α ◽  
Mouse Macrophages ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
Further Development

Inflammatory cytokines produced by activated macrophages largely contribute to the pathological signs of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is the predominant anti-inflammatory cytokine in the intestine, and its therapeutic efficacy for IBD has been clinically tested. Nevertheless, how the function of IL-10 is regulated in the intestinal microenvironment remains unknown, which largely hinders the further development of IL-10–based therapeutic strategies. Here, we found that the expression of phosphatase Shp2 was increased in colonic macrophages and blood monocytes from IBD patients compared with those from healthy controls. Shp2 deficiency in macrophages protects mice from colitis and colitis-driven colon cancer. Mechanistically, Shp2 disrupts IL-10–STAT3 signaling and its dependent anti-inflammatory response in human and mouse macrophages. Furthermore, a Shp2-inducing role of TNF-α is unveiled in our study. Collectively, our work identifies Shp2 as a detrimental factor for intestinal immune homeostasis and hopefully will be helpful in the future exploitation of IL-10 immunotherapy for IBD.

Apple peel polyphenols: a key player in the prevention and treatment of experimental inflammatory bowel disease

2016 ◽  
Vol 130 (23) ◽  
pp. 2217-2237 ◽  
Author(s):  
Marie-Claude Denis ◽  
Denis Roy ◽  
Pantea Rahmani Yeganeh ◽  
Yves Desjardins ◽  
Thibault Varin ◽  
...  
Keyword(s):  
Fruits And Vegetables ◽  
Intestinal Inflammation ◽  
Therapeutic Effects ◽  
Microbial Composition ◽  
Beneficial Effects ◽  
Apple Peel ◽  
Bowel Diseases ◽  
Clinical Benefits ◽  
Inflammatory Bowel ◽  
Underlying Mechanisms

Diets rich in fruits and vegetables may reduce oxidative stress (OxS) and inflammation via several mechanisms. These beneficial effects may be due to their high polyphenol content. The aims of the present study are to evaluate the preventive and therapeutic aspects of polyphenols in dried apple peel powder (DAPP) on intestinal inflammation while elucidating the underlying mechanisms and clinical benefits. Induction of intestinal inflammation in mice was performed by oral administration of the inflammatory agent dextran sulfate sodium (DSS) at 2.5% for 10 days. Physiological and supraphysiological doses of DAPP (200 and 400 mg/kg/day respectively) were administered by gavage for 10 days pre- and post-DSS treatment. DSS-mediated inflammation caused weight loss, shortening of the colon, dystrophic detachment of the epithelium, and infiltration of mono- and poly-morphonuclear cells in the colon. DSS induced an increase in lipid peroxidation, a down-regulation of antioxidant enzymes, an augmented expression of myeloperoxidase (MPO) and cyclooxygenase-2 (COX-2), an elevated production of prostaglandin E2 (PGE2) and a shift in mucosa-associated microbial composition. However, DAPP normalized most of these abnormalities in preventive or therapeutic situations in addition to lowering inflammatory cytokines while stimulating antioxidant transcription factors and modulating other potential healing pathways. The supraphysiological dose of DAPP in therapeutic situations also improved mitochondrial dysfunction. Relative abundance of Peptostreptococcaceae and Enterobacteriaceae bacteria was slightly decreased in DAPP-treated mice. In conclusion, DAPP exhibits powerful antioxidant and anti-inflammatory action in the intestine and is associated with the regulation of cellular signalling pathways and changes in microbiota composition. Evaluation of preventive and therapeutic effects of DAPP may be clinically feasible in individuals with intestinal inflammatory bowel diseases.

scholarly journals Studies on the Interleukin-10 Gene in Animal Models of Colitis

2001 ◽  
Vol 15 (8) ◽  
pp. 557-558
Author(s):  
Hugh J Freeman
Keyword(s):  
Inflammatory Bowel Disease ◽  
Animal Models ◽  
Bowel Disease ◽  
Inflammatory Process ◽  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Inflammatory Bowel ◽  
Deficient Mice

Cytokines play a role in the inflammatory process in colitis and may have therapeutic potential. Interleukin-10 (IL-10) has both immunomodulatory and anti-inflammatory properties. IL-10-deficient mice develop intestinal inflammation with increased tissue levels of other cytokines, including tumour necrosis factor-alpha. In patients with inflammatory bowel disease, impaired IL-10 production by lamina propria T cells occurs and human recombinant IL-10 improves clinical parameters in inflammatory bowel disease (eg, Crohn's disease). There seem to be conflicting results in differing animal models, and the timing of administration of IL-10 relative to onset of colitis may be critical, possibly due to rapid clearance of IL-10. Interestingly, in IL-10 gene-deficient mice raised in germ-free conditions, the intestinal inflammatory changes normally observed in conventional nongerm-free conditions are not detected, suggesting a role for luminal bacteria in the pathogenesis of the inflammatory process.

scholarly journals Intestinal microbiota and inflammatory bowel diseases

2021 ◽  
Vol 64 (9) ◽  
pp. 588-595
Author(s):  
Chang Soo Eun
Keyword(s):  
Intestinal Microbiota ◽  
Inflammatory Bowel Diseases ◽  
Intestinal Inflammation ◽  
Microbial Composition ◽  
Mucosal Permeability ◽  
Next Generation Sequencing Technology ◽  
Early Results ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
And Function

Background: The prevalence of inflammatory bowel diseases (IBD) has been rapidly increasing over the past several decades in Korea. IBD appears to be resulted from inappropriate and chronic activation of the mucosal immune system driven by stimuli such as intestinal microbiota and various environmental factors in genetically susceptible individuals.Current Concepts: Recent advances in next-generation sequencing technology have identified alterations in the composition and function of the intestinal microbiota in individuals with IBD. Dysbiosis in patients with IBD is characterized by decreased bacterial diversity combined with an expansion of putative aggressive species and a reduction in protective species. Altered microbial composition and function in IBD correlates with increased immune stimulation, epithelial dysfunction, or enhanced mucosal permeability. Thus, dysbiosis may play an essential role in the pathogenesis of IBD.Discussion and Conclusion: Although it is currently unclear whether dysbiosis is a cause or consequence of intestinal inflammation in IBD, several microbial-based and microbial-targeted therapies have yielded promising early results.

Bringing to Light the Risk of Colorectal Cancer in Inflammatory Bowel Disease: Mucosal Glycosylation as a Key Player

2021 ◽  
Author(s):  
Eduarda Leite-Gomes ◽  
Ana M Dias ◽  
Catarina M Azevedo ◽  
Beatriz Santos-Pereira ◽  
Mariana Magalhães ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Serum Proteins ◽  
Major Complication ◽  
Cancer Pathogenesis ◽  
Colon Inflammation ◽  
Inflammatory Bowel

Abstract Colitis-associated cancer is a major complication of inflammatory bowel disease remaining an important clinical challenge in terms of diagnosis, screening, and prognosis. Inflammation is a driving factor both in inflammatory bowel disease and cancer, but the mechanism underlying the transition from colon inflammation to cancer remains to be defined. Dysregulation of mucosal glycosylation has been described as a key regulatory mechanism associated both with colon inflammation and colorectal cancer development. In this review, we discuss the major molecular mechanisms of colitis-associated cancer pathogenesis, highlighting the role of glycans expressed at gut epithelial cells, at lamina propria T cells, and in serum proteins in the regulation of intestinal inflammation and its progression to colon cancer, further discussing its potential clinical and therapeutic applications.

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