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

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.

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The application of omics techniques to understand the role of the gut microbiota in inflammatory bowel disease

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284818822250 ◽

2019 ◽

Vol 12 ◽

pp. 175628481882225 ◽

Cited By ~ 14

Author(s):

Jonathan P. Segal ◽

Benjamin H. Mullish ◽

Mohammed Nabil Quraishi ◽

Animesh Acharjee ◽

Horace R. T. Williams ◽

...

Keyword(s):

Systems Biology ◽

Gut Microbiota ◽

Potential Role ◽

Intestinal Inflammation ◽

Clinical Care ◽

Complex Interaction ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Compositional Changes

The aetiopathogenesis of inflammatory bowel diseases (IBD) involves the complex interaction between a patient’s genetic predisposition, environment, gut microbiota and immune system. Currently, however, it is not known if the distinctive perturbations of the gut microbiota that appear to accompany both Crohn’s disease and ulcerative colitis are the cause of, or the result of, the intestinal inflammation that characterizes IBD. With the utilization of novel systems biology technologies, we can now begin to understand not only details about compositional changes in the gut microbiota in IBD, but increasingly also the alterations in microbiota function that accompany these. Technologies such as metagenomics, metataxomics, metatranscriptomics, metaproteomics and metabonomics are therefore allowing us a deeper understanding of the role of the microbiota in IBD. Furthermore, the integration of these systems biology technologies through advancing computational and statistical techniques are beginning to understand the microbiome interactions that both contribute to health and diseased states in IBD. This review aims to explore how such systems biology technologies are advancing our understanding of the gut microbiota, and their potential role in delineating the aetiology, development and clinical care of IBD.

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The Multifaceted Role of the Inflammasome in Inflammatory Bowel Diseases

The Scientific World JOURNAL ◽

10.1100/tsw.2011.139 ◽

2011 ◽

Vol 11 ◽

pp. 1536-1547 ◽

Cited By ~ 25

Author(s):

Donata Lissner ◽

Britta Siegmund

Keyword(s):

Inflammatory Bowel Disease ◽

Inflammatory Bowel Diseases ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Inflammasome Activation ◽

Specific Cell ◽

Epithelial Regeneration ◽

Bowel Diseases ◽

Inflammatory Bowel

Inflammasomes are intracellular multiprotein complexes that coordinate the maturation of interleukin (IL)-1β and IL-18 in response to pathogens and metabolic danger. Both cytokines have been linked to intestinal inflammation. However, recently evolving concepts ascribe a major role to the inflammasome in maintaining intestinal homeostasis. This review recapitulates its position in the development of inflammatory bowel disease, thereby outlining a model in which hypo- as well as hyperfunctionality can lead to an imbalance of the system, depending on the specific cell population affected. In the epithelium, the inflammasome is essential for regulation of permeability and epithelial regeneration through sensing of commensal microbes, while excessive inflammasome activation within the lamina propria contributes to severe intestinal inflammation.

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Comorbid Inflammatory Diseases of Digestive System and Eye

Ophthalmology in Russia ◽

10.18008/1816-5095-2021-1-20-29 ◽

2021 ◽

Vol 18 (1) ◽

pp. 20-29

Author(s):

S. A. Bulgakov ◽

G. M. Chernakova ◽

E. A. Kleshcheva ◽

S. V. Simonova

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Inflammatory Bowel Diseases ◽

Intestinal Inflammation ◽

Ophthalmological Examination ◽

Extraintestinal Manifestations ◽

Bowel Diseases ◽

Inflammatory Bowel

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases, which are often accompanied by inflammation of other organs. This article presents modern data on etiology, pathogenesis and clinical course of inflammatory bowel diseases, as well as information on extraintestinal eye manifestations of nonspecific ulcerative colitis and Crohn’s disease. The role of microbiota, genetic factors, immune system defects in pathogenesis of intestinal inflammation and extraintestinal eye manifestations is considered. The possibility the development of ophthalmopathology not only against the background of intestinal inflammation, but also as a consequence of therapeutic and surgical methods of treatment of ulcerative colitis and Crohn’s disease is noted. The peculiarities of the course of episcleritis/scleritis, keratitis, uveitis, chorioretinitis, optical neuritis for patients with inflammatory bowel diseases are considered. The presence of these complications may reflect the activity of the underlying disease, which in some cases requires correction of therapy. Anterior uveitis and episcleritis/scleritis are the most common extraintestinal manifestations of inflammatory bowel disease. Inflammation of tissues of the posterior segment of the eye and optic nerve against the background of ulcerative colitis and Crohn’s disease are less common, but are of clinical importance, as they can catastrophically damage the structures of the eye and, as a consequence, lead to complete blindness. Considering the possibility of mild clinical symptoms and asymptomatic course of inflammation in the eye envelopes, the importance of ophthalmological examination of all patients with ulcerative colitis and Crohn’s disease is emphasized. Aspects of modern therapy of ophthalmopathology and background intestinal inflammation are highlighted. Biological preparations — antagonists of pro-inflammatory cytokines — have been identified as the most promising in the treatment of inflammatory intestinal diseases and extraintestinal manifestations. The important role of proper nutrition and biologically active supplements containing omega-3 fatty acids, vitamin D, microelements, was noted as auxiliary therapy of both intestinal and extraintestinal inflammation.

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The Role of Thrombospondin 1 on Intestinal Inflammation and Carcinogenesis

Biomarker Insights ◽

10.4137/bmi.s630 ◽

2008 ◽

Vol 3 ◽

pp. BMI.S630 ◽

Cited By ~ 11

Author(s):

Linda S. Gutierrez

Keyword(s):

Colorectal Adenocarcinoma ◽

Intestinal Inflammation ◽

The United States ◽

Colorectal Carcinogenesis ◽

Therapeutic Effects ◽

Thrombospondin 1 ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Novel Therapeutic

Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) quite common in the United States and other Western countries. Patients suffering IBD are at greater risk of developing colorectal adenocarcinoma than the general population. Both, the adenoma-carcinoma and the inflammation-carcinogenesis processes are characterized by active angiogenesis. Recent studies also have shown that anti-angiogenesis might be a novel therapeutic approach for IBD. Thrombospondin 1 (TSP1) is an extracellular protein well known for its anti-angiogenic properties. TSP1 also has key functions in inflammation, which is assumed to be the primary cause for carcinogenesis in IBD. This review is focused on the role of TSP1 in colorectal carcinogenesis. The therapeutic effects of TSP derived-peptides on inhibiting the inflammation-carcinogenesis progression are also discussed.

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Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1813582116 ◽

2018 ◽

Vol 116 (3) ◽

pp. 970-975 ◽

Cited By ~ 41

Author(s):

Yue Li ◽

Marita Führer ◽

Ehsan Bahrami ◽

Piotr Socha ◽

Maja Klaudel-Dreszler ◽

...

Keyword(s):

Cell Death ◽

Intestinal Inflammation ◽

Intestinal Epithelial ◽

Loss Of Function ◽

Monogenic Disorders ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Human Immune

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

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Emerging Role of Exosomes in Diagnosis and Treatment of Infectious and Inflammatory Bowel Diseases

Cells ◽

10.3390/cells9051111 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1111 ◽

Cited By ~ 4

Author(s):

Anaïs Larabi ◽

Nicolas Barnich ◽

Hang Thi Thu Nguyen

Keyword(s):

Inflammatory Bowel Diseases ◽

Bacterial Infections ◽

Pathogenic Bacteria ◽

Intestinal Inflammation ◽

Current Knowledge ◽

Biological Fluids ◽

Bowel Diseases ◽

Therapeutic Molecules ◽

Inflammatory Bowel

To communicate with each other, cells release exosomes that transfer their composition, including lipids, proteins and nucleic acids, to neighboring cells, thus playing a role in various pathophysiological processes. During an infection with pathogenic bacteria, such as adherent-invasive E. coli (AIEC) associated with Crohn disease, exosomes secreted by infected cells can have an impact on the innate immune responses of surrounding cells to infection. Furthermore, inflammation can be amplified via the exosomal shuttle during infection with pathogenic bacteria, which could contribute to the development of the associated disease. Since these vesicles can be released in various biological fluids, changes in exosomal content may provide a means for the identification of non-invasive biomarkers for infectious and inflammatory bowel diseases. Moreover, evidence suggests that exosomes could be used as vaccines to prime the immune system to recognize and kill invading pathogens, and as therapeutic components relieving intestinal inflammation. Here, we summarize the current knowledge on the role of exosomes in bacterial infections and highlight their potential use as biomarkers, vaccines and conveyers of therapeutic molecules in inflammatory bowel diseases.

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5-Aminosalicylic Acid Chemoprevention in Inflammatory Bowel Diseases: Is It Necessary in the Age of Biologics and Small Molecules?

Inflammatory Intestinal Diseases ◽

10.1159/000518865 ◽

2021 ◽

pp. 1-8

Author(s):

Hans Herfarth ◽

Stephan R. Vavricka

Keyword(s):

Colorectal Cancer ◽

Inflammatory Bowel Diseases ◽

Intestinal Inflammation ◽

Therapeutic Option ◽

Mucosal Healing ◽

Janus Kinase ◽

Aminosalicylic Acid ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Meta Analyses

Background: Due to the increased incidence of colorectal cancer in inflammatory bowel diseases (IBDs), the value of chemoprevention for this patient group has been repeatedly debated in the past decade. This review describes available evidence and the current recommendations for chemoprevention in national and international guidelines IBD guidelines. Summary: 5-Aminosalicylic acid (5-ASA) compounds are the preferred therapeutic option for mild to moderate ulcerative colitis (UC). Aside from the known anti-inflammatory effects, their chemopreventive abilities have been described in vitro and in vivo. Pooling the increasing number of retrospective and population-based clinical studies over the last 15 years, 7 consecutive meta-analyses revealed partially conflicting results for the chemopreventive efficacy of 5-ASA, and thus, not all IBD guidelines currently recommend chemoprevention with mesalamine compounds. Accumulating evidence for decreasing the colorectal cancer (CRC) risk in support of thiopurines more recently shows a protective effect. This effect seems solely mediated by control of intestinal inflammation since, for this drug class, another mechanistic interference in IBD-associated CRC pathogenesis is not known. The results regarding chemopreventive efficacy for ursodeoxycholic acid or folic acid are equivocal, and the use of these medications to prevent CRC is not firmly established. Like UC, the risk of CRC is also significantly increased in patients with Crohn’s disease (CD), especially Crohn’s colitis. However, no published studies exclusively assess the effects of surveillance on the early detection of cancer or CRC chemoprevention in CD patients. In meta-analyses, which predominantly included UC patients, 5-ASA or thiopurines were not beneficial in small CD subgroups. The level of evidence for anti-TNFα agents, anti-integrin (e.g., vedolizumab), or anti-IL-12/IL-23 agents (e.g., ustekinumab) and Janus kinase inhibitors is currently too low or nonexistent to use them solely for chemoprevention in UC or CD patients. Key Message: Intestinal inflammation is one of the main risk factors for developing CRC in IBD, and all drugs that induce and maintain mucosal healing most likely also decrease the IBD-associated CRC risk. Thus, a therapeutic strategy of adding a 5-ASA therapy to a successfully mucosal healing-inducing therapy, for example, with a biologic or a small molecule merely to prevent CRC appears to be obsolete.

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Antimicrobial Peptides in Gastrointestinal Inflammation

International Journal of Inflammation ◽

10.4061/2010/910283 ◽

2010 ◽

Vol 2010 ◽

pp. 1-11 ◽

Cited By ~ 27

Author(s):

Simon Jäger ◽

Eduard F. Stange ◽

Jan Wehkamp

Keyword(s):

Antimicrobial Peptides ◽

Intestinal Inflammation ◽

Disease States ◽

Mucosal Surfaces ◽

Bowel Diseases ◽

Inflammatory Processes ◽

Complex Events ◽

Inflammatory Bowel ◽

Adaptive Immune Systems

Acute and chronic inflammations of mucosal surfaces are complex events in which the effector mechanisms of innate and adaptive immune systems interact with pathogenic and commensal bacteria. The role of constitutive and inducible antimicrobial peptides in intestinal inflammation has been investigated thoroughly over the recent years, and their involvement in various disease states is expanded ever more. Especially in the intestines, a critical balance between luminal bacteria and the antimicrobial peptides is essential, and a breakdown in barrier function by impaired production of defensins is already implicated in Crohn's disease. In this paper, we focus on the role of antimicrobial peptides in inflammatory processes along the gastrointestinal tract, while considering the resident and pathogenic flora encountered at the specific sites. The role of antimicrobial peptides in the primary events of inflammatory bowel diseases receives special attention.

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

Nutrients ◽

10.3390/nu11030516 ◽

2019 ◽

Vol 11 (3) ◽

pp. 516 ◽

Cited By ~ 13

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.

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Role of serum calprotectin in diagnosis of inﬂammatory bowel diseases in patients with ankylosing spondylitis (preliminary results)

Medical alphabet ◽

10.33667/2078-5631-2021-33-16-19 ◽

2021 ◽

pp. 16-19

Author(s):

G. V. Lukina ◽

P. I. Kulakova ◽

A. A. Novikov ◽

E. N. Alexandrova ◽

N. A. Savenkova ◽

...

Keyword(s):

New York ◽

Ankylosing Spondylitis ◽

Inflammatory Bowel Diseases ◽

Intestinal Inflammation ◽

Fecal Calprotectin ◽

Intestinal Pathology ◽

Bowel Diseases ◽

Seronegative Spondyloarthritis ◽

Inflammatory Bowel

Background. Patients with inﬂammatory bowel diseases (IBD) often have lesions of the musculoskeletal system, which is an extra-intestinal manifestation and mainly belongs to the group of seronegative spondyloarthritis (SPA). Ankylosing spondylitis (AS) is one of the main forms of diseases from the group of spondyloarthritis, associated with IBD. The frequency of AS in patients with IBD is of interest for elucidating the general pathophysiology of diseases. Colonoscopy is required to diagnose intestinal pathology. Colonoscopy in patients with AS to detect IBD, especially in the absence of intestinal symptoms, is very diffcult. Mainly for the diagnosis of IBD, the defnition of fecal calprotectin is used. Recently, there has been an interest in serum calprotectin, an increase in which is associated with a higher activity of the disease and is a marker of the intensity of inﬂammation in the intestine. However, there is currently no consensus on the clinical signifcance for serum calprotectin.The aim. To evaluate the role of serum calprotectin in diagnosis of inﬂammatory bowel disease in patients with ankylosing spondylitis.Materials and methods. In the analysis were included 50 patients with AS, fulflling the modifed New York criteria, among them were 36 (72%) men and 14 (28%) women, the mean age of patients was 42.5 ± 9.9, mean disease duration was 13.4 ± 8.7 years. All patients were examined with ESR, CRP, FC (range: 100–1800 µg/g), esophagogastroduodenoscopy, colonoscopy and quantitative analysis of the SC level using ELISA (Buhlmann MRP8/14 ELISA, range: 0.4–3.9 µg/ml).Results. All patients had a high disease activity, mean BASDAI was 5.3 ± 1.8, mean ASDAS CRP was 3.7 ± 1.01, mean ASDAS ESR was 3.6 ± 1.01. 78% patients had high FC level (more than 100 µg/g), while only 18% patients had an increase of SC level. IBD were diagnosed in 11 cases: 6 (12%) patients with CD and 5 (10%) patients with UC, in the remaining cases (78%) was no intestinal pathology. Only two patients with IBD had a high SC level. SC level was more correlated with ESR (r = 0.5) and CRP (r = 0.5) (p < 0.05) levels, than with FC level (r = 0.4) (p < 0.05).Conclusion. The results have shown that there was currently insuffcient data to assess the possibility of using SC in the diagnosis of IBD in patients with AS. There was a signifcant association between the SC, CRP and ESR, but not fecal calprotectin. Potentially SC may be more representative for systemic inﬂammation than intestinal inﬂammation.

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