Intestinal inflammation modulates the expression of ACE2 and TMPRSS2 and potentially overlaps with the pathogenesis of SARS-CoV-2 related disease

AbstractImmune dysregulation and cytokine release syndrome have emerged as pathological hallmarks of severe Coronavirus Disease 2019 (COVID-19), leading to the evaluation of cytokine antagonists as therapeutic agents. A number of immune-directed therapies being considered for COVID-19 patients are already in clinical use in chronic inflammatory conditions like inflammatory bowel disease (IBD). These considerations led us to systematically examine the intersections between COVID-19 and the GI tract during health and intestinal inflammation. We have observed that IBD medications, both biologic and non-biologic, do not significantly impact ACE2 and TMPRSS2 expression in the uninflamed intestines. Additionally, by comparing SARS CoV2-induced epithelial gene signatures with IBD-associated genes, we have identified a shared molecular subnetwork between COVID-19 and IBD. These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19.

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Loss of Nckx3 Exacerbates Experimental DSS-Induced Colitis in Mice through p53/NF-κB Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22052645 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2645

Author(s):

Dinh Nam Tran ◽

Seon Myeong Go ◽

Seon-Mi Park ◽

Eui-Man Jung ◽

Eui-Bae Jeung

Keyword(s):

Immune Response ◽

Cellular Proliferation ◽

Intestinal Inflammation ◽

Critical Role ◽

Experimental Colitis ◽

Innate Immune ◽

Inflammatory Conditions ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Microarray Analyses

Inflammatory bowel diseases (IBDs) comprises a range of chronic inflammatory conditions of the intestinal tract. The incidence and prevalence of IBDs are increasing worldwide, but the precise etiology of these diseases is not completely understood. Calcium signaling plays a regulatory role in cellular proliferation. Nckx3, a potassium-dependent Na+/Ca2+ exchanger, is not only expressed in the brain but also in the aortic, uterine, and intestinal tissues, which contain abundant smooth muscle cells. This study investigated the role of Nckx3 in intestinal inflammation. Microarray analyses revealed the upregulation of the innate immune response-associated genes in the duodenum of Nckx3 knockout (KO) mice. The Nckx3 KO mice also showed an increase in IBD- and tumorigenesis-related genes. Using dextran sodium sulfate (DSS)-induced experimental colitis mice models, the Nckx3 KO mice showed severe colitis. Furthermore, the pathways involving p53 and NF-κB signaling were significantly upregulated by the absence of Nckx3. Overall, Nckx3 plays a critical role in the innate immune and immune response and may be central to the pathogenesis of IBD.

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Clinical assessment of inflammatory bowel disease activity: a critical overview

Journal of Medical Science ◽

10.20883/medical.e26 ◽

2015 ◽

Vol 84 (2) ◽

pp. 113-125

Author(s):

Adam Fabisiak ◽

Natalia Murawska ◽

Anna Mokrowiecka ◽

Ewa Małecka-Panas ◽

Jakub Fichna

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Clinical Aspects ◽

Gi Tract ◽

Inflammatory Conditions ◽

Symptom Recognition ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Critical Overview ◽

Future Concepts

Crohn’s disease (CD) and ulcerative colitis (UC), which belong to the group of inflammatory bowel diseases (IBD), are chronic inflammatory conditions of the gastrointestinal (GI) tract. Over the last eighty years the overview of IBD has evolved, along with disease symptom recognition, hypotheses on etiology and recommendations for clinical treatment. This review focuses on the clinical aspects of IBD throughout the years and discusses the most recent and future concepts in IBD diagnosis.

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Microbiota-independent immunological effects of non-digestible oligosaccharides in the context of inflammatory bowel diseases

Proceedings of The Nutrition Society ◽

10.1017/s0029665120006953 ◽

2020 ◽

Vol 79 (4) ◽

pp. 468-478 ◽

Cited By ~ 1

Author(s):

Stefania Del Fabbro ◽

Philip C. Calder ◽

Caroline E. Childs

Keyword(s):

Inflammatory Bowel Diseases ◽

Immune Cell ◽

Intestinal Inflammation ◽

Mechanisms Of Action ◽

Mucosal Inflammation ◽

Disease States ◽

Inflammatory Conditions ◽

Bowel Diseases ◽

Inflammatory Bowel

The aim of the present paper is to review the effects of non-digestible oligosaccharides (NDO) on immunity, focusing on their microbiota-independent mechanisms of action, as well as to explore their potential beneficial role in inflammatory bowel diseases (IBD). IBD are chronic, inflammatory conditions of the gastrointestinal tract. Individuals with IBD have an aberrant immune response to commensal microbiota, resulting in extensive mucosal inflammation and increased intestinal permeability. NDO are prebiotic fibres well known for their role in supporting intestinal health through modulation of the gut microbiota. NDO reach the colon intact and are fermented by commensal bacteria, resulting in the production of SCFA with immunomodulatory properties. In disease states characterised by increased gut permeability, prebiotics may also bypass the gut barrier and directly interact with intestinal and systemic immune cells, as demonstrated in patients with IBD and in infants with an immature gut. In vitro models show that fructooligosaccharides, inulin and galactooligosaccharides exert microbiota-independent effects on immunity by binding to toll-like receptors on monocytes, macrophages and intestinal epithelial cells and by modulating cytokine production and immune cell maturation. Moreover, animal models and human supplementation studies demonstrate that some prebiotics, including inulin and lactulose, might reduce intestinal inflammation and IBD symptoms. Although there are convincing preliminary data to support NDO as immunomodulators in the management of IBD, their mechanisms of action are still unclear and larger standardised studies need to be performed using a wider range of prebiotics.

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Behavioral and neurophysiological taste responses to sweet and salt are diminished in a model of subclinical intestinal inflammation

Scientific Reports ◽

10.1038/s41598-020-74632-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

David W. Pittman ◽

Guangkuo Dong ◽

Alexandra M. Brantly ◽

Lianying He ◽

Tyler S. Nelson ◽

...

Keyword(s):

Intestinal Inflammation ◽

Sickness Behavior ◽

Taste Bud ◽

Chorda Tympani Nerve ◽

Inflammatory Conditions ◽

Taste Changes ◽

Infection And Inflammation ◽

Inflammatory Bowel ◽

Fat Feeding

Abstract There is strong evidence for gut-taste bud interactions that influence taste function, behavior and feeding. However, the effect of gut inflammation on this axis is unknown despite reports of taste changes in gastrointestinal (GI) inflammatory conditions. Lipopolysaccharide (LPS), an inflammatory stimulus derived from gram-negative bacteria, is present in the normal GI tract and levels increase during high-fat feeding and gut infection and inflammation. Recordings from the chorda tympani nerve (CT), which transmits taste information from taste buds on the anterior tongue to the brain, previously revealed a transient decrease in sucrose responses in mice that ingest LPS during a single overnight period. Here we test the effect of acute or chronic, weekly LPS gavage on licking behavior and CT responses. Using brief-access testing, rats treated with acute LPS and mice receiving acute or chronic LPS decreased licking responses to sucrose and saccharin and to NaCl in mice. In long-term (23 h) tests chronic LPS also reduced licking responses to saccharin, sucrose, and NaCl in mice. Neurophysiological recordings from the CT supported behavioral changes, demonstrating reduced responses to sucrose, saccharin, acesulfame potassium, glucose and NaCl in acute and chronic LPS groups compared to controls. Chronic LPS significantly elevated neutrophils in the small intestine and colon, but LPS was not detected in serum and mice did not display sickness behavior or lose weight. These results indicate that sweet and salt taste sensitivity could be reduced even in asymptomatic or mild localized gut inflammatory conditions such as inflammatory bowel disease.

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Going Beyond Bacteria: Uncovering the Role of Archaeome and Mycobiome in Inflammatory Bowel Disease

Frontiers in Physiology ◽

10.3389/fphys.2021.783295 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yashar Houshyar ◽

Luca Massimino ◽

Luigi Antonio Lamparelli ◽

Silvio Danese ◽

Federica Ungaro

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Intestinal Inflammation ◽

The Body ◽

Inflammatory Conditions ◽

Relapsing Remitting ◽

Health And Disease ◽

Inflammatory Bowel ◽

Chronic Intestinal Inflammation

Inflammatory Bowel Disease (IBD) is a multifaceted class of relapsing-remitting chronic inflammatory conditions where microbiota dysbiosis plays a key role during its onset and progression. The human microbiota is a rich community of bacteria, viruses, fungi, protists, and archaea, and is an integral part of the body influencing its overall homeostasis. Emerging evidence highlights dysbiosis of the archaeome and mycobiome to influence the overall intestinal microbiota composition in health and disease, including IBD, although they remain some of the least understood components of the gut microbiota. Nonetheless, their ability to directly impact the other commensals, or the host, reasonably makes them important contributors to either the maintenance of the mucosal tissue physiology or to chronic intestinal inflammation development. Therefore, the full understanding of the archaeome and mycobiome dysbiosis during IBD pathogenesis may pave the way to the discovery of novel mechanisms, finally providing innovative therapeutic targets that can soon implement the currently available treatments for IBD patients.

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Occult Blood in Feces Is Associated with Increased Risk of Psoriasis

Dermatology ◽

10.1159/000518625 ◽

2021 ◽

pp. 1-8

Author(s):

Hyun Jung Lee ◽

Kyungdo Han ◽

Hosim Soh ◽

Seong-Joon Koh ◽

Jong Pil Im ◽

...

Keyword(s):

Intestinal Inflammation ◽

Surrogate Marker ◽

Occult Blood ◽

National Health Insurance System ◽

Inflammatory Conditions ◽

Hazard Ratios ◽

Increased Risk ◽

Inflammatory Bowel ◽

Using Data ◽

Adjusted Model

Background: The fecal immunochemistry test (FIT) has been proposed as a surrogate marker of intestinal inflammation. Psoriasis is a chronic inflammatory skin disease that is linked to underlying systemic inflammatory conditions, including inflammatory bowel disease. Methods: We investigated the association between occult blood in feces and the risk of psoriasis using data from the National Health Insurance System. This study was conducted involving 1,395,147 individuals who underwent health examinations from January 2009 to December 2012 and were followed up until the end of 2017. Results: The incidence of psoriasis (per 1,000 person-years) was 3.76 versus 4.14 (FIT-negative versus FIT-positive group) during a median follow-up of 6.68 years. In the multivariable-adjusted model, the hazard ratios for psoriasis were 1.03 for one positive FIT result, 1.12 for two positive FIT results, and 1.34 for three positive FIT results compared with negative FIT results. Conclusion: The risk of psoriasis was significantly increased in patients with positive FIT results compared to the FIT-negative population.

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Recent Advances in ADAM17 Research: A Promising Target for Cancer and Inflammation

Mediators of Inflammation ◽

10.1155/2017/9673537 ◽

2017 ◽

Vol 2017 ◽

pp. 1-21 ◽

Cited By ~ 41

Author(s):

Marcia L. Moss ◽

Dmitry Minond

Keyword(s):

Rheumatoid Arthritis ◽

Inflammatory Bowel Disease ◽

Therapeutic Potential ◽

Therapeutic Agents ◽

Converting Enzyme ◽

Tumor Immunosurveillance ◽

Inflammatory Conditions ◽

Promising Target ◽

Inflammatory Bowel ◽

Cancer And Inflammation

Since its discovery, ADAM17, also known as TNFα converting enzyme or TACE, is now known to process over 80 different substrates. Many of these substrates are mediators of cancer and inflammation. The field of ADAM metalloproteinases is at a crossroad with many of the new potential therapeutic agents for ADAM17 advancing into the clinic. Researchers have now developed potential drugs for ADAM17 that are selective and do not have the side effects which were seen in earlier chemical entities that targeted this enzyme. ADAM17 inhibitors have broad therapeutic potential, with properties ranging from tumor immunosurveillance and overcoming drug and radiation resistance in cancer, as treatments for cardiac hypertrophy and inflammatory conditions such as inflammatory bowel disease and rheumatoid arthritis. This review focuses on substrates and inhibitors identified more recently for ADAM17 and their role in cancer and inflammation.

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Selecting Lactic Acid Bacteria for Their Safety and Functionality by Use of a Mouse Colitis Model

Applied and Environmental Microbiology ◽

10.1128/aem.00109-06 ◽

2006 ◽

Vol 72 (9) ◽

pp. 5799-5805 ◽

Cited By ~ 85

Author(s):

Catherine Daniel ◽

Sabine Poiret ◽

Denise Goudercourt ◽

Veronique Dennin ◽

Gregory Leyer ◽

...

Keyword(s):

Oral Administration ◽

Intestinal Inflammation ◽

Trinitrobenzene Sulfonic Acid ◽

Inflammatory Conditions ◽

Therapeutic Benefits ◽

Inflammatory Bowel ◽

High Doses ◽

Colitis Model

ABSTRACT Studies showed that specific probiotics might provide therapeutic benefits in inflammatory bowel disease. However, a rigorous screening of new probiotics is needed to study possible adverse interactions with the host, particularly when intended for administration to individuals with certain health risks. In this context, the objective of this study was to investigate the role of three lactobacilli (LAB) on intestinal inflammation and bacterial translocation using variations of the mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced acute colitis. We first compared the in vitro ability of LAB to survive gastrointestinal tract (GIT) conditions and their ability to persist in the GIT of mice following daily oral administration. As a control, we included a nonprobiotic Lactobacillus paracasei strain, previously isolated from an endocarditis patient. Feeding high doses of LAB strains to healthy and to TNBS-treated mice did not induce any detrimental effect or abnormal translocation of the bacteria. Oral administration of Lactobacillus salivarius Ls-33 had a significant preventive effect on colitis in mice, while Lactobacillus plantarum Lp-115 and Lactobacillus acidophilus NCFM did not. None of the three selected LAB strains translocated to extraintestinal organs of TNBS-treated mice. In contrast, L. paracasei exacerbated colitis under severe inflammatory conditions and translocated to extraintestinal organs. This study showed that evaluations of the safety and functionality of new probiotics are recommended. We conclude that not all lactobacilli have similar effects on intestinal inflammation and that selected probiotics such as L. salivarius Ls-33 may be considered in the prevention or treatment of intestinal inflammation.

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Amelioration of TNBS-induced colon inflammation in rats by phospholipase A2 inhibitor

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00463.2002 ◽

2003 ◽

Vol 285 (3) ◽

pp. G586-G592 ◽

Cited By ~ 25

Author(s):

M. Krimsky ◽

S. Yedgar ◽

L. Aptekar ◽

O. Schwob ◽

G. Goshen ◽

...

Keyword(s):

Intestinal Inflammation ◽

Intraperitoneal Administration ◽

Platelet Activating Factor ◽

Lipid Mediator ◽

Myeloperoxidase Activity ◽

Therapeutic Approaches ◽

Trinitrobenzenesulfonic Acid ◽

Inflammatory Conditions ◽

Key Enzyme ◽

Inflammatory Bowel

The pathophysiology of inflammatory bowel disease (IBD) involves the production of diverse lipid mediators, namely eicosanoids, lysophospholipids, and platelet-activating factor, in which phospholipase A2 (PLA2) is the key enzyme. Accordingly, it has been postulated that control of lipid mediator production by inhibition of PLA2 would be useful for the treatment of IBD. This hypothesis was tested in the present study by examining the therapeutic effect of a novel extracellular PLA2 inhibitor (ExPLI), composed of carboxymethylcellulose-linked phosphatidylethanolamine (CMPE), on trinitrobenzenesulfonic acid-induced colitis. Intraperitoneal administration of CMPE suppressed the colitis as measured by mortality rate, intestinal permeability, plasma PLA2 activity, intestinal myeloperoxidase activity, and histological morphometry. Current therapeutic approaches for inflammatory conditions focus on the selective control of a lipid mediator(s) (e.g., prostaglandins or leukotrienes). The present study supports the concept that inclusive control of lipid mediator production by PLA2 inhibition is a plausible approach to the treatment of colitis and introduces the ExPLIs as a prototype of a novel NSAID for the treatment of intestinal inflammation.

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Influence of the microenvironment on the modulation of the host response by the typhoid toxin

10.1101/2020.06.04.133686 ◽

2020 ◽

Author(s):

Océane C.B. Martin ◽

Deborah Butter ◽

Eleni Paparouna ◽

Sofia D.P. Theodorou ◽

Maria M. Haykal ◽

...

Keyword(s):

Dna Damage ◽

Intestinal Inflammation ◽

Inflammatory Conditions ◽

Damage Response ◽

Health And Disease ◽

Inflammatory Bowel ◽

Typhoid Toxin

SummaryBacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) in vitro. These toxins are produced by Gram negative bacteria, enriched in the microbiota of Inflammatory Bowel Disease (IBD) and colorectal cancer (CRC) patients. However, their role in infection remains poorly characterized. We have addressed the role of the typhoid toxin in the modulation of the host-microbial interaction in health and disease.Infection with a genotoxigenic Salmonella protected mice from intestinal inflammation. The toxin-induced DNA damage caused senescence in vivo, which was uncoupled from the inflammatory response, and associated with the maintenance of an anti-inflammatory environment. This effect was lost when infection occurred in mice suffering from inflammatory conditions that mimic Ulcerative Colitis, a form of IBD.These data highlight a complex context-dependent crosstalk between bacterial genotoxins-induced DDR and the host immune response, underlining an unexpected role for bacterial genotoxins.

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