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

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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Chronic colitis-induced visceral pain is associated with increased anxiety during quiescent phase

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00248.2018 ◽

2019 ◽

Vol 316 (6) ◽

pp. G692-G700 ◽

Cited By ~ 6

Author(s):

Emmeline Salameh ◽

Mathieu Meleine ◽

Guillaume Gourcerol ◽

Jean-Claude do Rego ◽

Jean-Luc do Rego ◽

...

Keyword(s):

Intestinal Inflammation ◽

Visceral Pain ◽

Myeloperoxidase Activity ◽

Therapeutic Approaches ◽

Chronic Colitis ◽

Functional Symptoms ◽

Tnf Α ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Novel Therapeutic

Inflammatory bowel diseases (IBD) are characterized by repetition of flares and remission periods leading to chronic postinflammatory sequelae. Among postinflammatory sequelae, one-third of patients with IBD are suffering from functional symptoms or psychological comorbidities that persist during remission. The aim of our study was to assess functional and behavioral sequelae of chronic colitis in rats with quiescent intestinal inflammation. Chronic colitis was induced by a weekly intrarectal injection of increasing concentrations of trinitrobenzene sulfonic acid (TNBS) for 3 wk (15–45 mg of TNBS) in 30 rats, whereas the control rats ( n = 24) received the vehicle. At 50 days post-TNBS, visceral sensitivity was assessed by visceromotor response to colorectal distension, and transient receptor potential vanilloid type 1 (TRPV1) expression was also quantified in the colon and dorsal root ganglia. Barrier function and inflammatory response were assessed by studying intestinal permeability, tight junction protein, myeloperoxidase activity, histological score, and cytokine production (IL-6, IL-10, and TNF-α). Anxiety behavioral tests were performed from 50 to 64 days after the last TNBS injection. Chronic TNBS induced 1) a visceral hypersensitivity ( P = 0.03), 2) an increased colon weight-to-length ratio ( P = 0.01), 3) higher inflammatory and fibrosis scores ( P = 0.0390 and P = 0.0016, respectively), and 4) a higher colonic IL-6 and IL-10 production ( P = 0.008 and P = 0.005, respectively) compared with control rats. Intestinal permeability, colonic production of TNF-α, myeloperoxidase activity, and TRPV1 expression did not differ among groups. Chronic TNBS increased anxiety-related behavior in the open-field test and in the acoustic stress test. In conclusion, chronic colitis induced functional sequelae such as visceral hypersensitivity and increased anxiety with a low-grade intestinal inflammation. Development of a representative animal model will allow defining novel therapeutic approaches to achieve a better management of IBD-related sequelae.NEW & NOTEWORTHY Patients with inflammatory bowel diseases have impaired quality of life. Therapeutic progress to control mucosal inflammation provides us an opportunity to develop novel approaches to understand mechanisms behind postinflammatory sequelae. We used a chronic colitis model to study long-term sequelae on visceral pain, gut barrier function, and psychological impact. Chronic colitis induced functional symptoms and increased anxiety in the remission period. It might define novel therapeutic approaches to achieve a better inflammatory bowel disease-related sequelae management.

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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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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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Circulatory effects of PAF-acether in newborn piglets

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.256.1.h205 ◽

1989 ◽

Vol 256 (1) ◽

pp. H205-H212 ◽

Cited By ~ 2

Author(s):

L. M. Bradley ◽

R. E. Goldstein ◽

G. Feuerstein ◽

J. F. Czaja

Keyword(s):

Cardiac Index ◽

Platelet Activating Factor ◽

Resistance Index ◽

Receptor Blocker ◽

Lipid Mediator ◽

Inhibitory Influence ◽

Newborn Piglets ◽

Inflammatory Conditions ◽

Circulatory Effects ◽

Potent Vasoconstrictor

Platelet-activating factor (PAF-acether) is a lipid mediator that can exhibit potent vasoconstrictor influence in the pulmonary vessels. Therefore, the release of PAF-acether during inflammatory conditions in newborns might cause deleterious increases in pulmonary vascular tone. Thirty-four anesthetized open-chest newborn piglets were given 0.01-1 nmol PAF-acether iv. In separate experiments, animals were untreated or treated with either indomethacin (a cyclooxygenase inhibitor), SQ 29548 (a thromboxane receptor blocker), or LY 171883 (a leukotriene receptor blocker). The primary hemodynamic change was a 67 to 1,537% increase in the pulmonary vascular resistance index (PVRI) (P less than 0.01): mean pulmonary artery pressure (PAP) rose significantly at all doses tested, whereas only the largest dose consistently decreased cardiac index. Treatment with indomethacin or SQ 29548 prevented the decrease in cardiac index and attenuated the PAF-acether-induced rises in PAP and PVRI. Vehicle and LY 171883 had no effect. The inhibitory influence of indomethacin and SQ 29548 suggests that an important component of PAF-acether's pulmonary vasoconstrictor action is mediated (at least in the newborn piglet) by cyclooxygenase products, most likely thromboxane.

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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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Huangqin-Tang Ameliorates TNBS-Induced Colitis by Regulating Effector and Regulatory CD4+T Cells

BioMed Research International ◽

10.1155/2015/102021 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 10

Author(s):

Ying Zou ◽

Wen-Yang Li ◽

Zheng Wan ◽

Bing Zhao ◽

Zhi-Wei He ◽

...

Keyword(s):

T Cells ◽

Transcription Factors ◽

Intestinal Inflammation ◽

Therapeutic Potential ◽

Experimental Colitis ◽

Treg Cells ◽

Dependent Manner ◽

Trinitrobenzenesulfonic Acid ◽

Inflammatory Bowel ◽

Dose Dependent

Huangqin-Tang decoction (HQT) is a classic traditional Chinese herbal formulation that is widely used to ameliorate the symptoms of gastrointestinal disorders, including inflammatory bowel disease (IBD). This study was designed to investigate the therapeutic potential and immunological regulatory activity of HQT in experimental colitis in rats. Using an animal model of colitis by intrarectally administering 2,4,6-trinitrobenzenesulfonic acid (TNBS), we found that administration of HQT significantly inhibited the severity of TNBS-induced colitis in a dose-dependent manner. In addition, treatment with HQT produced better results than that with mesalazine, as shown by improvedweight loss bleeding and diarrhoea scores, colon length, and intestinal inflammation. As for potential immunological regulation of HQT action, the percentages of Th1 and Th17 cells were reduced, but those Th2 and Treg cells were enhanced in LPMCs after HQT treatment. Additionally, HQT lowered the levels of Th1/Th17-associated cytokines but increased production of Th2/Treg-associated cytokines in the colon and MLNs. Furthermore, we observed a remarkable suppression of the Th1/Th17-associated transcription factors T-bet and ROR-γt. However, expression levels of the Th2/Treg-associated transcription factors GATA-3 and Foxp3 were enhanced during treatment with HQT. Our results suggest that HQT has the therapeutic potential to ameliorate TNBS-induced colitis symptoms. This protective effect is possibly mediated by its effects on CD4+T cells subsets.

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

10.1101/2020.05.21.109124 ◽

2020 ◽

Cited By ~ 3

Author(s):

Mayte Suárez-Fariñas ◽

Minami Tokuyama ◽

Gabrielle Wei ◽

Ruiqi Huang ◽

Alexandra Livanos ◽

...

Keyword(s):

Intestinal Inflammation ◽

Immune Dysregulation ◽

Therapeutic Agents ◽

Clinical Use ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Gi Tract ◽

Related Disease ◽

Inflammatory Conditions ◽

Inflammatory Bowel

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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Anti-inflammatory and antibacterial effects of human cathelicidin active fragment KR-12 in the mouse models of colitis: a novel potential therapy of inflammatory bowel diseases

Pharmacological Reports ◽

10.1007/s43440-020-00190-3 ◽

2020 ◽

Author(s):

Natalia Fabisiak ◽

Adam Fabisiak ◽

Anna Chmielowiec-Korzeniowska ◽

Leszek Tymczyna ◽

Wojciech Kamysz ◽

...

Keyword(s):

Mouse Models ◽

Inflammatory Bowel Diseases ◽

Intestinal Inflammation ◽

Therapeutic Option ◽

Microbiological Analysis ◽

Trinitrobenzenesulfonic Acid ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Anti Inflammatory ◽

Active Fragment

Abstract Introduction Inflammatory bowel diseases (IBD) are a group of chronic gastrointestinal tract disorders with complex etiology, with intestinal dysbiosis as the most prominent factor. In this study, we assessed the anti-inflammatory and antibacterial actions of the human cathelicidin LL-37 and its shortest active fragment, KR-12 in the mouse models of colitis. Materials and methods Mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) and dextran sulfate sodium (DSS) were used in the study. The extent of inflammation was evaluated based on the macro- and microscopic scores, quantification of myeloperoxidase (MPO) activity and microbiological analysis of stool samples. Results A preliminary study with LL-37 and KR-12 (1 mg/kg, ip, twice daily) showed a decrease in macroscopic and ulcer scores in the acute TNBS-induced model of colitis. We observed that KR-12 (5 mg/kg, ip, twice daily) reduced microscopic and ulcer scores in the semi-chronic and chronic TNBS-induced models of colitis compared with inflamed mice. Furthermore, qualitative and quantitative changes in colonic microbiota were observed: KR-12 (5 mg/kg, ip, twice daily) decreased the overall number of bacteria, Escherichia coli and coli group bacteria. In the semi-chronic DSS-induced model, KR-12 attenuated intestinal inflammation as demonstrated by a reduction in macroscopic score and colon damage score and MPO activity. Conclusions We demonstrated that KR-12 alleviates inflammation in four different mouse models of colitis what suggests KR-12 and cathelicidins as a whole are worth being considered as a potential therapeutic option in the treatment of IBD.

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