Increased visceral sensitivity to capsaicin after DSS-induced colitis in mice: spinal cord c-Fos expression and behavior

2007 ◽  
Vol 293 (4) ◽  
pp. G749-G757 ◽  
Author(s):  
Niels Eijkelkamp ◽  
Annemieke Kavelaars ◽  
Sigrid Elsenbruch ◽  
Manfred Schedlowski ◽  
Gerald Holtmann ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Pain Perception ◽  
Visceral Pain ◽  
Activity Index ◽  
Behavioral Responses ◽  
Disease Activity Index ◽  
Sensory Function ◽  
Visceral Hyperalgesia ◽  
Dss Colitis ◽  
Fos Expression

During acute and chronic inflammation visceral pain perception is altered. Conflicting data exist, however, on visceral pain perception in the postinflammatory phase. The aim of the present study was to investigate whether visceral pain perception is altered after resolution of dextran sodium sulfate (DSS)-induced inflammation of the colon. Visceral sensory function in mice was assessed by monitoring behavioral responses to intracolonic capsaicin instillation. Two hours later the number of c-Fos-positive neurons in lamina I/II and X of spinal cord segments T12/13–S1 was determined as a measure of neuronal activation. DSS colitis was induced by adding 1% of DSS to the drinking water. The course of DSS-induced colitis was assessed by determining the disease activity index score. Animals developed a transient colitis and had recovered at day 49. At this time point, cytokine levels and colon length were similar to control animals. Importantly, after resolution of DSS-induced colitis the behavioral response to intracolonic capsaicin was increased compared with control mice. Moreover, capsaicin-induced spinal cord neuronal c-Fos expression was significantly increased. Interestingly, after colitis animals also exhibited referred somatic hyperalgesia as measured with von Frey hairs on the abdominal wall. We conclude that postinflammatory visceral hyperalgesia occurs after resolution of DSS-induced colitis and that capsaicin-induced behavioral responses and spinal cord neuronal c-Fos activation are effective readouts for determination of visceral pain perception.

scholarly journals Isolation and Characterization of Potentially Probiotic Bacterial Strains from Mice: Proof of Concept for Personalized Probiotics

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1684 ◽  
Author(s):  
Larissa Celiberto ◽  
Roseli Pinto ◽  
Elizeu Rossi ◽  
Bruce Vallance ◽  
Daniela Cavallini
Keyword(s):  
Intestinal Inflammation ◽  
Activity Index ◽  
Disease Activity Index ◽  
Bacterial Strains ◽  
Dss Colitis ◽  
Isolation And Characterization ◽  
Inflammatory Bowel ◽  
Commercial Probiotics ◽  
Lower Disease Activity

Modulation of the gut microbiota through the use of probiotics has been widely used to treat or prevent several intestinal diseases. However, inconsistent results have compromised the efficacy of this approach, especially in severe conditions such as inflammatory bowel disease (IBD). The purpose of our study was to develop a personalized probiotic strategy and assess its efficacy in a murine model of intestinal inflammation. Commensal bacterial strains were isolated from the feces of healthy mice and then administered back to the host as a personalized treatment in dextran sodium sulfate (DSS)-induced colitis. Colonic tissues were collected for histological analysis and to investigate inflammatory markers such as Il-1β, Il-6, TGF-β, and Il-10, and the enzyme myeloperoxidase as a neutrophil marker. The group that received the personalized probiotic showed reduced susceptibility to DSS-colitis as compared to a commercial probiotic. This protection was characterized by a lower disease activity index and reduced histopathological damage in the colon. Moreover, the personalized probiotic was more effective in modulating the host immune response, leading to decreased Il-1β and Il-6 and increased TGF-β and Il-10 expression. In conclusion, our study suggests that personalized probiotics may possess an advantage over commercial probiotics in treating dysbiotic-related conditions, possibly because they are derived directly from the host’s own microbiota.

scholarly journals Spinal cord syndromes in patients with systemic lupus erythematosus: differentiating lupus myelitis, neuromyelitis optica, and multiple sclerosis

Lupus ◽  
2019 ◽  
Vol 28 (14) ◽  
pp. 1656-1662
Author(s):  
J N Williams ◽  
C B Speyer ◽  
D J Kreps ◽  
D J Kimbrough ◽  
K Costenbader ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Systemic Lupus Erythematosus ◽  
Spinal Cord ◽  
Disease Activity ◽  
Neuromyelitis Optica ◽  
Lupus Erythematosus ◽  
Clinical Laboratory ◽  
Activity Index ◽  
Disease Activity Index ◽  
Systemic Lupus

Objective Non-infectious myelitis in systemic lupus erythematosus (SLE) may be due to SLE myelitis, comorbid multiple sclerosis (MS), or neuromyelitis optica (NMO). We compared characteristics of these three conditions in SLE patients at a large academic institution. Methods We searched for neurologic diagnoses of SLE myelitis, NMO myelitis, and MS myelitis among 2297 patients with at least four 1997 American College of Rheumatology revised criteria for SLE between 2000 and 2015. Each subject was reviewed by a neurologist to confirm the underlying neurologic diagnosis. Demographic, clinical, laboratory, and radiographic data were extracted and compared using Fisher's exact test, analysis of variance, and Wilcoxon rank-sum test. Results Fifteen of the 2297 subjects with SLE (0.7%) met criteria for a spinal cord syndrome: seven had SLE myelitis, three had AQP4 seropositive NMO, and five had MS. The median SLE Disease Activity Index 2000 score at time of neurologic syndrome presentation was higher in SLE myelitis subjects (8, interquartile range (IQR) 7–16) compared with subjects with NMO (6, IQR 0–14) or MS (2, IQR 0–4), p = 0.02. Subjects with SLE myelitis were also more likely to have elevated anti-dsDNA antibodies at presentation (86%) compared with subjects with NMO (33%) or MS (0%), p = 0.03. Conclusion Myelitis occurs rarely among patients with SLE. Compared with subjects with SLE + NMO and subjects with SLE + MS, subjects with SLE myelitis had higher SLE disease activity at presentation.

scholarly journals A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis

2009 ◽  
Vol 296 (6) ◽  
pp. G1167-G1179 ◽  
Author(s):  
Ryan Ungaro ◽  
Masayuki Fukata ◽  
David Hsu ◽  
Yasmin Hernandez ◽  
Keith Breglio ◽  
...  
Keyword(s):  
Activity Index ◽  
Disease Activity Index ◽  
Mucosal Healing ◽  
Transfer Model ◽  
Innate Immune Responses ◽  
Murine Colitis ◽  
Dss Colitis ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Intestinal Repair

Dysregulated innate immune responses to commensal bacteria contribute to the development of inflammatory bowel disease (IBD). TLR4 is overexpressed in the intestinal mucosa of IBD patients and may contribute to uncontrolled inflammation. However, TLR4 is also an important mediator of intestinal repair. The aim of this study is to examine the effect of a TLR4 antagonist on inflammation and intestinal repair in two murine models of IBD. Colitis was induced in C57BL/6J mice with dextran sodium sulfate (DSS) or by transferring CD45Rbhi T cells into RAG1−/− mice. An antibody (Ab) against the TLR4/MD-2 complex or isotype control Ab was administered intraperitoneally during DSS treatment, recovery from DSS colitis, or induction of colitis in RAG1−/− mice. Colitis severity was assessed by disease activity index (DAI) and histology. The effect of the Ab on the inflammatory infiltrate was determined by cell isolation and immunohistochemistry. Mucosal expression of inflammatory mediators was analyzed by real-time PCR and ELISA. Blocking TLR4 at the beginning of DSS administration delayed the development of colitis with significantly lower DAI scores. Anti-TLR4 Ab treatment decreased macrophage and dendritic cell infiltrate and reduced mucosal expression of CCL2, CCL20, TNF-α, and IL-6. Anti-TLR4 Ab treatment during recovery from DSS colitis resulted in defective mucosal healing with lower expression of COX-2, PGE2, and amphiregulin. In contrast, TLR4 blockade had minimal efficacy in ameliorating inflammation in the adoptive transfer model of chronic colitis. Our findings suggest that anti-TLR4 therapy may decrease inflammation in IBD but may also interfere with colonic mucosal healing.

P152 EVALUATING THE EFFICACY OF GLUTAMATE CARBOXYPEPTIDASE II (GCPII) INHIBITORS IN “WILD-TYPE” MICE: LESSONS LEARNED FROM THE DEDICATOR OF CYTOKINESIS 2 MUTANT MOUSE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S6-S6
Author(s):  
Diane Peters ◽  
Lauren Norris ◽  
Barbara Slusher
Keyword(s):  
Therapeutic Target ◽  
Activity Index ◽  
Disease Activity Index ◽  
Lessons Learned ◽  
Target Protein ◽  
Loss Of Function ◽  
Wild Type ◽  
Glutamate Carboxypeptidase Ii ◽  
Dss Colitis ◽  
Glutamate Carboxypeptidase

Abstract Background Glutamate carboxypeptidase II (GCPII) is highly upregulated in human IBD and is a therapeutic target under active investigation by our laboratory. We recently published that a spontaneously occurring loss-of-function mutation in dedicator of cytokinesis 2 (Dock2Hsd) that was present in commercially-purchased “wild-type” C57Bl6/NHsd mice increased their sensitivity to DSS-colitis and caused them to closely resemble human IBD with respect to GCPII. The DSS-exposed Dock2Hsd mice had significantly elevated colon GCPII activities and were sensitive to treatment with the GCPII inhibitor, 2-PMPA. We hypothesized that if colitis of the same severity were to be induced in Dock2WT mice, that they would also exhibit heightened colon GCPII activity and would be equally sensitive to 2-PMPA treatment. Methods DSS-colitis was induced in weight-, age- and gender-matched C57Bl/6NHsd mice (Dock2Hsd and Dock2WT). Increasing concentrations of DSS were utilized (2.5%-4.0%) and disease activity index was monitored daily. Mice received once daily treatment with vehicle or GCPII inhibitor 2-PMPA (IP). Results With increased DSS concentrations (4%), a severe colitis could be established in the Dock2WT mice which closely resembled the disease seen in Dock2Hsd mice induced with 2.5% DSS. Interestingly, despite similarity in DAI scores and disease progression, the GCPII activity in colons of Dock2WT mice (4% DSS) remained significantly lower than that of Dock2Hsd mice (2.5% DSS) (p<0.001, t-test). Further, while 2-PMPA was effective in both groups, higher systemic doses were required in the IBD-resistant Dock2WT mice. Conclusions Following identification that the spontaneously occurring mutation Dock2Hsd influences murine DSS-colitis sensitivity and alters the activity of our therapeutic target protein, GCPII, in the colon, we sought to re-establish our DSS model using Dock2WT mice. While we were successfully able to recapitulate disease severity in the Dock2WT mice by increasing the DSS concentration from 2.5% to 4%, the underlying disease biology was not conserved. Despite having comparable DAI scores at study termination, Dock2WT mice had decreased GCPII activity in their colons relative to Dock2Hsd mice and were less sensitive to inhibition with the GCPII inhibitor, 2-PMPA. These data caution that target protein expression must be verified even with subtle changes to experimental method when utilizing the DSS-colitis model.

scholarly journals P015 Tricellulin overexpression protects against elevated macromolecule uptake in DSS colitis mice

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S137-S137
Author(s):  
F WEIß ◽  
I F M Lee ◽  
A Fromm ◽  
J C E Hu ◽  
T Breiderhoff ◽  
...  
Keyword(s):  
Weight Loss ◽  
Activity Index ◽  
Disease Activity Index ◽  
Experimental Colitis ◽  
Sodium Sulphate ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Central Tube ◽  
Dss Colitis ◽  
Inflammatory Processes

Abstract Background In Inflammatory bowel disease, intestinal homeostasis cannot be sustained due to an overreaction of the immune system and a disturbed epithelial barrier due to an impaired tight junction (TJ). At tricellular TJs (tTJs), which are formed where three cells meet, the TJ network is basolaterally expanded and forms a central tube which would be potentially large enough to allow for a paracellular passage of macromolecules. Under normal conditions, the tTJ protein tricellulin (Tric) seals the central tube against luminal uptake. However, in ulcerative colitis (UC), Tric is downregulated, resulting in increased uptake of macromolecules including antigens which may further support the inflammatory processes. Thus, we aimed to identify whether or not overexpression of Tric has a protective effect against inflammation. Methods We generated intestinal epithelial cell-specific overexpression of Tric in mice (B6.C-Tg(Vil-cre) Rosa26tgGFP-Tric). In Tric-overexpressing (Tric-OE) and in wild-type (wt) mice experimental colitis was induced by 3% dextran sodium sulphate (DSS) for 6 days. The effect was assessed by determining the disease activity index (DAI: weight loss, stool consistency, and stool bleeding) and the colon dimensions. Using chamber experiments were performed to determine permeabilities for ions and macromolecules of different sizes (4 and 10 kDa). Results No difference in weight loss was observed between wt and Tric-OE mice upon DSS treatment. However, Tric-OE mice suffered less from diarrhoea and had less bloody stools compared with wt mice resulting in a lower DAI. In addition, DSS caused a reduced colon length which was less prominent in Tric-OE mice than in wt mice. Functional analysis revealed higher permeabilities for Na+ and Cl− after DSS treatment with no significant differences between Tric-OE and wt mice. In contrast, permeabilities for macromolecules of both sizes were unchanged after DSS treatment in Tric-OE mice but elevated in wt-mice. Conclusion Tric-overexpression prevents the epithelial barrier from elevated paracellular uptake of macromolecules during DSS colitis without affecting ion permeability. This protects against DSS colitis as indicated by less affected clinical and structural outcome parameters, most likely via a reduction in a load of immunologically active macromolecules in the subepithelium.

scholarly journals The Importance of Hypoxia-Inducible Factors (HIF-1 and HIF-2) for the Pathophysiology of Inflammatory Bowel Disease

2020 ◽  
Vol 21 (22) ◽  
pp. 8551
Author(s):  
Evelyn L. Kerber ◽  
Claudia Padberg ◽  
Nora Koll ◽  
Vera Schuetzhold ◽  
Joachim Fandrey ◽  
...  
Keyword(s):  
Activity Index ◽  
Disease Activity Index ◽  
Conditional Knockout ◽  
Hypoxia Inducible Factors ◽  
Low Oxygen ◽  
Mesenteric Lymph Nodes ◽  
Acute Colitis ◽  
Myeloid Lineage ◽  
Dss Colitis ◽  
In Cells

(1) Background: Hypoxia is a common feature of inflammation when hypoxia inducible factors (HIFs) adapt cells to conditions of low oxygen tension and inflammation. We studied the role of HIF-1 and HIF-2 in cells of the myeloid lineage in a mouse model of acute colitis. (2) Methods: Mice with and without a conditional knockout for either Hif-1a or Hif-2a or Hif-1a and Hif-2a in cells of the myeloid lineage were treated with 2.5% dextran sodium sulfate (DSS) for 6 days to induce an acute colitis. We analyzed the course of inflammation with respect to macroscopic (disease activity index) and microscopic (histology score and immunohistochemical staining of immune cells) parameters and quantified the mRNA expression of cytokines and chemokines in the colon and the mesenteric lymph nodes. (3) Results: A conditional knockout of myeloid Hif-1a ameliorated whereas the knockout of Hif-2a aggravated murine DSS colitis by increased recruitment of neutrophils to deeper layers of the colon. This led to higher expression of Il6, Ifng, Cd11c, Cd4, and Cd8 in the colon but also induced anti-inflammatory mediators such as Foxp3 and Il10. A conditional knockout of Hif-1a and Hif-2a did not show any differences compared to wildtype mice. (4) Conclusions: Myeloid HIF-1α and HIF-2α play opposing roles in acute DSS colitis. Thus, not only a cell type specific, but also the isoform specific modulation of HIFs needs to be addressed in attempts to modify HIF for therapeutic purposes.

scholarly journals Study on the Mechanism Underlying the Regulation of the NMDA Receptor Pathway in Spinal Dorsal Horns of Visceral Hypersensitivity Rats by Moxibustion

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
L. D. Wang ◽  
J. M. Zhao ◽  
R. J. Huang ◽  
L. Y. Tan ◽  
Z. H. Hu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Irritable Bowel Syndrome ◽  
Visceral Pain ◽  
Intrathecal Injection ◽  
Visceral Hypersensitivity ◽  
Regulatory Function ◽  
Visceral Hyperalgesia ◽  
Spinal Dorsal ◽  
Dorsal Horns ◽  
Irritable Bowel

Visceral hypersensitivity is enhanced in irritable bowel syndrome (IBS) patients. Treatment of IBS visceral pain by moxibustion methods has a long history and rich clinical experience. In the clinic, moxibustion on the Tianshu (ST25) and Shangjuxu (ST37) acupoints can effectively treat bowel disease with visceral pain and diarrhea symptoms. To investigate the regulatory function of moxibustion on the Tianshu (ST25) and Shangjuxu (ST37) acupoints on spinal cord NR1, NR2B, and PKCεprotein and mRNA expression in irritable bowel syndrome (IBS) visceral hypersensitivity rats, we did some research. In the study, we found that moxibustion effectively relieved the IBS visceral hyperalgesia status of rats. Analgesic effect of moxibustion was similar to intrathecal injection of Ro 25-6981. The expression of NR1, NR2B, and PKCεin the spinal dorsal horns of IBS visceral hyperalgesia rats increased. Moxibustion on the Tianshu and Shangjuxu acupoints might inhibit the visceral hypersensitivity, simultaneously decreasing the expression of NR1, NR2B, and PKCεin spinal cord of IBS visceral hyperalgesia rats. Based on the above experimental results, we hypothesized NR1, NR2B, and PKCεof spinal cord could play an important role in moxibustion inhibiting the process of central sensitization and visceral hyperalgesia state.

scholarly journals Vagus Nerve Stimulation Promotes Epithelial Proliferation and Controls Colon Monocyte Infiltration During DSS-Induced Colitis

2021 ◽  
Vol 8 ◽  
Author(s):  
Elisa Meroni ◽  
Nathalie Stakenborg ◽  
Pedro J. Gomez-Pinilla ◽  
Michelle Stakenborg ◽  
Javier Aguilera-Lizarraga ◽  
...  
Keyword(s):  
Vagus Nerve ◽  
Nerve Stimulation ◽  
Vagus Nerve Stimulation ◽  
Activity Index ◽  
Disease Activity Index ◽  
Cytokine Expression ◽  
Epithelial Integrity ◽  
Sham Stimulation ◽  
Dss Colitis ◽  
Inflammatory Phase

Background: We previously showed increased susceptibility to dextran sulfate sodium (DSS)-induced colitis in vagotomized mice. Here, we evaluated whether vagus nerve stimulation (VNS) is able to reduce the severity of DSS colitis and aimed to unravel the mechanism involved.Methods: Colitis was induced in wild type mice by 2.5% DSS administration in drinking water for 5 days. VNS (5 Hz, 1 ms, 1 mA) was applied 1 day prior to and after 4 days of DSS administration to evaluate changes in epithelial integrity and inflammatory response, respectively. Epithelial integrity was assessed using TUNEL and Ki67 staining. Monocytes, immature and mature macrophages were sorted from colonic samples and gene expression levels of pro-inflammatory cytokines were studied.Results: VNS applied prior to DSS administration (i.e., prophylactic VNS) reduced disease activity index (VNS 0.8 ± 0.6 vs. sham 2.8 ± 0.7, p < 0.001, n = 5) and tended to improve histology score. Prophylactic VNS significantly increased epithelial cell proliferation and diminished apoptosis compared to sham stimulation. VNS applied at day 4 during DSS administration (i.e., therapeutic VNS) decreased the influx of monocytes, monocyte-derived macrophages and neutrophils, and significantly reduced pro-inflammatory cytokine expression (i.e., Tnfα and Cxcl1) in immature macrophages compared to sham stimulation.Conclusions: A single period of VNS applied prior to DSS exposure reduced DSS-induced colitis by an improvement in epithelial integrity. On the other hand, VNS applied during the inflammatory phase of DSS colitis reduced cytokine expression in immature macrophages. Our data further underscores the potential of VNS as novel therapeutic approach for inflammatory bowel diseases.

scholarly journals Use of the Rat Grimace Scale to Evaluate Visceral Pain in a Model of Chemotherapy-Induced Mucositis

Animals ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 678
Author(s):  
Rebecca P. George ◽  
Gordon S. Howarth ◽  
Alexandra L. Whittaker
Keyword(s):  
Animal Models ◽  
Pain Assessment ◽  
Visceral Pain ◽  
Activity Index ◽  
Disease Activity Index ◽  
Opioid Analgesics ◽  
Dark Agouti ◽  
Spontaneous Pain ◽  
Animal Models Of Disease ◽  
Models Of Disease

The rat grimace scale (RGS) is a measure of spontaneous pain that evaluates pain response. The ability to characterize pain through a non-invasive method has considerable utility for numerous animal models of disease, including mucositis, a painful, self-limiting side-effect of chemotherapy treatment. Preclinical studies investigating novel therapeutics for mucositis often focus on pathological outcomes and disease severity. These investigations fail to measure pain, in spite of reduction of pain being a key clinical therapeutic goal. This study assessed the utility of the RGS for pain assessment in a rat model of mucositis, and whether changes in disease activity index (DAI) and open field test (OFT) reflected the grimace responses recorded. Sixty tumor-bearing female Dark Agouti rats were injected with either saline or 5-Fluourouracil alone, or with co-administration of opioid analgesics. Whilst differences in DAI were observed between treatment groups, no difference in RGS scores or OFT were demonstrated. Significant increases in grimace scores were observed across time. However, whilst a statistically significant change may have been noted, the biological relevance is questionable in terms of practical usage, since an observer is only able to score whole numbers. Development of effective pain assessment methods in animal models is required to improve welfare, satisfy regulatory requirements, and increase translational validity of the model to human patients.

scholarly journals Amelioration of Colitis in Mouse Model by Exploring Antioxidative Potentials of an Indigenous Probiotic Strain ofLactobacillus fermentumLf1

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Ritu Chauhan ◽  
Aparna Sudhakaran Vasanthakumari ◽  
Harsh Panwar ◽  
Rashmi H. Mallapa ◽  
Raj Kumar Duary ◽  
...  
Keyword(s):  
Mouse Model ◽  
Activity Index ◽  
Disease Activity Index ◽  
Probiotic Strain ◽  
Treated Group ◽  
Control Group ◽  
Preliminary Screening ◽  
Antioxidant Enzyme System ◽  
Dss Colitis ◽  
New Strategy

Based on the preliminary screening of eight indigenous putative probioticLactobacilli,Lactobacillus fermentumLf1 was selected for assessing its antioxidative efficacy in DSS colitis mouse model based on its ability to enhance the expression of “Nrf2” by 6.43-fold and malondialdehyde (MDA) inhibition by 78.1  ±  0.24% in HT-29 cells under H2O2stress. The Disease Activity Index and histological scores of Lf1-treated mice were lower than the control group. However, expression of “Nrf2” was not observed in Lf1-treated mice. A significant increase in the expression of antioxidative enzymes such asSOD2 andTrxR-1 was recorded in both of the groups. The expression ofSOD2 was significantly downregulated in colitis-induced mice by −100.00-fold relative to control group, and the downregulation was considerably reduced to −37.04-fold in colitis Lf1 treatment group. Almost, a similar trend was recorded in case of “thioredoxin” expression, though “CAT” was refractile to expression. The Lf1-treated group had decreased malondialdehyde level as compared to colitis control (37.92  ±  6.31 versus 91.13  ±  5.76 μM/g). These results point towards Lf1-induced activation of the antioxidant enzyme system in the mouse model and its prospects to be explored as a new strategy for IBD management.

Sign in / Sign up

Export Citation Format

Share Document