A medicinal plant compound, capnoidine, prevents the onset of inflammation in a mouse model of colitis

Shepherd, Catherine; Giacomin, Paul; Navarro, Séverine; Miller, Catherine M.; Loukas, Alex; Wangchuk, Phurpa

doi:10.1016/j.jep.2017.09.024

Cited by 37 publications

(20 citation statements)

References 48 publications

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“…Each histological photomicrograph was blinded and then scored for changes in overall colon morphology and epithelial integrity. The cross sections of the colon tissues were scored for inflammation, edema, hyperplasia, ulceration, and number of goblet cells using a scoring matrix (74). An AxioCam Imager M1 (MRC ZEISS) was used for scoring the colon histology cross sections.…”

Section: Methodsmentioning

confidence: 99%

“…Data analyses. The data from groups of mice from 2 independent experiments (n ϭ10) were combined and the statistical analyses were performed using GraphPad Prism (version 7.0) as described earlier (74). Comparisons were made between groups of treated mice administered with TNBS and untreated mice administered with TNBS; P values of Ͻ 0.05 were considered significant.…”

Section: Cryomill Extraction Of Adult Worm Fractions For Gc-ms and Lcmentioning

confidence: 99%

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Hookworm-Derived Metabolites Suppress Pathology in a Mouse Model of Colitis and Inhibit Secretion of Key Inflammatory Cytokines in Primary Human Leukocytes

et al. 2019

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Iatrogenic hookworm therapy shows promise for treating disorders that result from a dysregulated immune system, including inflammatory bowel disease (IBD). Using a murine model of trinitrobenzenesulfonic acid-induced colitis and human peripheral blood mononuclear cells, we demonstrated that low-molecularweight metabolites derived from both somatic extracts (LMWM-SE) and excretorysecretory products (LMWM-ESP) of the hookworm, Ancylostoma caninum, display anti-inflammatory properties. Administration to mice of LMWM-ESP as well as sequentially extracted fractions of LMWM-SE using both methanol (SE-MeOH) and hexane-dichloromethane-acetonitrile (SE-HDA) resulted in significant protection against T cell-mediated immunopathology, clinical signs of colitis, and impaired histological colon architecture. To assess bioactivity in human cells, we stimulated primary human leukocytes with lipopolysaccharide in the presence of hookworm extracts and showed that SE-HDA suppressed ex vivo production of inflammatory cytokines. Gas chromatography-mass spectrometry (MS) and liquid chromatography-MS analyses revealed the presence of 46 polar metabolites, 22 fatty acids, and five short-chain fatty acids (SCFAs) in the LMWM-SE fraction and 29 polar metabolites, 13 fatty acids, and six SCFAs in the LMWM-ESP fraction. Several of these small metabolites, notably the SCFAs, have been previously reported to have anti-inflammatory properties in various disease settings, including IBD. This is the first report showing that hookworms secrete small molecules with both ex vivo and in vivo antiinflammatory bioactivity, and this warrants further exploration as a novel approach to the development of anti-inflammatory drugs inspired by coevolution of gutdwelling hookworms with their vertebrate hosts.

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Section: Methodsmentioning

confidence: 99%

Section: Cryomill Extraction Of Adult Worm Fractions For Gc-ms and Lcmentioning

confidence: 99%

Hookworm-Derived Metabolites Suppress Pathology in a Mouse Model of Colitis and Inhibit Secretion of Key Inflammatory Cytokines in Primary Human Leukocytes

et al. 2019

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“…Each histological photomicrograph was blinded and then scored for changes in overall colon morphology and epithelial integrity. The cross-sections of the colon tissues were scored for inflammation, edema, hyperplasia, ulceration and number of goblets cells using a scoring matrix (76). An AxioCam Imager –M1 (MRC ZEISS) was used for scoring the colon histology cross-sections.…”

Section: Methodsmentioning

confidence: 99%

“…The data from groups of mice from 2 independent experiments (N =10) were combined and the statistical analyses were performed using GraphPad Prism (version 7.0) as described earlier (76). Comparisons were made between the sample treatment + TNBS groups and the TNBS only group; P values of < 0.05 were considered significant.…”

Section: Methodsmentioning

confidence: 99%

Hookworm-derived small molecule extracts suppress pathology in a mouse model of colitis and inhibit secretion of key inflammatory cytokines in primary human leukocytes

Wangchuk

Constantinoiu

Kouremenos

et al. 2018

Preprint

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Iatrogenic hookworm therapy shows promise for treating disorders that result from 27 a dysregulated immune system, including inflammatory bowel disease (IBD). Here we use a 28 metabolomics approach to characterize the non-protein small molecule complement of 29 hookworms. Gas chromatography-mass spectrometry and liquid chromatography-mass 30 spectrometry analyses of somatic tissue extracts revealed the presence of 52 polar metabolites 31 and 22 non-polar components including short chain fatty acids (SCFA). Several of these small 32 metabolites, notably the SCFA, have been shown to have anti-inflammatory properties in various 33 diseases, including IBD. Using a murine model of colitis and human peripheral blood 34 mononuclear cells, we demonstrate that somatic tissue extracts of the hookworm Ancylostoma 35 caninum contain small molecules with anti-inflammatory activities. Of the five extracts tested, 36 two of them significantly protected mice against T cell-mediated immunopathology and weight 37 loss in a chemically-induced colitis model. Moreover, one of the anti-colitic extracts suppressed 38 ex vivo production of inflammatory cytokines from primary human leukocytes. While the origin 39 of the SCFA (parasite or host microbiota-derived) present in the hookworm somatic tissue 40 extracts cannot be ascertained from this study, it is possible that A. caninum may be actively 41 promoting an anti-inflammatory host microbiome by facilitating immune crosstalk through SCFA 42 production. 43 44 Short chain fatty acids; GC-MS; Metabolome 46 47 48 49 50 3 51 52Inflammatory Bowel Disease (IBD) is associated with chronic inflammation of the 53 digestive tract, and primarily includes ulcerative colitis (UC) and Crohn's disease (CD). The 54 etiology of IBD is not well established but it is usually characterized by inflammation, loss of 55 appetite and weight, chronic diarrhea, bloody stools, fever, rectal bleeding, abdominal pain, 56 fatigue, and anemia (1-3). IBD has been linked to many extra-intestinal manifestations (4) and 57 implicated with mental health problems (5). Current treatments for IBD include, 5-58 aminosalicylates, glucocorticosteroids, immunomodulators and biologics, and proctocolectomy 59 as a last resort when drug treatment fails. Many of these drugs are often associated with side-60 effects and various postoperative complications (6, 7). Frontline biologics such as treatment with 61 anti-TNF monoclonal antibodies are only efficacious in some patients and treatment does not 62 result in long term cure (8). Failure of these frontline treatments is associated with elevated risk 63 of colon cancer, and can result in the need for surgical removal of the colon (partial or full). 64There is therefore an urgent need for new and effective anti-inflammatory drugs to treat IBD. 65Guided by millennia of host-parasite co-evolution, we (9-13) and others (14-16) have 66 demonstrated the therapeutic properties of experimental hookworm infection to treat 67 gastrointestinal (GI) inflammatory diseases. Hookworms resident in ...

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“…TrkB-PLC/IP3 pathway is mainly consisted of protein-tyrosine kinase receptor B (TrkB), phospholipase C (PLC) and inositol triphosphate (IP3). After the specific binding of brain-derived neurotrophic factor (BDNF) to TrkB, TrkB is phosphorylated to p-TrkB, which activates the signal transduction of PLC/IP3 in the downstream, thereby playing roles in the increase of intracellular Ca 2+ concentration, the enhancement of nerve-muscle excitation conduction, the promotion of cell mobility in the intestinal smooth muscle, and the promotion of intestinal motility [14][15][16][17][18][19]. At present, there is no research showing the regulatory mechanism of TrkB-PLC/IP3 pathway on colitis.…”

Section: Introductionmentioning

confidence: 99%

Effect of TrkB-PLC/IP3 pathway on intestinal inflammatory factors and enterocyte apoptosis in mice with colitis

Sun

et al. 2020

Preprint

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Background This study aimed to explore the effect of TrkB-PLC/IP3 pathway on intestinal inflammatory factors and enterocyte apoptosis in mice with colitis.Methods Forty 8-week SPF C57BL/6J mice were randomly and averagely divided into normal group (healthy mice), control group (sham-operated mice), model group (model mice without any treatment), and K252a group (model mice with the treatment of 100 μmoL/kg TrkB-PLC/IP3 pathway inhibitor for 5 d before clysis). Mice in model and K252a groups were used to establish ulcerative colitis models after medication.Results There were no significant changes of the content of serum tumor necrosis factor-α (TNF-α) and TNF-γ and protein expressions of TNF-α and TNF-γ in the colon tissues (all P >0.05), a significant increase of disease activity index, colon mucosa damage index, tissue damage index scores, content and protein expressions of serum interleukin-4 (IL-4) and IL-8, and a significant decrease of content and protein expressions of serum IL-10 (all P <0.05) in model and K252a groups, as compared to normal and control groups. Mice in model and K252a groups had blocked enterocyte cycle progression, raised apoptosis ratio, significantly increased mRNA and protein expressions of Caspase3, Bax, FasL and Fas, and significantly reduced mRNA and protein expressions of p-TrkB, PLC-γ1, IP3 and Bcl-2 (all P <0.05). Moreover, intestinal inflammation and apoptosis induced by colitis in K252a group became more aggravated through the inhibition of TrkB-PLC/IP3 pathway activity.Conclusions Inhibition of TrkB-PLC/IP3 pathway can promote the expression of intestinal inflammatory factors and enterocyte apoptosis in mice with colitis.

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A medicinal plant compound, capnoidine, prevents the onset of inflammation in a mouse model of colitis

Cited by 37 publications

References 48 publications

Hookworm-Derived Metabolites Suppress Pathology in a Mouse Model of Colitis and Inhibit Secretion of Key Inflammatory Cytokines in Primary Human Leukocytes

Hookworm-Derived Metabolites Suppress Pathology in a Mouse Model of Colitis and Inhibit Secretion of Key Inflammatory Cytokines in Primary Human Leukocytes

Hookworm-derived small molecule extracts suppress pathology in a mouse model of colitis and inhibit secretion of key inflammatory cytokines in primary human leukocytes

Effect of TrkB-PLC/IP3 pathway on intestinal inflammatory factors and enterocyte apoptosis in mice with colitis

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