Dietary L-Tryptophan Regulates Colonic Serotonin Homeostasis in Mice with Dextran Sodium Sulfate-Induced Colitis

ABSTRACT Background L-tryptophan (Trp) has been reported to regulate gut immune responses during inflammation. However, the underlying mechanisms are largely unknown. Objective We investigated the role of Trp supplementation on the serotonin receptor (HTR)-mediated immune response in the colon of mice with dextran sodium sulfate (DSS)-induced colitis. Methods In Experiment 1, male C57BL/6 mice were randomly assigned to 1 of 4 groups: Control (Con) or L-Trp supplementation [0.1 mg/(g body weight·d) in drinking water] (Trp) with (+DSS) or without 2% DSS in drinking water from days 8 to 14 of the 17-d study. In Experiments 2 and 3, Trp + DSS (Expt. 2) or DSS (Expt. 3) mice were treated as described above and subcutaneously administered with HTR1A or HTR4 antagonists (or their combination) or an HTR2 agonist from days 8 to 14 of the 15-d study. Changes in immune cell phenotypes, inflammatory mediators, and related cell signaling molecules were assessed by flow cytometry, real-time PCR, or Western blot. The mRNA abundances of Trp hydroxylase (Tph1), serotonin reuptake transporter (Slc6a4), and Htr in the colon were also assessed. Results Trp supplementation before DSS treatment upregulated the expression of colonic Slc6a4 (0.49 compared with 0.30), Htr1a (1.14 compared with 0.65), and Htr4 (1.08 compared with 0.70), downregulated the expression of Htr2a (1.54 compared with 1.89), and decreased the colonic serotonin concentration (11.5 compared with 14.8 nmol/g tissue) (P < 0.01). Trp regulated the DSS-induced immune response partly through attenuating the activation of toll-like receptor 4 (TLR4)-STAT3 signaling and nucleus p-65. Either an HTR2 agonist or HTR1A and HTR4 antagonists reversed the effects of Trp. Conclusions In mice treated with DSS, Trp supplementation before DSS administration improved colonic immune responses partly by reducing colonic serotonin and subsequent interactions with HTR1A and HTR4, which are known to be present on neutrophils and macrophages.

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Effects of IRW and IQW on Oxidative Stress and Gut Microbiota in Dextran Sodium Sulfate-Induced Colitis

Cellular Physiology and Biochemistry ◽

10.1159/000495240 ◽

2018 ◽

Vol 51 (1) ◽

pp. 441-451 ◽

Cited By ~ 17

Author(s):

Gang Liu ◽

Wenxin Yan ◽

Sujuan Ding ◽

Hongmei Jiang ◽

Yong Ma ◽

...

Keyword(s):

Oxidative Stress ◽

Drinking Water ◽

Gut Microbiota ◽

Sodium Sulfate ◽

Dextran Sodium Sulfate ◽

Daily Weight Gain ◽

Control Group ◽

Unrestricted Access ◽

Hematoxylin And Eosin ◽

Colitis Model

Background/Aims: There are known links between inflammatory bowel disease (IBD) and changes in the microbiota of the gut and inflammation and oxidative stress. In this study, a colitis model induced by dextran sodium sulfate (DSS) in mice is used to evaluate whether the presence of bioactive peptides IRW (Ile-Arg-Trp) and IQW (Ile-Gln-Trp) peptides is advantageous. Methods: The mice were arbitrarily assigned to the following four groups: (i) control (untreated), (ii) dextran sodium sulfate (DSS) treated, (iii) IRW-DSS treated, and (iv) IQW-DSS treated. For 7 days, the control group subjects had unrestricted access to untreated drinking water, whereas the drinking water supplied to the subjects in the DSS, IRW-DSS, and IQW-DSS groups during this period consisted of 5% DSS solution. The colonic lesions were scored after hematoxylin and eosin staining. Serum antioxidant capacity was analyzed by 2,2’-azino-bis(3-ethylbenz-thiazoline-6-sulfonic acid) (ABTS) radical cation decolorization test and the microbiota in the colonic contents were sequenced by HiSeq2500 PE250. Results: The presence of DSS reduced daily weight gain, enhanced histopathology scores, and inhibited antioxidant enzyme expression. Superoxide dismutase, catalase, and glutathione peroxidase activities in the DSS-induced colitis model were significantly enhanced (P < 0.05) in the presence of dietary IRW and IQW. Furthermore, the Simpson index was significantly increased (P < 0.05) in the presence of dietary IRW and IQW compared to the control group. IRW and IQW increased the abundance of Coprococcus_1, Ruminococcaceae_UCG-014, and Desulfovibrio compared to the control group and DSS group. Furthermore, IQW decreased the abundance of Bacteroides in relation to the control group, but increased Parabacteroides. In addition, IRW increased the level of Anaerotruncus, Oscillibacter, and Ruminiclostridium_9 compared to the control group. Conclusion: This study concludes that the presence of IRW or IQW can mitigate DSS-induced oxidative stress by improving the activities of antioxidant enzymes, increasing intestinal microbial diversity and enhancing the abundance of gut microbiota, which may help maintain the homeostasis of host health and microenvironment in a DSS-induced mouse model, thus providing a potential further treatment for IBD patients.

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Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment

10.1101/2021.03.05.434041 ◽

2021 ◽

Author(s):

Flavia Camponovo ◽

Tamsin E Lee ◽

Jonathan Russell ◽

Lydia Burgert ◽

Jaline Gerardin ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Immune Escape ◽

Clinical Symptoms ◽

Disease Onset ◽

Clinical Malaria ◽

Individual Variability ◽

Switching Dynamics ◽

Underlying Mechanisms ◽

Parasite Dynamics

Background: Malaria blood-stage infection length and intensity are important drivers of disease and transmission; however, the underlying mechanisms of parasite growth and the host's immune response during infection remain largely unknown. Over the last 30 years, several mechanistic mathematical models of malaria parasite within-host dynamics have been published and used in malaria transmission models. Methods: We identified mechanistic within-host models of parasite dynamics through a review of published literature. For a subset of these, we reproduced model code and compared descriptive statistics between the models using fitted data. Through simulation and model analysis, we compare and discuss key features of the models, including assumptions on growth, immune response components, variant switching mechanisms, and inter-individual variability. Results: The assessed within-host malaria models generally replicate infection dynamics in malaria-na&iumlve individuals. However, there are substantial differences between the model dynamics after disease onset, and models do not always reproduce late infection parasitemia data used for calibration of the within host infections. Models have attempted to capture the considerable variability in parasite dynamics between individuals by including stochastic parasite multiplication rates; variant switching dynamics leading to immune escape; variable effects of the host immune responses; or via probabilistic events. For models that capture realistic length of infections, model representations of innate immunity explain early peaks in infection density that cause clinical symptoms, and model representations of antibody immune responses control the length of infection. Models differed in their assumptions concerning variant switching dynamics, reflecting uncertainty in the underlying mechanisms of variant switching revealed by recent clinical data during early infection. Overall, given the scarce availability of the biological evidence there is limited support for complex models. Conclusions: Our study suggests that much of the inter-individual variability observed in clinical malaria infections has traditionally been attributed in models to random variability, rather than mechanistic disease dynamics. Thus, we propose that newly developed models should assume simple immune dynamics that minimally capture mechanistic understandings and avoid over-parameterisation and large stochasticity which inaccurately represent unknown disease mechanisms.

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Immune response profiling of patients with spondyloarthritis reveals signalling networks mediating TNF-blocker function in vivo

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-218304 ◽

2020 ◽

pp. annrheumdis-2020-218304

Author(s):

Silvia Menegatti ◽

Vincent Guillemot ◽

Eleonora Latis ◽

Hanane Yahia-Cherbal ◽

Daniela Mittermüller ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Immune Cell ◽

Clinical Laboratory ◽

Prostaglandin E ◽

Macrophage Polarisation ◽

Tnf Blockers ◽

Tnf Blocker ◽

Therapeutic Responses

ObjectivesAntitumour necrosis factor (TNF) therapy has revolutionised treatment of several chronic inflammatory diseases, including spondyloarthritis (SpA). However, TNF inhibitors (TNFi) are not effective in all patients and the biological basis for treatment failure remains unknown. We have analysed induced immune responses to define the mechanism of action of TNF blockers in SpA and to identify immunological correlates of responsiveness to TNFi.MethodsImmune responses to microbial and pathway-specific stimuli were analysed in peripheral blood samples from 80 patients with axial SpA before and after TNFi treatment, using highly standardised whole-blood stimulation assays. Cytokines and chemokines were measured in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, and gene expression was monitored using nCounter assays.ResultsAnti-TNF therapy induced profound changes in patients’ innate immune responses. TNFi action was selective, and had only minor effects on Th1/Th17 immunity. Modular transcriptional repertoire analysis identified prostaglandin E2 synthesis and signalling, leucocyte recirculation, macrophage polarisation, dectin and interleukin (IL)-1 signalling, as well as the nuclear factor kappa B (NF-kB) transcription factor family as key pathways targeted by TNF blockers in vivo. Analysis of induced immune responses before treatment initiation revealed that expression of molecules associated with leucocyte adhesion and invasion, chemotaxis and IL-1 signalling are correlated with therapeutic responses to anti-TNF.ConclusionsWe show that TNFi target multiple immune cell pathways that cooperate to resolve inflammation. We propose that immune response profiling provides new insight into the biology of TNF-blocker action in patients and can identify signalling pathways associated with therapeutic responses to biological therapies.

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Protective effects of tryptophan-catabolizing Lactobacillus plantarum KLDS 1.0386 against dextran sodium sulfate-induced colitis in mice

Food & Function ◽

10.1039/d0fo02622k ◽

2020 ◽

Vol 11 (12) ◽

pp. 10736-10747

Author(s):

Jialu Shi ◽

Peng Du ◽

Qinggang Xie ◽

Nana Wang ◽

Huizhen Li ◽

...

Keyword(s):

Ulcerative Colitis ◽

Acetic Acid ◽

Gut Microbiota ◽

Lactobacillus Plantarum ◽

Sodium Sulfate ◽

Dextran Sodium Sulfate ◽

Protective Effects ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Indole 3 Acetic Acid

L. plantarum KLDS 1.0386 combined with tryptophan alleviates ulcerative colitis (UC) induced by dextran sodium sulfate (DSS) by increasing the level of indole-3-acetic acid (IAA), stimulating the AHR/IL-22/STAT3 signaling pathway and regulating gut microbiota in mice.

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Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity

Journal of Virology ◽

10.1128/jvi.00542-17 ◽

2017 ◽

Vol 91 (15) ◽

Cited By ~ 9

Author(s):

Ariana G. Bravo Cruz ◽

Aiguo Han ◽

Edward J. Roy ◽

Arielle B. Guzmán ◽

Rita J. Miller ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Immune Responses ◽

Vaccinia Virus ◽

Virus Replication ◽

Protective Immunity ◽

Immune Cell ◽

Innate Immune ◽

Innate Immune Responses ◽

Antiviral Immune Response

ABSTRACT All viruses strategically alter the antiviral immune response to their benefit. The vaccinia virus (VACV) K1 protein has multiple immunomodulatory effects in tissue culture models of infection, including NF-κB antagonism. However, the effect of K1 during animal infection is poorly understood. We determined that a K1L-less vaccinia virus (vΔK1L) was less pathogenic than wild-type VACV in intranasal and intradermal models of infection. Decreased pathogenicity was correlated with diminished virus replication in intranasally infected mice. However, in intradermally inoculated ears, vΔK1L replicated to levels nearly identical to those of VACV, implying that the decreased immune response to vΔK1L infection, not virus replication, dictated lesion size. Several lines of evidence support this theory. First, vΔK1L induced slightly less edema than vK1L, as revealed by histopathology and noninvasive quantitative ultrasound technology (QUS). Second, infiltrating immune cell populations were decreased in vΔK1L-infected ears. Third, cytokine and chemokine gene expression was decreased in vΔK1L-infected ears. While these results identified the biological basis for smaller lesions, they remained puzzling; because K1 antagonizes NF-κB in vitro, antiviral gene expression was expected to be higher during vΔK1L infection. Despite these diminished innate immune responses, vΔK1L vaccination induced a protective VACV-specific CD8+ T cell response and protected against a lethal VACV challenge. Thus, vΔK1L is the first vaccinia virus construct reported that caused a muted innate immune gene expression profile and decreased immune cell infiltration in an intradermal model of infection yet still elicited protective immunity. IMPORTANCE The vaccinia virus (VACV) K1 protein inhibits NF-κB activation among its other antagonistic functions. A virus lacking K1 (vΔK1L) was predicted to be less pathogenic because it would trigger a more robust antiviral immune response than VACV. Indeed, vΔK1L was less pathogenic in intradermally infected mouse ear pinnae. However, vΔK1L infection unexpectedly elicited dramatically reduced infiltration of innate immune cells into ears. This was likely due to decreased expression of cytokine and chemokine genes in vΔK1L-infected ears. As such, our finding contradicted observations from cell culture systems. Interestingly, vΔK1L conferred protective immunity against lethal VACV challenge. This suggests that the muted immune response triggered during vΔK1L infection remained sufficient to mount an effective protective response. Our results highlight the complexity and unpredictable nature of virus-host interactions, a relationship that must be understood to better comprehend virus pathogenesis or to manipulate viruses for use as vaccines.

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G protein-coupled receptor kinase-2-deficient mice are protected from dextran sodium sulfate-induced acute colitis

Physiological Genomics ◽

10.1152/physiolgenomics.00006.2018 ◽

2018 ◽

Vol 50 (6) ◽

pp. 407-415 ◽

Cited By ~ 1

Author(s):

Michael D. Steury ◽

Ho Jun Kang ◽

Taehyung Lee ◽

Peter C. Lucas ◽

Laura R. McCabe ◽

...

Keyword(s):

G Protein ◽

Knockout Mice ◽

Sodium Sulfate ◽

Immune Cell ◽

Dextran Sodium Sulfate ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

Acute Colitis ◽

Inflammatory Genes ◽

G Protein Coupled

G protein-coupled receptor kinase 2 (GRK2) is a serine/threonine kinase and plays a key role in different disease processes. Previously, we showed that GRK2 knockdown enhances wound healing in colonic epithelial cells. Therefore, we hypothesized that ablation of GRK2 would protect mice from dextran sodium sulfate (DSS)-induced acute colitis. To test this, we administered DSS to wild-type (GRK2+/+) and GRK2 heterozygous (GRK+/−) mice in their drinking water for 7 days. As predicted, GRK2+/− mice were protected from colitis as demonstrated by decreased weight loss (20% loss in GRK2+/+ vs. 11% loss in GRK2+/−). lower disease activity index (GRK2+/+ 9.1 vs GRK2+/− 4.1), and increased colon lengths (GRK2+/+ 4.7 cm vs GRK2+/− 5.3 cm). To examine the mechanisms by which GRK2+/− mice are protected from colitis, we investigated expression of inflammatory genes in the colon as well as immune cell profiles in colonic lamina propria, mesenteric lymph node, and in bone marrow. Our results did not reveal differences in immune cell profiles between the two genotypes. However, expression of inflammatory genes was significantly decreased in DSS-treated GRK2+/− mice compared with GRK2+/+. To understand the mechanisms, we generated myeloid-specific GRK2 knockout mice and subjected them to DSS-induced colitis. Similar to whole body GRK2 heterozygous knockout mice, myeloid-specific knockout of GRK2 was sufficient for the protection from DSS-induced colitis. Together our results indicate that deficiency of GRK2 protects mice from DSS-induced colitis and further suggests that the mechanism of this effect is likely via GRK2 regulation of inflammatory genes in the myeloid cells.

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A Catalogus Immune Muris of the mouse immune responses to diverse pathogens

Cell Death and Disease ◽

10.1038/s41419-021-04075-y ◽

2021 ◽

Vol 12 (9) ◽

Author(s):

Céline Barlier ◽

Diego Barriales ◽

Alexey Samosyuk ◽

Sascha Jung ◽

Srikanth Ravichandran ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Biomedical Applications ◽

Immune Cell ◽

Cell Types ◽

Computational Method ◽

Functional Responses ◽

Macrophage Cell ◽

Functional States

AbstractImmunomodulation strategies are crucial for several biomedical applications. However, the immune system is highly heterogeneous and its functional responses to infections remains elusive. Indeed, the characterization of immune response particularities to different pathogens is needed to identify immunomodulatory candidates. To address this issue, we compiled a comprehensive map of functional immune cell states of mouse in response to 12 pathogens. To create this atlas, we developed a single-cell-based computational method that partitions heterogeneous cell types into functionally distinct states and simultaneously identifies modules of functionally relevant genes characterizing them. We identified 295 functional states using 114 datasets of six immune cell types, creating a Catalogus Immune Muris. As a result, we found common as well as pathogen-specific functional states and experimentally characterized the function of an unknown macrophage cell state that modulates the response to Salmonella Typhimurium infection. Thus, we expect our Catalogus Immune Muris to be an important resource for studies aiming at discovering new immunomodulatory candidates.

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JP-8 jet fuel exposure suppresses the immune response to viral infections

Toxicology and Industrial Health ◽

10.1177/0748233708093781 ◽

2008 ◽

Vol 24 (4) ◽

pp. 209-216 ◽

Cited By ~ 5

Author(s):

DT Harris ◽

D Sakiestewa ◽

D Titone ◽

X He ◽

J Hyde ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Viral Infection ◽

Viral Infections ◽

Immune Cell ◽

Immunosuppressive Agents ◽

Interleukin 10 ◽

Jet Fuel ◽

Us Air Force ◽

Influenza Viral Infection

The US Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Previous work has reported that JP-8 exposure is immunosuppressive. Exposure of mice to JP-8 for 1 h/day resulted in immediate secretion of two immunosuppressive agents, namely, interleukin-10 and prostaglandin E2. Thus, it was of interest to determine if jet fuel exposure might alter the immune response to infectious agents. The Hong Kong influenza model was used for these studies. Mice were exposed to 1000 mg/m3 JP-8 (1 h/day) for 7 days before influenza viral infection. Animals were infected intra-nasally with virus and followed in terms of overall survival as well as immune responses. All surviving animals were killed 14 days after viral infection. In the present study, JP-8 exposure increased the severity of the viral infection by suppressing the anti-viral immune responses. That is, exposure of mice to JP-8 for 1 h/day for 7 days before infection resulted in decreased immune cell viability after exposure and infection, a greater than fourfold decrease in immune proliferative responses to mitogens, as well as an overall loss of CD3+, CD4+, and CD8+ T cells from the lymph nodes, but not the spleens, of infected animals. These changes resulted in decreased survival of the exposed and infected mice, with only 33% of animals surviving as compared with 50% of mice infected but not jet fuel–exposed (and 100% of mice exposed only to JP-8). Thus, short-term, low-concentration JP-8 jet fuel exposures have significant suppressive effects on the immune system which can result in increased severity of viral infections.

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Coenzyme Q10 and Vitamin D Interventions Could Ameliorate COVID-19 Related Cellular Bioenergetic Dysfunction and Cytokine Storms

Journal of Immunological Sciences ◽

10.29245/2578-3009/2021/3.1220 ◽

2021 ◽

Vol 1 (6) ◽

pp. 1-9

Author(s):

Darshna Yagnik

Keyword(s):

Vitamin D ◽

Immune Response ◽

Coenzyme Q10 ◽

Immune Cell ◽

Chronically Ill ◽

Abnormal Immune Response ◽

Cell Immunity ◽

Tract Infections ◽

Spread Of Infection ◽

Cell Phenotypes

The immune response to SARS-CoV-2 varies from asymptomatic or mild symptoms of high temperature, muscle aches and coughs lasting 7 to 14 days to lower respiratory tract infections leading to pneumonia and serious respiratory distress as well as long COVID-19. Complications occur due to an abnormal immune response which involves upregulation of multiple cytokines leading to sustained inflammation which results in the spread of infection to vital organs. The double vaccine roll out has been rapid however vaccine mediated antibodies are not 100% effective against future coronavirus variants which may become increasingly more resistant and easily transmissible to overcome host immunity. Invariably supportive therapies will be needed. Research has shown that coenzyme Q10 and vitamin D deficiencies can have detrimental effects on immune cell defence, function and cytokine secretion promoting inflammation and sepsis especially against microbes. Early interventions including supplementation of these factors could mitigate cellular dysfunction especially in relation to mitochondria bioenergetics and help maintain cell immunity. This is particularly important as chronically ill COVID-19 patients seem to display abnormal immune cell phenotypes in infected organs indicating this could contribute to disease progression. The immune response and proposed roles of Vitamin D and Coenzyme Q10 in COVID-19 are discussed.

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MiR-223 improves intestinal inﬂammation through inhibiting the IL-6/STAT3 signaling pathway in dextran sodium sulfate-induced experimental colitis

10.21203/rs.3.rs-84400/v1 ◽

2020 ◽

Author(s):

Juanjuan Zhang ◽

Chenyang Wang ◽

Zhen Guo ◽

Binlin Da ◽

Weiming Zhu ◽

...

Keyword(s):

Signaling Pathway ◽

Sodium Sulfate ◽

Quantitative Polymerase Chain Reaction ◽

Negative Control ◽

Dextran Sodium Sulfate ◽

Enzyme Linked Immunosorbent Assay ◽

Colonic Inflammation ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Tnf Α

Abstract Background: The pathogenesis of inflammatory bowel disease (IBD) has not yet been clarified and is closely related to several proinflammatory factors. MicroRNA-233 (miR-223) might be involved in the development of IBD; however, the mechanism underlying its pathogenesis is unclear. In this study, we attempted to determine the role of miR-223 in dextran sodium sulfate (DSS)-induced colitis and explore the involvement of the IL-6/STAT3 pathway in the development of intestinal mucosal inflammation.Methods: Male C57BL/6 mice were divided into six groups: control (WT) group, DSS group, DSS+miR-223 agomir (DSS+A) group, DSS+miR-223 agomir negative control (DSS+A+NC) group, DSS+miR-223 antagomir (DSS+AN) group and DSS+miR-223 antagomir negative control (DSS+AN+NC) group. Body weight, stool consistency, fecal blood and the disease activity index (DAI) score were recorded daily. The length of each colon was measured, and colonic inflammation was evaluated with hematoxylin and eosin (H&E) staining and histopathological scoring. The expression of myeloperoxidase (MPO), TNF-α, IL-6, IL-10 and IL-17 in the colonic tissues was measured by Enzyme-linked Immunosorbent Assay (ELISA) and real-time quantitative polymerase chain reaction (RT-qPCR). The mRNA expression of gp130, Bcl-2 and Bcl-xl in the colon was measured using RT-qPCR. The colonic levels of STAT3 and p-STAT3 were determined by Western blotting.Results: MiR-223 expression in the terminal ileum and colon was increased in the DSS group compared with the WT group. Colitis symptoms were significantly alleviated in the DSS+A group and exacerbated in the DSS+AN group after administration of the miR-223 agomir and antagomir, respectively. MPO, TNF-α, IL-6 and IL-17 were decreased and IL-10 was increased in the DSS+A group, but these changes were reversed in the DSS+AN group. Gp130 mRNA, p-STAT3, Bcl-2 and Bcl-xl in the colon declined in the DSS+A group, but these levels increased in the DSS+AN group.Conclusion: The upregulation of miR-223 by agomir administration alleviated colonic inflammation in a DSS-induced colitis model, which was likely mediated by inhibiting the production of proinflammatory cytokines via the IL-6/STAT3 signaling pathway. These findings provide evidence that miR-223 might have potential therapeutic implications in IBD.

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