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BACKGROUND: Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood. METHODS: The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2-/-Il2rg-/- mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly. RESULTS: Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4+ Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features-IL-23 and CD4+ Tems-that may have predictive potential for severe irAEs and ICIs response. CONCLUSIONS: Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.
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Antígeno CTLA-4 , Interleucina-23 , Animales , Ratones , Humanos , Antígeno CTLA-4/antagonistas & inhibidores , Interleucina-23/antagonistas & inhibidores , Interleucina-23/metabolismo , Femenino , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Modelos Animales de Enfermedad , Melanoma/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Masculino , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios RetrospectivosRESUMEN
Ulcerative colitis (UC) is a challenging inflammatory gastrointestinal disorder, whose therapies encounter limitations in overcoming insufficient colonic retention and rapid systemic clearance. In this study, we report an innovative polymeric prodrug nanoformulation for targeted UC treatment through sustained 5-aminosalicylic acid (5-ASA) delivery. Amphiphilic polymer-based 13.5 nm micelles were engineered to incorporate azo-linked 5-ASA prodrug motifs, enabling cleavage via colonic azoreductases. In vitro, micelles exhibited excellent stability under gastric/intestinal conditions while demonstrating controlled 5-ASA release over 24 h in colonic fluids. Orally administered micelles revealed prolonged 24-h retention and a high accumulation within inflamed murine colonic tissue. At an approximately 60% dose reduction from those most advanced recent studies, the platform halted DSS colitis progression and outperformed standard 5-ASA therapy through a 77-97% suppression of inflammatory markers. Histological analysis confirmed intact colon morphology and restored barrier protein expression. This integrated prodrug nanoformulation addresses limitations in colon-targeted UC therapy through localized bioactivation and tailored pharmacokinetics, suggesting the potential of nanotechnology-guided precision delivery to transform disease management.
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Colitis , Colon , Preparaciones de Acción Retardada , Mesalamina , Micelas , Nitrorreductasas , Polímeros , Profármacos , Animales , Profármacos/química , Profármacos/farmacocinética , Mesalamina/química , Mesalamina/farmacocinética , Nitrorreductasas/metabolismo , Ratones , Colon/metabolismo , Colon/patología , Polímeros/química , Colitis/tratamiento farmacológico , Colitis/metabolismo , Preparaciones de Acción Retardada/química , NADH NADPH Oxidorreductasas/metabolismo , Ratones Endogámicos C57BL , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , MasculinoRESUMEN
Rationale: The treatment of ulcerative colitis (UC) presents an ongoing clinical challenge. Emerging research has implicated that the cGAS-STING pathway promotes the progression of UC, but conflicting results have hindered the development of STING as a therapeutic target. In the current study, we aim to comprehensively elucidate the origins, downstream signaling and pathogenic roles of myeloid STING in colitis and colitis-associated carcinoma (CAC). Methods: Tmem173 fl/fl Lyz2-Cre ert2 mice were constructed for inducible myeloid-specific deletion of STING. RNA-sequencing, flow cytometry, and multiplex immunohistochemistry were employed to investigate immune responses in DSS-induced colitis or AOM/DSS-induced carcinogenesis. Colonic organoids, primary bone marrow derived macrophages and dendritic cells, and splenic T cells were used for in vitro studies. Results: We observed that myeloid STING knockout in adult mice inhibited macrophage maturation, reduced DC cell activation, and suppressed pro-inflammatory Th1 and Th17 cells, thereby protecting against both acute and chronic colitis and CAC. However, myeloid STING deletion in neonatal or tumor-present mice exhibited impaired immune tolerance and anti-tumor immunity. Furthermore, we found that TFAM-associated mtDNA released from damaged colonic organoids, rather than bacterial products, activates STING in dendritic cells in an extracellular vesicle-independent yet endocytosis-dependent manner. Both IRF3 and NF-κB are required for STING-mediated expression of IL-12 family cytokines, promoting Th1 and Th17 differentiation and contributing to excessive inflammation in colitis. Conclusions: Detection of the TFAM-mtDNA complex from damaged intestinal epithelium by myeloid STING exacerbates colitis through IL-12 cytokines, providing new evidence to support the development of STING as a therapeutic target for UC and CAC.
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ADN Mitocondrial , Células Dendríticas , Interleucina-12 , Mucosa Intestinal , Proteínas de la Membrana , Ratones Noqueados , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones , Interleucina-12/metabolismo , Interleucina-12/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/inmunología , Ratones Endogámicos C57BL , Colitis/patología , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/genética , Transducción de Señal , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/inmunología , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/genética , Neoplasias Asociadas a Colitis/metabolismo , Neoplasias Asociadas a Colitis/inmunología , Macrófagos/metabolismo , Macrófagos/inmunología , Modelos Animales de Enfermedad , Sulfato de DextranRESUMEN
Male infertility represents a significant public health concern. There is a negative impact of inflammatory bowel diseases (IBDs) on the male reproductive system. The aim of this study was to investigate whether oat beta-glucan (OBG) with different molar mass can modulate parameters of antioxidant defense and inflammatory response in the testes of adult Sprague-Dawley rats with TNBS-induced colitis and whether the OBG intervention can modulate the inflammatory response in association with the RAS system. Results: higher testicular superoxide dismutase (SOD), glutathione reductase (GR) activities and glutathione (GSH) concentration, and lower testosterone (T) level and glutathione peroxidase (GPx) activity, were observed in rats with colitis than in healthy control ones. TNBS-induced colitis resulted in decreased the angiotensin 1-7 (ANG 1-7) level in the testes of rats fed with low-molar mass OBG compared to control animals. Conclusions: although colitis induced moderate pro-oxidant changes in the gonads, it seems plausible that dietary intervention with different fractions of oat beta-glucans mass may support the maintenance of reproductive homeostasis via the stimulation of the local antioxidant defense system.
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Antioxidantes , Avena , Colitis , Ratas Sprague-Dawley , Testículo , beta-Glucanos , Animales , Masculino , beta-Glucanos/farmacología , beta-Glucanos/administración & dosificación , Testículo/metabolismo , Testículo/efectos de los fármacos , Antioxidantes/metabolismo , Avena/química , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/dietoterapia , Ratas , Angiotensina I/metabolismo , Ácido Trinitrobencenosulfónico , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Fragmentos de Péptidos/metabolismo , Glutatión/metabolismo , Testosterona/sangre , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismoRESUMEN
Rationale: The aryl hydrocarbon receptor (AhR) functions in the regulation of intestinal inflammation, but knowledge of the underlying mechanisms in innate immune cells is limited. Here, we investigated the role of AhR in modulating the functions of macrophages in inflammatory bowel disease pathogenesis. Methods: The cellular composition of intestinal lamina propria CD45+ leukocytes in a dextran sulfate sodium (DSS)-induced mouse colitis model was determined by single-cell RNA sequencing. Macrophage pyroptosis was quantified by analysis of lactate dehydrogenase release, propidium iodide staining, enzyme-linked immunosorbent assay, western blot, and flow cytometry. Differentially expressed genes were confirmed by RNA-seq, RT-qPCR, luciferase assay, chromatin immunoprecipitation, and immunofluorescence staining. Results: AhR deficiency mediated dynamic remodeling of the cellular composition of intestinal lamina propria (LP) CD45+ immune cells in a colitis model, with a significant increase in monocyte-macrophage lineage. Mice with AhR deficiency in myeloid cells developed more severe dextran sulfate sodium induced colitis, with concomitant increased macrophage pyroptosis. Dietary supplementation with an AhR pre-ligand, indole-3-carbinol, conferred protection against colitis while protection failed in mice lacking AhR in myeloid cells. Mechanistically, AhR signaling inhibited macrophage pyroptosis by promoting ornithine decarboxylase 1 (Odc1) transcription, to enhance polyamine biosynthesis. The increased polyamine, particularly spermine, inhibited NLRP3 inflammasome assembly and subsequent pyroptosis by suppressing K+ efflux. AHR expression was positively correlated with ODC1 in intestinal mucosal biopsies from patients with ulcerative colitis. Conclusions: These findings suggest a functional role for the AhR/ODC1/polyamine axis in maintaining intestinal homeostasis, providing potential targets for treatment of inflammatory bowel disease.
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Colitis , Sulfato de Dextran , Macrófagos , Poliaminas , Piroptosis , Receptores de Hidrocarburo de Aril , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , Animales , Ratones , Macrófagos/metabolismo , Macrófagos/inmunología , Colitis/metabolismo , Colitis/inducido químicamente , Colitis/patología , Humanos , Poliaminas/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones Noqueados , Inflamación/metabolismo , Masculino , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice BásicoRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) is a progressive and debilitating inflammatory disease of the gastrointestinal tract (GIT). Despite recent advances, precise treatment and noninvasive monitoring remain challenging. METHODS: Herein, we developed orally-administered, colitis-targeting and hyaluronic acid (HA)-modified, core-shell curcumin (Cur)- and cerium oxide (CeO2)-loaded nanoprobes (Cur@PC-HA/CeO2 NPs) for computed tomography (CT) imaging-guided treatment and monitoring of IBD in living mice. RESULTS: Following oral administration, high-molecular-weight HA maintains integrity with little absorption in the upper GIT, and then actively accumulates at local colitis sites owing to its colitis-targeting ability, leading to specific CT enhancement lasting for 24 h. The retained NPs are further degraded by hyaluronidase in the colon to release Cur and CeO2, thereby exerting anti-inflammatory and antioxidant effects. Combined with the ability of NPs to regulate intestinal flora, the oral NPs result in substantial relief in symptoms. Following multiple treatments, the gradually decreasing range of the colon with high CT attenuation correlates with the change in the clinical biomarkers, indicating the feasibility of treatment response and remission. CONCLUSION: This study provides a proof-of-concept for the design of a novel theranostic integration strategy for concomitant IBD treatment and the real-time monitoring of treatment responses.
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Cerio , Curcumina , Ácido Hialurónico , Enfermedades Inflamatorias del Intestino , Nanopartículas , Nanomedicina Teranóstica , Animales , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Ratones , Cerio/química , Curcumina/farmacología , Curcumina/química , Curcumina/uso terapéutico , Nanomedicina Teranóstica/métodos , Administración Oral , Nanopartículas/química , Ácido Hialurónico/química , Hialuronoglucosaminidasa/metabolismo , Tomografía Computarizada por Rayos X , Ratones Endogámicos C57BL , Colon/diagnóstico por imagen , Colon/patología , Colon/metabolismo , Humanos , Colitis/tratamiento farmacológicoRESUMEN
BACKGROUND: Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. RESULTS: Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. CONCLUSIONS: Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract.
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Modelos Animales de Enfermedad , Disbiosis , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Interleucina-10 , Animales , Humanos , Ratones , Enfermedades Inflamatorias del Intestino/microbiología , Disbiosis/microbiología , Interleucina-10/genética , Colitis/microbiología , Heces/microbiología , Colon/microbiología , Ratones Noqueados , Ratones Endogámicos C57BL , Femenino , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Inflamación , MasculinoRESUMEN
Hepatic factors secreted by the liver promote homeostasis and are pivotal for maintaining the liver-gut axis. Bile acid metabolism is one such example wherein, bile acid synthesis occurs in the liver and its biotransformation happens in the intestine. Dysfunctional interactions between the liver and the intestine stimulate varied pathological outcomes through its bidirectional portal communication. Indeed, aberrant bile acid metabolism has been reported in inflammatory bowel disease (IBD). However, the molecular mechanisms underlying these crosstalks that perpetuate intestinal permeability and inflammation remain obscure. Here, we identify a novel hepatic gene program regulated by Rela and Stat3 that accentuates the inflammation in an acute experimental colitis model. Hepatocyte-specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both the liver and the gut and shows a restricted colitogenic phenotype. On supplementation of chenodeoxycholic acid (CDCA), knock-out mice exhibit enhanced colitis-induced alterations. This study provides persuasive evidence for the development of multi-organ strategies for treating IBD and identifies a hepatocyte-specific Rela-Stat3 network as a promising therapeutic target.
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Ácidos y Sales Biliares , Colitis , Modelos Animales de Enfermedad , Hepatocitos , Ratones Noqueados , Factor de Transcripción STAT3 , Factor de Transcripción ReIA , Animales , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/genética , Colitis/patología , Hepatocitos/metabolismo , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIA/genética , Ratones , Ácidos y Sales Biliares/metabolismo , Regulación de la Expresión Génica , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BLRESUMEN
BACKGROUND/AIMS: This study aimed to investigate the possible positive effects of arbutin in a trinitrobenzene sulfonic acid (TNBS)- induced experimental colitis model, to compare it with mesalazine, which is used in treating inflammatory bowel disease and to observe the effect of its concomitant use. MATERIALS AND METHODS: Forty Wistar albino species male rats were randomized into 5 groups as control, colitis, colitis+arbutin (Arb), colitis+mesalazine (Mes), and colitis+mesalazine+arbutin (M+A). Proinflammatory cytokines [interleukin (IL)-6, IL-1ß, tumor necrosis factor alpha (TNF-α)] and oxidant/antioxidant parameters [malondialdehyde (MDA), superoxide dismutase inhibition (SOD) inhibition, myeloperoxidase (MPO), and catalase, glutathione peroxidase (GPx)] were processed from the samples. Histopathological evaluation evaluated goblet cell reduction, cellular infiltration, and mucosal loss. RESULTS: When the treatment groups and the TNBS group were compared, statistical significance was achieved in MDA, MPO, SOD inhibition, GPx values, IL-6, IL-1ß and TNF-α levels. Histopathological evaluation revealed a statistically significant decrease in the mucosal loss value in the group where mesalazine and arbutin were used together compared to the TNBS group. CONCLUSION: Our study's results elaborated that using arbutin alone or in combination with mesalazine produced positive effects in colitis-induced rats.
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Arbutina , Colitis , Modelos Animales de Enfermedad , Mesalamina , Peroxidasa , Ratas Wistar , Ácido Trinitrobencenosulfónico , Animales , Masculino , Arbutina/farmacología , Arbutina/uso terapéutico , Ratas , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Ácido Trinitrobencenosulfónico/toxicidad , Mesalamina/farmacología , Mesalamina/uso terapéutico , Peroxidasa/metabolismo , Superóxido Dismutasa/metabolismo , Citocinas/metabolismo , Malondialdehído/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Factor de Necrosis Tumoral alfa , Distribución Aleatoria , Glutatión Peroxidasa/metabolismo , Interleucina-1beta/metabolismo , Estrés Oxidativo/efectos de los fármacos , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéuticoRESUMEN
This study aimed to investigate whether class A1 scavenger receptor (SR-A1) regulated macrophage polarization and gut microbial alteration during intestinal inflammation of colitis. A murine colitis model was established by feeding with dextran sulfate sodium (DSS), and treatment groups were injected intravenously with SR-A1 antibody. Results showed a preventive effect on colitis symptoms and fewer inflammatory cell infiltrates in treatment groups. Down-regulation of inflammatory cytokines and up-regulation of anti-inflammatory cytokine related to macrophages were seen in murine PBMC and LPMC after injected with SR-A1 antibody. The percentage of M2 macrophages was also elevated in treatment groups. In addition, SR-A1 antibody treatment resulted in the decreased apoptosis and increased proliferation of colonic epithelial cells. Other findings indicated that SR-A1 antibody injection could mediate its anti-inflammatory effect via inhibiting TLR4-MyD88-NF-kB signaling pathway and alterating the gut microbiota composition. Our research identified SR-A1 as a potential therapeutic target in inflammatory bowel disease (IBD).
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Colitis , Microbioma Gastrointestinal , Macrófagos , Receptores Depuradores de Clase A , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Colitis/inmunología , Colitis/inducido químicamente , Colitis/microbiología , Colitis/metabolismo , Ratones , Macrófagos/inmunología , Macrófagos/metabolismo , Receptores Depuradores de Clase A/metabolismo , Sulfato de Dextran/toxicidad , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Transducción de Señal , Modelos Animales de Enfermedad , Citocinas/metabolismo , Anticuerpos , FN-kappa B/metabolismo , Ratones Endogámicos C57BL , Masculino , Apoptosis/efectos de los fármacosRESUMEN
Neutrophils (polymorphonuclear leukocytes, PMNs) comprise a major component of the immune cell infiltrate during acute mucosal inflammation and have an important role in molding the inflammatory tissue environment. While PMNs are essential to clearance of invading microbes, the major PMN antimicrobial enzyme myeloperoxidase (MPO) can also promote bystander tissue damage. We hypothesized that blocking MPO would attenuate acute colitis and prevent the development of chronic colitis by limiting bystander tissue damage. Using the acute and chronic dextran sodium sulfate model of murine colitis, we demonstrated that MPO-deficient mice experienced less inflammation and more rapidly resolved colitis relative to wild-type controls. Mechanistic studies demonstrated that activated MPO disrupted intestinal epithelial barrier function through the dysregulation of the epithelial tight junction proteins. Our findings revealed that activated MPO chlorinates tyrosine within several tight junction proteins, thereby promoting tight junction mislocalization and dysfunction. These observations in cell models and in murine colitis were validated in human intestinal biopsies from individuals with ulcerative colitis and revealed a strong correlation between disease severity (Mayo score) and tissue chlorinated tyrosine levels. In summary, these findings implicate MPO as a viable therapeutic target to limit bystander tissue damage and preserve mucosal barrier function during inflammation.
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Modelos Animales de Enfermedad , Mucosa Intestinal , Neutrófilos , Peroxidasa , Proteínas de Uniones Estrechas , Peroxidasa/metabolismo , Animales , Ratones , Humanos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Neutrófilos/metabolismo , Neutrófilos/inmunología , Proteínas de Uniones Estrechas/metabolismo , Colitis/patología , Colitis/metabolismo , Colitis/inducido químicamente , Halogenación , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones Noqueados , Sulfato de Dextran/toxicidad , Uniones Estrechas/metabolismo , Femenino , Ratones Endogámicos C57BL , Colitis Ulcerosa/patología , Colitis Ulcerosa/metabolismoRESUMEN
The association of hormonal contraception with increased risk of inflammatory bowel disease (IBD) observed in females suggests involvement of ovarian hormones, such as estradiol, and the estrogen receptors in the progression of intestinal inflammation. Here, we investigated the effects of prophylactic SERM2 and estradiol supplementation in dextran sulfate sodium-induced colitis using mice with intact ovaries and ovariectomized (OVX) female mice. We found that graded colitis score was threefold reduced in the OVX mice, compared to mice with intact ovaries. Estradiol supplementation, however, aggravated the colitis in OVX mice, increasing the colitis score to a similar level than what was observed in the intact mice. Further, we observed that immune infiltration and gene expression of inflammatory interleukins Il1b, Il6, and Il17a were up to 200-fold increased in estradiol supplemented OVX colitis mice, while a mild but consistent decrease was observed by SERM2 treatment in intact animals. Additionally, cyclo-oxygenase 2 induction was increased in the colon of colitis mice, in correlation with increased serum estradiol levels. Measured antagonist properties of SERM2, together with the other results presented here, indicates an exaggerating role of ERα signaling in colitis. Our results contribute to the knowledge of ovarian hormone effects in colitis and encourage further research on the potential use of ER antagonists in the colon, in order to alleviate inflammation.
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Colitis , Sulfato de Dextran , Estradiol , Receptor alfa de Estrógeno , Ovariectomía , Animales , Femenino , Receptor alfa de Estrógeno/metabolismo , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/tratamiento farmacológico , Ratones , Estradiol/farmacología , Estradiol/sangre , Ratones Endogámicos C57BL , Estrógenos/farmacología , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Interleucina-17/metabolismo , Colon/patología , Colon/efectos de los fármacos , Colon/metabolismo , Interleucina-6/metabolismo , Interleucina-1beta/metabolismoRESUMEN
Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly(ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, with an IBD patient cohort as well as two mouse colitis models, that is, IBD-mimicking oral dextran sulfate sodium (DSS) exposure and oral Salmonella infection. Parp14 was expressed in the human colon by cells in the lamina propria, but, in particular, by the epithelial cells with a granular staining pattern in the cytosol. The same expression pattern was evidenced in both mouse models. Parp14-deficiency caused increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss, and immune cell infiltration in DSS-exposed mice. The absence of Parp14 did not affect the mouse colon bacterial microbiota. Also, the colon leukocyte populations of Parp14-deficient mice were normal. In contrast, bulk tissue RNA-Seq demonstrated that the colon transcriptomes of Parp14-deficient mice were dominated by abnormalities in inflammation and infection responses both prior and after the DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.
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Colitis , Sulfato de Dextran , Ratones Endogámicos C57BL , Poli(ADP-Ribosa) Polimerasas , Animales , Femenino , Humanos , Masculino , Ratones , Colitis/genética , Colitis/inducido químicamente , Colitis/patología , Colon/patología , Colon/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/metabolismo , Ratones Noqueados , Poli(ADP-Ribosa) Polimerasas/metabolismo , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/deficienciaRESUMEN
Edible plant-derived nanovesicles (ePDNs) have shown potential as a non-pharmacological option for inflammatory bowel disease (IBD) by maintaining gut health and showing anti-inflammatory effects. However, the effects of Allium tuberosum-derived nanovesicles (ADNs) on colitis have not been studied to date. Here, we extracted exosome-like nanovesicles from Allium tuberosum and investigated whether they have an anti-inflammatory effect in RAW 264.7 cells and colitis mice. The results showed that ADNs reduced the elevated levels of inflammatory factors such as IL-1ß, IL-6, TNF-α, and NF-κB pathway-related proteins as a consequence of lipopolysaccharide (LPS) stimulation in RAW 264.7 cells. Furthermore, our mouse experiments demonstrated that ADNs could ameliorate dextran sulfate sodium (DSS)-induced colitis symptoms (e.g., increased disease activity index score, intestinal permeability, and histological appearance). Additionally, ADNs counteracted DSS-induced colitis by downregulating the expression of serum amyloid A (SAA), IL-1ß, IL-6, and TNF-α and increasing the expression of tight junction proteins (ZO-1 and occludin) and the anti-inflammatory cytokine IL-10. 16S rRNA gene sequencing showed that ADN intervention restored the gut microbial composition, which was similar to that of the DSS non-treated group, by decreasing the ratio of Firmicutes to Bacteroidetes and the relative abundance of Proteobacteria. Furthermore, ADNs induced acetic acid production along with an increase in the abundance of Lactobacillus. Overall, our findings suggest that ADN supplementation has a crucial role in maintaining gut health and is a novel preventive therapy for IBD.
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Antiinflamatorios , Colitis , Sulfato de Dextran , Microbioma Gastrointestinal , Animales , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Colitis/inducido químicamente , Sulfato de Dextran/efectos adversos , Antiinflamatorios/farmacología , Células RAW 264.7 , Ratones Endogámicos C57BL , Masculino , Modelos Animales de Enfermedad , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificaciónRESUMEN
Inflammatory bowel disease (IBD) is an immunologically complex disorder involving genetic, microbial, and environmental risk factors. Its global burden has continued to rise since industrialization, with epidemiological studies suggesting that ambient particulate matter (PM) in air pollution could be a contributing factor. Prior animal studies have shown that oral PM10 exposure promotes intestinal inflammation in a genetic IBD model and that PM2.5 inhalation exposure can increase intestinal levels of pro-inflammatory cytokines. PM10 and PM2.5 include ultrafine particles (UFP), which have an aerodynamic diameter of <0.10 µm and biophysical and biochemical properties that promote toxicity. UFP inhalation, however, has not been previously studied in the context of murine models of IBD. Here, we demonstrated that ambient PM is toxic to cultured Caco-2 intestinal epithelial cells and examined whether UFP inhalation affected acute colitis induced by dextran sodium sulfate and 2,4,6-trinitrobenzenesulfonic acid. C57BL/6J mice were exposed to filtered air (FA) or various types of ambient PM reaerosolized in the ultrafine size range at ~300 µg/m3, 6 h/day, 3-5 days/week, starting 7-10 days before disease induction. No differences in weight change, clinical disease activity, or histology were observed between the PM and FA-exposed groups. In conclusion, UFP inhalation exposure did not exacerbate intestinal inflammation in acute, chemically-induced colitis models.
Asunto(s)
Colitis , Sulfato de Dextran , Ratones Endogámicos C57BL , Material Particulado , Ácido Trinitrobencenosulfónico , Material Particulado/toxicidad , Animales , Colitis/inducido químicamente , Colitis/patología , Ratones , Humanos , Sulfato de Dextran/toxicidad , Células CACO-2 , Ácido Trinitrobencenosulfónico/toxicidad , Ácido Trinitrobencenosulfónico/efectos adversos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Células Epiteliales/metabolismo , Modelos Animales de Enfermedad , Masculino , Tamaño de la PartículaRESUMEN
A hundred million tons of young apples are thinned and discarded in the orchard per year, aiming to increase the yield and quality of apples. We fermented thinned young apples using a potential probiotic fungus, Eurotium cristatum, which notably disrupted the microstructure of raw samples, as characterized by the scanning electron microscope. Fermentation substantially altered the metabolite profiles of samples, which are predicted to alleviate colitis via regulating inflammatory response and response to lipopolysaccharide by using network pharmacology analysis. In vivo, oral gavage of water extracts of E. cristatum fermented young apples (E.YAP) effectively alleviated DSS-induced colitis, restored the histopathology damage, reduced the levels of inflammatory cytokines, and promoted colonic expressions of tight junction proteins. Moreover, E.YAP ameliorated gut dysbacteriosis by increasing abundances of Lactobacillus,Blautia, Muribaculaceae, and Prevotellaceae_UCG-001 while inhibiting Turicibacter, Alistipes, and Desulfovibrio. Importantly, E.YAP increased colonic bile acids, such as CA, TCA, DCA, TUDCA, and LCA, thereby alleviating colitis via PXR/NF-κB signaling. Furthermore, a synbiotic combination with Limosilactobacillus reuteri WX-94, a probiotic strain isolated from feces of healthy individuals with anti-inflammatory properties, augmented anticolitis capacities of E.YAP. Our findings demonstrate that E.YAP could be a novel, potent, food-based anti-inflammatory prebiotic for relieving inflammatory injuries.
Asunto(s)
Bacterias , Colitis , Eurotium , Fermentación , Malus , Ratones Endogámicos C57BL , Animales , Malus/química , Ratones , Colitis/microbiología , Colitis/metabolismo , Colitis/inducido químicamente , Humanos , Masculino , Eurotium/metabolismo , Eurotium/química , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Probióticos/administración & dosificación , Probióticos/farmacología , Frutas/química , Frutas/microbiología , Colon/microbiología , Colon/metabolismo , Colon/inmunologíaRESUMEN
Anticancer immunotherapies modulate the body's immune system to recognise and eradicate cancerous cells. However, stimulation of the body's immune system can also lead to a number of adverse effects when those immune cells target non-cancerous cells in the form of autoimmunity. One relatively common example of this off-target action is colitis.We present three patients who presented atypically with colitis, consequently, leading to a delayed diagnosis. These cases highlight the diverse ways a relatively common immune-related adverse event can present.
Asunto(s)
Colitis , Estreñimiento , Humanos , Estreñimiento/etiología , Colitis/inmunología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Diagnóstico TardíoAsunto(s)
Colitis , Infecciones por Citomegalovirus , Citomegalovirus , Hemorragia Gastrointestinal , Humanos , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/terapia , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/inmunología , Hemorragia Gastrointestinal/terapia , Hemorragia Gastrointestinal/etiología , Colitis/virología , Colitis/terapia , Colitis/complicaciones , Citomegalovirus/patogenicidad , Masculino , Receptores Quiméricos de Antígenos/inmunología , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Persona de Mediana EdadRESUMEN
BACKGROUND: Mesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects. METHODS: First, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-ß1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD. RESULTS: The therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-ß1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-ß1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis. CONCLUSIONS: MLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-ß1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients.
Asunto(s)
Diferenciación Celular , Colitis , Ganglios Linfáticos , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Linfocitos T Reguladores , Células Th17 , Factor de Crecimiento Transformador beta1 , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Humanos , Colitis/terapia , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Trasplante de Células Madre Mesenquimatosas/métodos , Ratones , Ganglios Linfáticos/metabolismo , Células Th17/metabolismo , Células Th17/inmunología , Cordón Umbilical/citología , Mesenterio/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos BALB C , Masculino , Enfermedades Inflamatorias del Intestino/terapia , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patologíaRESUMEN
Group 3 innate lymphoid cells (ILC3s) play key roles in intestinal inflammation. Olfactomedin 4 (OLFM4) is highly expressed in the colon and has a potential role in dextran sodium sulfate-induced colitis. However, the detailed mechanisms underlying the effects of OLFM4 on ILC3-mediated colitis remain unclear. In this study, we identify OLFM4 as a positive regulator of IL-22+ILC3. OLFM4 expression in colonic ILC3s increases substantially during intestinal inflammation in humans and mice. Compared to littermate controls, OLFM4-deficient (OLFM4-/-) mice are more susceptible to bacterial infection and display greater resistance to anti-CD40 induced innate colitis, together with impaired IL-22 production by ILC3, and ILC3s from OLFM4-/-mice are defective in pathogen resistance. Besides, mice with OLFM4 deficiency in the RORγt compartment exhibit the same trend as in OLFM4-/-mice, including colonic inflammation and IL-22 production. Mechanistically, the decrease in IL-22+ILC3 caused by OLFM4 deficiency involves the apoptosis signal-regulating kinase 1 (ASK1)- p38 MAPK signaling-dependent downregulation of RAR-related orphan receptor gamma (RORγt) protein. The OLFM4-metadherin (MTDH) complex upregulates p38/RORγt signaling, which is necessary for IL-22+ILC3 activation. The findings indicate that OLFM4 is a novel regulator of IL-22+ILC3 and essential for modulating intestinal inflammation and tissue homeostasis.