RESUMO
The gut microbiota promotes immune system development in early life, but the interactions between the gut metabolome and immune cells in the neonatal gut remain largely undefined. Here, we demonstrate that the neonatal gut is uniquely enriched with neurotransmitters, including serotonin, and that specific gut bacteria directly produce serotonin while down-regulating monoamine oxidase A to limit serotonin breakdown. We found that serotonin directly signals to T cells to increase intracellular indole-3-acetaldehdye and inhibit mTOR activation, thereby promoting the differentiation of regulatory T cells, both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice resulted in long-term T cell-mediated antigen-specific immune tolerance toward both dietary antigens and commensal bacteria. Together, our study has uncovered an important role for specific gut bacteria to increase serotonin availability in the neonatal gut and identified a function of gut serotonin in shaping T cell response to dietary antigens and commensal bacteria to promote immune tolerance in early life.
Assuntos
Microbioma Gastrointestinal , Serotonina , Animais , Camundongos , Bactérias , Tolerância Imunológica , AntígenosRESUMO
Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω-6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recommendations for optimal LA intake. Given the importance of LA in the human diet, it is crucial to better understand the molecular mechanisms underlying its potential colon cancer-promoting effects. Using LC-MS/MS-based targeted lipidomics, we find that the cytochrome P450 (CYP) monooxygenase pathway is a major pathway for LA metabolism in vivo. Furthermore, CYP monooxygenase is required for the colon cancer-promoting effects of LA, since the LA-rich diet fails to exacerbate colon cancer in CYP monooxygenase-deficient mice. Finally, CYP monooxygenase mediates the pro-cancer effects of LA by converting LA to epoxy octadecenoic acids (EpOMEs), which have potent effects on promoting colon tumorigenesis via gut microbiota-dependent mechanisms. Overall, these results support that CYP monooxygenase-mediated conversion of LA to EpOMEs plays a crucial role in the health effects of LA, establishing a unique mechanistic link between dietary fatty acid intake and cancer risk. These results could help in developing more effective dietary guidelines for optimal LA intake and identifying subpopulations that may be especially vulnerable to LA's negative effects.
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Neoplasias do Colo , Ácido Linoleico , Humanos , Camundongos , Animais , Ácido Linoleico/farmacologia , Ácido Linoleico/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Eicosanoides , Sistema Enzimático do Citocromo P-450/metabolismo , Dieta , Neoplasias do Colo/etiologiaRESUMO
Triclosan (TCS) is a widespread antimicrobial agent that is associated with many adverse health outcomes. Its gut toxicity has been attributed to the molecular modifications mediated by commensal microbes, but microbial transformations of TCS derivatives in the gut lumen are still largely unknown. Aromatic hydroxylation is the predominant oxidative metabolism of TCS that linked to its toxicological effects in host tissues. Here, we aimed to reveal the biological fates of hydroxyl-TCS (OH-TCS) in the colon, where intestinal microbes mainly reside. Unlike the profiles generated via host metabolism, OH-TCS species remain unconjugated in human stools from a cohort study. Through tracking molecular compositions in mouse intestinal tract, elevated abundance of free-form OH-TCS while reduced abundance of conjugated forms was observed in the colon digesta and mucosa. Using antibiotic-treated and germ-free mice, as well as in vitro approaches, we demonstrate that gut microbiota-encoded enzymes efficiently convert glucuronide/sulfate-conjugated OH-TCS, which are generated from host metabolism, back to their bioactive free-forms in colon tissues. Thus, host-gut microbiota metabolic interactions of TCS derivatives were proposed. These results shed light on the crucial roles of microbial metabolism in TCS toxicity, and highlight the importance of incorporating gut microbial transformations in health risk assessment of environmental chemicals.
Assuntos
Microbioma Gastrointestinal , Triclosan , Camundongos , Humanos , Animais , Triclosan/metabolismo , Estudos de Coortes , Colo , Estresse OxidativoRESUMO
BACKGROUND: In utero transmission of SARS coronavirus 2 (SARS-CoV-2) has not been fully investigated. We investigated whether newborns of mothers with COVID-19 during pregnancy might harbor SARS-CoV-2 in the gastrointestinal tract. METHODS: This cohort study investigated stool from 14 newborns born at 25-41 weeks admitted at delivery to our urban academic hospital whose mothers had COVID-19 during pregnancy. Eleven mothers had COVID-19 resolved more than 10 weeks before delivery. Newborn stool was evaluated for SARS-CoV-2 RNA, Spike protein, and induction of inflammatory cytokines interleukin-6 (IL-6) and interferon-γ (IFN-γ) in macrophages. RESULTS: Despite negative SARS CoV-2 nasal PCRs from all newborns, viral RNAs and Spike protein were detected in the stool of 11 out of 14 newborns as early as the first day of life and increased over time in 6. Stool homogenates from all 14 newborns elicited elevated inflammatory IL-6 and IFN-γ from macrophages. Most newborns were clinically well except for one death from gestational autoimmune liver disease and another who developed necrotizing enterocolitis. CONCLUSIONS: These findings suggest in utero transmission of SARS-CoV-2 and possible persistent intestinal viral reservoirs in the newborns. Further investigation is required to understand the mechanisms and their clinical implications. IMPACT: SARS-CoV-2 RNAs or Spike protein was detected in the stool of 11 out of 14 preterm newborns born to mothers with resolved COVID-19 weeks prior to delivery despite negative newborn nasal PCR swabs. These novel findings suggest risk of in utero SARS-CoV-2 transmission to the fetal intestine during gestation. The presence of SARS-CoV-2 RNAs and Spike protein in the intestines of newborns may potentially impact the development of the gut microbiome and the immune system; the long-term health impact on the preterm infants should be further investigated.
Assuntos
COVID-19 , Complicações Infecciosas na Gravidez , Gravidez , Feminino , Recém-Nascido , Humanos , SARS-CoV-2 , Estudos de Coortes , RNA Viral , Glicoproteína da Espícula de Coronavírus , Interleucina-6 , Recém-Nascido Prematuro , Complicações Infecciosas na Gravidez/diagnóstico , Transmissão Vertical de Doenças InfecciosasRESUMO
The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.
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COVID-19 , Microbioma Gastrointestinal , Animais , Antivirais/uso terapêutico , Ácidos Graxos Voláteis , Masculino , Mamíferos/metabolismo , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2RESUMO
In recent decades there has been a dramatic increase in the incidence and prevalence of inflammatory bowel disease (IBD), a chronic inflammatory disease of the intestinal tissues and a major risk factor of developing colon cancer. While accumulating evidence supports that the rapid increase of IBD is mainly caused by exposure to environmental risk factors, the identities of the risk factors, as well as the mechanisms connecting environmental exposure with IBD, remain largely unknown. Triclosan (TCS) and triclocarban (TCC) are high-volume chemicals that are used as antimicrobial ingredients in consumer and industrial products. They are ubiquitous contaminants in the environment and are frequently detected in human populations. Recent studies showed that exposure to TCS/TCC, at human exposure-relevant doses, increases the severity of colitis and exacerbates colon tumorigenesis in mice, suggesting that they could be risk factors of IBD and associated diseases. The gut toxicities of these compounds require the presence of gut microbiota, since they fail to induce colonic inflammation in mice lacking the microbiota. Regarding the functional roles of the microbiota involved, gut commensal microbes and specific microbial ß-glucuronidase (GUS) enzymes mediate colonic metabolism of TCS, leading to metabolic reactivation of TCS in the colon and contributing to its subsequent gut toxicity. Overall, these results support that these commonly used compounds could be environmental risk factors of IBD and associated diseases through gut microbiota-dependent mechanisms.
Assuntos
Carbanilidas , Colite , Neoplasias do Colo , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Triclosan , Animais , Carbanilidas/toxicidade , Colite/induzido quimicamente , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/epidemiologia , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Camundongos , Fatores de Risco , Triclosan/toxicidadeRESUMO
The gut microbiome elicits antigen-specific immunoglobulin G (IgG) at steady state that cross-reacts to pathogens to confer protection against systemic infection. The role of gut microbiome-specific IgG antibodies in the development of the gut microbiome and immunity against enteric pathogens in early life, however, remains largely undefined. In this study, we show that gut microbiome-induced maternal IgG is transferred to the neonatal intestine through maternal milk via the neonatal Fc receptor and directly inhibits Citrobacter rodentium colonization and attachment to the mucosa. Enhanced neonatal immunity against oral C. rodentium infection was observed after maternal immunization with a gut microbiome-derived IgG antigen, outer membrane protein A, or induction of IgG-inducing gut bacteria. Furthermore, by generating a gene-targeted mouse model with complete IgG deficiency, we demonstrate that IgG knockout neonates are more susceptible to C. rodentium infection and exhibit alterations of the gut microbiome that promote differentiation of interleukin-17A-producing γδ T cells in the intestine, which persist into adulthood and contribute to increased disease severity in a dextran sulfate sodium-induced mouse model of colitis. Together, our studies have defined a critical role for maternal gut microbiome-specific IgG antibodies in promoting immunity against enteric pathogens and shaping the development of the gut microbiome and immune cells in early life.
Assuntos
Colite , Infecções por Enterobacteriaceae , Microbioma Gastrointestinal , Animais , Citrobacter rodentium , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/prevenção & controle , Imunoglobulina G , CamundongosRESUMO
Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial ß-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.
Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Carcinógenos/antagonistas & inibidores , Colite/prevenção & controle , Neoplasias Colorretais/prevenção & controle , Glucuronidase/antagonistas & inibidores , Inibidores de Glicosídeo Hidrolases/farmacologia , Triclosan/antagonistas & inibidores , Animais , Anti-Infecciosos Locais/química , Anti-Infecciosos Locais/metabolismo , Anti-Infecciosos Locais/toxicidade , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Biotransformação , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinógenos/química , Carcinógenos/metabolismo , Carcinógenos/toxicidade , Colite/induzido quimicamente , Colite/enzimologia , Colite/microbiologia , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/patologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Expressão Gênica , Glucuronidase/química , Glucuronidase/genética , Glucuronidase/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Triclosan/química , Triclosan/metabolismo , Triclosan/toxicidadeRESUMO
Significant opportunities remain for pharmacologically enhancing the clinical effectiveness of proton and carbon ion-based radiotherapies to achieve both tumor cell radiosensitization and normal tissue radioprotection. We investigated whether pretreatment with the hydroxamate-based histone deacetylase inhibitors (HDACi) SAHA (vorinostat), M344, and PTACH impacts radiation-induced DNA double-strand break (DSB) induction and repair, cell killing, and transformation (acquisition of anchorage-independent growth in soft agar) in human normal and tumor cell lines following gamma ray and light ion irradiation. Treatment of normal NFF28 primary fibroblasts and U2OS osteosarcoma, A549 lung carcinoma, and U87MG glioma cells with 5-10 µM HDACi concentrations 18 h prior to cesium-137 gamma irradiation resulted in radiosensitization measured by clonogenic survival assays and increased levels of colocalized gamma-H2AX/53BP1 foci induction. We similarly tested these HDACi following irradiation with 200 MeV protons, 290 MeV/n carbon ions, and 350 MeV/n oxygen ions delivered in the Bragg plateau region. Unlike uniform gamma ray radiosensitization, effects of HDACi pretreatment were unexpectedly cell type and ion species-dependent with C-12 and O-16 ion irradiations showing enhanced G0/G1-phase fibroblast survival (radioprotection) and in some cases reduced or absent tumor cell radiosensitization. DSB-associated foci levels were similar for proton-irradiated DMSO control and SAHA-treated fibroblast cultures, while lower levels of induced foci were observed in SAHA-pretreated C-12 ion-irradiated fibroblasts. Fibroblast transformation frequencies measured for all radiation types were generally LET-dependent and lowest following proton irradiation; however, both gamma and proton exposures showed hyperlinear transformation induction at low doses (≤25 cGy). HDACi pretreatments led to overall lower transformation frequencies at low doses for all radiation types except O-16 ions but generally led to higher transformation frequencies at higher doses (>50 cGy). The results of these in vitro studies cast doubt on the clinical efficacy of using HDACi as radiosensitizers for light ion-based hadron radiotherapy given the mixed results on their radiosensitization effectiveness and related possibility of increased second cancer induction.
RESUMO
Metabolic transformations play critical roles in the bioavailability and toxicities of environmental pollutants and toxicants. However, most previous research has focused on the metabolic reactions in host tissues, the gut microbiota-mediated biotransformation of environmental compounds is understudied. Using triclocarban (TCC) as a model environmental compound, here we study the metabolic fate of TCC in gut tissues and determine the roles of gut microbiota involved. We find that compared with other tissues, the colon tissue has a unique metabolic profile of TCC, with high abundance of the parent compound TCC and its free-form metabolites. Using a variety of approaches including antibiotic-mediated suppression of gut bacteria in vivo, germ-free mice, and in vitro culture of fecal bacteria, we found that the unique metabolic profile of TCC in the colon is mediated by the actions of gut microbiota. Overall, our findings support that gut microbiota plays important roles in colonic metabolism of TCC, highlighting the importance to consider the contributions of gut microbiota in toxicology evaluation of environmental compounds.
Assuntos
Carbanilidas , Microbioma Gastrointestinal , Animais , Carbanilidas/toxicidade , Colo , Fezes , CamundongosRESUMO
Triclosan (TCS) is a widespread antimicrobial agent with many adverse health risks. Its hepatoxicity invariably points to the activation of constitutive androstane receptor (CAR), which regulates cytochrome P450 (CYP) genes that are critical for oxidative metabolism. Here, we provide the theoretical and experimental evidences showing that metabolic activation of TCS frequently occurs through aromatic hydroxylation in mammals. CYP-mediated oxidation was predicted to take place at each aromatic CâH bond. Molecular docking and in vitro approaches reveal oxidative reaction could be efficiently catalyzed by CAR-regulated CYP2B6 enzyme. Parallel reaction monitoring (PRM) high-resolution mass spectrometry was utilized to identify and profile TCS oxidative metabolites in paired mouse liver, bile, feces, plasma and urine. We found multiple hydroxylated isomers including the products generated via the NIH shift of chlorine, as well as their subsequent conjugates. These metabolites showed isomer-specific retention in mice. Glucuronide conjugates are more readily excreted than the sulfates. Moreover, for the first time, isomeric hydroxylated metabolites were detected in the urine and stool of human subjects used TCS-contained household and personal care products. Collectively, these findings suggest that hydroxylation is an important, yet often underestimated element that worth considering to fully evaluate the biological fates and health risks of TCS.
Assuntos
Triclosan , Animais , Hidroxilação , Mamíferos , Camundongos , Simulação de Acoplamento Molecular , Oxirredução , Triclosan/toxicidadeRESUMO
Pregnancy induces unique changes in maternal immune responses and metabolism. Drastic physiologic adaptations, in an intricately coordinated fashion, allow the maternal body to support the healthy growth of the fetus. The gut microbiome plays a central role in the regulation of the immune system, metabolism, and resistance to infections. Studies have reported changes in the maternal microbiome in the gut, vagina, and oral cavity during pregnancy; it remains unclear whether/how these changes might be related to maternal immune responses, metabolism, and susceptibility to infections during pregnancy. Our understanding of the concerted adaption of these different aspects of the human physiology to promote a successful pregnant remains limited. Here, we provide a comprehensive documentation and discussion of changes in the maternal microbiome in the gut, oral cavity, and vagina during pregnancy, metabolic changes and complications in the mother and newborn that may be, in part, driven by maternal gut dysbiosis, and, lastly, common infections in pregnancy. This review aims to shed light on how dysregulation of the maternal microbiome may underlie obstetrical metabolic complications and infections.
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Early life is a critical time window for the neonatal gut to be progressively populated with different bacterial species that collectively promote gut maturation. A fully developed and healthy gut microbiome in neonates is an important driver for the development of other aspects of health. Unlike the relatively stable gut microbiome in adults, the developing gut microbiome in neonates exhibits higher plasticity and adaptability. This also underscores the unique window of opportunity for intervention or preventive measures to improve long-term health through modulations of the gut microbiome in early life. Better understanding of the neonatal gut microbiome - how it arises and how it impacts immune cell development - will help us appreciate the underpinnings of immune-related diseases. Here, we examine recent findings on the neonatal gut microbiome and discuss their implications for understanding this important driver of the maturation of the immune system and immunity against infections in early life.
Assuntos
Microbioma Gastrointestinal , Recém-Nascido/imunologia , Intestinos/imunologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Humanos , Imunidade , Recém-Nascido/crescimento & desenvolvimento , Intestinos/crescimento & desenvolvimento , Intestinos/microbiologiaRESUMO
Intestinal barrier dysfunction, which leads to translocation of bacteria or toxic bacterial products from the gut into bloodstream and results in systemic inflammation, is a key pathogenic factor in many human diseases. However, the molecular mechanisms leading to intestinal barrier defects are not well understood, and there are currently no available therapeutic approaches to target intestinal barrier function. Here we show that soluble epoxide hydrolase (sEH) is an endogenous regulator of obesity-induced intestinal barrier dysfunction. We find that sEH is overexpressed in the colons of obese mice. In addition, pharmacologic inhibition or genetic ablation of sEH abolishes obesity-induced gut leakage, translocation of endotoxin lipopolysaccharide or bacteria, and bacterial invasion-induced adipose inflammation. Furthermore, systematic treatment with sEH-produced lipid metabolites, dihydroxyeicosatrienoic acids, induces bacterial translocation and colonic inflammation in mice. The actions of sEH are mediated by gut bacteria-dependent mechanisms, since inhibition or genetic ablation of sEH fails to attenuate obesity-induced gut leakage and adipose inflammation in mice lacking gut bacteria. Overall, these results support that sEH is a potential therapeutic target for obesity-induced intestinal barrier dysfunction, and that sEH inhibitors, which have been evaluated in human clinical trials targeting other human disorders, could be promising agents for prevention and/or treatment.
Assuntos
Translocação Bacteriana , Epóxido Hidrolases/imunologia , Enteropatias/enzimologia , Intestinos/enzimologia , Obesidade/complicações , Tecido Adiposo/imunologia , Animais , Bactérias/genética , Bactérias/isolamento & purificação , Fenômenos Fisiológicos Bacterianos , Epóxido Hidrolases/genética , Microbioma Gastrointestinal , Humanos , Enteropatias/etiologia , Enteropatias/imunologia , Enteropatias/microbiologia , Intestinos/imunologia , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/enzimologia , Obesidade/genéticaRESUMO
The neonatal gut microbiome undergoes dynamic changes in response to many nutritional and environmental variables. A recent study by Singer et al. in Nature Medicine elucidates several mechanisms to inhibit the expansion of gut-derived pathobionts in a dysbiotic neonatal gut and prevent these pathobionts from disseminating systemically and causing sepsis in neonatal mice.
Assuntos
Microbioma Gastrointestinal , Sepse , Animais , Animais Recém-Nascidos , Disbiose , CamundongosRESUMO
Polysaccharides are known as one of the most important bioactive compounds in Flammulina velutipes. However, there is no accurate and comprehensive assessment method to evaluate and authenticate F. velutipes polysaccharides (FVPs) from different sources. In this study, a multiple fingerprint analysis method including scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and high-performance liquid chromatography (HPLC) was established. The inhibitory activities of FVPs against HepG2 were measured and introduced into multiple linear regression (MLR) analysis to investigate fingerprint-activity relationship. The principal component analysis (PCA) scores showed that the polysaccharides extracted from 20 batches of different F. velutipes were highly similar, and substandard samples could be distinguished from the authentic polysaccharides clearly. The glucuronic acid could be considered as a marker for discrimination of white and yellow F. velutipes polysaccharides in HPLC fingerprints. Moreover, the HPLC fingerprint-growth inhibitory activity relationship illuminated that monosaccharides composition played an important role on the HepG2 growth inhibitory activity, and activity-associated markers (mannose, rhamnose, xylose, and galactose) were chosen to assess FVPs from different sources. The suggested HPLC fingerprint-activity relationship method provides an integrated strategy for the quality control of F. velutipes and its related products.
Assuntos
Flammulina/química , Polissacarídeos/normas , Controle de Qualidade , Cromatografia Líquida de Alta Pressão/métodos , Células Hep G2 , Humanos , Microscopia Eletrônica de Varredura/métodos , Polissacarídeos/química , Análise de Componente Principal , Espectroscopia de Infravermelho com Transformada de Fourier/métodosRESUMO
Triclocarban (TCC) is a widely used antimicrobial ingredient in consumer products and is a ubiquitous contaminant in the environment. In 2016, the FDA removed TCC from over-the-counter handwashing products, but this compound is still approved for use in many other personal care products. A better understanding of its impact on human health could lead to significant impact for public health and regulatory policies. Here we show that exposure to low-dose TCC exaggerated the severity of colitis and exacerbated the development of colitis-associated colon tumorigenesis, via gut microbiota-dependent mechanisms. Exposure to TCC increased dextran sodium sulfate (DSS)- and interleukin 10 (IL-10) knockout-induced colitis, and exaggerated azoxymethane (AOM)/DSS-induced colon tumorigenesis in mice. Regarding the mechanisms, TCC exposure reduced the diversity and altered the composition of gut microbiota and failed to promote DSS-induced colitis in mice lacking the microbiota, supporting that the presence of the microbiota is critical for the pro-colitis effects of TCC. Together, these results support TCC could be a novel risk factor for colitis and colitis-associated colon cancer, and further regulatory policies on this compound could be needed.
Assuntos
Anti-Infecciosos Locais/efeitos adversos , Carbanilidas/efeitos adversos , Transformação Celular Neoplásica/efeitos dos fármacos , Colite/induzido quimicamente , Neoplasias do Colo/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Anti-Infecciosos Locais/farmacologia , Bifidobacterium longum subspecies infantis/crescimento & desenvolvimento , Carbanilidas/farmacologia , Colite/microbiologia , Colite/patologia , Neoplasias do Colo/patologia , Sulfato de Dextrana , Humanos , Inflamação/induzido quimicamente , Interleucina-10/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poluentes Químicos da Água/efeitos adversosRESUMO
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Furthermore, it is well established that obese individuals have high risks of developing CRC, and obesity-associated CRC represents an unmet medical problem in the United States. Using a metabolomics approach, our recent research supports that the cytochrome P450 (CYP) monooxygenase/soluble epoxide hydrolase (sEH)-mediated eicosanoid pathway could play critical roles in the pathogenesis of CRC and obesity-associated CRC. Here in this review, we discuss recent studies about the roles of the CYP/sEH eicosanoid pathway in the pathogenesis of these diseases.
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Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the United States. It is important to discover novel cellular targets which are crucial in the pathogenesis of CRC, which could facilitate development of mechanism-based strategies to reduce the risks of CRC. Emerging studies support that the cytochrome P450 (CYP) monooxygenase/soluble epoxide hydrolase (sEH) pathway and their eicosanoid metabolites play critical roles in colonic inflammation and CRC, and could be therapeutically explored for treating or preventing CRC. Here in this review, we discuss recent studies about the roles of the CYP/sEH eicosanoid pathway in the pathogenesis of colonic inflammation and CRC.
Assuntos
Carcinogênese , Neoplasias Colorretais , Sistema Enzimático do Citocromo P-450 , Eicosanoides , Transdução de Sinais , Carcinogênese/metabolismo , Neoplasias Colorretais/fisiopatologia , Sistema Enzimático do Citocromo P-450/metabolismo , Eicosanoides/metabolismo , Epóxido Hidrolases/metabolismo , HumanosRESUMO
Frying in vegetable oil is a popular cooking and food processing method worldwide; as a result, the oils used for frying are widely consumed by the general public and it is of practical importance to better understand their health impacts. To date, the effects of frying oil consumption on human health are inconclusive, making it difficult to establish dietary recommendations or guidelines. Here we show that dietary administration of frying oil, which was prepared under the conditions of good commercial practice, exaggerated dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colon tumorigenesis in mice. In addition, dietary administration of frying oil impaired intestinal barrier function, enhanced translocation of lipopolysaccharide (LPS) and bacteria from the gut into the systemic circulation, and increased tissue inflammation. Finally, to explore the potential compounds involved in the actions of the frying oil, we isolated polar compounds from the frying oil and found that administration of the polar compounds exacerbated DSS-induced colitis in mice. Together, our results showed that dietary administration of frying oil exaggerated development of inflammatory bowel disease (IBD) and IBD-associated colon tumorigenesis in mice, and these effects could be mediated by the polar compounds in the frying oil.