11 research outputs found
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ENVIRONMENTAL RISK FACTORS FOR INFLAMMATORY BOWEL DISEASE: TRICLOSAN AND OTHER CONSUMER ANTIMICROBIALS
Inflammatory bowel disease (IBD) has become a serious health problem since the incidence and prevalence of IBD has dramatically increased throughout the world. There is evidence that environmental factors are primarily responsible for the increase of IBD, therefore, it is important to identify novel environmental risk factors to reduce the risk of IBD and its associated diseases. Antimicrobials used in consumer products might serve as environmental risk factors for IBD and its associated diseases. Triclosan (TCS), triclocarban (TCC), benzalkonium chloride (BAC), benzethonium chloride (BET), and chloroxylenol (PCMX) are widely used antimicrobial ingredients in consumer products and are ubiquitous contaminants in the environment. In 2016, the FDA removed TCS and TCC from over-the-counter handwashing products while allowing additional time to develop new safety and efficacy data for BAC, BET, and PCMX. Therefore, it is important and timely to better understand the effects of these antimicrobials on human health. Currently, there not much known about how chronic exposure to low-dose consumer antimicrobials affects gut health. Here, using various in vitro and animal models, we found that: 1) TCS is metabolically re-activated in the gut by the actions of gut microbiota, leading to the accumulation of microbiota-derived toxic metabolites in the colon and resulting in gut-specific toxicity; 2) exposure to low-dose TCC exaggerated the severity of colitis and exacerbated the development of colitis-associated colon tumorigenesis, via gut microbiota-dependent mechanisms; and 3) exposure to low doses of BAC, BET, and PCMX, increases dextran sodium sulfate (DSS)-induced colonic inflammation and exposure to BAC increases azoxymethane (AOM)/DSS-induced colon tumorigenesis in mice. Together, these results support that chronic exposure to consumer antimicrobials could be a novel risk factor for colitis and colitis-associated colon cancer through gut microbiota-dependent mechanisms. A better understanding of the impact antimicrobials on human health, specifically gut health, could lead to significant influence on public health and regulatory policies
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Effects of high-fat diet on plasma profiles of eicosanoid metabolites in mice
Obesity is a serious health problem in the US and is associated with increased risks of various human diseases. To date, the mechanisms by which obesity increases the risks of a wide range of human diseases are not well understood. Here we used a LC-MS/MS-based lipidomics, which can analyze >100 bioactive lipid mediators produced by cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes, to analyze plasma profiles of lipid mediators in high-fat diet induced obesity in C57BL/6 mice. Our results show that the plasma concentrations of epoxyoctadecenoic acids (EpOMEs, also termed as leukotoxins) are significantly increased in plasma of high-fat diet-fed mice, in addition, EpOMEs are among the most abundant lipid mediators detected in mouse plasma. Since substantial studies have shown that EpOMEs and their metabolites have a large array of detrimental effects on health, enhanced levels of EpOMEs could contribute to the pathology of obesity
Maternal Microbiome and Infections in Pregnancy
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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Soluble epoxide hydrolase is an endogenous regulator of obesity-induced intestinal barrier dysfunction and bacterial translocation
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
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Lipidomic profiling reveals soluble epoxide hydrolase as a therapeutic target of obesity-induced colonic inflammation
Obesity is associated with enhanced colonic inflammation, which is a major risk factor for colorectal cancer. Considering the obesity epidemic in Western countries, it is important to identify novel therapeutic targets for obesity-induced colonic inflammation, to develop targeted strategies for prevention. Eicosanoids are endogenous lipid signaling molecules involved in regulating inflammation and immune responses. Using an LC-MS/MS-based lipidomics approach, we find that obesity-induced colonic inflammation is associated with increased expression of soluble epoxide hydrolase (sEH) and its eicosanoid metabolites, termed fatty acid diols, in colon tissue. Furthermore, we find that pharmacological inhibition or genetic ablation of sEH reduces colonic concentrations of fatty acid diols, attenuates obesity-induced colonic inflammation, and decreases obesity-induced activation of Wnt signaling in mice. Together, these results support that sEH could be a novel therapeutic target for obesity-induced colonic inflammation and associated diseases
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A common antimicrobial additive increases colonic inflammation and colitis-associated colon tumorigenesis in mice
Triclosan (TCS) is a high-volume chemical used as an antimicrobial ingredient in more than 2000 consumer products, such as toothpaste, cosmetics, kitchenware, and toys. We report that brief exposure to TCS, at relatively low doses, causes low-grade colonic inflammation, increases colitis, and exacerbates colitis-associated colon cancer in mice. Exposure to TCS alters gut microbiota in mice, and its proinflammatory effect is attenuated in germ-free mice. In addition, TCS treatment increases activation of Toll-like receptor 4 (TLR4) signaling in vivo and fails to promote colitis in Tlr4-/- mice. Together, our results demonstrate that this widely used antimicrobial ingredient could have adverse effects on colonic inflammation and associated colon tumorigenesis through modulation of the gut microbiota and TLR4 signaling. Together, these results highlight the need to reassess the effects of TCS on human health and potentially update policies regulating the use of this widely used antimicrobial
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Targeted Metabolomics Identifies the Cytochrome P450 Monooxygenase Eicosanoid Pathway as a Novel Therapeutic Target of Colon Tumorigenesis
Colon cancer is the third most common cancer and the second leading cause of cancer-related death in the United States, emphasizing the need for the discovery of new cellular targets. Using a metabolomics approach, we report here that epoxygenated fatty acids (EpFA), which are eicosanoid metabolites produced by cytochrome P450 (CYP) monooxygenases, were increased in both the plasma and colon of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer mice. CYP monooxygenases were overexpressed in colon tumor tissues and colon cancer cells. Pharmacologic inhibition or genetic ablation of CYP monooxygenases suppressed AOM/DSS-induced colon tumorigenesis in vivo. In addition, treatment with 12,13-epoxyoctadecenoic acid (EpOME), which is a metabolite of CYP monooxygenase produced from linoleic acid, increased cytokine production and JNK phosphorylation in vitro and exacerbated AOM/DSS-induced colon tumorigenesis in vivo. Together, these results demonstrate that the previously unappreciated CYP monooxygenase pathway is upregulated in colon cancer, contributes to its pathogenesis, and could be therapeutically explored for preventing or treating colon cancer. SIGNIFICANCE: This study finds that the previously unappreciated CYP monooxygenase eicosanoid pathway is deregulated in colon cancer and contributes to colon tumorigenesis
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Targeted metabolomics identifies the cytochrome P450 monooxygenase eicosanoid pathway as a novel therapeutic target of colon tumorigenesis
Colon cancer is the third most common cancer and the second leading cause of cancer-related death in the United States, emphasizing the need for the discovery of new cellular targets. Using a metabolomics approach, we report here that epoxygenated fatty acids (EpFA), which are eicosanoid metabolites produced by cytochrome P450 (CYP) monooxygenases, were increased in both the plasma and colon of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer mice. CYP monooxygenases were overexpressed in colon tumor tissues and colon cancer cells. Pharmacologic inhibition or genetic ablation of CYP monooxygenases suppressed AOM/DSS-induced colon tumorigenesis in vivo. In addition, treatment with 12,13-epoxyoctadecenoic acid (EpOME), which is a metabolite of CYP monooxygenase produced from linoleic acid, increased cytokine production and JNK phosphorylation in vitro and exacerbated AOM/DSS-induced colon tumorigenesis in vivo. Together, these results demonstrate that the previously unappreciated CYP monooxygenase pathway is upregulated in colon cancer, contributes to its pathogenesis, and could be therapeutically explored for preventing or treating colon cancer. SIGNIFICANCE: This study finds that the previously unappreciated CYP monooxygenase eicosanoid pathway is deregulated in colon cancer and contributes to colon tumorigenesis