Consumption of Select Dietary Emulsifiers Exacerbates the Development of Spontaneous Intestinal Adenoma

Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APCmin mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers’ impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host–microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.

Download Full-text

Abstract 14849: Gender Differences in Impact of CYP2C19 Polymorphism and Low Grade Inflammation on Coronary Spasm in Patients with Vasospastic Angina (VSA)

Circulation ◽

10.1161/circ.130.suppl_2.14849 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Tomonori Akasaka ◽

Seiji Hokimoto ◽

Noriaki Tabata ◽

Kenji Sakamoto ◽

Kenichi Tsujita ◽

...

Keyword(s):

Coronary Artery ◽

Coronary Artery Spasm ◽

Coronary Spasm ◽

Control Group ◽

Low Grade ◽

Cyp2c19 Genotype ◽

Loss Of Function ◽

Hs Crp ◽

The Impact ◽

Low Grade Inflammation

Background: Several cytochrome P450 (CYP) enzyme families have been identified in extra hepatic tissues such as heart, vasculature, kidney, and lung. CYP2C19 localized in vascular smooth muscle and endothelium contributes to the regulation of vascular tone and homeostasis. However, it is unknown whether CYP2C19 genotype is associated with the vascular tonus in patients with VSA. The aim of this study was to examine the impact of CYP2C19 genotype on coronary artery spasm in patients with VSA. Methods: We examined the distribution of CYP2C19 genotype in patients with VSA (n=129) who were diagnosed by intra-coronary acetylcholine infusion test and healthy subjects (n=455) as control group. CYP2C19 genotypes were divided into 3 groups; (1) CYP2C19*1/*1: EM, (2) one loss-of-function allele (*1/*2, *1/*3: IM), and (3) two loss-of-function alleles (*2/*2, *2/*3, *3/*3: PM). Moreover, we measured the level of high-sensitive CRP (hs-CRP) as a degree of low glade inflammation in each group. Results: The ratios of CYP2C19 genotype (EM, IM, and PM) were 30, 42, and 28% in VSA group, and 32, 49, and 19% in control group. In short, PM frequency was significantly higher in VSA than in control (28% vs 19%, P=0.026). In VSA group, the ratios of CYP2C19 genotype were 36, 44, and 20% in male, and 20, 39, and 41% in female, respectively. Briefly, the PM frequency was significantly higher in female than in male (41% vs 20%, P<0.001). Moreover, the level of hs-CRP was significantly higher in VSA group than in control group (0.17±0.367 vs 0.10.±0.240, P=0.02). When patients were stratified by gender, the level of hs-CRP was significantly higher in VSA group in female (0.11±0.198 vs 0.06±0.105, P=0.031) and male (0.20±0.438 vs 0.12±0.277, P=0.044). Multivariate analysis for coronary spasm indicated high age, hypertension, and high level of hs-CRP as predictive factors among all subjects. PM is a predictive factor for coronary spasm in female group only (OR3.1, 95%RI 1.525-6.317, P=0.002), but not in male (OR0.829, 95%RI 0.453-1.518, P=0.543). Conclusion: The CYP2C19 two loss-of-function alleles (PM) and low grade inflammation may be associated with pathophysiology of coronary artery spasm and the regulation of coronary tonus, especially in female.

Download Full-text

Abstract 14862: Gender Differences in Impact of CYP2C19 Polymorphism and Low Grade Inflammation on Coronary Microvascular Disease

Circulation ◽

10.1161/circ.130.suppl_2.14862 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Tomonori Akasaka ◽

Seiji Hokimoto ◽

Noriaki Tabata ◽

Kenji Sakamoto ◽

Kenichi Tsujita ◽

...

Keyword(s):

Microvascular Disease ◽

Control Group ◽

Female Group ◽

Low Grade ◽

Cyp2c19 Genotype ◽

Loss Of Function ◽

Disease Group ◽

Hs Crp ◽

The Impact ◽

Low Grade Inflammation

Background: Specific CYPs localized in vascular smooth muscle and endothelium contribute to the regulation of vascular tone and homeostasis. CYP2C19 two loss-of-function alleles (PM) were found to be an independent risk factor for diabetic retinopathy, and PM is associated with the coronary spasm especially in female. However, it is unknown whether CYP2C19 genotype is associated with the coronary microvascular disease. The aim was to evaluate the impact of CYP2C19 genotype on coronary microvascular disease. Methods: We examined CYP2C19 genotype in patients with microvascular disease (n=40) who were diagnosed by intra-coronary acetylcholine infusion test and healthy subjects (n=455) as control group. We defined the coronary microvascular disease that have no epicardial spasm and have angina, ischemic ECG changes, reduced coronary blood flow, or inversion of lactic acid level between intra-coronary and coronary sinus. CYP2C19 genotypes were divided into 3 groups; (1) CYP2C19*1/*1: EM, (2) one loss-of-function allele (*1/*2, *1/*3: IM), and (3) two loss-of-function alleles (*2/*2, *2/*3, *3/*3: PM). Results: The ratios of CYP2C19 genotype (EM, IM, and PM) were 33, 35, and 32% in microvascular disease group, and 32, 49, and 19% in control group. In short, PM frequency was significantly higher in microvascular disease group (32%vs19%,P=0.039). In microvascular disease group, the ratios of CYP2C19 genotype (EM, IM, and PM) were 44, 38, and 19% in male, and 25, 33, and 42% in female, respectively. Briefly, the PM frequency was significantly higher in female than in male (42%vs19%,P=0.011). Moreover, the level of hs-CRP was significantly higher in microvascular disease group (0.37±0.908 vs 0.10±0.240, P<0.001). Multivariate analysis for microvascular disease indicated that gender, high age, smoking, hypertension, and the high level of hs-CRP are predictive factors among all subjects. PM is a predictive factor for microvascular disease in female group only (OR3.214, 95%RI 1.286-8.034, P=0.012), but not in male (OR0.909, 95%RI 0.251-3.285, P=0.884). Conclusion: The CYP2C19 two loss-of-function alleles (PM) and low grade inflammation may be associated with pathophysiology of coronary microvascular disease, especially in female.

Download Full-text

Nut consumption is inversely associated with both cancer and total mortality in a Mediterranean population: prospective results from the Moli-sani study

British Journal Of Nutrition ◽

10.1017/s0007114515002378 ◽

2015 ◽

Vol 114 (5) ◽

pp. 804-811 ◽

Cited By ~ 27

Author(s):

Marialaura Bonaccio ◽

Augusto Di Castelnuovo ◽

Amalia De Curtis ◽

Simona Costanzo ◽

Francesca Bracone ◽

...

Keyword(s):

Total Mortality ◽

Risk Groups ◽

Population Based ◽

Low Grade ◽

Mediterranean Population ◽

The Metabolic Syndrome ◽

Inflammatory Status ◽

The Impact ◽

Low Grade Inflammation ◽

Nut Intake

AbstractNut intake has been associated with reduced inflammatory status and lower risk of CVD and mortality. The aim of this study was to examine the relationship between nut consumption and mortality and the role of inflammation. We conducted a population-based prospective investigation on 19 386 subjects enrolled in the Moli-sani study. Food intake was recorded by the Italian version of the European Project Investigation into Cancer and Nutrition FFQ. C-reactive protein, leucocyte and platelet counts and the neutrophil:lymphocyte ratio were used as biomarkers of low-grade inflammation. Hazard ratios (HR) were calculated using multivariable Cox proportional hazard models. During a median follow-up of 4·3 years, 334 all-cause deaths occurred. As compared with subjects who never ate nuts, rare intake (≤2 times/month) was inversely associated with mortality (multivariable HR=0·68; 95 % CI 0·54, 0·87). At intake ≥8 times/month, a greater protection was observed (HR=0·53; 0·32, 0·90). Nut intake (v. no intake) conveyed a higher protection to individuals poorly adhering to the Mediterranean diet (MD). A significant reduction in cancer deaths (HR=0·64; 95 % CI 0·44, 0·94) was also observed, whereas the impact on CVD deaths was limited to an inverse, but not significant, trend. Biomarkers of low-grade inflammation were reduced in nut consumers but did not account for the association with mortality. In conclusion, nut intake was associated with reduced cancer and total mortality. The protection was stronger in individuals with lower adherence to MD, whereas it was similar in high-risk groups (diabetics, obese, smokers or those with the metabolic syndrome), as compared with low-risk subjects. Inflammation did not explain the observed relationship.

Download Full-text

Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

10.2337/figshare.14687523 ◽

2021 ◽

Author(s):

Emelyne Lécuyer ◽

Tiphaine Le Roy ◽

Aurélie Gestin ◽

Amélie Lacombe ◽

Catherine Philippe ◽

...

Keyword(s):

Dendritic Cells ◽

Metabolic Diseases ◽

Intestinal Inflammation ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Low Grade ◽

Obesity And Diabetes ◽

Tolerogenic Dendritic Cells ◽

Tolerogenic Function ◽

And Function

Excess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes. The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice) are challenged with a high-fat diet. Those mice display resistance to DIO and metabolic alterations. The DIO-resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses. Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic disease management.

Download Full-text

Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

10.1101/2020.10.22.350033 ◽

2020 ◽

Author(s):

Emelyne Lécuyer ◽

Tiphaine Le Roy ◽

Aurélie Gestin ◽

Amélie Lacombe ◽

Catherine Philippe ◽

...

Keyword(s):

Dendritic Cells ◽

Metabolic Diseases ◽

Intestinal Inflammation ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Low Grade ◽

Obesity And Diabetes ◽

Tolerogenic Dendritic Cells ◽

Tolerogenic Function ◽

And Function

ABSTRACTExcess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes.The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice), are challenged with a high fat diet.Those mice display resistance to DIO and metabolic alterations. The DIO resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses.Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by a lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic diseases management.

Download Full-text

Western-style diet impedes colonization and clearance of Citrobacter rodentium

PLoS Pathogens ◽

10.1371/journal.ppat.1009497 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1009497

Author(s):

Junqing An ◽

Xu Zhao ◽

Yanling Wang ◽

Juan Noriega ◽

Andrew T. Gewirtz ◽

...

Keyword(s):

Host Defense ◽

Pathogenic Bacteria ◽

Short Chain Fatty Acids ◽

Low Grade ◽

Microbiota Composition ◽

Citrobacter Rodentium ◽

Colonization Resistance ◽

The Impact ◽

Low Grade Inflammation ◽

Gut Pathogen

Western-style diet (WSD), which is high in fat and low in fiber, lacks nutrients to support gut microbiota. Consequently, WSD reduces microbiota density and promotes microbiota encroachment, potentially influencing colonization resistance, immune system readiness, and thus host defense against pathogenic bacteria. Here we examined the impact of WSD on infection and colitis in response to Citrobacter rodentium. We observed that, relative to mice consuming standard rodent grain-based chow (GBC), feeding WSD starkly altered the dynamics of Citrobacter infection, reducing initial colonization and inflammation but frequently resulting in persistent infection that associated with low-grade inflammation and insulin resistance. WSD’s reduction in initial Citrobacter virulence appeared to reflect that colons of GBC-fed mice contain microbiota metabolites, including short-chain fatty acids, especially acetate, that drive Citrobacter growth and virulence. Citrobacter persistence in WSD-fed mice reflected inability of resident microbiota to out-compete it from the gut lumen, likely reflecting the profound impacts of WSD on microbiota composition. These studies demonstrate potential of altering microbiota and their metabolites by diet to impact the course and consequence of infection following exposure to a gut pathogen.

Download Full-text

Obesity and COVID-19: immune and metabolic derangement as a possible link to adverse clinical outcomes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00198.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. E105-E109 ◽

Cited By ~ 21

Author(s):

Emmanouil Korakas ◽

Ignatios Ikonomidis ◽

Foteini Kousathana ◽

Konstantinos Balampanis ◽

Aikaterini Kountouri ◽

...

Keyword(s):

Strong Association ◽

Host Cells ◽

Low Grade ◽

Metabolic Derangement ◽

Innate And Adaptive Immunity ◽

Monocyte Chemoattractant ◽

Pyrin Domain ◽

And Function ◽

Low Grade Inflammation ◽

Receptor Family

Recent reports have shown a strong association between obesity and the severity of COVID-19 infection, even in the absence of other comorbidities. After infecting the host cells, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a hyperinflammatory reaction through the excessive release of cytokines, a condition known as “cytokine storm,” while inducing lymphopenia and a disrupted immune response. Obesity is associated with chronic low-grade inflammation and immune dysregulation, but the exact mechanisms through which it exacerbates COVID-19 infection are not fully clarified. The production of increased amounts of cytokines such as TNFα, IL-1, IL-6, and monocyte chemoattractant protein (MCP-1) lead to oxidative stress and defective function of innate and adaptive immunity, whereas the activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome seems to play a crucial role in the pathogenesis of the infection. Endothelial dysfunction and arterial stiffness could favor the recently discovered infection of the endothelium by SARS-CoV-2, whereas alterations in cardiac structure and function and the prothrombotic microenvironment in obesity could provide a link for the increased cardiovascular events in these patients. The successful use of anti-inflammatory agents such as IL-1 and IL-6 blockers in similar hyperinflammatory settings, like that of rheumatoid arthritis, has triggered the discussion of whether such agents could be administrated in selected patients with COVID-19 disease.

Download Full-text

Epigenetic mechanisms driving tumor supportive microenvironment differentiation and function: a role in cancer therapy?

Epigenomics ◽

10.2217/epi-2019-0165 ◽

2020 ◽

Vol 12 (2) ◽

pp. 157-169 ◽

Cited By ~ 5

Author(s):

Marvin Sylvestre ◽

Karin Tarte ◽

David Roulois

Keyword(s):

Stromal Cell ◽

Somatic Mutations ◽

Tumor Development ◽

Cell Subset ◽

Heterogeneous Population ◽

Cancer Associated Fibroblasts ◽

Epigenetic Mechanisms ◽

Immunosuppressive Microenvironment ◽

And Function ◽

The Impact

The tumor microenvironment (TME) plays a central role in tumor development and drug resistance. Within TME, the stromal cell subset, called cancer-associated fibroblasts, is a heterogeneous population originating from poorly characterized precursors. Since cancer-associated fibroblasts do not acquire somatic mutations, other mechanisms like epigenetic regulation, could be involved in the development of these cells and in the acquisition of tumor supportive phenotypes. Moreover, such epigenetic modulations have been correlated to the emergence of an immunosuppressive microenvironment facilitating tumor evasion. These findings underline the need to deepen our knowledge on epigenetic mechanisms driving TME development and function, and to understand the impact of epigenetic drugs that could be used in future to target both tumor cells and their TME.

Download Full-text

TFEB is a master regulator of tumor-associated macrophages in breast cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000543 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000543 ◽

Cited By ~ 3

Author(s):

Yong Li ◽

Johnie Hodge ◽

Qing Liu ◽

Junfeng Wang ◽

Yuzhen Wang ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Tumor Growth ◽

Gene Expression Profile ◽

Expression Profile ◽

Breast Tumor ◽

Tumor Development ◽

Tumor Associated Macrophages ◽

And Function ◽

The Impact

BackgroundTumor-associated macrophages (TAMs) play key roles in the development of many malignant solid tumors including breast cancer. They are educated in the tumor microenvironment (TME) to promote tumor growth, metastasis, and therapy resistance. However, the phenotype of TAMs is elusive and how to regulate them for therapeutic purpose remains unclear; therefore, TAM-targeting therapies have not yet achieved clinical success. The purposes of this study were to examine the role of transcription factor EB (TFEB) in regulating TAM gene expression and function and to determine if TFEB activation can halt breast tumor development.MethodsMicroarrays were used to analyze the gene expression profile of macrophages (MΦs) in the context of breast cancer and to examine the impact of TFEB overexpression. Cell culture studies were performed to define the mechanisms by which TFEB affects MΦ gene expression and function. Mouse studies were carried out to investigate the impact of MΦ TFEB deficiency or activation on breast tumor growth. Human cancer genome data were analyzed to reveal the prognostic value of TFEB and its regulated genes.ResultsTAM-mimic MΦs display a unique gene expression profile, including significant reduction in TFEB expression. TFEB overexpression favorably modulates TAM gene expression through multiple signaling pathways. Specifically, TFEB upregulates suppressor of cytokine signaling 3 (SOCS3) and peroxisome proliferator-activated receptor γ (PPARγ) expression and autophagy/lysosome activities, inhibits NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome and hypoxia-inducible factor (HIF)-1α mediated hypoxia response, and thereby suppresses an array of effector molecules in TAMs including arginase 1, interleukin (IL)-10, IL-1β, IL-6 and prostaglandin E2. MΦ-specific TFEB deficiency promotes, while activation of TFEB using the natural disaccharide trehalose halts, breast tumor development by modulating TAMs. Analysis of human patient genome database reveals that expression levels of TFEB, SOCS3 and PPARγ are positive prognostic markers, while HIF-1α is a negative prognostic marker of breast cancer.ConclusionsOur study identifies TFEB as a master regulator of TAMs in breast cancer. TFEB controls TAM gene expression and function through multiple autophagy/lysosome-dependent and independent pathways. Therefore, pharmacological activation of TFEB would be a promising therapeutic approach to improve the efficacy of existing treatment including immune therapies for breast cancer by favorably modulating TAM function and the TME.

Download Full-text

New Insights about Regulatory T Cells Distribution and Function with Exercise: The Role of Immunometabolism

Current Pharmaceutical Design ◽

10.2174/1381612826666200305125210 ◽

2020 ◽

Vol 26 (9) ◽

pp. 979-990 ◽

Cited By ~ 7

Author(s):

Gilson P. Dorneles ◽

Aline A.Z. dos Passos ◽

Pedro R.T. Romão ◽

Alessandra Peres

Keyword(s):

T Cells ◽

Chronic Diseases ◽

Experimental Studies ◽

Treg Cells ◽

Metabolic Phenotype ◽

Acid Oxidation ◽

Low Grade ◽

And Function ◽

Low Grade Inflammation

A lack of physical activity is linked to the development of many chronic diseases through a chronic low-grade inflammation state. It is now well accepted that the immune system plays a central role in the development of several chronic diseases, including insulin resistance, type 2 diabetes, atherosclerosis, heart failure and certain types of cancer. Exercise elicits a strong anti-inflammatory response independently of weight loss and can be a useful non-pharmacologic strategy to counteract the low-grade inflammation. The CD4+CD25+CD127- FoxP3+ Regulatory T (Treg) cells are a unique subset of helper T-cells, which regulate immune response and establish self-tolerance through the secretion of immunoregulatory cytokines, such as IL-10 and TGF-β, and the suppression of the function and activity of many immune effector cells (including monocytes/macrophages, dendritic cells, CD4+ and CD8+ T cells, and Natural Killers). The metabolic phenotype of Tregs are regulated by the transcription factor Foxp3, providing flexibility in fuel choice, but a preference for higher fatty acid oxidation. In this review, we focus on the mechanisms by which exercise - both acute and chronic - exerts its antiinflammatory effects through Treg cells mobilization. Furthermore, we discuss the implications of immunometabolic changes during exercise for the modulation of Treg phenotype and its immunosuppressive function. This narrative review focuses on the current knowledge regarding the role of Treg cells in the context of acute and chronic exercise using data from observational and experimental studies. Emerging evidence suggests that the immunomodulatory effects of exercise are mediated by the ability of exercise to adjust and improve Tregs number and function.

Download Full-text