RESUMEN
Dietary soluble fibers are fermented by gut bacteria into short-chain fatty acids (SCFA), which are considered broadly health-promoting. Accordingly, consumption of such fibers ameliorates metabolic syndrome. However, incorporating soluble fiber inulin, but not insoluble fiber, into a compositionally defined diet, induced icteric hepatocellular carcinoma (HCC). Such HCC was microbiota-dependent and observed in multiple strains of dysbiotic mice but not in germ-free nor antibiotics-treated mice. Furthermore, consumption of an inulin-enriched high-fat diet induced both dysbiosis and HCC in wild-type (WT) mice. Inulin-induced HCC progressed via early onset of cholestasis, hepatocyte death, followed by neutrophilic inflammation in liver. Pharmacologic inhibition of fermentation or depletion of fermenting bacteria markedly reduced intestinal SCFA and prevented HCC. Intervening with cholestyramine to prevent reabsorption of bile acids also conferred protection against such HCC. Thus, its benefits notwithstanding, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC.
Asunto(s)
Carcinoma Hepatocelular/etiología , Colestasis/complicaciones , Fibras de la Dieta/metabolismo , Disbiosis/complicaciones , Fermentación , Microbioma Gastrointestinal , Neoplasias Hepáticas/etiología , Animales , Carcinoma Hepatocelular/microbiología , Línea Celular Tumoral , Colestasis/microbiología , Dieta Alta en Grasa/efectos adversos , Disbiosis/microbiología , Inulina/efectos adversos , Neoplasias Hepáticas/microbiología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND & AIMS: Pathogenesis of hepatocellular carcinoma (HCC), which kills millions annually, is poorly understood. Identification of risk factors and modifiable determinants and mechanistic understanding of how they impact HCC are urgently needed. METHODS: We sought early prognostic indicators of HCC in C57BL/6 mice, which we found were prone to developing this disease when fed a fermentable fiber-enriched diet. Such markers were used to phenotype and interrogate stages of HCC development. Their human relevance was tested using serum collected prospectively from an HCC/case-control cohort. RESULTS: HCC proneness in mice was dictated by the presence of congenitally present portosystemic shunt (PSS), which resulted in markedly elevated serum bile acids (BAs). Approximately 10% of mice from various sources exhibited PSS/cholemia, but lacked an overt phenotype when fed standard chow. However, PSS/cholemic mice fed compositionally defined diets, developed BA- and cyclooxygenase-dependent liver injury, which was exacerbated and uniformly progressed to HCC when diets were enriched with the fermentable fiber inulin. Such progression to cholestatic HCC associated with exacerbated cholemia and an immunosuppressive milieu, both of which were required in that HCC was prevented by impeding BA biosynthesis or neutralizing interleukin-10 or programmed death protein 1. Analysis of human sera revealed that elevated BA was associated with future development of HCC. CONCLUSIONS: PSS is relatively common in C57BL/6 mice and causes silent cholemia, which predisposes to liver injury and HCC, particularly when fed a fermentable fiber-enriched diet. Incidence of silent PSS/cholemia in humans awaits investigation. Regardless, measuring serum BA may aid HCC risk assessment, potentially alerting select individuals to consider dietary or BA interventions.
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Carcinoma Hepatocelular , Enfermedades del Sistema Digestivo , Neoplasias Hepáticas , Humanos , Ratones , Animales , Neoplasias Hepáticas/etiología , Carcinoma Hepatocelular/etiología , Ratones Endogámicos C57BL , Prótesis e Implantes , Fibras de la DietaRESUMEN
BACKGROUND AND AIMS: Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress. METHODS: We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation. From chemically induced colitis in mice, as well as humans with inflammatory bowel disease, we developed techniques to isolate the dominant swarmers. We developed swarm-deficient but growth and swim-competent mutant bacteria as isogenic controls. We performed bacterial reinoculation studies in mice with colitis, fecal 16S, and meta-transcriptomic analyses, as well as in vitro microbial interaction studies. RESULTS: We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers, in contrast to their mutant strains, abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family of Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal meta-transcriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants; however, because SM3, but not mutants, induced S24-7 in vivo, we concluded that swarming plays an essential role in disseminating SM3 in vivo. CONCLUSIONS: Overall, our work identified a new but counterintuitive paradigm in which intestinal stress allows for the emergence of swarming bacteria; however, these bacteria act to heal intestinal inflammation.
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Colitis/microbiología , Enterobacter/fisiología , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino/microbiología , Mucosa Intestinal/microbiología , Cicatrización de Heridas , Adulto , Anciano , Anciano de 80 o más Años , Animales , Técnicas Bacteriológicas , Colitis/patología , Colitis/prevención & control , Modelos Animales de Enfermedad , Disbiosis , Enterobacter/clasificación , Heces/microbiología , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Viabilidad Microbiana , Persona de Mediana Edad , Movimiento , Probióticos , Repitelización , Adulto JovenRESUMEN
With an aging global population, identifying novel therapeutics are necessary to increase longevity and decrease the deterioration of essential end organs such as the vasculature. Secondary alcohol, 1,3-butanediol (1,3-BD), is commonly administered to stimulate the biosynthesis of the most abundant ketone body ß-hydroxybutyrate (ßHB), in lieu of nutrient deprivation. However, suprapharmacological concentrations of 1,3-BD are necessary to significantly increase systemic ßHB, and 1,3-BD per se can cause vasodilation at nanomolar concentrations. Therefore, we hypothesized that 1,3-BD could be a novel antiaging therapeutic, independent of ßHB biosynthesis. To test this hypothesis, we administered a low-dose (5%) 1,3-BD to young and old Wistar-Kyoto (WKY) rats via drinking water for 4 wk and measured indices of vascular function and metabolism posttreatment. We observed that low-dose 1,3-BD was sufficient to reverse age-associated endothelial-dependent and -independent dysfunction, and this was not associated with increased ßHB bioavailability. Further analysis of the direct vasodilator mechanisms of 1,3-BD revealed that it is predominantly an endothelium-dependent vasodilator through activation of potassium channels and nitric oxide synthase. In summary, we report that 1,3-BD, at a concentration that does not stimulate ßHB biosynthesis, could be a nutraceutical that can reverse the age-associated decline in vascular function. These results emphasize that 1,3-BD has multiple, concentration-dependent mechanisms of action. Therefore, we suggest alternative approaches to study the physiological and cardiovascular effects of ßHB.NEW & NOTEWORTHY 1,3-Butanediol (1,3-BD) is often administered to stimulate the biosynthesis of the most abundant ketone body, ß-hydroxybutyrate (ßHB), and its purported salubrious effects. Here, we report that a low dose of 1,3-BD (5%) is sufficient to reverse age-associated vascular dysfunction, independent of ßHB. Therefore, low-dose 1,3-BD could be a novel therapeutic to increase blood flow and improve the quality of life in the elderly.
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Cuerpos Cetónicos , Calidad de Vida , Ácido 3-Hidroxibutírico/farmacología , Animales , Butileno Glicoles , Ratas , Ratas Endogámicas WKYRESUMEN
BACKGROUND: Bacterial flagellin is a major target of innate and adaptive immunity, both of which can promote and/or compensate for deficiencies in each other's function. METHODS: To investigate the role of innate immune detection of flagellin irrespective of adaptive immunity, we examined the consequences of loss of Toll-like receptor 5 (T5) and/or Nod-like receptor 4 (N4) upon a Rag1-deficient background. RESULTS: Mice lacking Toll-like receptor 5 and Rag1 (T5/Rag-DKO) exhibited frequent lethal Pasteurellaceae-containing abscesses that prevented breeding of these mice. Mice lacking Toll-like receptor 5, Nod-like receptor 4, and Rag1 (T5/N4/Rag-TKO) also resulted in sporadic lethal abdominal abscesses caused by similar Pasteurellaceae. In the absence of such infections, relative to Rag1-KO, T5/N4/Rag-TKO mice exhibited microbiota encroachment, low-grade inflammation, microbiota dysbiosis, and, moreover were highly prone to Citrobacter infection and developed severe colitis when adoptively transferred with colitogenic T cells. Relative proneness of T5/N4/Rag-TKO mice to T-cell colitis was ablated by antibiotics while fecal microbiota transplant from T5/N4/Rag-TKO mice to wild-type mice transferred proneness to Citrobacter infection, indicating that dysbiosis in T5/N4/Rag-TKO mice contributed to these phenotypes. CONCLUSIONS: These results demonstrate a critical role for innate immune detection of flagellin, especially in the intestinal tract and particularly in hosts deficient in adaptive immunity.
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Colitis , Flagelina/inmunología , Proteínas de Homeodominio , Inmunidad Innata , Proteínas NLR , Receptor Toll-Like 5 , Inmunidad Adaptativa , Animales , Disbiosis , Proteínas de Homeodominio/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas NLR/genética , Receptor Toll-Like 5/genéticaRESUMEN
Integration of microbiota in a host begins at birth and progresses during adolescence, forming a multidirectional system of physiological interactions. Here, we present an instantaneous effect of natural, bacterial gut colonization on the acceleration of longitudinal and radial bone growth in germ-free born, 7-wk-old male rats. Changes in bone mass and structure were analyzed after 10 days following the onset of colonization through cohousing with conventional rats and revealed unprecedented acceleration of bone accrual in cortical and trabecular compartments, increased bone tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in the tibia diaphysis. In addition, the number of small in size adipocytes increased, whereas the number of megakaryocytes decreased, in the bone marrow of conventionalized germ-free rats indicating that not only bone mass but also bone marrow environment is under control of gut microbiota signaling. The changes in bone status paralleled with a positive shift in microbiota composition toward short-chain fatty acids (SCFA)-producing microbes and a considerable increase in cecal SCFA concentrations, specifically butyrate. Furthermore, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels. Elevated serum levels of 25-hydroxy vitamin D and alkaline phosphatase pointed toward an active process of bone formation. The acute stimulatory effect on bone growth occurred independently of body mass increase. Overall, the presented model of conventionalized germ-free rats could be used to study microbiota-based therapeutics for combatting dysbiosis-related bone disorders.
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Bacterias/genética , Bacterias/metabolismo , Desarrollo Óseo/fisiología , Células de la Médula Ósea/metabolismo , Microbioma Gastrointestinal/genética , Vida Libre de Gérmenes , Interacciones Microbiota-Huesped/genética , Osteogénesis/fisiología , Adipocitos/metabolismo , Animales , Densidad Ósea/fisiología , Proliferación Celular/fisiología , Condrocitos/metabolismo , Coprofagia , Disbiosis , Ácidos Grasos Volátiles/análisis , Ácidos Grasos Volátiles/metabolismo , Heces/microbiología , Masculino , ARN Ribosómico 16S/genética , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE OF REVIEW: To review the current knowledge on interactions between dietary factors and microRNAs (miRNAs) in essential hypertension (EH) pathogenesis. RECENT FINDINGS: There exists an integration of maintenance signals generated by genetic, epigenetic, immune, and environmental (e.g., dietary) factors that work to sustain balance in the gut-liver axis. It is well established that an imbalance in this complex, intertwined system substantially increases the risk for EH. As such, pertinent research has been taken to decipher how each signal operates in isolation and together in EH progression. Recent literature indicates that both macro- and micronutrients interrupt regulatory miRNA expressions and thus, alter multiple cellular processes that contribute to EH and its comorbidities. We highlight how carbohydrates, lipids, proteins, salt, and potassium modify miRNA signatures during EH. The disruption in miRNA expression can negatively impact communication systems such as over activating the renin-angiotensin-aldosterone system, modulating the vascular smooth muscle cell phenotype, and promoting angiogenesis to favor EH. We also delineate the prognostic value of miRNAs in EH and discuss the pros and cons of surgical vs dietary prophylactic approaches in EH prevention. We propose that dietary-dependent perturbation of the miRNA profile is one mechanism within the gut-liver axis that dictates EH development.
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Hipertensión , MicroARNs , Epigénesis Genética , Hipertensión Esencial , Humanos , Hipertensión/genética , Hígado/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Sistema Renina-AngiotensinaRESUMEN
Lipocalin 2 (Lcn2) is a multifunctional innate immune protein that limits microbial overgrowth. Our previous study demonstrated that the gut microbiota directly induces intestinal Lcn2 production, and Lcn2-deficient (Lcn2-/-) mice exhibit gut dysbiosis. Coincidentally, gut dysbiosis is associated with metabolic syndrome pathogenesis, and elevated Lcn2 levels has been considered a potential clinical biomarker of metabolic syndrome. Yet whether Lcn2 mitigates or exacerbates metabolic syndrome remains inconclusive. Our objective was to determine whether Lcn2 deficiency-induced compositional changes in gut microbiota contribute to gain in adiposity in aged mice. Utilizing Lcn2-/- mice and their wild-type (WT) littermates, we measured metabolic markers, including fasting blood glucose, serum lipids, fat pad weight, and insulin resistance at ages 3, 6, and 9 mo old. Relative to WT mice, aged Lcn2-/- mice exhibited a gain in adiposity associated with numerous features of metabolic syndrome, including insulin resistance and dyslipidemia. Surprisingly, supplementation with a high-fat diet did not further aggravate metabolic syndrome that spontaneously occurs in Lcn2-/- mice by 6 mo of age. Interestingly, chow-fed Lcn2-/- mice displayed marked differences in the bacterial abundance and metabolomic profile of the gut microbiota compared with WT mice. Overall, our results demonstrate that Lcn2 is essential to maintain metabolic and gut microbiotal homeostasis, where deficiency induces spontaneous delayed onset of metabolic syndrome.
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Envejecimiento/metabolismo , Disbiosis/complicaciones , Disbiosis/metabolismo , Dislipidemias/complicaciones , Microbioma Gastrointestinal/genética , Lipocalina 2/deficiencia , Síndrome Metabólico/complicaciones , Síndrome Metabólico/metabolismo , Tejido Adiposo , Adiposidad/genética , Animales , Glucemia/análisis , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Disbiosis/sangre , Disbiosis/microbiología , Dislipidemias/sangre , Dislipidemias/microbiología , Femenino , Microbioma Gastrointestinal/inmunología , Homeostasis/genética , Lipocalina 2/genética , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/metabolismoRESUMEN
Here we postulate that the heritability of complex disease traits previously ascribed solely to the inheritance of the nuclear and mitochondrial genomes is broadened to encompass a third component of the holobiome, the microbiome. To test this, we expanded on the selectively bred low capacity runner/high capacity runner (LCR/HCR) rat exercise model system into four distinct rat holobiont model frameworks including matched and mismatched host nuclear and mitochondrial genomes. Vertical selection of varying nuclear and mitochondrial genomes resulted in differential acquisition of the microbiome within each of these holobiont models. Polygenic disease risk of these novel models were assessed and subsequently correlated with patterns of acquisition and contributions of their microbiomes in controlled laboratory settings. Nuclear-mitochondrial-microbiotal interactions were not for exercise as a reporter of health, but significantly noted for increased adiposity, increased blood pressure, compromised cardiac function, and loss of long-term memory as reporters of disease susceptibility. These findings provide evidence for coselection of the microbiome with nuclear and mitochondrial genomes as an important feature impacting the heritability of complex diseases.
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Núcleo Celular/genética , Microbioma Gastrointestinal/genética , Predisposición Genética a la Enfermedad , Genoma Mitocondrial , Adiposidad/genética , Animales , Conducta Animal , Presión Sanguínea/genética , Peso Corporal/genética , Enfermedades Cardiovasculares/genética , Cognición , ADN Mitocondrial/genética , Condicionamiento Físico Animal , Ratas , Factores de Riesgo , Selección Genética , Remodelación Ventricular/genéticaRESUMEN
Functional fermentable fibers are considered essential for a healthy diet. Recently, we demonstrated that gut microbiota dysbiotic mice fed an inulin-containing diet (ICD) developed hepatocellular carcinoma (HCC) within 6 mo. In particular, a subset of Toll-like receptor 5-deficient (T5KO) mice prone to HCC exhibited rapid onset of hyperbilirubinemia (HB) and cholemia; these symptoms provide rationale that ICD induces cholestasis. Our objective in the present study was to determine whether inulin-fed T5KO-HB mice exhibit other known consequences of cholestasis, including essential fatty acid and fat-soluble vitamin deficiencies. Here, we measured hepatic fatty acids and serum vitamin A and D levels from wild-type (WT), T5KO low bilirubin (LB) and T5KO-HB mice fed ICD for 4 wk. Additionally, hepatic RNAseq and proteomics were performed to ascertain other metabolic alterations. Compared with WT and T5KO-LB, T5KO-HB mice exhibited steatorrhea, i.e., ~50% increase in fecal lipids. This could contribute to the significant reduction of linoleate in hepatic neutral lipids in T5KO-HB mice. Additionally, serum vitamins A and D were ~50% reduced in T5KO-HB mice, which was associated with metabolic compromises. Overall, our study highlights that fermentable fiber-induced cholestasis is further characterized by depletion of macro-and micronutrients.NEW & NOTEWORTHY Feeding a dietary, fermentable fiber diet to a subset of Toll-like receptor 5 deficient (T5KO) mice induces early onset hyperbilirubinemia and cholemia that later manifests to hepatocellular carcinoma (HCC). Our study highlights that fermentable fiber-induced cholestasis is characterized with modest macro- and micronutrient deficiencies that may further contribute to hepatic biliary disease. Compared with chemical induction, immunization, surgery, or genetic manipulation, these findings provide a novel approach to study the cholestatic subtype of HCC.
Asunto(s)
Fibras de la Dieta , Hígado Graso/metabolismo , Absorción Intestinal , Inulina , Metabolismo de los Lípidos , Hígado/metabolismo , Síndromes de Malabsorción/metabolismo , Receptor Toll-Like 5/deficiencia , Deficiencia de Vitamina A/metabolismo , Deficiencia de Vitamina D/metabolismo , Animales , Ácidos y Sales Biliares/metabolismo , Colestasis/genética , Colestasis/metabolismo , Colestasis/patología , Modelos Animales de Enfermedad , Hígado Graso/genética , Hígado Graso/patología , Fermentación , Hígado/patología , Síndromes de Malabsorción/genética , Síndromes de Malabsorción/patología , Masculino , Ratones Noqueados , Receptor Toll-Like 5/genética , Deficiencia de Vitamina A/genética , Deficiencia de Vitamina D/genéticaRESUMEN
OBJECTIVE: Diets rich in fermentable fibres provide an array of health benefits; however, many patients with IBD report poor tolerance to fermentable fibre-rich foods. Intervention studies with dietary fibres in murine models of colonic inflammation have yielded conflicting results on whether fibres ameliorate or exacerbate IBD. Herein, we examined how replacing the insoluble fibre, cellulose, with the fermentable fibres, inulin or pectin, impacted murine colitis resulting from immune dysregulation via inhibition of interleukin (IL)-10 signalling and/or innate immune deficiency (Tlr5KO). DESIGN: Mice were fed with diet containing either cellulose, inulin or pectin and subjected to weekly injections of an IL-10 receptor (αIL-10R) neutralising antibody. Colitis development was examined by serological, biochemical, histological and immunological parameters. RESULTS: Inulin potentiated the severity of αIL10R-induced colitis, while pectin ameliorated the disease. Such exacerbation of colitis following inulin feeding was associated with enrichment of butyrate-producing bacteria and elevated levels of caecal butyrate. Blockade of butyrate production by either metronidazole or hops ß-acids ameliorated colitis severity in inulin-fed mice, whereas augmenting caecal butyrate via tributyrin increased colitis severity in cellulose containing diet-fed mice. Elevated butyrate levels were associated with increased IL-1ß activity, while inhibition of the NOD-like receptor protein 3 by genetic, pharmacologic or dietary means markedly reduced colitis. CONCLUSION: These results not only support the notion that fermentable fibres have the potential to ameliorate colitis but also caution that, in some contexts, prebiotic fibres can lead to gut dysbiosis and surfeit colonic butyrate that might exacerbate IBD.
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Colitis/metabolismo , Fibras de la Dieta/metabolismo , Microbioma Gastrointestinal/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad Aguda , Animales , Colitis/dietoterapia , Colitis/microbiología , Modelos Animales de Enfermedad , Fermentación , Masculino , Ratones , Ratones Endogámicos NODRESUMEN
Neutrophils are the primary immune cells that respond to inflammation and combat microbial transgression. To thrive, the bacteria residing in their mammalian host have to withstand the antibactericidal responses of neutrophils. We report that enterobactin (Ent), a catecholate siderophore expressed by Escherichia coli, inhibited PMA-induced generation of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) in mouse and human neutrophils. Ent also impaired the degranulation of primary granules and inhibited phagocytosis and bactericidal activity of neutrophils, without affecting their migration and chemotaxis. Molecular analysis revealed that Ent can chelate intracellular labile iron that is required for neutrophil oxidative responses. Other siderophores (pyoverdine, ferrichrome, deferoxamine) likewise inhibited ROS and NETs in neutrophils, thus indicating that the chelation of iron may largely explain their inhibitory effects. To counter iron theft by Ent, neutrophils rely on the siderophore-binding protein lipocalin 2 (Lcn2) in a "tug-of-war" for iron. The inhibition of neutrophil ROS and NETs by Ent was augmented in Lcn2-deficient neutrophils compared with wild-type neutrophils but was rescued by the exogenous addition of recombinant Lcn2. Taken together, our findings illustrate the novel concept that microbial siderophore's iron-scavenging property may serve as an antiradical defense system that neutralizes the immune functions of neutrophils.
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Enterobactina/metabolismo , Enterobactina/farmacología , Trampas Extracelulares/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Sideróforos/farmacología , Animales , Quimiotaxis/efectos de los fármacos , Enterobactina/química , Escherichia coli/química , Trampas Extracelulares/efectos de los fármacos , Humanos , Hierro/metabolismo , Lipocalina 2/genética , Lipocalina 2/metabolismo , Lipocalina 2/farmacología , Ratones , Neutrófilos/inmunología , Neutrófilos/patología , Fagocitosis/efectos de los fármacos , Sideróforos/metabolismo , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Hypertension, or elevated blood pressure (BP), has been extensively researched over decades and clearly demonstrated to be caused due to a combination of host genetic and environmental factors. Although much research remains to be conducted to pin-point the precise genetic elements on the host genome that control BP, new lines of evidence are emerging to indicate that, besides the host genome, the genomes of all indigenous commensal micro-organisms, collectively referred to as the microbial metagenome or microbiome, are important, but largely understudied, determinants of BP. Unlike the rigid host genome, the microbiome or the "second genome" can be altered by diet or microbiotal transplantation in the host. This possibility is attractive from the perspective of exploiting the microbiotal composition for clinical management of inherited hypertension. Thus, focusing on the limited current literature supporting a role for the microbiome in BP regulation, this review highlights the need to further explore the role of the co-existence of host and the microbiota as an organized biological unit called the "holobiont" in the context of BP regulation.
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Hipertensión/genética , Hipertensión/microbiología , Metagenoma , Microbiota , Animales , Humanos , RatonesAsunto(s)
Hiperplasia Nodular Focal , Microbioma Gastrointestinal , Microbiota , Humanos , Regeneración Hepática , HígadoRESUMEN
Lipocalin 2 (Lcn2), an innate immune protein, has emerged as a critical iron regulatory protein during physiological and inflammatory conditions. As a bacteriostatic factor, Lcn2 obstructs the siderophore iron-acquiring strategy of bacteria and thus inhibits bacterial growth. As part of host nutritional immunity, Lcn2 facilitates systemic, cellular, and mucosal hypoferremia during inflammation, in addition to stabilizing the siderophore-bound labile iron pool. In this review, we summarize recent advances in understanding the interaction between Lcn2 and iron, and its effects in various inflammatory diseases. Lcn2 exerts mostly a protective role in infectious and inflammatory bowel diseases, whereas both beneficial and detrimental functions have been documented in neurodegenerative diseases, metabolic syndrome, renal disorders, skin disorders, and cancer. Further animal and clinical studies are necessary to unveil the multifaceted roles of Lcn2 in iron dysregulation during inflammation and to explore its therapeutic potential for treating inflammatory diseases.
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Homeostasis , Inflamación , Hierro/metabolismo , Lipocalina 2/metabolismo , Animales , Bacterias/efectos de los fármacos , Humanos , Lipocalina 2/inmunologíaRESUMEN
KEY POINTS: A high-fat diet (60% kcal from fat) is associated with motility disorders inducing constipation and loss of nitrergic myenteric neurons in the proximal colon. Gut microbiota dysbiosis, which occurs in response to HFD, contributes to endotoxaemia. High levels of lipopolysaccharide lead to apoptosis in cultured myenteric neurons that express Toll-like receptor 4 (TLR4). Consumption of a Western diet (WD) (35% kcal from fat) for 6 weeks leads to gut microbiota dysbiosis associated with altered bacterial metabolites and increased levels of plasma free fatty acids. These disorders precede the nitrergic myenteric cell loss observed in the proximal colon. Mice lacking TLR4 did not exhibit WD-induced myenteric cell loss and dysmotility. Lipopolysaccharide-induced in vitro enteric neurodegeneration requires the presence of palmitate and may be a result of enhanced NO production. The present study highlights the critical role of plasma saturated free fatty acids that are abundant in the WD with respect to driving enteric neuropathy and colonic dysmotility. ABSTRACT: The consumption of a high-fat diet (HFD) is associated with myenteric neurodegeneration, which in turn is associated with delayed colonic transit and constipation. We examined the hypothesis that an inherent increase in plasma free fatty acids (FFA) in the HFD together with an HFD-induced alteration in gut microbiota contributes to the pathophysiology of these disorders. C57BL/6 mice were fed a Western diet (WD) (35% kcal from fat enriched in palmitate) or a purified regular diet (16.9% kcal from fat) for 3, 6, 9 and 12 weeks. Gut microbiota dysbiosis was investigated by fecal lipopolysaccharide (LPS) measurement and metabolomics (linear trap quadrupole-Fourier transform mass spectrometer) analysis. Plasma FFA and LPS levels were assessed, in addition to colonic and ileal nitrergic myenteric neuron quantifications and motility. Compared to regular diet-fed control mice, WD-fed mice gained significantly more weight without blood glucose alteration. Dysbiosis was exhibited after 6 weeks of feeding, as reflected by increased fecal LPS and bacterial metabolites and concomitant higher plasma FFA. The numbers of nitrergic myenteric neurons were reduced in the proximal colon after 9 and 12 weeks of WD and this was also associated with delayed colonic transit. WD-fed Toll-like receptor 4 (TLR4)-/- mice did not exhibit myenteric cell loss or dysmotility. Finally, LPS (0.5-2 ng·ml-1 ) and palmitate (20 and 30 µm) acted synergistically to induce neuronal cell death in vitro, which was prevented by the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. In conclusion, WD-feeding results in increased levels of FFA and microbiota that, even in absence of hyperglycaemia or overt endotoxaemia, synergistically induce TLR4-mediated neurodegeneration and dysmotility.
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Colon/fisiología , Dieta Occidental , Receptor Toll-Like 4/fisiología , Tejido Adiposo/metabolismo , Animales , Colon/metabolismo , Colon/microbiología , Citocinas/metabolismo , Ácidos Grasos no Esterificados/sangre , Ácidos Grasos no Esterificados/metabolismo , Heces/química , Femenino , Flagelina/metabolismo , Microbioma Gastrointestinal , Células HEK293 , Humanos , Lipocalina 2/metabolismo , Lipopolisacáridos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/fisiología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
Green tea-derived polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been extensively studied for its antioxidant and anti-inflammatory properties in models of inflammatory bowel disease, yet the underlying molecular mechanism is not completely understood. Herein, we demonstrate that EGCG can potently inhibit the proinflammatory enzyme myeloperoxidase in vitro in a dose-dependent manner over a range of physiologic temperatures and pH values. The ability of EGCG to mediate its inhibitory activity is counter-regulated by the presence of iron and lipocalin 2. Spectral analysis indicated that EGCG prevents the peroxidase-catalyzed reaction by reverting the reactive peroxidase heme (compound I:oxoiron) back to its native inactive ferric state, possibly via the exchange of electrons. Further, administration of EGCG to dextran sodium sulfate-induced colitic mice significantly reduced the colonic myeloperoxidase activity and alleviated proinflammatory mediators associated with gut inflammation. However, the efficacy of EGCG against gut inflammation is diminished when orally coadministered with iron. These findings indicate that the ability of EGCG to inhibit myeloperoxidase activity is one of the mechanisms by which it exerts mucoprotective effects and that counter-regulatory factors such as dietary iron and luminal lipocalin 2 should be taken into consideration for optimizing clinical management strategies for inflammatory bowel disease with the use of EGCG treatment.
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Proteínas de Fase Aguda/metabolismo , Catequina/análogos & derivados , Inflamación/metabolismo , Hierro de la Dieta/metabolismo , Lipocalinas/metabolismo , Proteínas Oncogénicas/metabolismo , Peroxidasa/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Animales , Antioxidantes/metabolismo , Catequina/metabolismo , Sulfato de Dextran/metabolismo , Modelos Animales de Enfermedad , Humanos , Lipocalina 2 , Ratones Endogámicos C57BL , TéRESUMEN
PURPOSE OF REVIEW: Disturbances of the intestinal microbiota have been increasingly implicated in driving various diseases associated with a broad range of chronic inflammatory state. Such diseases have increased in incidence since the mid-20th century, and have roughly correlated with societal changes in food production during this period. RECENT FINDINGS: Considering how changes in diet may have impacted gut microbiota and exploring whether targeted modulations of diet might be a means of optimizing microbiota composition to promote health. SUMMARY: Recent literature demonstrates that modulation of diet has potential to both beneficially and detrimentally impact microbiota composition and how it interacts with its host. Herein, we discuss recent studies by ourselves and others that demonstrate the potential for changes in diet to have profound impacts on the gut microbiota in ways that can have beneficial or detrimental effects on host health.
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Dieta , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino/etiología , Dieta/efectos adversos , Fibras de la Dieta/farmacología , Disbiosis/etiología , Aditivos Alimentarios/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Interacciones Huésped-Patógeno/efectos de los fármacos , HumanosRESUMEN
Stearoyl-CoA desaturase-1 (SCD1) is a lipogenic enzyme involved in the de novo biosynthesis of oleate (C18:1, n9), a major fatty acid in the phospholipids of lipid bilayers of cell membranes. Accordingly, Scd1KO mice display substantially reduced oleate in cell membranes. An altered SCD1 level was observed during intestinal inflammation; however, its role in modulating inflammatory bowel disease remains elusive. Herein, we investigated the colitogenic capacity of Scd1KO effector T cells by employing the adoptive T-cell transfer colitis model. Splenic effector T cells (CD4+CD25-) from age- and sex-matched wild-type (WT) and Scd1KO mice were isolated by FACS and intraperitoneally administered to Rag1KO mice, which were monitored for the development of colitis. At day 60 postcell transfer, Rag1KO mice that received Scd1KO CD4+CD25- T cells displayed accelerated and exacerbated colitis than mice receiving WT CD4+CD25- T cells. Intriguingly, Scd1KO CD4+CD25- T cells display augmented inflammatory cytokine profile and cellular membrane fluidity with a concomitant increase in proinflammatory saturated fatty acids, which we postulate to potentially underlie their augmented colitogenic potential.
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Colitis/metabolismo , Mucosa Intestinal/metabolismo , Estearoil-CoA Desaturasa/metabolismo , Traslado Adoptivo , Animales , Colitis/genética , Colitis/inmunología , Citocinas/metabolismo , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Intestinos/inmunología , Ratones , Ratones Noqueados , Estearoil-CoA Desaturasa/genéticaRESUMEN
Iron is an essential transition metal ion for virtually all aerobic organisms, yet its dysregulation (iron overload or anemia) is a harbinger of many pathologic conditions. Hence, iron homeostasis is tightly regulated to prevent the generation of catalytic iron (CI) which can damage cellular biomolecules. In this study, we investigated the role of iron-binding/trafficking innate immune protein, lipocalin 2 (Lcn2, aka siderocalin) on iron and CI homeostasis using Lcn2 knockout (KO) mice and their WT littermates. Administration of iron either systemically or via dietary intake strikingly upregulated Lcn2 in the serum, urine, feces, and liver of WT mice. However, similarly-treated Lcn2KO mice displayed elevated CI, augmented lipid peroxidation and other indices of organ damage markers, implicating that Lcn2 responses may be protective against iron-induced toxicity. Herein, we also show a negative association between serum Lcn2 and CI in the murine model of dextran sodium sulfate (DSS)-induced colitis. The inability of DSS-treated Lcn2KO mice to elicit hypoferremic response to acute colitis, implicates the involvement of Lcn2 in iron homeostasis during inflammation. Using bone marrow chimeras, we further show that Lcn2 derived from both immune and non-immune cells participates in CI regulation. Remarkably, exogenous rec-Lcn2 supplementation suppressed CI levels in Lcn2KO serum and urine. Collectively, our results suggest that Lcn2 may facilitate hypoferremia, suppress CI generation and prevent iron-mediated adverse effects.