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The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20 deficiency in ILC2s spontaneously triggers the circuit and, unexpectedly, promotes adaptive small-intestinal lengthening and remodeling. Circuit activation occurs upon weaning and is enabled by dietary polysaccharides that render mice permissive for Tritrichomonas colonization, resulting in luminal accumulation of acetate and succinate, metabolites of the protist hydrogenosome. Tuft cells express GPR91, the succinate receptor, and dietary succinate, but not acetate, activates ILC2s via a tuft-, TRPM5-, and IL-25-dependent pathway. Also induced by parasitic helminths, circuit activation and small intestinal remodeling impairs infestation by new helminths, consistent with the phenomenon of concomitant immunity. We describe a metabolic sensing circuit that may have evolved to facilitate mutualistic responses to luminal pathosymbionts.
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Intestino Delgado/fisiologia , Tritrichomonas/metabolismo , Acetatos/metabolismo , Animais , Fibras na Dieta/metabolismo , Metabolismo Energético , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/parasitologia , Interleucinas/genética , Interleucinas/metabolismo , Mucosa Intestinal/citologia , Intestino Delgado/microbiologia , Intestino Delgado/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microbiota , Plasmídeos/genética , Plasmídeos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Ácido Succínico/metabolismo , Canais de Cátion TRPM/metabolismo , Tritrichomonas/crescimento & desenvolvimento , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismoRESUMO
The majority of patients with obesity, insulin resistance, and metabolic syndrome have hypertension, but the mechanisms of hypertension are poorly understood. In these patients, impaired sodium excretion is critical for the genesis of Na(+)-sensitive hypertension, and prior studies have proposed a role for the epithelial Na(+) channel (ENaC) in this syndrome. We characterized high fat-fed mice as a model in which to study the contribution of ENaC-mediated Na(+) reabsorption in obesity and insulin resistance. High fat-fed mice demonstrated impaired Na(+) excretion and elevated blood pressure, which was significantly higher on a high-Na(+) diet compared with low fat-fed control mice. However, high fat-fed mice had no increase in ENaC activity as measured by Na(+) transport across microperfused cortical collecting ducts, electrolyte excretion, or blood pressure. In addition, we found no difference in endogenous urinary aldosterone excretion between groups on a normal or high-Na(+) diet. High fat-fed mice provide a model of metabolic syndrome, recapitulating obesity, insulin resistance, impaired natriuresis, and a Na(+)-sensitive elevation in blood pressure. Surprisingly, in contrast to previous studies, our data demonstrate that high fat feeding of mice impairs natriuresis and produces elevated blood pressure that is independent of ENaC activity and likely caused by increased Na(+) reabsorption upstream of the aldosterone-sensitive distal nephron.
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Pressão Sanguínea/efeitos dos fármacos , Canais Epiteliais de Sódio/metabolismo , Resistência à Insulina , Obesidade/metabolismo , Sódio/farmacologia , Aldosterona/urina , Animais , Ritmo Circadiano , Dieta Hiperlipídica , Túbulos Renais Coletores/efeitos dos fármacos , Túbulos Renais Coletores/metabolismo , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Natriurese , Néfrons/efeitos dos fármacos , Néfrons/metabolismo , Obesidade/etiologia , Sódio/urina , Sódio na Dieta/efeitos adversosRESUMO
Diet-induced obesity is often modeled by comparing mice fed high-fat diet (HFD), which is made from purified ingredients, vs. normal chow diet (NCD), which is a low-fat assemblage of relatively unrefined plant and animal products. The mechanism by which HFD promotes adiposity is complex but thought to involve low-grade inflammation and altered gut microbiota. The goal of this study was to investigate the extent to which HFD-induced adiposity is driven by fat content vs. other factors that differentiate HFD vs. NCD. Mice were fed NCD, HFD, or other compositionally defined diets (CDD), designed to mimic NCD and/or explore the role of HFD components. A range of metabolic parameters reflecting low-grade inflammation and adiposity were assayed. Relative to NCD, HFD, and to a lesser, but, nonetheless, significant extent, CDD induced increased adiposity, indicating both lipid content and other aspects of HFD are obesogenic. Moreover, HFD and CDD induced a rapid and marked loss of cecal and colonic mass. Such CDD-induced effects were not affected by adjusting dietary protein levels/types but could be largely eliminated by exchanging insoluble fiber (cellulose) for soluble fiber (inulin). Replacing cellulose with inulin in HFD also protected mice against decreased intestinal mass, hyperphagia, and increased adiposity. Such beneficial effects of inulin were microbiota dependent, correlated with elevated fecal short-chain fatty acid levels analyzed via (1)H-NMR-based metabolomics and were partially recapitulated by administration of short-chain fatty acid. HFD-induced obesity is strongly promoted by its lack of soluble fiber, which supports microbiota-mediated intestinal tissue homeostasis that prevents inflammation driving obesity and metabolic syndrome.
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Tecido Adiposo/metabolismo , Adiposidade , Dieta Hiperlipídica/efeitos adversos , Fibras na Dieta/metabolismo , Obesidade/etiologia , Animais , Gorduras na Dieta/metabolismo , Microbioma Gastrointestinal , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Impacts of dietary fiber on intestinal inflammation are complex, but some specific semi-purified fibers, particularly psyllium, can protect humans and rodents against colitis. Mechanisms underlying such protection are not fully understood but may involve activation of the FXR bile acid receptor. Obesity and its associated consequences, referred to as metabolic syndrome, are associated with, and promoted by, low-grade inflammation in a variety of tissues including the intestine. Hence, we examined whether psyllium might ameliorate the low-grade intestinal inflammation that occurs in diet-induced obesity and, moreover, the extent to which it might ameliorate adiposity and/or dysglycemia in this disease model. We observed that enriching a high-fat diet with psyllium provided strong protection against the low-grade gut inflammation and metabolic consequences that were otherwise induced by the obesogenic diet. Such protection was fully maintained in FXR-deficient mice, indicating that distinct mechanisms mediate psyllium's protection against colitis and metabolic syndrome. Nor did psyllium's protection associate with, or require, fermentation or IL-22 production, both of which are key mediators of beneficial impacts of some other dietary fibers. Psyllium's beneficial impacts were not evident in germfree mice but were observed in Altered Schaedler Flora mice, in which psyllium modestly altered relative and absolute abundance of the small number of taxa present in these gnotobiotic mice. Thus, psyllium protects mice against diet-induced obesity/metabolic syndrome by a mechanism independent of FXR and fermentation but nonetheless requires the presence of at least a minimal microbiota.
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Colite , Microbioma Gastrointestinal , Síndrome Metabólica , Psyllium , Humanos , Animais , Camundongos , Síndrome Metabólica/prevenção & controle , Dieta Ocidental , Obesidade/prevenção & controle , Fibras na Dieta , InflamaçãoRESUMO
BACKGROUND & AIMS: Fiber-rich foods promote health, but mechanisms by which they do so remain poorly defined. Screening fiber types, in mice, revealed psyllium had unique ability to ameliorate 2 chronic inflammatory states, namely, metabolic syndrome and colitis. We sought to determine the mechanism of action of the latter. METHODS: Mice were fed grain-based chow, which is naturally rich in fiber or compositionally defined diets enriched with semi-purified fibers. Mice were studied basally and in models of chemical-induced and T-cell transfer colitis. RESULTS: Relative to all diets tested, mice consuming psyllium-enriched compositionally defined diets were markedly protected against both dextran sulfate sodium- and T-cell transfer-induced colitis, as revealed by clinical-type, histopathologic, morphologic, and immunologic parameters. Such protection associated with stark basal changes in the gut microbiome but was independent of fermentation and, moreover, maintained in mice harboring a minimal microbiota (ie, Altered Schaedler Flora). Transcriptomic analysis revealed psyllium induced expression of genes mediating bile acids (BA) secretion, suggesting that psyllium's known ability to bind BA might contribute to its ability to prevent colitis. As expected, psyllium resulted in elevated level of fecal BA, reflecting their removal from enterohepatic circulation but, in stark contrast to the BA sequestrant cholestyramine, increased serum BA levels. Moreover, the use of BA mimetics that activate the farnesoid X receptor (FXR), as well as the use of FXR-knockout mice, suggested that activation of FXR plays a central role in psyllium's protection against colitis. CONCLUSIONS: Psyllium protects against colitis via altering BA metabolism resulting in activation of FXR, which suppresses pro-inflammatory signaling.
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Colite , Psyllium , Camundongos , Animais , Psyllium/efeitos adversos , Ácidos e Sais Biliares , Promoção da Saúde , Colite/induzido quimicamente , Colite/prevenção & controle , Colite/metabolismo , Inflamação , Camundongos KnockoutRESUMO
Background: Purified diets (PDs) contain refined ingredients with one main nutrient, allowing for greater control relative to grain-based diets (GBDs), which contain unrefined grains and animal byproducts. Traditional PDs like the American Institute of Nutrition (AIN)-76A (76A) and AIN-93G (93G) can negatively impact metabolic and gut health when fed long term, in part due to lower total fiber, no soluble fiber, and higher sucrose content. Objective: Two studies were conducted to determine how PDs with reduced sucrose and increased fiber (soluble and insoluble) influence metabolic and gut health in mice compared with traditional AIN PDs or GBDs. Methods: In study 1, C57Bl/6N mice (n = 75) consumed a GBD [LabDiet 5002 (5002)], 76A, 93G, or 2 PDs with reduced sucrose and higher fiber for 88 d. Body composition and metabolic parameters were assessed. In study 2, C57Bl/6N mice (n = 54) consumed either 2 GBDs (LabDiet 5001 or 5002) or PDs with different types/levels of fiber for 14 d. Microbiome alterations and predicted functional metagenomic changes were measured. Results: The PD with 75 g cellulose and 25 g inulin per 4084 kcals marginally influenced body weight and adiposity, but improved glucose tolerance relative to 93G (P = 0.0131) and 76A (P = 0.0014). Cecal and colonic weights were lower in mice fed cellulose-based PDs compared with those fed GBDs and soluble-fiber PDs. Soluble-fiber PDs reduced alpha diversity and showed similar beta diversity, which differed from cellulose-based PDs and GBDs. Certain genera associated with improved gut health such as Bifidobacteria and Akkermansia were significantly elevated by soluble-fiber PDs (P ≤ 0.01). Metabolic pathways related to carbohydrate and fatty acid metabolism were affected by PDs. Conclusions: PDs formulated with lower sucrose and increased fiber content, particularly soluble fiber, blunted elevations in metabolic parameters and favorably impacted the microbiota and metagenome in C57BL/6N mice.
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Nonalcoholic fatty liver disease (NAFLD) is intricately linked to metabolic disease (including obesity, glucose intolerance, and insulin resistance) and encompasses a spectrum of disorders including steatosis, nonalcoholic steatohepatitis (NASH), and fibrosis. Rodents consuming high-fat (HF; â¼40 kcal% fat including fats containing higher concentrations of saturated and trans fats), high-fructose (HFr), and high-cholesterol (HC) diets display many clinically relevant characteristics of NASH, along with other metabolic disorders. C57BL/6 mice are the most commonly used animal model because they can develop significant metabolic disorders including severe NASH with fibrosis after months of feeding, but other models also are susceptible. The significant number of diets that contain these different factors (i.e., HF, HFr, and HC), either alone or in combination, makes the choice of diet difficult. This methodology review describes the efficacy of these nutrient manipulations on the NAFLD phenotype in mice, rats, guinea pigs, hamsters, and nonhuman primates.
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BACKGROUND & AIMS: Nourishment of gut microbiota via consumption of fermentable fiber promotes gut health and guards against metabolic syndrome. In contrast, how dietary fiber impacts type 1 diabetes is less clear. METHODS: To examine impact of dietary fibers on development of type 1 diabetes in the streptozotocin (STZ)-induced and spontaneous non-obese diabetes (NOD) models, mice were fed grain-based chow (GBC) or compositionally defined diets enriched with a fermentable fiber (inulin) or an insoluble fiber (cellulose). Spontaneous (NOD mice) or STZ-induced (wild-type mice) diabetes was monitored. RESULTS: Relative to GBC, low-fiber diets exacerbated STZ-induced diabetes, whereas diets enriched with inulin, but not cellulose, strongly protected against or treated it. Inulin's restoration of glycemic control prevented loss of adipose depots, while reducing food and water consumption. Inulin normalized pancreatic function and markedly enhanced insulin sensitivity. Such amelioration of diabetes was associated with alterations in gut microbiota composition and was eliminated by antibiotic administration. Pharmacologic blockade of fermentation reduced inulin's beneficial impact on glycemic control, indicating a role for short-chain fatty acids (SCFA). Furthermore, inulin's microbiota-dependent anti-diabetic effect associated with SCFA-independent restoration of interleukin 22, which was necessary and sufficient to ameliorate STZ-induced diabetes. Inulin-enriched diets significantly delayed diabetes in NOD mice. CONCLUSIONS: Fermentable fiber confers microbiota-dependent increases in SCFA and interleukin 22 that, together, may have potential to prevent and/or treat type 1 diabetes.
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Bactérias/classificação , Diabetes Mellitus Tipo 1/tratamento farmacológico , Fibras na Dieta/administração & dosagem , Ácidos Graxos Voláteis/metabolismo , Interleucinas/metabolismo , Inulina/administração & dosagem , Animais , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/microbiologia , Fibras na Dieta/farmacologia , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Inulina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Tamanho do Órgão/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/fisiopatologia , Estreptozocina/efeitos adversos , Resultado do Tratamento , Interleucina 22RESUMO
Refined foods are commonly depleted in certain bioactive components that are abundant in 'natural' (plant) foods. Identification and addition of these 'missing' bioactives in the diet is, therefore, necessary to counteract the deleterious impact of convenience food. In this study, multiomics approaches were employed to assess the addition of the popular supplementary soluble dietary fibers inulin and psyllium, both in isolation and in combination with a refined animal feed. A 16S rRNA sequencing and 1H NMR metabolomic investigation revealed that, whilst inulin mediated an increase in Bifidobacteria, psyllium elicited a broader microbial shift, with Parasutterella and Akkermansia being increased and Enterorhabdus and Odoribacter decreased. Interestingly, the combination diet benefited from both inulin and psyllium related microbial changes. Psyllium mediated microbial changes correlated with a reduction of glucose (R -0.67, -0.73, respectively, p < 0.05) and type 2 diabetes associated metabolites: 3-methyl-2-oxovaleric acid (R -0.72, -0.78, respectively, p < 0.05), and citrulline (R -0.77, -0.71, respectively, p < 0.05). This was in line with intestinal and hepatic carbohydrate response (e.g., Slc2a2, Slc2a5, Khk and Fbp1) and hepatic lipogenesis (e.g., Srebf1 and Fasn), which were significantly reduced under psyllium addition. Although established in the liver, the intestinal response associated with psyllium was absent in the combination diet, placing greater significance upon the established microbial, and subsequent metabolomic, shift. Our results therefore highlight the heterogeneity that exists between distinct dietary fibers in the context of carbohydrate uptake and metabolism, and supports psyllium containing combination diets, for their ability to negate the impact of a refined diet.
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Fibras na Dieta/farmacologia , Suplementos Nutricionais , Inulina/farmacologia , Psyllium/farmacologia , Ração Animal , Animais , Dieta/métodos , Fast Foods , Microbioma Gastrointestinal/efeitos dos fármacos , Glucose/metabolismo , Intestinos/metabolismo , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Compostos Fitoquímicos/farmacologia , RNA Ribossômico 16S/análiseRESUMO
OBJECTIVE: Fish oil (FO), and specifically omega 3 fatty acids, has favorable effects on cardiovascular outcomes. The aim of this study was to investigate the effects of FO on the process of macrophage reverse cholesterol transport (RCT) in an in vivo mouse model. METHODS AND RESULTS: C57BL/6J mice were fed a FO diet, whereas control mice were fed diets containing alternative sources of fats, soybean oil (SO), and coconut oil (CO) for 4 weeks. Macrophage RCT was assessed by injecting [(3)H]cholesterol-labeled J774 macrophages intraperitoneally into mice. After 48 hours, tissues were harvested and feces were collected. An increase in the excretion of macrophage-derived [(3)H]-tracer recovered in fecal neutral sterols for FO-fed mice was observed (273% versus SO and 182% versus CO). FO also decreased [(3)H]-tracer in hepatic cholesteryl ester compared to SO and CO by 76% and 56%, respectively. To specifically determine the effect of FO on the fate of HDL-derived cholesterol, mice fed FO or SO diets were injected with HDL labeled with [(3)H]cholesteryl oleate, and the disappearance of [(3)H]-tracer from blood and its excretion in feces was measured. There was no significant difference in the fractional catabolic rate of [(3)H]cholesteryl oleate-HDL between the 2 groups. However, there was a 242% increase in the excretion of HDL-derived [(3)H]-tracer recovered in fecal neutral sterols in FO-fed mice, concordant with significantly increased expression of hepatic Abcg5 and Abcg8 mRNA. CONCLUSIONS: As measured by this tracer-based assay, FO promoted reverse cholesterol transport, primarily by enhancement of the hepatic excretion of macrophage-derived and HDL-derived cholesterol.
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Colesterol/metabolismo , Óleos de Peixe/farmacologia , Macrófagos/metabolismo , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/fisiologia , Animais , Transporte Biológico , Células Cultivadas , Ésteres do Colesterol/metabolismo , Feminino , Lipídeos/sangue , Lipoproteínas/fisiologia , Lipoproteínas HDL/metabolismo , Proteínas de Membrana Transportadoras/fisiologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Nonalcoholic fatty liver disease (NAFLD) is a complex spectrum of disorders ranging from simple benign steatosis to more aggressive forms of nonalcoholic steatohepatitis (NASH) and fibrosis. Although not every patient with NAFLD/NASH develops liver complications, if left untreated it may eventually lead to cirrhosis and hepatocellular carcinoma. Purified diets formulated with specific nutritional components can drive the entire spectrum of NAFLD in rodent models. Although they may not perfectly replicate the clinical and histological features of human NAFLD, they provide a model to gain further understanding of disease progression in humans. Owing to the growing demand of diets for NAFLD research, and for our further understanding of how manipulation of dietary components can alter disease development, we outlined several commonly used dietary approaches for rodent models, including mice, rats, and hamsters, time frames required for disease development and whether other metabolic diseases commonly associated with NAFLD in humans occur.
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The reproducibility of experimental data is challenged by many factors in both clinical and preclinical research. In preclinical studies, several factors may be responsible, and diet is one variable that is commonly overlooked, especially by those not trained in nutrition. In particular, grain-based diets contain complex ingredients, each of which can provide multiple nutrients, non-nutrients, and contaminants, which may vary from batch to batch. Thus, even when choosing the same grain-based diet used in the past by others, its composition will likely differ. In contrast, purified diets contain refined ingredients that offer the ability to control the composition much more closely and maintain consistency from one batch to the next, while minimizing the presence of non-nutrients and contaminants. In this article, we provide several different examples or scenarios showing how the diet choice can alter data interpretation, potentially affecting reproducibility and knowledge gained within any given field of study.
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SCOPE: Previous studies have suggested that diets rich in omega-3 and low in omega-6 long-chain polyunsaturated fatty acids (PUFAs) can limit the development of metabolic syndrome (MetS). Transgenic soybeans yielding oils enriched for omega-3 PUFAs represent a new and readily-available option for incorporating omega-3 PUFAs into diets to provide health benefits. METHODS AND RESULTS: Transgenic soybean oils, enriched for either stearidonic acid (SDA) or eicosapentaenoic acid (EPA), are incorporated into diets to test their effects on limiting the development of MetS in a mouse model of diet-induced obesity. Supplementation with SDA- but not EPA-enriched oils improved features of MetS compared to feeding a control wild-type oil. Because previous studies have linked the gut microorganism Akkermansia muciniphila to the metabolic effects of feeding omega-3 PUFAs, the causal contribution of A. muciniphila to mediating the metabolic benefits provided by SDA-enriched diets is investigated. Although A. muciniphila is not required for SDA-induced metabolic improvements, this microorganism does modulate levels of saturated and mono-unsaturated fatty acids in host adipose tissues. CONCLUSION: Together, these findings support the utilization of SDA-enriched diets to modulate weight gain, glucose metabolism, and fatty acid profiles of liver and adipose tissue.
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Ácidos Graxos Ômega-3/farmacologia , Glucose/metabolismo , Obesidade/dietoterapia , Óleo de Soja/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Akkermansia/efeitos dos fármacos , Akkermansia/fisiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Ácido Eicosapentaenoico/farmacologia , Ácidos Graxos Insaturados/farmacocinética , Alimentos Fortificados , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/microbiologia , Plantas Geneticamente Modificadas , Óleo de Soja/química , Óleo de Soja/genética , Aumento de Peso/efeitos dos fármacosRESUMO
Poor diet reporting and improperly controlling laboratory animal diet continues to reduce our ability to interpret data effectively in animal studies. In order to make the best use of our resources and improve research transparency, proper reporting methods that include a diet design are essential to improving our understanding of the links between gut health and metabolic disease onset. This unit will focus on the importance of diet choice in laboratory animal studies, specifically as it relates to gut health, microbiome, and metabolic disease development. The two most commonly used diet types, grain-based (GB) diets, and purified ingredient diets, will each be described, with particular emphasis on their differences in dietary fiber. A further description of how these diet types and fiber can affect gut morphology and microbiota will be provided as well as how purified ingredient diets may be improved upon. © 2018 by John Wiley & Sons, Inc.
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[This corrects the article DOI: 10.1186/s12986-018-0243-5.].
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Diets used to induce metabolic disease are generally high in fat and refined carbohydrates and importantly, are usually made with refined, purified ingredients. However, researchers will often use a low fat grain-based (GB) diet containing unrefined ingredients as the control diet. Such a comparison between two completely different diet types makes it impossible to draw conclusions regarding the phenotypic differences driven by diet. While many compositional differences can account for this, one major difference that could have the greatest impact between GB and purified diets is the fiber content, both in terms of the level and composition. We will review recent data showing how fiber differences between GB diets and purified diets can significantly influence gut health and microbiota, which itself can affect metabolic disease development. Researchers need to consider the control diet carefully in order to make the best use of precious experimental resources.
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Dietary supplementation with fermentable fiber suppresses adiposity and the associated parameters of metabolic syndrome. Microbiota-generated fiber-derived short-chain fatty acids (SCFAs) and free fatty acid receptors including GPR43 are thought to mediate these effects. We find that while fermentable (inulin), but not insoluble (cellulose), fiber markedly protected mice against high-fat diet (HFD)-induced metabolic syndrome, the effect was not significantly impaired by either inhibiting SCFA production or genetic ablation of GPR43. Rather, HFD decimates gut microbiota, resulting in loss of enterocyte proliferation, leading to microbiota encroachment, low-grade inflammation (LGI), and metabolic syndrome. Enriching HFD with inulin restored microbiota loads, interleukin-22 (IL-22) production, enterocyte proliferation, and antimicrobial gene expression in a microbiota-dependent manner, as assessed by antibiotic and germ-free approaches. Inulin-induced IL-22 expression, which required innate lymphoid cells, prevented microbiota encroachment and protected against LGI and metabolic syndrome. Thus, fermentable fiber protects against metabolic syndrome by nourishing microbiota to restore IL-22-mediated enterocyte function.
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Dieta Hiperlipídica/efeitos adversos , Fibras na Dieta/uso terapêutico , Ácidos Graxos Voláteis/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/microbiologia , Inulina/uso terapêutico , Receptores Acoplados a Proteínas G/genética , Adiposidade/efeitos dos fármacos , Animais , Bifidobacterium/crescimento & desenvolvimento , Proliferação de Células/efeitos dos fármacos , Suplementos Nutricionais , Células Epiteliais/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Interleucinas/genética , Mucosa Intestinal/citologia , Mucosa Intestinal/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/prevenção & controle , Interleucina 22RESUMO
The incidence of diet-induced metabolic disease has soared over the last half-century, despite national efforts to improve health through universal dietary recommendations. Studies comparing dietary patterns of populations with health outcomes have historically provided the basis for healthy diet recommendations. However, evidence that population-level diet responses are reliable indicators of responses across individuals is lacking. This study investigated how genetic differences influence health responses to several popular diets in mice, which are similar to humans in genetic composition and the propensity to develop metabolic disease, but enable precise genetic and environmental control. We designed four human-comparable mouse diets that are representative of those eaten by historical human populations. Across four genetically distinct inbred mouse strains, we compared the American diet's impact on metabolic health to three alternative diets (Mediterranean, Japanese, and Maasai/ketogenic). Furthermore, we investigated metabolomic and epigenetic alterations associated with diet response. Health effects of the diets were highly dependent on genetic background, demonstrating that individualized diet strategies improve health outcomes in mice. If similar genetic-dependent diet responses exist in humans, then a personalized, or "precision dietetics," approach to dietary recommendations may yield better health outcomes than the traditional one-size-fits-all approach.
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Dietética , Metabolismo Energético , Nível de Saúde , Animais , Composição Corporal , Dieta , Modelos Animais de Doenças , Glucose/metabolismo , Humanos , Fígado/metabolismo , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Camundongos , FenótipoRESUMO
BACKGROUND: Lack of dietary fiber has been suggested to increase the risk of developing various chronic inflammatory diseases, whereas supplementation of diets with fiber might offer an array of health-promoting benefits. Consistent with this theme, we recently reported that in mice, compositionally defined diets that are made with purified ingredients and lack fermentable fiber promote low-grade inflammation and metabolic syndrome, both of which could be ameliorated by supplementation of such diets with the fermentable fiber inulin. METHODS: Herein, we examined if, relative to a grain-based mouse diet (chow), compositionally defined diet consumption would impact development of intestinal inflammation induced by dextran sulfate sodium (DSS) and moreover, whether DSS-induced colitis might also be attenuated by diets supplemented with inulin. RESULTS: Analogous to their promotion of low-grade inflammation, compositionally defined diet of high- and low-fat content with cellulose increased the severity of DSS-induced colitis relative to chow. However, in contrast to the case of low-grade inflammation, addition of inulin, but not the insoluble fiber cellulose, further exacerbated the severity of colitis and its associated clinical manifestations (weight loss and bleeding) in both low- and high-fat diets. CONCLUSIONS: While inulin, and perhaps other fermentable fibers, can ameliorate low-grade inflammation and associated metabolic disease, it also has the potential to exacerbate disease severity in response to inducers of acute colitis.
Assuntos
Colite/patologia , Sulfato de Dextrana/toxicidade , Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Fibras na Dieta/administração & dosagem , Suplementos Nutricionais , Inflamação/patologia , Animais , Colite/induzido quimicamente , Fermentação , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Redução de PesoRESUMO
The current study sought to examine whether leptin injections following a weight reduction in diet-induced obese rats would reduce both the enhanced food intake and body weight (BW) regain observed during the refeeding phase. Female Wistar rats (n = 100, 20 per group) were divided into 5 groups: (1) LEP rats were fed a high-fat (HF) diet (35% wt/wt) for 8 weeks to induce obesity and were then food-restricted (50% ad libitum) with a fortified high-fat diet for 2 weeks to induce a 20% BW loss. These rats were then refed the HF diet ad libtum for another 11 weeks. They were given leptin injections (200 microg/kg BW, twice daily, intraperitoneally ) for 19 days concomitant with the onset of refeeding. (2) SAL rats were treated in the same manner as LEP rats except that they were given saline injections; (3) PF rats were treated like SAL rats except that they were pair-fed with the LEP rats; (4) HFC rats were fed HF diet ad libitum; and (5) LFC rats were fed a low-fat (LF) diet (AIN-93M) ad libitum. Ten rats from each group were killed after leptin treatment and at the end of the study. Food and caloric intakes were monitored, and body composition and plasma glucose, insulin, and leptin levels were assessed at death. Leptin injections after a weight reduction briefly reduced energy intake during the first week only. After 19 days of treatment and to the end of the study, LEP and SAL rats were similar in energy intake, BW (LEP: 393 +/- 11.2 g, SAL: 371 +/- 14.1; difference not significant [NS]) and total body fat percent (LEP: 19.3 +/- 1.5, SAL: 17.6 +/- 1.5; NS). Leptin treatment induced hyperinsulinemia and insulin resistance. All of the metabolic abnormalities observed at the end of treatment period disappeared at the end of the study (8 weeks post-leptin injection). We conclude that bolus leptin injections to manipulate leptin circadian rhythm in diet-induced obese rats after a weight reduction caused temporary insulin resistance and hyperinsulinemia, and were ineffective in influencing food intake, BW, and fat content. Leptin resistance was evident following 1 week of treatment in this study. Leptin treatment had no effect on body fat content both short-term and long-term. Exogenous leptin treatment may, in the long run, increase leptin resistance in diet-induced obese animals. Hence, long-term leptin treatment may not be beneficial to obese individuals consuming a HF diet.