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Human microbiome research is an actively developing area of inquiry, with ramifications for our lifestyles, our interactions with microbes, and how we treat disease. Advances depend on carefully executed, controlled, and reproducible studies. Here, we provide a Primer for researchers from diverse disciplines interested in conducting microbiome research. We discuss factors to be considered in the design, execution, and data analysis of microbiome studies. These recommendations should help researchers to enter and contribute to this rapidly developing field.
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Técnicas Microbiológicas , Microbiota , Animales , Archaea/clasificación , Archaea/genética , Archaea/aislamiento & purificación , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Guías como Asunto , Humanos , Reacción en Cadena de la Polimerasa , RibotipificaciónRESUMEN
Host genetics and the gut microbiome can both influence metabolic phenotypes. However, whether host genetic variation shapes the gut microbiome and interacts with it to affect host phenotype is unclear. Here, we compared microbiotas across >1,000 fecal samples obtained from the TwinsUK population, including 416 twin pairs. We identified many microbial taxa whose abundances were influenced by host genetics. The most heritable taxon, the family Christensenellaceae, formed a co-occurrence network with other heritable Bacteria and with methanogenic Archaea. Furthermore, Christensenellaceae and its partners were enriched in individuals with low body mass index (BMI). An obese-associated microbiome was amended with Christensenella minuta, a cultured member of the Christensenellaceae, and transplanted to germ-free mice. C. minuta amendment reduced weight gain and altered the microbiome of recipient mice. Our findings indicate that host genetics influence the composition of the human gut microbiome and can do so in ways that impact host metabolism.
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Bacterias/clasificación , Bacterias/aislamiento & purificación , Heces/microbiología , Microbiota , Animales , Bacterias/metabolismo , Índice de Masa Corporal , Femenino , Tracto Gastrointestinal/microbiología , Vida Libre de Gérmenes , Humanos , Masculino , Ratones , Obesidad/microbiología , Gemelos Dicigóticos , Gemelos MonocigóticosRESUMEN
The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine. Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro, might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century. Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.
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Colitis/inducido químicamente , Colitis/microbiología , Dieta/efectos adversos , Emulsionantes/efectos adversos , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/microbiología , Síndrome Metabólico/inducido químicamente , Síndrome Metabólico/microbiología , Adiposidad/efectos de los fármacos , Animales , Carboximetilcelulosa de Sodio/administración & dosificación , Carboximetilcelulosa de Sodio/efectos adversos , Colitis/patología , Emulsionantes/administración & dosificación , Heces/microbiología , Femenino , Tracto Gastrointestinal/patología , Vida Libre de Gérmenes , Inflamación/inducido químicamente , Inflamación/microbiología , Inflamación/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Síndrome Metabólico/patología , Ratones , Microbiota/efectos de los fármacos , Obesidad/inducido químicamente , Obesidad/microbiología , Obesidad/patología , Polisorbatos/administración & dosificación , Polisorbatos/efectos adversosRESUMEN
OBJECTIVE: Proton pump inhibitors (PPIs) are drugs used to suppress gastric acid production and treat GI disorders such as peptic ulcers and gastro-oesophageal reflux. They have been considered low risk, have been widely adopted, and are often over-prescribed. Recent studies have identified an increased risk of enteric and other infections with their use. Small studies have identified possible associations between PPI use and GI microbiota, but this has yet to be carried out on a large population-based cohort. DESIGN: We investigated the association between PPI usage and the gut microbiome using 16S ribosomal RNA amplification from faecal samples of 1827 healthy twins, replicating results within unpublished data from an interventional study. RESULTS: We identified a significantly lower abundance in gut commensals and lower microbial diversity in PPI users, with an associated significant increase in the abundance of oral and upper GI tract commensals. In particular, significant increases were observed in Streptococcaceae. These associations were replicated in an independent interventional study and in a paired analysis between 70 monozygotic twin pairs who were discordant for PPI use. We propose that the observed changes result from the removal of the low pH barrier between upper GI tract bacteria and the lower gut. CONCLUSIONS: Our findings describe a significant impact of PPIs on the gut microbiome and should caution over-use of PPIs, and warrant further investigation into the mechanisms and their clinical consequences.
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Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de la Bomba de Protones/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tracto Gastrointestinal Superior , Adulto JovenRESUMEN
Studies of the familial Parkinson disease-related proteins PINK1 and Parkin have demonstrated that these factors promote the fragmentation and turnover of mitochondria following treatment of cultured cells with mitochondrial depolarizing agents. Whether PINK1 or Parkin influence mitochondrial quality control under normal physiological conditions in dopaminergic neurons, a principal cell type that degenerates in Parkinson disease, remains unclear. To address this matter, we developed a method to purify and characterize neural subtypes of interest from the adult Drosophila brain. Using this method, we find that dopaminergic neurons from Drosophila parkin mutants accumulate enlarged, depolarized mitochondria, and that genetic perturbations that promote mitochondrial fragmentation and turnover rescue the mitochondrial depolarization and neurodegenerative phenotypes of parkin mutants. In contrast, cholinergic neurons from parkin mutants accumulate enlarged depolarized mitochondria to a lesser extent than dopaminergic neurons, suggesting that a higher rate of mitochondrial damage, or a deficiency in alternative mechanisms to repair or eliminate damaged mitochondria explains the selective vulnerability of dopaminergic neurons in Parkinson disease. Our study validates key tenets of the model that PINK1 and Parkin promote the fragmentation and turnover of depolarized mitochondria in dopaminergic neurons. Moreover, our neural purification method provides a foundation to further explore the pathogenesis of Parkinson disease, and to address other neurobiological questions requiring the analysis of defined neural cell types.
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Dopamina/metabolismo , Proteínas de Drosophila/genética , Drosophila/genética , Mitocondrias/fisiología , Mutación , Neuronas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Animales , Potenciales de la MembranaRESUMEN
Resistant starch (RS) consumption can have beneficial effects on metabolic health, but the response, in terms of effects on the gut microbiota and host physiology, varies between individuals. Factors predicting the response to RS are not yet established and would be useful for developing precision nutrition approaches that maximize the benefits of dietary fiber intake. We sought to identify predictors of gut microbiota response to RS supplementation. We enrolled 76 healthy adults into a 7-week crossover study with 59 individuals completing the study. Participants consumed RS type 2 (RS2), RS type 4 (RS4), and digestible starch, for 10 d each with 5-d washout periods in between. We collected fecal and saliva samples and food records during each treatment period. We performed 16S rRNA gene sequencing and measured fecal short-chain fatty acids (SCFAs), salivary amylase (AMY1) gene copy number, and salivary amylase activity (SAA). Dietary fiber intake was predictive of the relative abundance of several amplicon sequence variants (ASVs) at the end of both RS treatments. AMY1-related metrics were not predictive of response to RS. SAA was only predictive of the relative abundance of one ASV after digestible starch supplementation. Interestingly, SCFA concentrations increased the most during digestible starch supplementation. Treatment order (the order of consumption of RS2 and RS4), alpha diversity, and a subset of ASVs were predictive of SCFA changes after RS supplementation. Based on our findings, dietary fiber intake and gut microbiome composition would be informative if assessed prior to recommending RS supplementation because these data can be used to predict changes in specific ASVs and fecal SCFA concentrations. These findings lay a foundation to support the premise that using a precision nutrition approach to optimize the benefits of dietary fibers such as RS could be an effective strategy to compensate for the low consumption of dietary fiber nationwide.
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Bacterias , Estudios Cruzados , Fibras de la Dieta , Suplementos Dietéticos , Ácidos Grasos Volátiles , Heces , Microbioma Gastrointestinal , ARN Ribosómico 16S , Saliva , Almidón , Humanos , Fibras de la Dieta/metabolismo , Fibras de la Dieta/administración & dosificación , Masculino , Femenino , Heces/microbiología , Heces/química , Adulto , Ácidos Grasos Volátiles/metabolismo , Ácidos Grasos Volátiles/análisis , Almidón/metabolismo , Saliva/microbiología , Saliva/química , Suplementos Dietéticos/análisis , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/metabolismo , ARN Ribosómico 16S/genética , Adulto Joven , Persona de Mediana Edad , Almidón Resistente/metabolismoRESUMEN
Across microbiome studies, fecal and oral samples are stored and processed in different ways, which could affect the observed microbiome composition. Here, we compared treatment methods, which included both storage conditions and processing methods, applied to samples prior to DNA extraction to determine how each affects microbial community diversity as assessed by 16S rRNA gene sequencing. We collected dental swab, saliva, and fecal samples from 10 individuals, with three technical replicates per treatment method. We assessed four methods of processing fecal samples prior to DNA extraction. We also compared different fractions of frozen saliva and dental samples to fresh samples. We found that lyophilized fecal samples, fresh whole saliva samples, and the supernatant fraction of thawed dental samples retained the highest levels of alpha diversity in samples. The supernatant fraction of thawed saliva samples had the second highest alpha diversity compared to fresh. Then we investigated the differences in microbes between different treatments at the domain and phylum levels as well as identified the amplicon sequence variants (ASVs) that were significantly different between the methods producing the highest alpha diversity and the other treatment methods. Lyophilized fecal samples had a greater prevalence of Archaea as well as a greater ratio of Firmicutes to Bacteroidetes compared to the other treatment methods. Our results provide practical considerations, not only for selection of processing method, but also for comparing results across studies that use these methods. Our findings also indicate differences in treatment method could be a confounding factor influencing the presence, absence, or differential abundance of microbes reported in conflicting studies.
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In microbiome studies, fecal and oral samples are stored and processed in different ways, which could affect the observed microbiome composition. In this study, we compared storage and processing methods applied to samples prior to DNA extraction to determine how each affected microbial community diversity as assessed by 16S rRNA gene sequencing. We collected dental swabs, saliva, and fecal samples from 10 individuals, with three technical replicates per condition. We assessed four methods of storing and processing fecal samples prior to DNA extraction. We also compared different fractions of thawed saliva and dental samples to fresh samples. We found that lyophilized fecal samples, fresh whole saliva samples, and the supernatant fraction of thawed dental samples had the highest levels of alpha diversity. The supernatant fraction of thawed saliva samples had the second highest evenness compared to fresh saliva samples. Then, we investigated the differences in observed community composition at the domain and phylum levels and identified the amplicon sequence variants (ASVs) that significantly differed in relative abundance between the conditions. Lyophilized fecal samples had a greater prevalence of Archaea as well as a greater ratio of Firmicutes to Bacteroidetes compared to the other conditions. Our results provide practical considerations not only for the selection of storage and processing methods but also for comparing results across studies. Differences in processing and storage methods could be a confounding factor influencing the presence, absence, or differential abundance of microbes reported in conflicting studies.
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Resistant starch (RS) consumption can have beneficial effects on human health, but the response, in terms of effects on the gut microbiota and host physiology, varies between individuals. Factors predicting the response to RS are not yet established and would be useful for developing precision nutrition approaches that maximize the benefits of dietary fiber intake. We sought to identify predictors of gut microbiota response to RS supplementation. We enrolled 76 healthy adults into a seven-week crossover study. Participants consumed RS type 2 (RS2), RS type 4 (RS4), and a digestible starch, for ten days each with five-day washout periods in between. We collected fecal and saliva samples and food records before and during each treatment period. We performed 16S rRNA gene sequencing and measured fecal short-chain fatty acids (SCFAs), salivary amylase gene copy number, and salivary amylase activity (SAA). Dietary fiber intake was predictive of relative abundance of several amplicon sequence variants (ASVs) at the end of both RS treatments. Treatment order (the order of consumption of RS2 and RS4), alpha diversity, and a subset of ASVs were predictive of SCFA changes after RS supplementation. SAA was only predictive of the relative abundance of ASVs after digestible starch supplementation. Based on our findings, dietary fiber intake and gut microbiome composition would be informative if assessed prior to recommending RS supplementation. Using a precision nutrition approach to optimize the benefits of dietary fibers such as RS could be an effective strategy to compensate for the low consumption of dietary fiber nationwide.
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Loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) or parkin genes, which encode a mitochondrially localized serine/threonine kinase and a ubiquitin-protein ligase, respectively, result in recessive familial forms of Parkinsonism. Genetic studies in Drosophila indicate that PINK1 acts upstream of Parkin in a common pathway that influences mitochondrial integrity in a subset of tissues, including flight muscle and dopaminergic neurons. The mechanism by which PINK1 and Parkin influence mitochondrial integrity is currently unknown, although mutations in the PINK1 and parkin genes result in enlarged or swollen mitochondria, suggesting a possible regulatory role for the PINK1/Parkin pathway in mitochondrial morphology. To address this hypothesis, we examined the influence of genetic alterations affecting the machinery that governs mitochondrial morphology on the PINK1 and parkin mutant phenotypes. We report that heterozygous loss-of-function mutations of drp1, which encodes a key mitochondrial fission-promoting component, are largely lethal in a PINK1 or parkin mutant background. Conversely, the flight muscle degeneration and mitochondrial morphological alterations that result from mutations in PINK1 and parkin are strongly suppressed by increased drp1 gene dosage and by heterozygous loss-of-function mutations affecting the mitochondrial fusion-promoting factors OPA1 and Mfn2. Finally, we find that an eye phenotype associated with increased PINK1/Parkin pathway activity is suppressed by perturbations that reduce mitochondrial fission and enhanced by perturbations that reduce mitochondrial fusion. Our studies suggest that the PINK1/Parkin pathway promotes mitochondrial fission and that the loss of mitochondrial and tissue integrity in PINK1 and parkin mutants derives from reduced mitochondrial fission.
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Proteínas del Citoesqueleto/genética , Proteínas de Drosophila/metabolismo , Proteínas de Unión al GTP/genética , Fusión de Membrana/genética , Mitocondrias/ultraestructura , Enfermedad de Parkinson/patología , Proteínas Quinasas/metabolismo , Animales , Proteínas del Citoesqueleto/metabolismo , Drosophila/genética , Drosophila/metabolismo , Drosophila/ultraestructura , Proteínas de Drosophila/genética , Ojo/anatomía & histología , Ojo/metabolismo , Proteínas de Unión al GTP/metabolismo , Dosificación de Gen , Humanos , Proteínas de la Membrana/metabolismo , Mitocondrias/genética , Dilatación Mitocondrial , Mutación , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/genética , Proteínas Quinasas/genética , Ubiquitina-Proteína LigasasRESUMEN
Nutrition research is plagued by the reproducibility crisis. Reconciling nutrition studies involving microbiome data presents a modern challenge for researchers. In this issue of Cell Host & Microbe, Bisanz et al., 2019 demonstrate a comprehensive methodology for meta-analysis of microbiome sequence data from high-fat-diet intervention studies.
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Microbioma Gastrointestinal , Microbiota , Dieta Alta en Grasa , Reproducibilidad de los ResultadosRESUMEN
Host genetic variation influences microbiome composition. While studies have focused on associations between the gut microbiome and specific alleles, gene copy number (CN) also varies. We relate microbiome diversity to CN variation of the AMY1 locus, which encodes salivary amylase, facilitating starch digestion. After imputing AMY1-CN for â¼1,000 subjects, we identified taxa differentiating fecal microbiomes of high and low AMY1-CN hosts. In a month-long diet intervention study, we show that diet standardization drove gut microbiome convergence, and AMY1-CN correlated with oral and gut microbiome composition and function. The microbiomes of low-AMY1-CN subjects had enhanced capacity to break down complex carbohydrates. High-AMY1-CN subjects had higher levels of salivary Porphyromonas; their gut microbiota had increased abundance of resistant starch-degrading microbes, produced higher levels of short-chain fatty acids, and drove higher adiposity when transferred to germ-free mice. This study establishes AMY1-CN as a genetic factor associated with microbiome composition and function.
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Amilasas/genética , Tracto Gastrointestinal/microbiología , Dosificación de Gen , Microbiota , Boca/microbiología , Saliva/enzimología , Animales , Vida Libre de Gérmenes , Humanos , RatonesRESUMEN
Commonly prescribed antibiotics are known to alter human microbiota. We hypothesized that triclosan and triclocarban, components of many household and personal care products (HPCPs), may alter the oral and gut microbiota, with potential consequences for metabolic function and weight. In a double-blind, randomized, crossover study, participants were given triclosan- and triclocarban (TCS)-containing or non-triclosan/triclocarban (nTCS)-containing HPCPs for 4 months and then switched to the other products for an additional 4 months. Blood, stool, gingival plaque, and urine samples and weight data were obtained at baseline and at regular intervals throughout the study period. Blood samples were analyzed for metabolic and endocrine markers and urine samples for triclosan. The microbiome in stool and oral samples was then analyzed. Although there was a significant difference in the amount of triclosan in the urine between the TCS and nTCS phases, no differences were found in microbiome composition, metabolic or endocrine markers, or weight. Though this study was limited by the small sample size and imprecise administration of HPCPs, triclosan at physiologic levels from exposure to HPCPs does not appear to have a significant or important impact on human oral or gut microbiome structure or on a panel of metabolic markers. IMPORTANCE Triclosan and triclocarban are commonly used commercial microbicides found in toothpastes and soaps. It is unknown what effects these chemicals have on the human microbiome or on endocrine function. From this randomized crossover study, it appears that routine personal care use of triclosan and triclocarban neither exerts a major influence on microbial communities in the gut and mouth nor alters markers of endocrine function in humans.
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Inflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases quality of life. Endoplasmic reticulum (ER)-associated degradation (ERAD) is responsible for the clearance of misfolded proteins; however, its role in disease pathogenesis remains largely unexplored. Here we show that the expression of SEL1L and HRD1, the most conserved branch of mammalian ERAD, is significantly reduced in ileal Crohn's disease (CD). Consistent with this observation, laboratory mice with enterocyte-specific Sel1L deficiency (Sel1L(ΔIEC)) develop spontaneous enteritis and have increased susceptibility to Toxoplasma gondii-induced ileitis. This is associated with profound defects in Paneth cells and a disproportionate increase of Ruminococcus gnavus, a mucolytic bacterium with known association with CD. Surprisingly, whereas both ER stress sensor IRE1α and effector CHOP are activated in the small intestine of Sel1L(ΔIEC) mice, they are not solely responsible for ERAD deficiency-associated lesions seen in the small intestine. Thus our study points to a constitutive role of Sel1L-Hrd1 ERAD in epithelial cell biology and the pathogenesis of intestinal inflammation in CD.
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Enterocitos/metabolismo , Proteínas/fisiología , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Apoptosis , Duodeno/metabolismo , Duodeno/patología , Estrés del Retículo Endoplásmico , Degradación Asociada con el Retículo Endoplásmico , Endorribonucleasas/fisiología , Enteritis/metabolismo , Enteritis/patología , Femenino , Microbioma Gastrointestinal , Haploinsuficiencia , Homeostasis , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Células de Paneth/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Factor de Transcripción CHOP/fisiologíaRESUMEN
Soil microorganisms found in the root zone impact plant growth and development, but the potential to harness these benefits is hampered by the sheer abundance and diversity of the players influencing desirable plant traits. Here, we report a high level of reproducibility of soil microbiomes in altering plant flowering time and soil functions when partnered within and between plant hosts. We used a multi-generation experimental system using Arabidopsis thaliana Col to select for soil microbiomes inducing earlier or later flowering times of their hosts. We then inoculated the selected microbiomes from the tenth generation of plantings into the soils of three additional A. thaliana genotypes (Ler, Be, RLD) and a related crucifer (Brassica rapa). With the exception of Ler, all other plant hosts showed a shift in flowering time corresponding with the inoculation of early- or late-flowering microbiomes. Analysis of the soil microbial community using 16 S rRNA gene sequencing showed distinct microbiota profiles assembling by flowering time treatment. Plant hosts grown with the late-flowering-associated microbiomes showed consequent increases in inflorescence biomass for three A. thaliana genotypes and an increase in total biomass for B. rapa. The increase in biomass was correlated with two- to five-fold enhancement of microbial extracellular enzyme activities associated with nitrogen mineralization in soils. The reproducibility of the flowering phenotype across plant hosts suggests that microbiomes can be selected to modify plant traits and coordinate changes in soil resource pools.
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Flores/crecimiento & desarrollo , Microbiota , Microbiología del Suelo , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Biomasa , Brassica rapa/crecimiento & desarrollo , Genotipo , Reproducibilidad de los Resultados , Suelo/químicaRESUMEN
Dissimilatory metal-reducing bacteria are widespread in terrestrial ecosystems, especially in anaerobic soils and sediments. Thermodynamically, dissimilatory metal reduction is more favorable than sulfate reduction and methanogenesis but less favorable than denitrification and aerobic respiration. It is critical to understand the complex relationships, including the absence or presence of terminal electron acceptors, that govern microbial competition and coexistence in anaerobic soils and sediments, because subsurface microbial processes can effect greenhouse gas emissions from soils, possibly resulting in impacts at the global scale. Here, we elucidated the effect of an inexhaustible, ferrous-iron and humic-substance mimicking terminal electron acceptor by deploying potentiostatically poised electrodes in the sediment of a very specific stream riparian zone in Upstate New York state. At two sites within the same stream riparian zone during the course of 6 weeks in the spring of 2013, we measured CH4 and N2/N2O emissions from soil chambers containing either poised or unpoised electrodes, and we harvested biofilms from the electrodes to quantify microbial community dynamics. At the upstream site, which had a lower vegetation cover and highest soil temperatures, the poised electrodes inhibited CH4 emissions by â¼45% (when normalized to remove temporal effects). CH4 emissions were not significantly impacted at the downstream site. N2/N2O emissions were generally low at both sites and were not impacted by poised electrodes. We did not find a direct link between bioelectrochemical treatment and microbial community membership; however, we did find a correspondence between environment/function and microbial community dynamics.
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The present study investigated the inheritance of dietary fat, carbohydrate, and kilocalorie intake traits in an F(2) population derived from an intercross between C57BL/6J (fat-preferring) and CAST/EiJ (carbohydrate-preferring) mice. Mice were phenotyped for self-selected food intake in a paradigm which provided for 10 days a choice between two macronutrient diets containing 78/22% of energy as a composite of either fat/protein or carbohydrate/protein. Quantitative trait locus (QTL) analysis identified six significant loci for macronutrient intake: three for fat intake on chromosomes (Chrs) 8 (Mnif1), 18 (Mnif2), and X (Mnif3), and three for carbohydrate intake on Chrs 17 (Mnic1), 6 (Mnic2), and X (Mnic3). An absence of interactions among these QTL suggests the existence of separate mechanisms controlling the intake of fat and carbohydrate. Two significant QTL for cumulative kilocalorie intake, adjusted for baseline body weight, were found on Chrs 17 (Kcal1) and 18 (Kcal2). Without body weight adjustment, another significant kcal locus appeared on distal Chr 2 (Kcal3). These macronutrient and kilocalorie QTL, with the exception of loci on Chrs 8 and X, encompassed chromosomal regions influencing body weight gain and adiposity in this F2 population. These results provide new insight into the genetic basis of naturally occurring variation in nutrient intake phenotypes.
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Carbohidratos de la Dieta , Grasas de la Dieta , Ingestión de Alimentos/genética , Ingestión de Energía/genética , Conducta Alimentaria , Sitios de Carácter Cuantitativo , Animales , Peso Corporal/genética , Colipasas/genética , Cruzamientos Genéticos , Proteínas en la Dieta , Precursores Enzimáticos , Femenino , Glucosa/análisis , Humanos , Cinética , Masculino , Ratones , Obesidad/genética , Fenotipo , Precursores de Proteínas/genéticaRESUMEN
Chronic intake of Western diet has driven an epidemic of obesity and metabolic syndrome, but how it induces mortality remains unclear. Here, we show that chronic intake of a high-fat diet (HFD), not a low-fat diet, leads to severe pulmonary damage and mortality in mice deficient in Toll-like receptors 2 and 4 (DKO). Diet-induced pulmonary lesions are blocked by antibiotic treatment and are transmissible to wild-type mice upon either cohousing or fecal transplantation, pointing to the existence of bacterial pathogens. Indeed, diet and innate deficiency exert significant impact on gut microbiota composition. Thus, chronic intake of HFD promotes severe pulmonary damage and mortality in DKO mice in part via gut dysbiosis, a finding that may be important for immunodeficient patients, particularly those on chemotherapy or radiotherapy, where gut-microbiota-caused conditions are often life threatening.