Host Metabolic State Research Articles

Dietary and metabolic effects on intestinal stem cells in health and disease.

Diet and nutritional metabolites exhibit wide-ranging effects on health and disease partly by altering tissue composition and function. With rapidly rising rates of obesity, there is particular interest in how obesogenic diets influence tissue homeostasis and risk of tumorigenesis; epidemiologically, these diets have a positive correlation with various cancers, including colorectal cancer. The gastrointestinal tract is a highly specialized, continuously renewing tissue with a fundamental role in nutrient uptake and is, in turn, influenced by diet composition and host metabolic state. Intestinal stem cells are found at the base of the intestinal crypt and can generate all mature lineages that comprise the intestinal epithelium and are uniquely influenced by host diet, metabolic by-products and energy dynamics. Similarly, tumour growth and metabolism can also be shaped by nutrient availability and host diet. In this Review, we discuss how different diets and metabolic changes influence intestinal stem cells in homeostatic and pathological conditions, as well as tumorigenesis. We also discuss how dietary changes and composition affect the intestinal epithelium and its surrounding microenvironment.

Changes in gut microbiota and metabolism associated with phenotypic plasticity in the honey bee Apis mellifera.

Honey bees exhibit an elaborate social structure based in part on an age-related division of labor. Young workers perform tasks inside the hive, while older workers forage outside the hive, tasks associated with distinct diets and metabolism. Critical to colony fitness, the work force can respond rapidly to changes in the environment or colony demography and assume emergency tasks, resulting in young foragers or old nurses. We hypothesized that both task and age affect the gut microbiota consistent with changes to host diet and physiology. We performed two experiments inducing precocious foragers and reverted nurses, then quantified tissue-specific gut microbiota and host metabolic state associated with nutrition, immunity and oxidative stress. In the precocious forager experiment, both age and ontogeny explained differences in midgut and ileum microbiota, but host gene expression was best explained by an interaction of these factors. Precocious foragers were nutritionally deficient, and incurred higher levels of oxidative damage relative to age-matched nurses. In the oldest workers, reverted nurses, the oxidative damage associated with age and past foraging was compensated by high Vitellogenin expression, which exceeded that of young nurses. Host-microbial interactions were evident throughout the dataset, highlighted by an age-based increase of Gilliamella abundance and diversity concurrent with increased carbonyl accumulation and CuZnSOD expression. The results in general contribute to an understanding of ecological succession of the worker gut microbiota, defining the species-level transition from nurse to forager.

Diverse Control Mechanisms of the Interleukin-1 Cytokine Family

The majority of interleukin-1 (IL-1) family cytokines lack amino terminal secretion signals or transmembrane domains for secretion along the conventional biosynthetic pathway. Yet, these factors must be translocated from the cytoplasm across the plasma membrane into the extracellular space in order to regulate inflammation. Recent work has identified an array of mechanisms by which IL-1 family cytokines can be released into the extracellular space, with supramolecular organizing centers known as inflammasomes serving as dominant drivers of this process. In this review, we discuss current knowledge of the mechanisms of IL-1 family cytokine synthesis, processing, and release from cells. Using this knowledge, we propose a model whereby host metabolic state dictates the route of IL-1β secretion, with implications for microbial infection and sterile inflammation.

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism

ObjectivesGut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome’s functional composition...

An Emiliania huxleyi pan-transcriptome reveals basal strain specificity in gene expression patterns

Emiliania huxleyi is a cosmopolitan coccolithophore widespread in temperate oceans. This unicellular photoautotroph forms massive recurring blooms that play an important role in large biogeochemical cycles of carbon and sulfur, which play a role in climate change. The mechanism of bloom formation and demise, controlled by giant viruses that routinely infect these blooms, is poorly understood. We generated a pan-transcriptome of E. huxleyi, derived from three strains with different susceptibility to viral infection. Expression profiling of E. huxleyi sensitive and resistant strains showed major basal differences, including many genes that are induced upon viral infection. This suggests that basal gene expression can affect the host metabolic state and the susceptibility of E. huxleyi to viruses. Due to its ecological importance, the pan-transcriptome and its protein translation, applicable to many E. huxleyi strains, is a powerful resource for investigation of eukaryotic microbial communities.

Impaired Intestinal Barrier and Tissue Bacteria: Pathomechanisms for Metabolic Diseases.

An intact intestinal barrier, representing the interface between inner and outer environments, is an integral regulator of health. Among several factors, bacteria and their products have been evidenced to contribute to gut barrier impairment and its increased permeability. Alterations of tight junction integrity - caused by both external factors and host metabolic state - are important for gut barrier, since they can lead to increased influx of bacteria or bacterial components (endotoxin, bacterial DNA, metabolites) into the host circulation. Increased systemic levels of bacterial endotoxins and DNA have been associated with an impaired metabolic host status, manifested in obesity, insulin resistance, and associated cardiovascular complications. Bacterial components and cells are distributed to peripheral tissues via the blood stream, possibly contributing to metabolic diseases by increasing chronic pro-inflammatory signals at both tissue and systemic levels. This response is, along with other yet unknown mechanisms, mediated by toll like receptor (TLR) transduction and increased expression of pro-inflammatory cytokines, which in turn can further increase intestinal permeability leading to a detrimental positive feedback loop. The modulation of gut barrier function through nutritional and other interventions, including manipulation of gut microbiota, may represent a potential prevention and treatment target for metabolic diseases.

Erhöhte Darmpermeabilität: Pathomechanismus für metabolische Erkrankungen?

The intestinal barrier is an interface between ourselves and our environments and therefore an integral regulator of health. Among other factors, gut barrier integrity is regulated by bacteria and bacterial metabolites, which have been evidenced to have both protective or detrimental effects on gut integrity and permeability. Similarly, both external and internal factors related to host metabolic state can lead to alterations of tight junction integrity and hence to increased influx of bacteria or bacterial components into the host circulation. This so-called ‘metabolic endotoxemia’ has been associated with impaired metabolic host status, aggravation of existing obesity, increase in insulin resistance, and onset of cardiovascular events. From the gut, bacteria and their components and metabolites are further transported through the blood to peripheral tissues, where they can induce chronic pro-inflammatory signals at the tissue and systemic level. This, in turn, can further increase intestinal permeability leading to a detrimental feedback loop. Modulation of gut barrier function through nutritional or medicinal interventions, including manipulation of gut microbiota by pre-, pro- or synbiotics, represents a promising prevention and treatment target for metabolic diseases. Prerequisite for microbiome based targeted prevention and treatment options is a better understanding of the interactions between the microbiome and cardiovascular health.

Seasonal arbuscular mycorrhiza colonization dynamic displays genotype-specific pattern in Iris sibirica L.

Arbuscular mycorrhiza (AM) is a widespread symbiotic association between plants and Glomeromycota fungi, that brings nutritional-derived benefits for phytobiont. Influence of plant breeding on arbuscular mycorrhiza susceptibility is a topic of current interest that can have many practical implications. Insights into whether new cultivars have a lower mycorrhizal potential, are critical for optimization of AM use. Aim of this research was to conduct a comparative assessment of AM colonization across a phenophase gradient in two Iris sibirica genotypes: one displaying the wild traits versus a modern reblooming cultivar with double flowers. Analysis showed that both Iris sibirica genotypes developed Paris-morphotype. Results indicated that on average the genotype with simple flowers had a higher AM colonization frequency (84.44±2.15) compared to the new cultivar with double flowers (52.22±6.09). Significant influence was exercised both by genotype (p<0.001) as well as by phenophase (p=0.0013), over colonization frequency. The genotypes displayed contrasting colonization dynamics: highest AM frequency level occurred in spring for the genotype with simple flowers, and in autumn for the one with double flowers. Results suggest that host metabolic state has regulating role over functionality of established AM-symbiotic association according to plant nutritional requirements, while fungi might also respond to increased or decreased carbon flux in the plant, associated with geophyte phenology.

Single-cell glycolytic activity regulates membrane tension and HIV-1 fusion.

There has been resurgence in determining the role of host metabolism in viral infection yet deciphering how the metabolic state of single cells affects viral entry and fusion remains unknown. Here, we have developed a novel assay multiplexing genetically-encoded biosensors with single virus tracking (SVT) to evaluate the influence of global metabolic processes on the success rate of virus entry in single cells. We found that cells with a lower ATP:ADP ratio prior to virus addition were less permissive to virus fusion and infection. These results indicated a relationship between host metabolic state and the likelihood for virus-cell fusion to occur. SVT revealed that HIV-1 virions were arrested at hemifusion in glycolytically-inactive cells. Interestingly, cells acutely treated with glycolysis inhibitor 2-deoxyglucose (2-DG) become resistant to virus infection and also display less surface membrane cholesterol. Addition of cholesterol in these in glycolytically-inactive cells rescued the virus entry block at hemifusion and enabled completion of HIV-1 fusion. Further investigation with FRET-based membrane tension and membrane order reporters revealed a link between host cell glycolytic activity and host membrane order and tension. Indeed, cells treated with 2-DG possessed lower plasma membrane lipid order and higher tension values, respectively. Our novel imaging approach that combines lifetime imaging (FLIM) and SVT revealed not only changes in plasma membrane tension at the point of viral fusion, but also that HIV is less likely to enter cells at areas of higher membrane tension. We therefore have identified a connection between host cell glycolytic activity and membrane tension that influences HIV-1 fusion in real-time at the single-virus fusion level in live cells.

Distinct amino acid and lipid perturbations characterize acute versus chronic malaria.

Chronic malaria is a major public health problem and significant challenge for disease eradication efforts. Despite its importance, the biological factors underpinning chronic malaria are not fully understood. Recent studies have shown that host metabolic state can influence malaria pathogenesis and transmission, but its role in chronicity is not known. Here, with the goal of identifying distinct modifications in the metabolite profiles of acute versus chronic malaria, metabolomics was performed on plasma from Plasmodium-infected humans and nonhuman primates with a range of parasitemias and clinical signs. In rhesus macaques infected with Plasmodium coatneyi, significant alterations in amines, carnitines, and lipids were detected during a high parasitemic acute phase and many of these reverted to baseline levels once a low parasitemic chronic phase was established. Plasmodium gene expression, studied in parallel in the macaques, revealed transcriptional changes in amine, fatty acid, lipid and energy metabolism genes, as well as variant antigen genes. Furthermore, a common set of amines, carnitines, and lipids distinguished acute from chronic malaria in plasma from human Plasmodium falciparum cases. In summary, distinct host-parasite metabolic environments have been uncovered that characterize acute versus chronic malaria, providing insights into the underlying host-parasite biology of malaria disease progression.

Host Respiration Rate and Injury-Derived Cues Drive Host Preference by an Ectoparasite of Fruit Flies.

Host bioenergetics and energy fluxes can be applied to measure the ecological and physiological effects of parasitism. By measuring changes in host metabolic rate, one can estimate the physiological costs of infection. Additionally, metabolic rate dictates the rate of resource conversion within a host and, by extension, the resources available to a parasite. We hypothesize that parasites are selected to respond to cues that indicate high resource availability, that is, host metabolic state. We investigated whether an ectoparasite mite (Macrocheles subbadius) can differentiate between potential hosts (Drosophilia nigrospiracula) on the basis of relative carbon dioxide output as measured by respirometry. In pairwise choice tests, mites were allowed to choose between two size-matched fruit flies with differing metabolic rates or levels of CO2 output. Our results showed that mites preferentially infect flies with relatively higher respiration rates. Accordingly, we investigated whether fly respiratory rate (measured by CO2 production) changes in response to injury, potentially explaining a previously reported preference for injured flies. We also tested whether chemical cues released during injury influence preference for injured hosts. We determined that fly exudate (mostly consisting of hemolymph) applied to an uninjured fly released at the site of injury significantly increased the likelihood of infection, but injury did not significantly change the CO2 output of the flies. Our results suggest that parasites are relying on chemical cues not only for host finding but also to discriminate between hosts on the basis of the rate of respiration, with potentially important implications for the metabolic theory of ecology.

Human adipose cells in vitro are either refractory or responsive to insulin, reflecting host metabolic state.

While intercellular communication processes are frequently characterized by switch-like transitions, the endocrine system, including the adipose tissue response to insulin, has been characterized by graded responses. Yet here individual cells from adipose tissue biopsies are best described by a switch-like transition between the basal and insulin-stimulated states for the trafficking of the glucose transporter GLUT4. Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells. Furthermore, subjects exhibiting high systemic insulin sensitivity indices (SI) have high fractions of responsive adipose cells in vitro, while subjects exhibiting decreasing SI have increasing fractions of refractory cells in vitro. Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI. Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

Drosophila microbiota modulates host metabolic gene expression via IMD/NF-κB signaling.

Most metazoans engage in mutualistic interactions with their intestinal microbiota. Despite recent progress the molecular mechanisms through which microbiota exerts its beneficial influences on host physiology are still largely uncharacterized. Here we use axenic Drosophila melanogaster adults associated with a standardized microbiota composed of a defined set of commensal bacterial strains to study the impact of microbiota association on its host transcriptome. Our results demonstrate that Drosophila microbiota has a marked impact on the midgut transcriptome and promotes the expression of genes involved in host digestive functions and primary metabolism. We identify the IMD/Relish signaling pathway as a central regulator of this microbiota-mediated transcriptional response and we reveal a marked transcriptional trade-off between the midgut response to its beneficial microbiota and to bacterial pathogens. Taken together our results indicate that microbiota association potentiates host nutrition and host metabolic state, two key physiological parameters influencing host fitness. Our work paves the way to subsequent mechanistic studies to reveal how these microbiota-dependent transcriptional signatures translate into host physiological benefits.

Composition of Dietary Fat Source Shapes Gut Microbiota Architecture and Alters Host Inflammatory Mediators in Mouse Adipose Tissue

Growing evidence shows that dietary factors can dramatically alter the gut microbiome in ways that contribute to metabolic disturbance and progression of obesity. In this regard, mesenteric adipose tissue has been implicated in mediating these processes through the elaboration of proinflammatory adipokines. In this study, we examined the relationship of these events by determining the effects of dietary fat content and source on gut microbiota, as well as the effects on adipokine profiles of mesenteric and peripheral adipocytes. Adult male C57Bl/6 mice were fed milk fat-based, lard-based (saturated fatty acid sources), or safflower oil (polyunsaturated fatty acid)-based high-fat diets for 4 weeks. Body mass and food consumption were measured. Stool 16S ribosomal RNA (rRNA) was isolated and analyzed via terminal restriction fragment length polymorphism as well as variable V3-4 sequence tags via next-generation sequencing. Mesenteric and gonadal adipose samples were analyzed for both lipogenic and inflammatory mediators via quantitative real-time polymerase chain reaction. High-fat feedings caused more weight gain with concomitant increases in caloric consumption relative to low-fat diets. In addition, each of the high-fat diets induced dramatic and specific 16S rRNA phylogenic profiles that were associated with different inflammatory and lipogenic mediator profiles of mesenteric and gonadal fat depots. Our findings support the notion that dietary fat composition can both reshape the gut microbiota and alter host adipose tissue inflammatory/lipogenic profiles. They also demonstrate the interdependency of dietary fat source, commensal gut microbiota, and inflammatory profile of mesenteric fat that can collectively affect the host metabolic state.

Interconnected Metabolism of Host Plants and Obligate Biotrophic Pathogens

Downy mildew disease, caused by obligate biotrophic oomycetes in the family Peronsporaceae, affects a wide range of flowering plants, including numerous monocot and dicot crops. Species from the Hyaloperonospora genus are causal agents of downy mildew in Arabidopsis thaliana and many other Cruciferae species, including crops such as broccoli, cabbage, and canola, and the Arabidopsis/ Hyaloperonospora arabidopsidis pathosystem is an established model for downy mildews (Coates and Beynon, 2010). Obligate biotrophic parasites depend on living host cells for their growth and reproduction (reviewed in O’Connell and Panstruga, 2006). This means that, following successful infection, the parasite must establish connections within plant cells (e.g., haustoria) and obtain nourishment from the host without causing immediate host cell death. Therefore, changes in the metabolic state of the host might be expected to influence the growth of obligate biotrophic pathogens and the development of disease. In new work, Stuttmann et al. (pages 2788–2803) describe two distinct mutants of Arabidopsis ,b oth of which show increased resistance to H. arabidopsidis (Hpa) resulting from a disruption in amino acid metabolism causing overaccumulation of the amino acid Thr. Although the mutant plants overaccumulated all three Asp-derived amino acids, Thr, Ile, and Met, enhanced resistance was found to be related specifically to Thr accumulation. Mutant plants that overaccumulate only Met were not hyperresistant to Hpa, and pretreatment of plants with Thr, but not Ile, led to reduced Hpa sporulation (see figure). In addition, the mutations did not cause constitutive plant defense activation, and enhanced resistance did not appear to be linked to plant immunity. Rather, the effect appeared to be due to a loss of susceptibility (i.e., Thr overaccumulation somehow rendered the plant unsuitable for Hpa infection). Interestingly, this effect was specific for Hpa susceptibility, since pretreatment of plants with Thr did not affect sporulation of another obligate biotroph, the powdery mildew ascomycete Golovinomyces orontii (Go). The authors addressed the question of how overaccumulation of Thr might affect Hpa but not Go. Excess Thr is known to be toxic to Arabidopsis, and, indeed, the mutants described in this study were smaller than wild-type plants. An assessment of genes and biochemical pathway components present in the different phyla provided support for the notion that oomycetes and plants might use similar pathways of amino acid biosynthesis and metabolism in a distinct manner from the more distantly related ascomycete. Thus, the toxic effect of high Thr accumulation might be shared among plants and oomycetes, but not by the fungal ascomycete Go. These data provide solid examples of how plant host metabolic state can influence growth and pathogenicity of adapted biotrophic pathogens.

Perturbation of Arabidopsis Amino Acid Metabolism Causes Incompatibility with the Adapted Biotrophic Pathogen Hyaloperonospora arabidopsidis

Reliance of biotrophic pathogens on living plant tissues to propagate implies strong interdependence between host metabolism and nutrient uptake by the pathogen. However, factors determining host suitability and establishment of infection are largely unknown. We describe a loss-of-inhibition allele of ASPARTATE KINASE2 and a loss-of-function allele of DIHYDRODIPICOLINATE SYNTHASE2 identified in a screen for Arabidopsis thaliana mutants with increased resistance to the obligate biotrophic oomycete Hyaloperonospora arabidopsidis (Hpa). Through different molecular mechanisms, these mutations perturb amino acid homeostasis leading to overaccumulation of the Asp-derived amino acids Met, Thr, and Ile. Although detrimental for the plant, the mutations do not cause defense activation, and both mutants retain full susceptibility to the adapted obligate biotrophic fungus Golovinomyces orontii (Go). Chemical treatments mimicking the mutants' metabolic state identified Thr as the amino acid suppressing Hpa but not Go colonization. We conclude that perturbations in amino acid homeostasis render the mutant plants unsuitable as an infection substrate for Hpa. This may be explained by deployment of the same amino acid biosynthetic pathways by oomycetes and plants. Our data show that the plant host metabolic state can, in specific ways, influence the ability of adapted biotrophic strains to cause disease.

Colorectal cancer: molecules and populations.

The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.