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1.  Biogeography of the Intestinal Mucosal and Lumenal Microbiome in the Rhesus Macaque 
Cell host & microbe  2015;17(3):385-391.
Summary
The gut microbiome is widely studied by fecal sampling, but the extent to which stool reflects the commensal composition at intestinal sites is poorly understood. We investigated this relationship in rhesus macaques by 16S sequencing feces and paired lumenal and mucosal samples from 10 sites distal to the jejunum. Stool composition correlated highly with the colonic lumen and mucosa, and moderately with the distal small intestine. The mucosal microbiota varied most based on location and was enriched in oxygen-tolerant taxa (e.g. Helicobacter, Treponema), while the lumenal microbiota showed inter-individual variation and obligate anaerobe enrichment (e.g. Firmicutes). This mucosal and lumenal community variability corresponded to functional differences, such as nutrient availability. Additionally, Helicobacter, Faecalibacterium, and Lactobacillus levels in stool were highly predictive of their abundance at most other gut sites. These results quantify the composition and biogeographic relationships between gut microbial communities in macaques and support fecal sampling for translational studies.
doi:10.1016/j.chom.2015.01.015
PMCID: PMC4369771  PMID: 25732063
2.  Metabolome-wide association study of phenylalanine in plasma of common marmosets 
Amino acids  2014;47(3):589-601.
Little systematic knowledge exists concerning the impacts of cumulative lifelong exposure, termed the exposome, on requirements for nutrients. Phenylalanine (Phe) is an essential dietary amino acid with an aromatic ring structure similar to endogenous metabolites, dietary compounds and environmental agents. Excess plasma Phe in genetic disease or nutritional deficiency of Phe has adverse health consequences. In principle, structurally similar chemicals interfering with Phe utilization could alter Phe requirement at an individual level. As a strategy to identify components of the exposome that could interfere with Phe utilization, we tested for metabolites correlating with Phe concentration in plasma of a non-human primate species, common marmosets (Callithrix jacchus). The results of tests for more than 5000 chemical features detected by high-resolution metabolomics showed 17 positive correlations with Phe metabolites and other amino acids. Positive and negative correlations were also observed for 33 other chemicals, which included matches to endogenous metabolites and dietary, microbial and environmental chemicals in database searches. Chemical similarity analysis showed many of the matches had high structural similarity to Phe. Together, the results show that chemicals in marmoset plasma could impact Phe utilization. Such chemicals could contribute to early lifecycle developmental disorders when neurological development is vulnerable to Phe levels.
doi:10.1007/s00726-014-1893-x
PMCID: PMC4329081  PMID: 25526869
Amino acid; Bioinformatics; Dietary exposome; Metabolomics; Phenylalanine
4.  Metabolic Characterization of the Common Marmoset (Callithrix jacchus) 
PLoS ONE  2015;10(11):e0142916.
High-resolution metabolomics has created opportunity to integrate nutrition and metabolism into genetic studies to improve understanding of the diverse radiation of primate species. At present, however, there is very little information to help guide experimental design for study of wild populations. In a previous non-targeted metabolomics study of common marmosets (Callithrix jacchus), Rhesus macaques, humans, and four non-primate mammalian species, we found that essential amino acids (AA) and other central metabolites had interspecies variation similar to intraspecies variation while non-essential AA, environmental chemicals and catabolic waste products had greater interspecies variation. The present study was designed to test whether 55 plasma metabolites, including both nutritionally essential and non-essential metabolites and catabolic products, differ in concentration in common marmosets and humans. Significant differences were present for more than half of the metabolites analyzed and included AA, vitamins and central lipid metabolites, as well as for catabolic products of AA, nucleotides, energy metabolism and heme. Three environmental chemicals were present at low nanomolar concentrations but did not differ between species. Sex and age differences in marmosets were present for AA and nucleotide metabolism and warrant additional study. Overall, the results suggest that quantitative, targeted metabolomics can provide a useful complement to non-targeted metabolomics for studies of diet and environment interactions in primate evolution.
doi:10.1371/journal.pone.0142916
PMCID: PMC4651467  PMID: 26581102
5.  Specific Pathogen-Free Status Alters Immunophenotype in Rhesus Macaques: Implications for the Study of Simian Immunodeficiency Virus 
AIDS Research and Human Retroviruses  2011;27(10):1033-1042.
Abstract
The repertoire of viruses to which research primates are exposed, even in the absence of clinical disease, may contribute to experimental confounding. In this study we examined whether standard specific pathogen-free (SPF) rhesus macaques exposed to a wider spectrum of enzootic viruses and expanded SPF macaques derived to exclude a greater number of viral agents would display alterations in immune activation or immune cell populations. Given the impact of immunophenotype on human immunodeficiency virus (HIV) progression and the importance of the simian immunodeficiency virus (SIV) model for the study of HIV pathogenesis, we elected to additionally examine the impact of SPF status on the capacity of peripheral blood mononuclear cells (PBMCs) to support SIV replication. The expanded SPF group displayed significant immune alterations including increased serum interleukin (IL)-15 and a greater in vitro elaboration of GM-CSF, IL1ra, VEGF, IL-10, IL12/23, and MIP-1b. Consistent with reduced viral antigenic exposure in expanded SPF macaques, decreased CD4+ and CD8+ transitional and effector memory (TEM) cell populations were observed. Expanded SPF PBMC cultures also demonstrated an increased peak (192.61 ng/ml p27) and area under the curve in in vitro SIV production (1968.64 ng/ml p27) when compared to standard SPF macaques (99.32 ng/ml p27; p=0.03 and 915.17 ng/ml p27; p=0.03, respectively). In vitro SIV replication did not correlate with CD4+ TEM cell counts but was highly correlated with serum IL-15 in the subset of animals examined. Findings suggest that an altered immunophenotype associated with the maintenance of primates under differing levels of bioexclusion has the potential to impact the outcome of SIV studies and models for which the measurement of immunologic endpoints is critical.
doi:10.1089/aid.2010.0155
PMCID: PMC3186704  PMID: 21391843
6.  MetabNet: An R Package for Metabolic Association Analysis of High-Resolution Metabolomics Data 
Liquid-chromatography high-resolution mass spectrometry provides capability to measure >40,000 ions derived from metabolites in biologic samples. This presents challenges to confirm identities of known chemicals and delineate potential metabolic pathway associations of unidentified chemicals. We provide an R package for metabolic network analysis, MetabNet, to perform targeted metabolome-wide association study of specific metabolites to facilitate detection of their related metabolic pathways and network structures.
doi:10.3389/fbioe.2015.00087
PMCID: PMC4464066  PMID: 26125020
metabolomics; metabolite identification; metabolic networks; metabolic pathways; targeted MWAS; choline
7.  Characterization of plasma thiol redox potential in a common marmoset model of aging☆ 
Redox Biology  2013;1(1):387-393.
Due to its short lifespan, ease of use and age-related pathologies that mirror those observed in humans, the common marmoset (Callithrix jacchus) is poised to become a standard nonhuman primate model of aging. Blood and extracellular fluid possess two major thiol-dependent redox nodes involving cysteine (Cys), cystine (CySS), glutathione (GSH) and glutathione disulfide (GSSG). Alteration in these plasma redox nodes significantly affects cellular physiology, and oxidation of the plasma Cys/CySS redox potential (EhCySS) is associated with aging and disease risk in humans. The purpose of this study was to determine age-related changes in plasma redox metabolites and corresponding redox potentials (Eh) to further validate the marmoset as a nonhuman primate model of aging. We measured plasma thiol redox states in marmosets and used existing human data with multivariate adaptive regression splines (MARS) to model the relationships between age and redox metabolites. A classification accuracy of 70.2% and an AUC of 0.703 were achieved using the MARS model built from the marmoset redox data to classify the human samples as young or old. These results show that common marmosets provide a useful model for thiol redox biology of aging.
Graphical abstract
Highlights
•Characterization of the Common Marmoset as a model for aging research.•Plasma thiol redox measurements in marmosets ranging in age from 2–16 years.•Similar to humans, marmosets exhibit age-related alterations in plasma thiol redox metabolites.•Marmoset redox data can be used to classify humans as young or old.
doi:10.1016/j.redox.2013.06.003
PMCID: PMC3757708  PMID: 24024176
Cysteine; Cystine; Glutathione; Marmoset; Plasma
8.  High-performance metabolic profiling of plasma from seven mammalian species for simultaneous environmental chemical surveillance and bioeffect monitoring 
Toxicology  2012;295(1-3):47-55.
High-performance metabolic profiling (HPMP) by Fourier-transform mass spectrometry coupled to liquid chromatography gives relative quantification of thousands of chemicals in biologic samples but has had little development for use in toxicology research. In principle, the approach could be useful to detect complex metabolic response patterns to toxicologic exposures and to detect unusual abundances or patterns of potentially toxic chemicals. As an initial study to develop these possible uses, we applied HPMP and bioinformatics analysis to plasma of humans, rhesus macaques, marmosets, pigs, sheep, rats and mice to determine: 1) whether more chemicals are detected in humans living in a less controlled environment than captive species, and 2) whether a subset of plasma chemicals with similar inter-species and intra-species variation could be identified for use in comparative toxicology. Results show that the number of chemicals detected was similar in humans (3221) and other species (range 2537 to 3373). Metabolite patterns were most similar within species and separated samples according to family and order. A total of 1485 chemicals were common to all species; 37% of these matched chemicals in human metabolomic databases and included chemicals in 137 out of 146 human metabolic pathways. Probability-based modularity clustering separated 644 chemicals, including many endogenous metabolites, with inter-species variation similar to intra-species variation. The remaining chemicals had greater inter-species variation and included environmental chemicals as well as GSH and methionine. Together, the data suggest that HPMP provides a platform that can be useful within human populations and controlled animal studies to simultaneously evaluate environmental exposures and biological responses to such exposures.
doi:10.1016/j.tox.2012.02.007
PMCID: PMC3332037  PMID: 22387982
metabolomics; plasma; mass spectrometry; probability-based modularity clustering; exposome
9.  Differential contribution of dietary fat and monosaccharide to metabolic syndrome in the common marmoset (Callithrix jacchus) 
Obesity (Silver Spring, Md.)  2010;19(6):1145-1156.
There is a critical need for animal models to study aspects type 2 diabetes mellitus pathogenesis and prevention. While the rhesus macaque is such an established model, the common marmoset has added benefits including reduced zoonotic risks, shorter life span, and a predisposition to birth twins demonstrating chimerism. The marmoset as a model organism for the study of metabolic syndrome has not been fully evaluated. Marmosets fed high-fat or glucose-enriched diets were followed longitudinally to observe effects on morphometric and metabolic measures. Effects on pancreatic histomorphometry and vascular pathology were examined terminally. The glucose–enriched diet group developed an obese phenotype and a prolonged hyperglycemic state evidenced by a rapid and persistent increase in mean glycosylated hemoglobin (HgbA1c) observed as early as week 16. In contrast, marmosets fed a high-fat diet did not maintain an obese phenotype and demonstrated a delayed increase in HgbA1c that did not reach statistical significance until week 40. Consumption of either diet resulted in profound pancreatic islet hyperplasia suggesting a compensation for increased insulin requirements. Although the high fat diet group developed atherosclerosis of increased severity, the presence of lesions correlated with glucose intolerance only in the glucose-enriched diet group. The altered timing of glucose dysregulation, differential contribution to obesity, and variation in vascular pathology suggests mechanisms of effect specific to dietary nutrient content. Feeding nutritionally modified diets to common marmosets recapitulates aspects of metabolic disease and represents a model that may prove instrumental to elucidating the contribution of nutrient excess to disease development.
doi:10.1038/oby.2010.303
PMCID: PMC3099141  PMID: 21164504
10.  Non-Human Primate Model of Kaposi's Sarcoma-Associated Herpesvirus Infection 
PLoS Pathogens  2009;5(10):e1000606.
Since Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) was first identified in Kaposi's sarcoma (KS) lesions of HIV-infected individuals with AIDS, the basic biological understanding of KSHV has progressed remarkably. However, the absence of a proper animal model for KSHV continues to impede direct in vivo studies of viral replication, persistence, and pathogenesis. In response to this need for an animal model of KSHV infection, we have explored whether common marmosets can be experimentally infected with human KSHV. Here, we report the successful zoonotic transmission of KSHV into common marmosets (Callithrix jacchus, Cj), a New World primate. Marmosets infected with recombinant KSHV rapidly seroconverted and maintained a vigorous anti-KSHV antibody response. KSHV DNA and latent nuclear antigen (LANA) were readily detected in the peripheral blood mononuclear cells (PBMCs) and various tissues of infected marmosets. Remarkably, one orally infected marmoset developed a KS-like skin lesion with the characteristic infiltration of leukocytes by spindle cells positive for KSHV DNA and proteins. These results demonstrate that human KSHV infects common marmosets, establishes an efficient persistent infection, and occasionally leads to a KS-like skin lesion. This is the first animal model to significantly elaborate the important aspects of KSHV infection in humans and will aid in the future design of vaccines against KSHV and anti-viral therapies targeting KSHV coinfected tumor cells.
Author Summary
Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8), the most recently identified human tumor-inducing virus, has been linked to Kaposi's sarcoma, pleural effusion lymphomas and multicentric Castleman's disease. In fact, KSHV accounts for a large proportion of the cancer deaths in Africa. Further, the incidence of KSHV in the US and Europe has greatly increased due to the AIDS pandemic. Despite these pressing human health problems, studies of KSHV infection are greatly hampered by the lack of cell culture and animal models. To address this serious need, we set out to develop an animal model for KSHV infection. In this manuscript, we report the successful zoonotic transmission of KSHV into common marmosets (Callithrix jacchus, Cj), a New World primate. Our study demonstrates that experimental KSHV infection of the common marmoset is highly analogous to its infection of humans, including the means of infection, sustained serological responses, latent infection of PBMCs, virus persistence, and KS-like skin lesion development, although the latter was infrequent in experimental KSHV infections. This model thus provides a unique opportunity to dissect the molecular mechanisms of KSHV infection, persistence, and pathogenesis directly in primates.
doi:10.1371/journal.ppat.1000606
PMCID: PMC2745662  PMID: 19798430

Results 1-10 (10)