Xin Zhou

All Publications

• Nonlinear dynamics of multi-omics profiles during human aging. Nature aging Shen, X., Wang, C., Zhou, X., Zhou, W., Hornburg, D., Wu, S., Snyder, M. P. 2024

  Abstract

  Aging is a complex process associated with nearly all diseases. Understanding the molecular changes underlying aging and identifying therapeutic targets for aging-related diseases are crucial for increasing healthspan. Although many studies have explored linear changes during aging, the prevalence of aging-related diseases and mortality risk accelerates after specific time points, indicating the importance of studying nonlinear molecular changes. In this study, we performed comprehensive multi-omics profiling on a longitudinal human cohort of 108 participants, aged between 25 years and 75 years. The participants resided in California, United States, and were tracked for a median period of 1.7 years, with a maximum follow-up duration of 6.8 years. The analysis revealed consistent nonlinear patterns in molecular markers of aging, with substantial dysregulation occurring at two major periods occurring at approximately 44 years and 60 years of chronological age. Distinct molecules and functional pathways associated with these periods were also identified, such as immune regulation and carbohydrate metabolism that shifted during the 60-year transition and cardiovascular disease, lipid and alcohol metabolism changes at the 40-year transition. Overall, this research demonstrates that functions and risks of aging-related diseases change nonlinearly across the human lifespan and provides insights into the molecular and biological pathways involved in these changes.

  View details for DOI 10.1038/s43587-024-00692-2

  View details for PubMedID 39143318

  View details for PubMedCentralID 3341616

• Dynamic Human Gut Microbiome and Immune Shifts During an Immersive Psychosocial Therapeutic Program. bioRxiv : the preprint server for biology Zhou, X., Ganz, A. B., Rayner, A., Cheng, T. Y., Oba, H., Rolnik, B., Lancaster, S., Lu, X., Li, Y., Johnson, J. S., Hoyd, R., Spakowicz, D. J., Slavich, G. M., Snyder, M. P. 2024

  Abstract

  Background: Depression is a leading cause of disability worldwide yet its underlying factors, particularly microbial associations, are poorly understood.Methods: We examined the longitudinal interplay between the microbiome and immune system in the context of depression during an immersive psychosocial intervention. 142 multi-omics samples were collected from 52 well-characterized participants before, during, and three months after a nine-day inquiry-based stress reduction program.Results: We found that depression was associated with both an increased presence of putatively pathogenic bacteria and reduced microbial beta-diversity. Following the intervention, we observed reductions in neuroinflammatory cytokines and improvements in several mental health indicators. Interestingly, participants with a Prevotella -dominant microbiome showed milder symptoms when depressed, along with a more resilient microbiome and more favorable inflammatory cytokine profile, including reduced levels of CXCL-1.Conclusions: Our findings reveal a protective link between the Prevotella-dominant microbiome and depression, associated with a less inflammatory environment and moderated symptoms. These insights, coupled with observed improvements in neuroinflammatory markers and mental health from the intervention, highlight potential avenues for microbiome-targeted therapies in depression management.

  View details for DOI 10.1101/2024.06.26.600881

  View details for PubMedID 38979211

• Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease. Cell host & microbe Zhou, X., Shen, X., Johnson, J. S., Spakowicz, D. J., Agnello, M., Zhou, W., Avina, M., Honkala, A., Chleilat, F., Chen, S. J., Cha, K., Leopold, S., Zhu, C., Chen, L., Lyu, L., Hornburg, D., Wu, S., Zhang, X., Jiang, C., Jiang, L., Jiang, L., Jian, R., Brooks, A. W., Wang, M., Contrepois, K., Gao, P., Rose, S. M., Tran, T. D., Nguyen, H., Celli, A., Hong, B. Y., Bautista, E. J., Dorsett, Y., Kavathas, P. B., Zhou, Y., Sodergren, E., Weinstock, G. M., Snyder, M. P. 2024

  Abstract

  To understand the dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune, and clinical markers of microbiomes from four body sites in 86 participants over 6 years. We found that microbiome stability and individuality are body-site specific and heavily influenced by the host. The stool and oral microbiome are more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. We identify individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlate across body sites, suggesting systemic dynamics influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals show altered microbial stability and associations among microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease.

  View details for DOI 10.1016/j.chom.2024.02.012

  View details for PubMedID 38479397

• Dynamic lipidome alterations associated with human health, disease and ageing. Nature metabolism Hornburg, D., Wu, S., Moqri, M., Zhou, X., Contrepois, K., Bararpour, N., Traber, G. M., Su, B., Metwally, A. A., Avina, M., Zhou, W., Ubellacker, J. M., Mishra, T., Schüssler-Fiorenza Rose, S. M., Kavathas, P. B., Williams, K. J., Snyder, M. P. 2023

  Abstract

  Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report >800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed >1,500 plasma samples from 112 participants followed for up to 9 years (average 3.2 years) to define the distinct physiological roles of complex lipid subclasses, including large and small triacylglycerols, ester- and ether-linked phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, cholesterol esters and ceramides. Our findings reveal dynamic changes in the plasma lipidome during respiratory viral infection, insulin resistance and ageing, suggesting that lipids may have roles in immune homoeostasis and inflammation regulation. Individuals with insulin resistance exhibit disturbed immune homoeostasis, altered associations between lipids and clinical markers, and accelerated changes in specific lipid subclasses during ageing. Our dataset based on longitudinal deep lipidome profiling offers insights into personalized ageing, metabolic health and inflammation, potentially guiding future monitoring and intervention strategies.

  View details for DOI 10.1038/s42255-023-00880-1

  View details for PubMedID 37697054

  View details for PubMedCentralID 7736650

• Single-cell sequencing of PBMC characterizes a distinct inflammatory monocyte subset in Lyme disease patients with Post-Treatment Lyme Disease Syndrome (PTLD) Chen, X., Zhou, X., Ji, X., Miranda, M., Rebman, A., Kathuria, K., Robinson, W. H., Aucott, J., Davis, M. M. AMER ASSOC IMMUNOLOGISTS. 2023

  View details for DOI 10.4049/jimmunol.210.Supp.155.18

  View details for Web of Science ID 001106506501370

• Association between the dynamics of the gut microbiota and responsiveness to mental health therapy Zhou, X., Ganz, A. B., Lu, X., Li, Y., Snyder, M. AMER ASSOC IMMUNOLOGISTS. 2023

  View details for Web of Science ID 001106506503167

• Simultaneous profiling of host expression and microbial abundance by spatial metatranscriptome sequencing GENOME RESEARCH Lyu, L., Li, X., Feng, R., Zhou, X., Guha, T. K., Yu, X., Chen, G., Yao, Y., Su, B., Zou, D., Snyder, M. P., Chen, L. 2023; 33 (3): 401-411

  View details for DOI 10.1101/gr.277178.122

  View details for Web of Science ID 000963913000007

• Gut microbiota analyses of Saudi populations for type 2 diabetes-related phenotypes reveals significant association. BMC microbiology Al-Muhanna, F. A., Dowdell, A. K., Al Eleq, A. H., Albaker, W. I., Brooks, A. W., Al-Sultan, A. I., Al-Rubaish, A. M., Alkharsah, K. R., Sulaiman, R. M., Al-Quorain, A. A., Cyrus, C., Alali, R. A., Vatte, C., Robinson, F. L., Zhou, X., Snyder, M. P., Almuhanna, A. F., Keating, B. J., Piening, B. D., Al-Ali, A. K. 2022; 22 (1): 301

  Abstract

  Large-scale gut microbiome sequencing has revealed key links between microbiome dysfunction and metabolic diseases such as type 2 diabetes (T2D). To date, these efforts have largely focused on Western populations, with few studies assessing T2D microbiota associations in Middle Eastern communities where T2D prevalence is now over 20%. We analyzed the composition of stool 16S rRNA from 461 T2D and 119 non-T2D participants from the Eastern Province of Saudi Arabia. We quantified the abundance of microbial communities to examine any significant differences between subpopulations of samples based on diabetes status and glucose level.In this study we performed the largest microbiome study ever conducted in Saudi Arabia, as well as the first-ever characterization of gut microbiota T2D versus non-T2D in this population. We observed overall positive enrichment within diabetics compared to healthy individuals and amongst diabetic participants; those with high glucose levels exhibited slightly more positive enrichment compared to those at lower risk of fasting hyperglycemia. In particular, the genus Firmicutes was upregulated in diabetic individuals compared to non-diabetic individuals, and T2D was associated with an elevated Firmicutes/Bacteroidetes ratio, consistent with previous findings.Based on diabetes status and glucose levels of Saudi participants, relatively stable differences in stool composition were perceived by differential abundance and alpha diversity measures. However, community level differences are evident in the Saudi population between T2D and non-T2D individuals, and diversity patterns appear to vary from well-characterized microbiota from Western cohorts. Comparing overlapping and varying patterns in gut microbiota with other studies is critical to assessing novel treatment options in light of a rapidly growing T2D health epidemic in the region. As a rapidly emerging chronic condition in Saudi Arabia and the Middle East, T2D burdens have grown more quickly and affect larger proportions of the population than any other global region, making a regional reference T2D-microbiome dataset critical to understanding the nuances of disease development on a global scale.

  View details for DOI 10.1186/s12866-022-02714-8

  View details for PubMedID 36510121

• KMT2D-NOTCH Mediates Coronary Abnormalities in Hypoplastic Left Heart Syndrome. Circulation research Yu, Z., Zhou, X., Liu, Z., Pastrana-Gomez, V., Liu, Y., Guo, M., Tian, L., Nelson, T. J., Wang, N., Mital, S., Chitayat, D., Wu, J. C., Rabinovitch, M., Wu, S. M., Snyder, M. P., Miao, Y., Gu, M. 2022: 101161CIRCRESAHA122320783

  View details for DOI 10.1161/CIRCRESAHA.122.320783

  View details for PubMedID 35762338

• Precision environmental health monitoring by longitudinal exposome and multi-omics profiling. Genome research Gao, P., Shen, X., Zhang, X., Jiang, C., Zhang, S., Zhou, X., Schüssler-Fiorenza Rose, S. M., Snyder, M. 2022

  Abstract

  Conventional environmental health studies have primarily focused on limited environmental stressors at the population level, which lacks the power to dissect the complexity and heterogeneity of individualized environmental exposures. Here, as a pilot case study, we integrated deep-profiled longitudinal personal exposome and internal multi-omics to systematically investigate how the exposome shapes a single individual's phenome. We annotated thousands of chemical and biological components in the personal exposome cloud and found they were significantly correlated with thousands of internal biomolecules, which was further cross-validated using corresponding clinical data. Our results showed that agrochemicals and fungi predominated in the highly diverse and dynamic personal exposome, and the biomolecules and pathways related to the individual's immune system, kidney, and liver were highly associated with the personal external exposome. Overall, this data-driven longitudinal monitoring study shows the potential dynamic interactions between the personal exposome and internal multi-omics, as well as the impact of the exposome on precision health by producing abundant testable hypotheses.

  View details for DOI 10.1101/gr.276521.121

  View details for PubMedID 35667843

• Exploring disease interrelationships in patients with lymphatic disorders: A single center retrospective experience. Clinical and translational medicine Rockson, S. G., Zhou, X., Zhao, L., Hosseini, D. K., Jiang, X., Sweatt, A. J., Kim, D., Tian, W., Snyder, M. P., Nicolls, M. R. 2022; 12 (4): e760

  Abstract

  The lymphatic contribution to the circulation is of paramount importance in regulating fluid homeostasis, immune cell trafficking/activation and lipid metabolism. In comparison to the blood vasculature, the impact of the lymphatics has been underappreciated, both in health and disease, likely due to a less well-delineated anatomy and function. Emerging data suggest that lymphatic dysfunction can be pivotal in the initiation and development of a variety of diseases across broad organ systems. Understanding the clinical associations between lymphatic dysfunction and non-lymphatic morbidity provides valuable evidence for future investigations and may foster the discovery of novel biomarkers and therapies.We retrospectively analysed the electronic medical records of 724 patients referred to the Stanford Center for Lymphatic and Venous Disorders. Patients with an established lymphatic diagnosis were assigned to groups of secondary lymphoedema, lipoedema or primary lymphovascular disease. Individuals found to have no lymphatic disorder were served as the non-lymphatic controls. The prevalence of comorbid conditions was enumerated. Pairwise co-occurrence pattern analyses, validated by Jaccard similarity tests, was utilised to investigate disease-disease interrelationships.Comorbidity analyses underscored the expected relationship between the presence of secondary lymphoedema and those diseases that damage the lymphatics. Cardiovascular conditions were common in all lymphatic subgroups. Additionally, statistically significant alteration of disease-disease interrelationships was noted in all three lymphatic categories when compared to the control population.The presence or absence of a lymphatic disease significantly influences disease interrelationships in the study cohorts. As a physiologic substrate, the lymphatic circulation may be an underappreciated participant in disease pathogenesis. These relationships warrant further, prospective scrutiny and study.

  View details for DOI 10.1002/ctm2.760

  View details for PubMedID 35452183

• Exploratory studies of oral and fecal microbiome in healthy human aging. Frontiers in aging Zhou, X., Wang, B., Demkowicz, P. C., Johnson, J. S., Chen, Y., Spakowicz, D. J., Zhou, Y., Dorsett, Y., Chen, L., Sodergren, E., Kuchel, G. A., Weinstock, G. M. 2022; 3: 1002405

  Abstract

  Growing evidence has linked an altered host fecal microbiome composition with health status, common chronic diseases, and institutionalization in vulnerable older adults. However, fewer studies have described microbiome changes in healthy older adults without major confounding diseases or conditions, and the impact of aging on the microbiome across different body sites remains unknown. Using 16S ribosomal RNA gene sequencing, we reconstructed the composition of oral and fecal microbiomes in young (23-32; mean = 25years old) and older (69-94; mean = 77years old) healthy community-dwelling research subjects. In both body sites, we identified changes in minor bacterial operational taxonomic units (OTUs) between young and older subjects. However, the composition of the predominant bacterial species of the healthy older group in both microbiomes was not significantly different from that of the young cohort, which suggests that dominant bacterial species are relatively stable with healthy aging. In addition, the relative abundance of potentially pathogenic genera, such as Rothia and Mycoplasma, was enriched in the oral microbiome of the healthy older group relative to the young cohort. We also identified several OTUs with a prevalence above 40% and some were more common in young and others in healthy older adults. Differences with aging varied for oral and fecal samples, which suggests that members of the microbiome may be differentially affected by aging in a tissue-specific fashion. This is the first study to investigate both oral and fecal microbiomes in the context of human aging, and provides new insights into interactions between aging and the microbiome within two different clinically relevant sites.

  View details for DOI 10.3389/fragi.2022.1002405

  View details for PubMedID 36338834

• The Impact of SARS-CoV-2 on the Human Immune System and Microbiome INFECTIOUS MICROBES & DISEASES Wang, C., Zhou, X., Wang, M., Chen, X. 2021; 3 (1): 14-21

  View details for DOI 10.1097/IM9.0000000000000045

  View details for Web of Science ID 000730626200004

• The Impact of SARS-CoV-2 on the Human Immune System and Microbiome. Infectious microbes & diseases Wang, C., Zhou, X., Wang, M., Chen, X. 2021; 3 (1): 14-21

  Abstract

  A recent outbreak of coronavirus disease 2019 (COVID-19) caused by the single-stranded enveloped RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into a global pandemic, after it was first reported in Wuhan in December 2019. SARS-CoV-2 is an emerging virus, and little is known about the basic characteristics of this pathogen, the underlying mechanism of infection, and the potential treatments. The immune system has been known to be actively involved in viral infections. To facilitate the development of COVID-19 treatments, the understanding of immune regulation by this viral infection is urgently needed. This review describes the mechanisms of immune system involvement in viral infections and provides an overview of the dysregulation of immune responses in COVID-19 patients in recent studies. Furthermore, we emphasize the role of gut microbiota in regulating immunity and summarized the impact of SARS-CoV-2 infection on the composition of the microbiome. Overall, this review provides insights for understanding and developing preventive and therapeutic strategies by regulating the immune system and microbiota.

  View details for DOI 10.1097/IM9.0000000000000045

  View details for PubMedID 38630064

  View details for PubMedCentralID PMC8011344

• Single-Cell Transcriptomic Analysis and Patient-Specific IPSCs Reveal Dysregulated Cell Cycle in Coronary Endothelial Cell in Hypoplastic Left Heart Syndrome Gu, M., Miao, Y., Zhou, X., Tian, L., Martin, M., Nelson, T. J. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for DOI 10.1161/res.127.suppl_1.238

  View details for Web of Science ID 000606541500031

• Longitudinal Analysis of Serum Cytokine Levels and Gut Microbial Abundance Links IL-17/IL-22 with Clostridia and Insulin Sensitivity in Humans. Diabetes Zhou, X. n., Johnson, J. S., Spakowicz, D. n., Zhou, W. n., Zhou, Y. n., Sodergren, E. n., Snyder, M. n., Weinstock, G. M. 2020

  Abstract

  Recent studies using mouse models suggest that interaction between the gut microbiome and IL-17/IL-22 producing cells plays a role in the development of metabolic diseases. We investigated this relationship in humans using data from the prediabetes study of the Integrated Human Microbiome Project (iHMP). Specifically, we addressed the hypothesis that early in the onset of metabolic diseases there is a decline in serum levels of IL-17/IL-22, with concomitant changes in the gut microbiome. Clustering iHMP study participants on the basis of longitudinal IL-17/IL-22 profiles identified discrete groups. Individuals distinguished by low levels of IL-17/IL-22 were linked to established markers of metabolic disease, including insulin sensitivity. These individuals also displayed gut microbiome dysbiosis, characterized by decreased diversity, and IL-17/IL-22-related declines in the phylum Firmicutes, class Clostridia, and order Clostridiales. This ancillary analysis of the iHMP data therefore supports a link between the gut microbiome, IL-17/IL-22 and the onset of metabolic diseases. This raises the possibility for novel, microbiome-related therapeutic targets that may effectively alleviate metabolic diseases in humans as they do in animal models.

  View details for DOI 10.2337/db19-0592

  View details for PubMedID 32366680

• New statistical method identifies cytokines that distinguish stool microbiomes. Scientific reports Yang, D., Johnson, J., Zhou, X., Deych, E., Shands, B., Hanson, B., Sodergren, E., Weinstock, G., Shannon, W. D. 2019; 9 (1): 20082

  Abstract

  Regressing an outcome or dependent variable onto a set of input or independent variables allows the analyst to measure associations between the two so that changes in the outcome can be described by and predicted by changes in the inputs. While there are many ways of doing this in classical statistics, where the dependent variable has certain properties (e.g., a scalar, survival time, count), little progress on regression where the dependent variable are microbiome taxa counts has been made that do not impose extremely strict conditions on the data. In this paper, we propose and apply a new regression model combining the Dirichlet-multinomial distribution with recursive partitioning providing a fully non-parametric regression model. This model, called DM-RPart, is applied to cytokine data and microbiome taxa count data and is applicable to any microbiome taxa count/metadata, is automatically fit, and intuitively interpretable. This is a model which can be applied to any microbiome or other compositional data and software (R package HMP) available through the R CRAN website.

  View details for DOI 10.1038/s41598-019-56397-9

  View details for PubMedID 31882682

  View details for PubMedCentralID PMC6934614

• Estradiol Alters Hippocampal Gene Expression during the Estrous Cycle. Endocrine research Iqbal, J., Tan, Z. N., Li, M. X., Chen, H. B., Ma, B., Zhou, X., Ma, X. M. 2019: 1-18

  Abstract

  Estrogen (E2) modulates a wide range of neural functions such as spine formation, synaptic plasticity, and neurotransmission in the hippocampus. Dendritic spines and synapse numbers in hippocampal neurons of female rats cyclically fluctuate across the estrous cycle, but the key genes responsible for these fluctuations are still unknown. In order to address this question, we explore the hippocampal transcriptome via RNA-sequencing (RNA-seq) at the proestrus (PE) and estrus (ES) stages in female rats. At standard fold-change selection criteria, 37 differentially expressed genes (DEGs) were found in PE vs. ES groups (FDR adjusted p-value (q)<0.05). The transcriptional changes identified by RNA-seq were confirmed by quantitative real-time PCR. To gain insight into the function of the DEGs, the E2-regulated genes were annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes database (KEGG). Based on GO and KEGG pathways, the identified DEGs of PE vs. ES stages are involved in extracellular matrix formation, regulation of actin cytoskeleton, oxidative stress, neuroprotection, immune system, oligodendrocyte maturation and myelination, signal transduction pathways, growth factor signaling, retinoid signaling, aging, cellular process, metabolism and transport. The profiles of the gene expression in the hippocampus identified at the PE vs. ES stages were compared with the gene expression profiles in ovariectomized (OVX) rats receiving E2 replacement via RNA-seq and qPCR. The profiles of gene expression between the OVX+E2 and the estrous cycle were different and the possible causes were discussed.

  View details for DOI 10.1080/07435800.2019.1674868

  View details for PubMedID 31608702

• Composition and predictive functional analysis of bacterial communities inhabiting Chinese Cordyceps insight into conserved core microbiome BMC MICROBIOLOGY Xia, F., Zhou, X., Liu, Y., Li, Y., Bai, X., Zhou, X. 2019; 19: 105

  Abstract

  Over the past few decades, most attention to Chinese Cordyceps-associated endogenous microorganism was focused on the fungal community that creates critical bioactive components. Bacterial community associated with Chinese Cordyceps has been previously described; however, most studies were only presenting direct comparisons in the Chinese Cordyceps and its microenvironments. In the current study, our objectives were to reveal the bacterial community structure composition and predict their function.We collected samples of Chinese Cordyceps from five sites located in the Qinghai-Tibet Plateau and used a high throughput sequencing method to compare Chinese Cordyceps-associated bacterial community composition and diversity quantitatively across sites. The results indicated that for the Chinese Cordyceps-associated bacterial community there is no single core microbiome, which was dominated by the both Proteobacteria and Actinobacteria. Predictive functional profiling suggested a location specific function pattern for Chinese Cordyceps and bacteria in the external mycelial cortices involved in the biosynthesis of active constituents.This study is firstly used high throughput sequencing method to compare the bacterial communities inhabiting Chinese Cordyceps and its microhabitat and to reveal composition functional capabilities of the bacteria, which will accelerate the study of the functions of bacterial communities in the micro-ecological system of Chinese Cordyceps.

  View details for DOI 10.1186/s12866-019-1472-0

  View details for Web of Science ID 000468899100003

  View details for PubMedID 31122191

  View details for PubMedCentralID PMC6533680

• Longitudinal multi-omics of host-microbe dynamics in prediabetes. Nature Zhou, W., Sailani, M. R., Contrepois, K., Zhou, Y., Ahadi, S., Leopold, S. R., Zhang, M. J., Rao, V., Avina, M., Mishra, T., Johnson, J., Lee-McMullen, B., Chen, S., Metwally, A. A., Tran, T. D., Nguyen, H., Zhou, X., Albright, B., Hong, B., Petersen, L., Bautista, E., Hanson, B., Chen, L., Spakowicz, D., Bahmani, A., Salins, D., Leopold, B., Ashland, M., Dagan-Rosenfeld, O., Rego, S., Limcaoco, P., Colbert, E., Allister, C., Perelman, D., Craig, C., Wei, E., Chaib, H., Hornburg, D., Dunn, J., Liang, L., Rose, S. M., Kukurba, K., Piening, B., Rost, H., Tse, D., McLaughlin, T., Sodergren, E., Weinstock, G. M., Snyder, M. 2019; 569 (7758): 663–71

  Abstract

  Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2Dbetter, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host-microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.

  View details for DOI 10.1038/s41586-019-1236-x

  View details for PubMedID 31142858

• Impact of Age, Caloric Restriction, and Influenza Infection on Mouse Gut Microbiome: An Exploratory Study of the Role of Age-Related Microbiome Changes on Influenza Responses FRONTIERS IN IMMUNOLOGY Bartley, J. M., Zhou, X., Kuchel, G. A., Weinstock, G. M., Haynes, L. 2017; 8: 1164

  Abstract

  Immunosenescence refers to age-related declines in the capacity to respond to infections such as influenza (flu). Caloric restriction represents a known strategy to slow many aging processes, including those involving the immune system. More recently, some changes in the microbiome have been described with aging, while the gut microbiome appears to influence responses to flu vaccination and infection. With these considerations in mind, we used a well-established mouse model of flu infection to explore the impact of flu infection, aging, and caloric restriction on the gut microbiome. Young, middle-aged, and aged caloric restricted (CR) and ad lib fed (AL) mice were examined after a sublethal flu infection. All mice lost 10-20% body weight and, as expected for these early time points, losses were similar at different ages and between diet groups. Cytokine and chemokine levels were also similar with the notable exception of IL-1α, which rose more than fivefold in aged AL mouse serum, while it remained unchanged in aged CR serum. Fecal microbiome phyla abundance profiles were similar in young, middle-aged, and aged AL mice at baseline and at 4 days post flu infection, while increases in Proteobacteria were evident at 7 days post flu infection in all three age groups. CR mice, compared to AL mice in each age group, had increased abundance of Proteobacteria and Verrucomicrobia at all time points. Interestingly, principal coordinate analysis determined that diet exerts a greater effect on the microbiome than age or flu infection. Percentage body weight loss correlated with the relative abundance of Proteobacteria regardless of age, suggesting flu pathogenicity is related to Proteobacteria abundance. Further, several microbial Operational Taxonomic Units from the Bacteroidetes phyla correlated with serum chemokine/cytokines regardless of both diet and age suggesting an interplay between flu-induced systemic inflammation and gut microbiota. These exploratory studies highlight the impact of caloric restriction on fecal microbiome in both young and aged animals, as well as the many complex relationships between flu responses and gut microbiota. Thus, these preliminary studies provide the necessary groundwork to examine how gut microbiota alterations may be leveraged to influence declining immune responses with aging.

  View details for DOI 10.3389/fimmu.2017.01164

  View details for Web of Science ID 000411178700001

  View details for PubMedID 28979265

  View details for PubMedCentralID PMC5611400

• SIMILAR BACTERIAL SIGNATURES IN INTESTINAL TISSUES, MILK, AND DENDRITIC CELLS OF LACTATING MICE SUGGEST A POSSIBLE ENTERO-MAMMARY PATHWAY Zhou, X., Voigt, A., Paveglio, S., Weinstock, G., Matson, A., Davidovics, Z. W B SAUNDERS CO-ELSEVIER INC. 2017: S172

  View details for DOI 10.1016/S0016-5085(17)30893-4

  View details for Web of Science ID 000403140300511

• Tropism of CPMV to Professional Antigen Presenting Cells Enables a Platform to Eliminate Chronic Infections ACS BIOMATERIALS SCIENCE & ENGINEERING Wen, A. M., Le, N., Zhou, X., Steinmetz, N. F., Poplcin, D. L. 2015; 1 (11): 1050–54

  Abstract

  Chronic viral infections (e.g., HIV, HBV, HCV) represent a significant source of morbidity and mortality with over 500 million people infected worldwide. Dendritic cells (DCs) and macrophages are key cell types for productive viral replication and persistent systemic infection. We demonstrate that the plant virus cowpea mosaic virus (CPMV) displays tropism for such antigen presenting cells in both mice and humans, thus making it an ideal candidate for targeted drug delivery toward viral infections. Furthermore, we show inhibition of a key host protein for viral infection, site-1 protease (S1P), using the small molecule PF-429242 in the model pathogen arenavirus lymphocytic choriomeningitis virus (LCMV) limits viral growth. By packaging PF-429242 in CPMV, we are able to control drug release and efficiently deliver the drug. This sets the groundwork for utilizing the natural tropism of CPMV for a therapeutic approach that specifically targets cell types most commonly subverted by chronic viruses.

  View details for DOI 10.1021/acsbiomaterials.5b00344

  View details for Web of Science ID 000369348500001

  View details for PubMedID 27280157

  View details for PubMedCentralID PMC4894745

• Langerhans Cell Hyperplasia From Molluscum Contagiosum. The American Journal of dermatopathology Hatter, A. D., Zhou, X., Honda, K., Popkin, D. L. 2015; 37 (8): e93-5

  Abstract

  Langerhans cell histiocytosis (LCH) carries a prognosis, which ranges from benign to potentially fatal. There is currently little framework to decipher metrics, which predict the benign versus aggressive nature of LCH. We wanted to determine whether molluscum contagiosum virus (MCV) DNA could be isolated from a cutaneous lesion, demonstrating Langerhans cell hyperplasia resembling LCH in a patient with both. Polymerase chain reaction on biopsy-proven MCV and the hyperplastic lesion has been performed. Two specific regions within the MCV genome were detected from both biopsies. The authors report our findings and suggest that some MCV can produce histological lesions resembling LCH, similar to the literature on scabies mimicking LCH. Efforts to find a reactive "driver" in LCH may significantly inform the clinical scenario.

  View details for DOI 10.1097/DAD.0000000000000201

  View details for PubMedID 25140667

  View details for PubMedCentralID PMC4334759

• JcLEA, a Novel LEA-Like Protein from Jatropha curcas, Confers a High Level of Tolerance to Dehydration and Salinity in Arabidopsis thaliana PLOS ONE Liang, J., Zhou, M., Zhou, X., Jin, Y., Xu, M., Lin, J. 2013; 8 (12): e83056

  Abstract

  Jatropha curcas L. is a highly drought and salt tolerant plant species that is typically used as a traditional folk medicine and biofuel crop in many countries. Understanding the molecular mechanisms that underlie the response to various abiotic environmental stimuli, especially to drought and salt stresses, in J. curcas could be important to crop improvement efforts. In this study, we cloned and characterized the gene for a late embryogenesis abundant (LEA) protein from J. curcas that we designated JcLEA. Sequence analyses showed that the JcLEA protein belongs to group 5, a subgroup of the LEA protein family. In young seedlings, expression of JcLEA is significantly induced by abscisic acid (ABA), dehydration, and salt stress. Subcellular localization analysis shows that that JcLEA protein is distributed in both the nucleus and cytoplasm. Moreover, based on growth status and physiological indices, the overexpression of JcLEA in transgenic Arabidopsis plants conferred increased resistance to both drought and salt stresses compared to the WT. Our data suggests that the group 5 JcLEA protein contributes to drought and salt stress tolerance in plants. Thus, JcLEA is a potential candidate gene for plant genetic modification.

  View details for DOI 10.1371/journal.pone.0083056

  View details for Web of Science ID 000329325200034

  View details for PubMedID 24391737

  View details for PubMedCentralID PMC3877014

• Role of Lymphocytic Choriomeningitis Virus (LCMV) in Understanding Viral Immunology: Past, Present and Future VIRUSES-BASEL Zhou, X., Ramachandran, S., Mann, M., Popkin, D. L. 2012; 4 (11): 2650–69

  Abstract

  Lymphocytic choriomeningitis virus (LCMV) is a common infection of rodents first identified over eighty years ago in St. Louis, MO, U.S.A. It is best known for its application in immunological studies. The history of LCMV closely correlates with the development of modern immunology. With the use of LCMV as a model pathogen several key concepts have emerged: Major Histocompatibility Complex (MHC) restriction, T cell memory, persistent infections, T cell exhaustion and the key role of immune pathology in disease. Given the phenomenal infrastructure within this field (e.g., defined immunodominant and subdominant epitopes to all T cell receptor specificities as well as the cognate tetramers for enumeration in vivo) the study of LCMV remains an active and productive platform for biological research across the globe to this day. Here we present a historical primer that highlights several breakthroughs since the discovery of LCMV. Next, we highlight current research in the field and conclude with our predictions for future directions in the remarkable field of LCMV research.

  View details for DOI 10.3390/v4112650

  View details for Web of Science ID 000311429900011

  View details for PubMedID 23202498

  View details for PubMedCentralID PMC3509666

• Molecular cloning and functional analysis of the gene encoding geranylgeranyl diphosphate synthase from Jatropha curcas AFRICAN JOURNAL OF BIOTECHNOLOGY Lin, J., Jin, Y., Zhou, X., Wang, J. 2010; 9 (23): 3342–51

  View details for Web of Science ID 000278589300002

• PURIFICATION AND CHARACTERIZATION OF CURCIN, A TOXIC LECTIN FROM THE SEED OF JATROPHA CURCAS PREPARATIVE BIOCHEMISTRY & BIOTECHNOLOGY Lin, J., Zhou, X., Wang, J., Jiang, P., Tang, K. 2010; 40 (2): 107–18

  Abstract

  The seed of the plant Jatropha curcas contains a toxic protein, designated as curcin, which was purified to apparent homogeneity by the combined use of chromatography on Sephdex G-100. The molecular weight of 28.2 kDa and the pI of 8.54 were determined. The protein was found to be a glycoprotein; the total neutral-surge content was 4.91%. It strongly inhibits the protein synthesis of rabbit reticulocyte lysate, with an IC(50) of 0.42 nM. It was determined by Edman that the sequence of the N-terminal thirty-two amino acids was: A-G/Y-S/K-T/A-P/D-T-L-T-I-T-Y-D-A-T/A-A-D-K-K-N-Y-A-Q-F-I-K-D-L-R-E-A-F/A-G. The isolated curcin had a hemagglutinating activity, when its concentration was more than 7.8 mg/L. The secondary structure of curcin was analyzed by Circular Dichroism (CD) spectrum. The result shows the curcin contains alpha-helix (22.3%), beta-sheet (43.5%), and random coil and corner (34.2%). The results of acute toxicity in mice show that mice oral semi-lethal dose LD(50) was 104.737 +/- 29.447 mg/kg; mice parenteral semi-lethal dose LD(50) was 67.20 +/- 10.445 mg/kg.

  View details for DOI 10.1080/10826060903558588

  View details for Web of Science ID 000275274900002

  View details for PubMedID 20213572

• Hepatoma Cell Growth Inhibition by Inducing Apoptosis with Polysaccharide Isolated from Turkey Tail Medicinal Mushroom, Trametes versicolor (L.: Fr.) Lloyd (Aphyllophoromycetideae) INTERNATIONAL JOURNAL OF MEDICINAL MUSHROOMS Cai, X., Pi, Y., Zhou, X., Tian, L., Qiao, S., Lin, J. 2010; 12 (3): 257–63

  View details for DOI 10.1615/IntJMedMushr.v12.i3.40

  View details for Web of Science ID 000283889200004

• Molecular cloning, characterization and functional analysis of a 3-hydroxy-3-methylglutaryl coenzyme A reductase gene from Jatropha curcas AFRICAN JOURNAL OF BIOTECHNOLOGY Lin, J., Jin, Y., Zhou, M., Zhou, X., Wang, J. 2009; 8 (15): 3455–62

  View details for Web of Science ID 000270306200010

• AFLP analysis of genetic diversity in main cultivated strains of Ganoderma spp. AFRICAN JOURNAL OF BIOTECHNOLOGY Wu, S., Guo, X., Zhou, X., Li, X., Chen, Y., Lin, J. 2009; 8 (15): 3448–54

  View details for Web of Science ID 000270306200009