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Open Access Publications from the University of California

Scholarly Works (20 results)

  • Thesis
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UC San Diego Electronic Theses and Dissertations (2019)

It would be next to impossible to list the many people who have supported and helped me get to where I am today. My trajectory from birth to graduate school has not been linear. I have always had a natural curiosity about the world around me; starting from my time growing up as an illegal immigrant in the city of Los Angeles, to my time served as rifleman in the United State Marine Corps, and my current position as a scientist. The richness of these experiences has had a profound influence on the way I approach life. Through it all, Patricia, my mother, sacrificed everything and made this possible. Cristina, my younger sister, has been a constant reminder that I have an obligation as an older brother to make her proud. Arpa, my love and joy, has walked this crucible called graduate school next to me, and has been a constant source of love and encouragement. To the three most important people in my life, thank you for everything.

My success as a scientist can be attributed to the various scientist I can call mentors and friends. Professor Jamil Momand, my undergraduate advisor and research mentor, introduced me to the field of biochemistry and encourage me to pursue my Ph.D.. Thank you for your guidance and support. Professor Pieter C. Dorrestein, my Ph.D mentor, provided me with a once in a life time experience graduate education in mass spectrometry and its application in life sciences. I cannot express how thankful I am for your mentorship, guidance, and support. The environment that you have cultivated in the Dorrestein lab provided me with the tools and opportunities to grow and succeed as a researcher. I will always appreciate everything that you have done for me. I would also like to thank my committee members for their role in my graduate education, thank you Professor Rob Knight, Professor Rachel Dutton, Professor Susan S. Golden, and Professor Jose Pruneda-Paz.

Chapter 2, in full, is a reprint of the material as it appears in Journal of The American Society for Mass Spectrometry 2019. da Silva, R. R; Vargas, F; Ernst, M; Nguyen, N. H; Bolleddu, S; del Rosario, K. K; Tsunoda, S. M; Dorrestein, P. C; Jarmusch, A. K.; Springer US, 2018. The dissertation author was a primary investigator and author of this paper.

Chapter 3, in full, has been submitted for publication of the material as it may appear in Rapid Communications in Mass Spectrometry, 2019, Vargas, F; Weldon, K. C; Sikora, N; Wang, M; Zhang, Z; Gentry, E. C; Panitchpakdi, M. W; Caraballo, M; Dorrestein, P. C; Jarmusch, A. K.; John Wiley & Sons, 2019. The dissertation author was the primary investigator and author of this paper.

Chapter 4, in full, has been submitted for publication of the material as it may appear in Frontiers in Psychiatry, 2019, Vargas, F; Dethloff, F; Emmanuel, E; Quinn, R; Park, D. I; Herzog, D. P, Müller, M. B; Gentry, E. C; Knight, R; Gonzalez, A; Dorrestein, P. C; Turck, C. W.; Frontiers Media, 2019. The dissertation author was the primary investigator and author of this paper.

Chapter 5, in full, has been submitted for publication of the material as it may appear in Scientific Reports, 2019, Thompson, R. S; Vargas, F; Dorrestein, P. C; Chichlowski, M; Berg, B. M; Fleshner, M.; Nature Publishing Group, 2019. The dissertation author was a primary investigator and author of this paper.

Chapter 6, in full, has been submitted for publication of the material as it may appear in Sleep, 2019, Bowers, S. J; Vargas, F; Gonzalez, A; He, S; Jiang, P; Dorrestein, P. C; Knight, R; Wright, K. P; Lowry, C. A; Fleshner, M; Vitaerna, M. H; Turek, F. W.; Oxford University Press, 2019. The dissertation author was a primary investigator and author of this paper.

  • 4 supplemental PDFs
Cover page: A cross species metabolomics analysis on the effect of biological stressors such as depression and sleep loss on the host metabolome
  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2018)
Trypanosoma cruzi parasites are the causative agents of Chagas disease. These parasites infect cardiac and gastrointestinal tissues, leading to local inflammation and tissue damage. Digestive Chagas disease is associated with perturbations in food absorption, intestinal traffic and defecation. However, the impact of T. cruzi infection on the gut microbiota and metabolome have yet to be characterized. In this study, we applied mass spectrometry-based metabolomics and 16S rRNA sequencing to profile infection-associated alterations in fecal bacterial composition and fecal metabolome through the acute-stage and into the chronic stage of infection, in a murine model of Chagas disease. We observed joint microbial and chemical perturbations associated with T. cruzi infection. These included alterations in conjugated linoleic acid (CLA) derivatives and in specific members of families Ruminococcaceae and Lachnospiraceae, as well as alterations in secondary bile acids and members of order Clostridiales. These results highlight the importance of multi-'omics' and poly-microbial studies in understanding parasitic diseases in general, and Chagas disease in particular.
    Cover page: Experimental Chagas disease-induced perturbations of the fecal microbiome and metabolome
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2019)
    Drug monitoring is crucial for providing accurate and effective care; however, current methods (e.g., blood draws) are inconvenient and unpleasant. We aim to develop a non-invasive method for the detection and monitoring of drugs via human skin. The initial development toward this aim required information about which drugs, taken orally, can be detected via the skin. Untargeted liquid chromatography-mass spectrometry (LC-MS) was used as it was unclear if drugs, known drug metabolites, or other transformation products were detectable. In accomplishing our aim, we analyzed samples obtained by swabbing the skin of 15 kidney transplant recipients in five locations (forehead, nasolabial area, axillary, backhand, and palm), bilaterally, on two different clinical visits. Untargeted LC-MS data were processed using molecular networking via the Global Natural Products Social Molecular Networking platform. Herein, we report the qualitative detection and location of drugs and drug metabolites. For example, escitalopram/citalopram and diphenhydramine, taken orally, were detected in forehead, nasolabial, and hand samples, whereas N-acetyl-sulfamethoxazole, a drug metabolite, was detected in axillary samples. In addition, chemicals associated with environmental exposure were also detected from the skin, which provides insight into the multifaceted chemical influences on our health. The proof-of-concept results presented support the finding that the LC-MS and data analysis methodology is currently capable of the qualitative assessment of the presence of drugs directly via human skin.
      Cover page: Initial Development toward Non-Invasive Drug Monitoring via Untargeted Mass Spectrometric Analysis of Human Skin
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      • Peer Reviewed
      UC San Diego Previously Published Works (2022)
      Human milk is the optimal infant nutrition. However, although human-derived metabolites (such as lipids and oligosaccharides) in human milk are regularly reported, the presence of exogenous chemicals (such as drugs, food, and synthetic compounds) are often not addressed. To understand the types of exogenous compounds that might be present, human milk (n = 996) was analyzed by untargeted metabolomics. This analysis revealed that lifestyle molecules, such as medications and their metabolites, and industrial sources, such as plasticizers, cosmetics, and other personal care products, are found in human milk. We provide further evidence that some of these lifestyle molecules are also detectable in the newborn's stool. Thus, this study gives important insight into the types of exposures infants receiving human milk might ingest due to the lifestyle choices, exposure, or medical status of the lactating parent.
        Cover page: An untargeted metabolomics analysis of exogenous chemicals in human milk and transfer to the infant.
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2024)
        Despite substantial evidence supporting the efficacy of prebiotics for promoting host health and stress resilience, few experiments present evidence documenting the dynamic changes in microbial ecology and fecal microbially modified metabolites over time. Furthermore, the literature reports a lack of reproducible effects of prebiotics on specific bacteria and bacterial-modified metabolites. The current experiments examined whether consumption of diets enriched in prebiotics (galactooligosaccharides (GOS) and polydextrose (PDX)), compared to a control diet, would consistently impact the gut microbiome and microbially modified bile acids over time and between two research sites. Male Sprague Dawley rats were fed control or prebiotic diets for several weeks, and their gut microbiomes and metabolomes were examined using 16S rRNA gene sequencing and untargeted LC-MS/MS analysis. Dietary prebiotics altered the beta diversity, relative abundance of bacterial genera, and microbially modified bile acids over time. PICRUSt2 analyses identified four inferred functional metabolic pathways modified by the prebiotic diet. Correlational network analyses between inferred metabolic pathways and microbially modified bile acids revealed deoxycholic acid as a potential network hub. All these reported effects were consistent between the two research sites, supporting the conclusion that dietary prebiotics robustly changed the gut microbial ecosystem. Consistent with our previous work demonstrating that GOS/PDX reduces the negative impacts of stressor exposure, we propose that ingesting a diet enriched in prebiotics facilitates the development of a health-promoting gut microbial ecosystem.
          Cover page: A Prebiotic Diet Containing Galactooligosaccharides and Polydextrose Produces Dynamic and Reproducible Changes in the Gut Microbial Ecosystem in Male Rats.
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          UC San Diego Previously Published Works (2020)
          It has been established in recent years that the gut microbiome plays a role in health and disease, potentially via alterations in metabolites that influence host physiology. Although sleep disruption and gut dysbiosis have been associated with many of the same diseases, studies investigating the gut microbiome in the context of sleep disruption have yielded inconsistent results, and have not assessed the fecal metabolome. We exposed mice to five days of sleep disruption followed by four days of ad libitum recovery sleep, and assessed the fecal microbiome and fecal metabolome at multiple timepoints using 16S rRNA gene amplicons and untargeted LC-MS/MS mass spectrometry. We found global shifts in both the microbiome and metabolome in the sleep-disrupted group on the second day of recovery sleep, when most sleep parameters had recovered to baseline levels. We observed an increase in the Firmicutes:Bacteroidetes ratio, along with decreases in the genus Lactobacillus, phylum Actinobacteria, and genus Bifidobacterium in sleep-disrupted mice compared to control mice. The latter two taxa remained low at the fourth day post-sleep disruption. We also identified multiple classes of fecal metabolites that were differentially abundant in sleep-disrupted mice, some of which are physiologically relevant and commonly influenced by the microbiome. This included bile acids, and inference of microbial functional gene content suggested reduced levels of the microbial bile salt hydrolase gene in sleep-disrupted mice. Overall, this study adds to the evidence base linking disrupted sleep to the gut microbiome and expands it to the fecal metabolome, identifying sleep disruption-sensitive bacterial taxa and classes of metabolites that may serve as therapeutic targets to improve health after poor sleep.
            Cover page: Repeated sleep disruption in mice leads to persistent shifts in the fecal microbiome and metabolome
            • Article
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            UC San Diego Previously Published Works (2020)
            Staphylococcus aureus bacteremia (SaB) causes significant disease in humans, carrying mortality rates of ∼25%. The ability to rapidly predict SaB patient responses and guide personalized treatment regimens could reduce mortality. Here, we present a resource of SaB prognostic biomarkers. Integrating proteomic and metabolomic techniques enabled the identification of >10,000 features from >200 serum samples collected upon clinical presentation. We interrogated the complexity of serum using multiple computational strategies, which provided a comprehensive view of the early host response to infection. Our biomarkers exceed the predictive capabilities of those previously reported, particularly when used in combination. Last, we validated the biological contribution of mortality-associated pathways using a murine model of SaB. Our findings represent a starting point for the development of a prognostic test for identifying high-risk patients at a time early enough to trigger intensive monitoring and interventions.
              Cover page: Mortality Risk Profiling of Staphylococcus aureus Bacteremia by Multi-omic Serum Analysis Reveals Early Predictive and Pathogenic Signatures
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2020)
              Recent interest in the role of microbiota in health and disease has implicated gut microbiota dysbiosis in psychiatric disorders including major depressive disorder. Several antidepressant drugs that belong to the class of selective serotonin reuptake inhibitors have been found to display antimicrobial activities. In fact, one of the first antidepressants discovered serendipitously in the 1950s, the monoamine-oxidase inhibitor Iproniazid, was a drug used for the treatment of tuberculosis. In the current study we chronically treated DBA/2J mice for 2 weeks with paroxetine, a selective serotonin reuptake inhibitor, and collected fecal pellets as a proxy for the gut microbiota from the animals after 7 and 14 days. Behavioral testing with the forced swim test revealed significant differences between paroxetine- and vehicle-treated mice. Untargeted mass spectrometry and 16S rRNA profiling of fecal pellet extracts showed several primary and secondary bile acid level, and microbiota alpha diversity differences, respectively between paroxetine- and vehicle-treated mice, suggesting that microbiota functions are altered by the drug. In addition to their lipid absorbing activities bile acids have important signaling activities and have been associated with gastrointestinal diseases and colorectal cancer. Antidepressant drugs like paroxetine should therefore be used with caution to prevent undesirable side effects.
                Cover page: Paroxetine Administration Affects Microbiota and Bile Acid Levels in Mice
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2022)
                Sleep disruption is a challenging and exceedingly common physiological state that contributes to a wide range of biochemical and molecular perturbations and has been linked to numerous adverse health outcomes. Modern society exerts significant pressure on the sleep/wake cycle via myriad factors, including exposure to electric light, psychological stressors, technological interconnection, jet travel, shift work, and widespread use of sleep-affecting compounds. Interestingly, recent research has identified a link between the microbiome and the regulation of sleep, suggesting that interventions targeting the microbiome may offer unique therapeutic approaches to challenges posed by sleep disruption. In this study, we test the hypothesis that administration of a prebiotic diet containing galactooligosaccharides (GOS) and polydextrose (PDX) in adult male rats improves sleep in response to repeated sleep disruption and during recovery sleep. We found that animals fed the GOS/PDX prebiotic diet for 4 weeks exhibit increased non-rapid eye movement (NREM) and rapid eye movement (REM) sleep during 5 days of sleep disruption and increased total sleep time during 24 h of recovery from sleep disruption compared to animals fed a control diet, despite similar baseline sleep characteristics. Further, the GOS/PDX prebiotic diet led to significant changes in the fecal microbiome. Consistent with previous reports, the prebiotic diet increased the relative abundance of the species Parabacteroides distasonis, which positively correlated with sleep parameters during recovery sleep. Taken together, these findings suggest that the GOS/PDX prebiotic diet may offer an approach to improve resilience to the physiologic challenge of sleep disruption, in part through impacts on the microbiome.
                  Cover page: A Prebiotic Diet Alters the Fecal Microbiome and Improves Sleep in Response to Sleep Disruption in Rats
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2020)
                  Antibiotics are a mainstay of modern medicine, but as they kill their target pathogen(s), they often affect the commensal microbiota. Antibiotic-induced microbiome dysbiosis is a growing research focus and health concern, often assessed via analysis of fecal samples. However, such analysis does not inform how antibiotics influence the microbiome across the whole host or how such changes subsequently alter host chemistry. In this study, we investigated the acute (1 day postadministration) and delayed (6 days postadministration) effects of a single parenteral dose of two common antibiotics, ampicillin or vancomycin, on the global metabolome and microbiome of mice across 77 different body sites from 25 different organs. The broader-spectrum agent ampicillin had the greatest impact on the microbiota in the lower gastrointestinal tract (cecum and colon), where microbial diversity is highest. In the metabolome, the greatest effects were seen 1 day posttreatment, and changes in metabolite abundances were not confined to the gut. The local abundance of ampicillin and its metabolites correlated with increased metabolome effect size and a loss of alpha diversity versus control mice. Additionally, small peptides were elevated in the lower gastrointestinal tract of mice 1 day after antibiotic treatment. While a single parenteral dose of antibiotic did not drastically alter the microbiome, nevertheless, changes in the metabolome were observed both within and outside the gut. This study provides a framework for how whole-organism -omics approaches can be employed to understand the impact of antibiotics on the entire host.IMPORTANCE We are just beginning to understand the unintended effects of antibiotics on our microbiomes and health. In this study, we aimed to define an approach by which one could obtain a comprehensive picture of (i) how antibiotics spatiotemporally impact commensal microbes throughout the gut and (ii) how these changes influence host chemistry throughout the body. We found that just a single dose of antibiotic altered host chemistry in a variety of organs and that microbiome alterations were not uniform throughout the gut. As technological advances increase the feasibility of whole-organism studies, we argue that using these approaches can provide further insight on both the wide-ranging effects of antibiotics on health and how to restore microbial communities to mitigate these effects.
                    Cover page: Evaluating Organism-Wide Changes in the Metabolome and Microbiome following a Single Dose of Antibiotic
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