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Lloyd-Price, Jason

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Lloyd-Price

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Jason

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Lloyd-Price, Jason
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    Growth Effects of N-Acylethanolamines on Gut Bacteria Reflect Altered Bacterial Abundances in Inflammatory Bowel Disease
    (Springer Science and Business Media LLC, 2020-01-20) Fornelos, Nadine; Franzosa, Eric; Bishai, Jason; Annand, John W.; Oka, Akihiko; Lloyd-Price, Jason; Arthur, Timothy D.; Garner, Ashley; Avila-Pacheco, Julian; Haiser, Henry J.; Tolonen, Andrew C.; Porter, Jeffrey A.; Clish, Clary B.; Sartor, R. Balfour; Huttenhower, Curtis; Vlamakis, Hera; Xavier, Ramnik J.; Xavier
    Inflammatory bowel diseases (IBD) are associated with alterations in gut microbial abundances and lumenal metabolite concentrations, but the effects of specific metabolites on the gut microbiota in health and disease remain largely unknown. Here, we analyzed the influences of metabolites that are differentially abundant in IBD on the growth and physiology of gut bacteria that are also differentially abundant in IBD. We found that N-acylethanolamines (NAEs), a class of endogenously-produced signaling lipids elevated in the stool of IBD patients and a T-cell transfer model of colitis, stimulated growth of species overrepresented in IBD and inhibited that of species depleted in IBD in vitro. Using metagenomic sequencing, we recapitulated the effects of NAEs in complex microbial communities ex vivo, with Proteobacteria blooming and Bacteroidetes declining in the presence of NAEs. Metatranscriptomic analysis of the same communities identified components of the respiratory chain as important for the metabolism of NAEs, and this was verified using a mutant deficient for respiratory complex I. In this study, we identified NAEs as a class of metabolites that are elevated in IBD and have the potential to shift gut microbiota toward an IBD-like composition.
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    Multi-Omics of the Gut Microbial Ecosystem in Inflammatory Bowel Diseases
    (Springer Science and Business Media LLC, 2019-05) Lloyd-Price, Jason; Arze, Cesar; Schirmer, Melanie; Andrews, Elizabeth; Ajami, Nadim J.; Brislawn, Colin J.; Courtney, Holly; Gonzalez, Antonio; Graeber, Thomas G.; Hall, A. Brantley; Mallick, Himel; Rahnavard, Gholamali; Sauk, Jenny; Shungin, Dmitry; Vázquez-Baeza, Yoshiki; White, Richard A.; Braun, Jonathan; Denson, Lee A.; Jansson, Janet K.; Knight, Robert; Kugathasan, Subra; McGovern, Dermot P. B.; Stappenbeck, Thaddeus S.; Vlamakis, Hera; Huttenhower, Curtis; Ananthakrishnan, Ashwin; Avila-Pacheco, Julian; Poon, Tiffany; Bonham, Kevin; Casero, David; Lake, Kathleen; Landers, Carol; Plichta, Damian; Prasad, Mahadev; Winter, Harland; Clish, Clary; Franzosa, Eric; Xavier, Ramnik; Petrosino, Joseph
    Inflammatory bowel diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), affect several million individuals worldwide. CD and UC are complex diseases and heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Extensive study has focused on individual contributing factors. As part of the Integrative Human Microbiome Project (HMP2), 132 subjects were followed one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each, in total 2,965 stool, biopsy, and blood specimens). These provide a comprehensive view of the gut microbiome’s functional dysbiosis during IBD activity, showing a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (e.g. among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and host serum antibody levels. Disease was also marked by greater temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to the dysregulation. The study’s infrastructure resources, results, and data, available through the Inflammatory Bowel Disease Multi'omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in IBD.
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    Publication
    The healthy human microbiome
    (BioMed Central, 2016) Lloyd-Price, Jason; Abu-Ali, Galeb; Huttenhower, Curtis
    Humans are virtually identical in their genetic makeup, yet the small differences in our DNA give rise to tremendous phenotypic diversity across the human population. By contrast, the metagenome of the human microbiome—the total DNA content of microbes inhabiting our bodies—is quite a bit more variable, with only a third of its constituent genes found in a majority of healthy individuals. Understanding this variability in the “healthy microbiome” has thus been a major challenge in microbiome research, dating back at least to the 1960s, continuing through the Human Microbiome Project and beyond. Cataloguing the necessary and sufficient sets of microbiome features that support health, and the normal ranges of these features in healthy populations, is an essential first step to identifying and correcting microbial configurations that are implicated in disease. Toward this goal, several population-scale studies have documented the ranges and diversity of both taxonomic compositions and functional potentials normally observed in the microbiomes of healthy populations, along with possible driving factors such as geography, diet, and lifestyle. Here, we review several definitions of a ‘healthy microbiome’ that have emerged, the current understanding of the ranges of healthy microbial diversity, and gaps such as the characterization of molecular function and the development of ecological therapies to be addressed in the future.
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    Global Chemical Impact of the Microbiome Includes Novel Bile Acid Conjugations
    (Springer Nature, 2020-02-26) Quinn, Robert; Melnik, Alexey; Vrbanac, Alison; Patras, Kathryn; Christy, Mitchell; Zsolt, Bodai; Belda-Ferre, Pedro; Tripathi, Anupriya; Chung, Lawton; Quinn, Melissa; Humphrey, Greg; Panitchpakdi, Morgan; Weldon, Kelly; Aksenov, Alexander; da Silva, Ricardo; Avila-Pacheco, Julian; Clish, Clary; Bae, Sena; Mallick, Himel; Franzosa, Eric; Lloyd-Price, Jason; Bussell, Robert; Thron, Taren; Nelson, Andrew; Wang, Mingxun; Leszczynski, Eric; Vargas, Fernando; Gauglitz, Julia; Meehan, Michael; Gentry, Emily; Arthur, Timothy; Downes, Michael; Fu, Ting; Welch, Ryan; Komor, Alexis; Poulsen, Orit; Boland, Brigid; Chang, John; Sandborn, William; Lim, Meerana; Garg, Neha; Lumeng, Julie; Xavier, Ramnik; Kazmierczak, Barbara; Jain, Ruchi; Egan, Marie; Rhee, Kyung; Ferguson, David; Evans, Ronald; Raffatellu, Manuela; Vlamakis, Hera; Haddad, Gabriel; Siegel, Dionicio; Huttenhower, Curtis; Mazmanian, Sarkis; Nizet, Victor; Knight, Rob; Dorrestein, Pieter
    A mosaic of cross-phyla chemical interactions occurs between all metazoans and their microbiomes. In humans, the gut harbors the heaviest microbial load, but many organs, particularly those with a mucosal surface, associate with highly adapted and evolved microbial consortia. The microbial residents within these organ systems are increasingly well characterized, yielding a good understanding of human microbiome composition. However, we have yet to elucidate the full chemical impact the microbiome exerts on an animal and the breadth of the chemical diversity it contributes. A number of molecular families are known to be shaped by the microbiome including short-chain fatty acids, indoles, complex polysaccharides, host sphingolipids and bile acids. These metabolites profoundly affect host physiology and are being explored for their roles in both health and disease. Considering the diversity of the human microbiome, numbering over 40,000 operational taxonomic units, a plethora of molecular diversity remains to be discovered. In this study we used novel mass spectrometry informatics and visualization approaches to provide an untargeted assessment of the chemical contributions of the microbiome to an entire mammal by comparing germ-free (GF) and specific-pathogen free (SPF) animals. We found that the microbiome affected the chemistry of all murine organs. These affects were highlighted by novel amino acid conjugations of host bile acids that have evaded characterization despite the extensive research on bile acid chemistry. These new bile acid conjugates were enriched in dysbiotic disease states and directly agonized the farnesoid X receptor (FXR) resulting in changes in host bile acid metabolism.