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Franzosa, Eric

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Franzosa

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Franzosa, Eric
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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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    Alterations in oral bacterial communities are associated with risk factors for oral and oropharyngeal cancer
    (Nature Publishing Group UK, 2017) Börnigen, Daniela; Ren, Boyu; Pickard, Robert; Li, Jingfeng; Ozer, Enver; Hartmann, Erica M.; Xiao, Weihong; Tickle, Timothy; Rider, Jennifer; Gevers, Dirk; Franzosa, Eric; Davey, Mary Ellen; Gillison, Maura L.; Huttenhower, Curtis
    Oral squamous cell carcinomas are a major cause of morbidity and mortality, and tobacco usage, alcohol consumption, and poor oral hygiene are established risk factors. To date, no large-scale case-control studies have considered the effects of these risk factors on the composition of the oral microbiome, nor microbial community associations with oral cancer. We compared the composition, diversity, and function of the oral microbiomes of 121 oral cancer patients to 242 age- and gender-matched controls using a metagenomic multivariate analysis pipeline. Significant shifts in composition and function of the oral microbiome were observed with poor oral hygiene, tobacco smoking, and oral cancer. Specifically, we observed dramatically altered community composition and function after tooth loss, with smaller alterations in current tobacco smokers, increased production of antioxidants in individuals with periodontitis, and significantly decreased glutamate metabolism metal transport in oral cancer patients. Although the alterations in the oral microbiome of oral cancer patients were significant, they were of substantially lower effect size relative to microbiome shifts after tooth loss. Alterations following tooth loss, itself a major risk factor for oral cancer, are likely a result of severe ecological disruption due to habitat loss but may also contribute to the development of the disease.
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    Host genetic variation and its microbiome interactions within the Human Microbiome Project
    (BioMed Central, 2018) Kolde, Raivo; Franzosa, Eric; Rahnavard, Gholamali; Hall, Andrew Brantley; Vlamakis, Hera; Stevens, Christine; Daly, Mark; Xavier, Ramnik; Huttenhower, Curtis
    Background: Despite the increasing recognition that microbial communities within the human body are linked to health, we have an incomplete understanding of the environmental and molecular interactions that shape the composition of these communities. Although host genetic factors play a role in these interactions, these factors have remained relatively unexplored given the requirement for large population-based cohorts in which both genotyping and microbiome characterization have been performed. Methods: We performed whole-genome sequencing of 298 donors from the Human Microbiome Project (HMP) healthy cohort study to accompany existing deep characterization of their microbiomes at various body sites. This analysis yielded an average sequencing depth of 32x, with which we identified 27 million (M) single nucleotide variants and 2.3 M insertions-deletions. Results: Taxonomic composition and functional potential of the microbiome covaried significantly with genetic principal components in the gastrointestinal tract and oral communities, but not in the nares or vaginal microbiota. Example associations included validation of known associations between FUT2 secretor status, as well as a variant conferring hypolactasia near the LCT gene, with Bifidobacterium longum abundance in stool. The associations of microbial features with both high-level genetic attributes and single variants were specific to particular body sites, highlighting the opportunity to find unique genetic mechanisms controlling microbiome properties in the microbial communities from multiple body sites. Conclusions: This study adds deep sequencing of host genomes to the body-wide microbiome sequences already extant from the HMP healthy cohort, creating a unique, versatile, and well-controlled reference for future studies seeking to identify host genetic modulators of the microbiome. Electronic supplementary material The online version of this article (10.1186/s13073-018-0515-8) contains supplementary material, which is available to authorized users.
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    Fluoride Depletes Acidogenic Taxa in Oral but Not Gut Microbial Communities in Mice
    (American Society for Microbiology, 2017) Yasuda, Koji; Hsu, Tiffany; Gallini, Carey; Mclver, Lauren J.; Schwager, Emma; Shi, Andy; DuLong, Casey; Schwager, Randall N.; Abu-Ali, Galeb; Franzosa, Eric; Garrett, Wendy; Huttenhower, Curtis; Morgan, Xochitl C.
    ABSTRACT Fluoridation of drinking water and dental products prevents dental caries primarily by inhibiting energy harvest in oral cariogenic bacteria (such as Streptococcus mutans and Streptococcus sanguinis), thus leading to their depletion. However, the extent to which oral and gut microbial communities are affected by host fluoride exposure has been underexplored. In this study, we modeled human fluoride exposures to municipal water and dental products by treating mice with low or high levels of fluoride over a 12-week period. We then used 16S rRNA gene amplicon and shotgun metagenomic sequencing to assess fluoride’s effects on oral and gut microbiome composition and function. In both the low- and high-fluoride groups, several operational taxonomic units (OTUs) belonging to acidogenic bacterial genera (such as Parabacteroides, Bacteroides, and Bilophila) were depleted in the oral community. In addition, fluoride-associated changes in oral community composition resulted in depletion of gene families involved in central carbon metabolism and energy harvest (2-oxoglutarate ferredoxin oxidoreductase, succinate dehydrogenase, and the glyoxylate cycle). In contrast, fluoride treatment did not induce a significant shift in gut microbial community composition or function in our mouse model, possibly due to absorption in the upper gastrointestinal tract. Fluoride-associated perturbations thus appeared to have a selective effect on the composition of the oral but not gut microbial community in mice. Future studies will be necessary to understand possible implications of fluoride exposure for the human microbiome. IMPORTANCE: Fluoride has been added to drinking water and dental products since the 1950s. The beneficial effects of fluoride on oral health are due to its ability to inhibit the growth of bacteria that cause dental caries. Despite widespread human consumption of fluoride, there have been only two studies of humans that considered the effect of fluoride on human-associated microbial communities, which are increasingly understood to play important roles in health and disease. Notably, neither of these studies included a true cross-sectional control lacking fluoride exposure, as study subjects continued baseline fluoride treatment in their daily dental hygiene routines. To our knowledge, this work (in mice) is the first controlled study to assess the independent effects of fluoride exposure on the oral and gut microbial communities. Investigating how fluoride interacts with host-associated microbial communities in this controlled setting represents an effort toward understanding how common environmental exposures may potentially influence health.
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    Signatures of Pleiotropy, Economy and Convergent Evolution in a Domain-Resolved Map of Human–Virus Protein–Protein Interaction Networks
    (Public Library of Science, 2013) Garamszegi, Sara; Franzosa, Eric; Xia, Yu
    A central challenge in host-pathogen systems biology is the elucidation of general, systems-level principles that distinguish host-pathogen interactions from within-host interactions. Current analyses of host-pathogen and within-host protein-protein interaction networks are largely limited by their resolution, treating proteins as nodes and interactions as edges. Here, we construct a domain-resolved map of human-virus and within-human protein-protein interaction networks by annotating protein interactions with high-coverage, high-accuracy, domain-centric interaction mechanisms: (1) domain-domain interactions, in which a domain in one protein binds to a domain in a second protein, and (2) domain-motif interactions, in which a domain in one protein binds to a short, linear peptide motif in a second protein. Analysis of these domain-resolved networks reveals, for the first time, significant mechanistic differences between virus-human and within-human interactions at the resolution of single domains. While human proteins tend to compete with each other for domain binding sites by means of sequence similarity, viral proteins tend to compete with human proteins for domain binding sites in the absence of sequence similarity. Independent of their previously established preference for targeting human protein hubs, viral proteins also preferentially target human proteins containing linear motif-binding domains. Compared to human proteins, viral proteins participate in more domain-motif interactions, target more unique linear motif-binding domains per residue, and contain more unique linear motifs per residue. Together, these results suggest that viruses surmount genome size constraints by convergently evolving multiple short linear motifs in order to effectively mimic, hijack, and manipulate complex host processes for their survival. Our domain-resolved analyses reveal unique signatures of pleiotropy, economy, and convergent evolution in viral-host interactions that are otherwise hidden in the traditional binary network, highlighting the power and necessity of high-resolution approaches in host-pathogen systems biology.
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    Functional profiling of the gut microbiome in disease-associated inflammation
    (BioMed Central, 2013) Börnigen, Daniela; Morgan, Xochitl C; Franzosa, Eric; Ren, Boyu; Xavier, Ramnik; Garrett, Wendy; Huttenhower, Curtis
    The microbial residents of the human gut are a major factor in the development and lifelong maintenance of health. The gut microbiota differs to a large degree from person to person and has an important influence on health and disease due to its interaction with the human immune system. Its overall composition and microbial ecology have been implicated in many autoimmune diseases, and it represents a particularly important area for translational research as a new target for diagnostics and therapeutics in complex inflammatory conditions. Determining the biomolecular mechanisms by which altered microbial communities contribute to human disease will be an important outcome of current functional studies of the human microbiome. In this review, we discuss functional profiling of the human microbiome using metagenomic and metatranscriptomic approaches, focusing on the implications for inflammatory conditions such as inflammatory bowel disease and rheumatoid arthritis. Common themes in gut microbial ecology have emerged among these diverse diseases, but they have not yet been linked to targetable mechanisms such as microbial gene and genome composition, pathway and transcript activity, and metabolism. Combining these microbial activities with host gene, transcript and metabolic information will be necessary to understand how and why these complex interacting systems are altered in disease-associated inflammation.
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    A reproducible approach to high-throughput biological data acquisition and integration
    (PeerJ Inc., 2015) Börnigen, Daniela; Moon, Yo Sup; Rahnavard, Gholamali; Waldron, Levi; McIver, Lauren; Shafquat, Afrah; Franzosa, Eric; Miropolsky, Larissa; Sweeney, Christopher; Morgan, Xochitl C.; Garrett, Wendy; Huttenhower, Curtis
    Modern biological research requires rapid, complex, and reproducible integration of multiple experimental results generated both internally and externally (e.g., from public repositories). Although large systematic meta-analyses are among the most effective approaches both for clinical biomarker discovery and for computational inference of biomolecular mechanisms, identifying, acquiring, and integrating relevant experimental results from multiple sources for a given study can be time-consuming and error-prone. To enable efficient and reproducible integration of diverse experimental results, we developed a novel approach for standardized acquisition and analysis of high-throughput and heterogeneous biological data. This allowed, first, novel biomolecular network reconstruction in human prostate cancer, which correctly recovered and extended the NFκB signaling pathway. Next, we investigated host-microbiome interactions. In less than an hour of analysis time, the system retrieved data and integrated six germ-free murine intestinal gene expression datasets to identify the genes most influenced by the gut microbiota, which comprised a set of immune-response and carbohydrate metabolism processes. Finally, we constructed integrated functional interaction networks to compare connectivity of peptide secretion pathways in the model organisms Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa.
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    Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes
    (BioMed Central, 2016) Yassour, Moran; Lim, Mi Young; Yun, Hyun Sun; Tickle, Timothy L.; Sung, Joohon; Song, Yun-Mi; Lee, Kayoung; Franzosa, Eric; Morgan, Xochitl C.; Gevers, Dirk; Lander, Eric; Xavier, Ramnik; Birren, Bruce W.; Ko, GwangPyo; Huttenhower, Curtis
    Background: Obesity and type 2 diabetes (T2D) are linked both with host genetics and with environmental factors, including dysbioses of the gut microbiota. However, it is unclear whether these microbial changes precede disease onset. Twin cohorts present a unique genetically-controlled opportunity to study the relationships between lifestyle factors and the microbiome. In particular, we hypothesized that family-independent changes in microbial composition and metabolic function during the sub-clinical state of T2D could be either causal or early biomarkers of progression. Methods: We collected fecal samples and clinical metadata from 20 monozygotic Korean twins at up to two time points, resulting in 36 stool shotgun metagenomes. While the participants were neither obese nor diabetic, they spanned the entire range of healthy to near-clinical values and thus enabled the study of microbial associations during sub-clinical disease while accounting for genetic background. Results: We found changes both in composition and in function of the sub-clinical gut microbiome, including a decrease in Akkermansia muciniphila suggesting a role prior to the onset of disease, and functional changes reflecting a response to oxidative stress comparable to that previously observed in chronic T2D and inflammatory bowel diseases. Finally, our unique study design allowed us to examine the strain similarity between twins, and we found that twins demonstrate strain-level differences in composition despite species-level similarities. Conclusions: These changes in the microbiome might be used for the early diagnosis of an inflamed gut and T2D prior to clinical onset of the disease and will help to advance toward microbial interventions. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0271-6) contains supplementary material, which is available to authorized users.
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    A conserved bacterial protein induces pancreatic beta cell expansion during zebrafish development
    (eLife Sciences Publications, Ltd, 2016) Hill, Jennifer Hampton; Franzosa, Eric; Huttenhower, Curtis; Guillemin, Karen
    Resident microbes play important roles in the development of the gastrointestinal tract, but their influence on other digestive organs is less well explored. Using the gnotobiotic zebrafish, we discovered that the normal expansion of the pancreatic β cell population during early larval development requires the intestinal microbiota and that specific bacterial members can restore normal β cell numbers. These bacteria share a gene that encodes a previously undescribed protein, named herein BefA (β Cell Expansion Factor A), which is sufficient to induce β cell proliferation in developing zebrafish larvae. Homologs of BefA are present in several human-associated bacterial species, and we show that they have conserved capacity to stimulate β cell proliferation in larval zebrafish. Our findings highlight a role for the microbiota in early pancreatic β cell development and suggest a possible basis for the association between low diversity childhood fecal microbiota and increased diabetes risk. DOI: http://dx.doi.org/10.7554/eLife.20145.001