Publications by authors named "Jessie A Turnbaugh"

9 Publications

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Ketogenic Diets Alter the Gut Microbiome Resulting in Decreased Intestinal Th17 Cells.

Cell 2020 06 20;181(6):1263-1275.e16. Epub 2020 May 20.

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address:

Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. In vitro and in vivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions.
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http://dx.doi.org/10.1016/j.cell.2020.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293577PMC
June 2020

Non-catalytic ubiquitin binding by A20 prevents psoriatic arthritis-like disease and inflammation.

Nat Immunol 2020 04 16;21(4):422-433. Epub 2020 Mar 16.

Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

A20 is an anti-inflammatory protein that is strongly linked to human disease. Here, we find that mice expressing three distinct targeted mutations of A20's zinc finger 7 (ZF7) ubiquitin-binding motif uniformly developed digit arthritis with features common to psoriatic arthritis, while mice expressing point mutations in A20's OTU or ZF4 motifs did not exhibit this phenotype. Arthritis in A20 mice required T cells and MyD88, was exquisitely sensitive to tumor necrosis factor and interleukin-17A, and persisted in germ-free conditions. A20 cells exhibited prolonged IκB kinase activity that drove exaggerated transcription of late-phase nuclear factor-κB response genes in vitro and in prediseased mouse paws in vivo. In addition, mice expressing double-mutant A20 proteins in A20's ZF4 and ZF7 motifs died perinatally with multi-organ inflammation. Therefore, A20's ZF4 and ZF7 motifs synergistically prevent inflammatory disease in a non-catalytic manner.
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http://dx.doi.org/10.1038/s41590-020-0634-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195210PMC
April 2020

Meta-Analysis Reveals Reproducible Gut Microbiome Alterations in Response to a High-Fat Diet.

Cell Host Microbe 2019 08 16;26(2):265-272.e4. Epub 2019 Jul 16.

Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address:

Multiple research groups have shown that diet impacts the gut microbiome; however, variability in experimental design and quantitative assessment have made it challenging to assess the degree to which similar diets have reproducible effects across studies. Through an unbiased subject-level meta-analysis framework, we re-analyzed 27 dietary studies including 1,101 samples from rodents and humans. We demonstrate that a high-fat diet (HFD) reproducibly changes gut microbial community structure. Finer taxonomic analysis revealed that the most reproducible signals of a HFD are Lactococcus species, which we experimentally demonstrate to be common dietary contaminants. Additionally, a machine-learning approach defined a signature that predicts the dietary intake of mice and demonstrated that phylogenetic and gene-centric transformations of this model can be translated to humans. Together, these results demonstrate the utility of microbiome meta-analyses in identifying robust and reproducible features for mechanistic studies in preclinical models.
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http://dx.doi.org/10.1016/j.chom.2019.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708278PMC
August 2019

The N-terminal, polybasic region of PrP(C) dictates the efficiency of prion propagation by binding to PrP(Sc).

J Neurosci 2012 Jun;32(26):8817-30

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Prion propagation involves a templating reaction in which the infectious form of the prion protein (PrP(Sc)) binds to the cellular form (PrP(C)), generating additional molecules of PrP(Sc). While several regions of the PrP(C) molecule have been suggested to play a role in PrP(Sc) formation based on in vitro studies, the contribution of these regions in vivo is unclear. Here, we report that mice expressing PrP deleted for a short, polybasic region at the N terminus (residues 23-31) display a dramatically reduced susceptibility to prion infection and accumulate greatly reduced levels of PrP(Sc). These results, in combination with biochemical data, demonstrate that residues 23-31 represent a critical site on PrP(C) that binds to PrP(Sc) and is essential for efficient prion propagation. It may be possible to specifically target this region for treatment of prion diseases as well as other neurodegenerative disorders due to β-sheet-rich oligomers that bind to PrP(C).
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http://dx.doi.org/10.1523/JNEUROSCI.1103-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433751PMC
June 2012

The toxicity of a mutant prion protein is cell-autonomous, and can be suppressed by wild-type prion protein on adjacent cells.

PLoS One 2012 12;7(3):e33472. Epub 2012 Mar 12.

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.

Insight into the normal function of PrP(C), and how it can be subverted to produce neurotoxic effects, is provided by PrP molecules carrying deletions encompassing the conserved central region. The most neurotoxic of these mutants, Δ105-125 (called ΔCR), produces a spontaneous neurodegenerative illness when expressed in transgenic mice, and this phenotype can be dose-dependently suppressed by co-expression of wild-type PrP. Whether the toxic activity of ΔCR PrP and the protective activity or wild-type PrP are cell-autonomous, or can be exerted on neighboring cells, is unknown. To investigate this question, we have utilized co-cultures of differentiated neural stem cells derived from mice expressing ΔCR or wild-type PrP. Cells from the two kinds of mice, which are marked by the presence or absence of GFP, are differentiated together to yield neurons, astrocytes, and oligodendrocytes. As a surrogate read-out of ΔCR PrP toxicity, we assayed sensitivity of the cells to the cationic antibiotic, Zeocin. In a previous study, we reported that cells expressing ΔCR PrP are hypersensitive to the toxic effects of several cationic antibiotics, an effect that is suppressed by co-expression of wild type PrP, similar to the rescue of the neurodegenerative phenotype observed in transgenic mice. Using this system, we find that while ΔCR-dependent toxicity is cell-autonomous, the rescuing activity of wild-type PrP can be exerted in trans from nearby cells. These results provide important insights into how ΔCR PrP subverts a normal physiological function of PrP(C), and the cellular mechanisms underlying the rescuing process.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033472PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299791PMC
August 2012

Prion protein at the crossroads of physiology and disease.

Trends Neurosci 2012 Feb 1;35(2):92-103. Epub 2011 Dec 1.

Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.

The presence of the cellular prion protein (PrP(C)) on the cell surface is critical for the neurotoxicity of prions. Although several biological activities have been attributed to PrP(C), a definitive demonstration of its physiological function remains elusive. In this review, we discuss some of the proposed functions of PrP(C), focusing on recently suggested roles in cell adhesion, regulation of ionic currents at the cell membrane and neuroprotection. We also discuss recent evidence supporting the idea that PrP(C) may function as a receptor for soluble oligomers of the amyloid β peptide and possibly other toxic protein aggregates. These data suggest surprising new connections between the physiological function of PrP(C) and its role in neurodegenerative diseases beyond those caused by prions.
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http://dx.doi.org/10.1016/j.tins.2011.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273588PMC
February 2012

A naturally occurring C-terminal fragment of the prion protein (PrP) delays disease and acts as a dominant-negative inhibitor of PrPSc formation.

J Biol Chem 2011 Dec 24;286(51):44234-44242. Epub 2011 Oct 24.

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118. Electronic address:

The cellular prion protein (PrPC) undergoes constitutive proteolytic cleavage between residues 111/112 to yield a soluble N-terminal fragment (N1) and a membrane-anchored C-terminal fragment (C1). The C1 fragment represents the major proteolytic fragment of PrPC in brain and several cell types. To explore the role of C1 in prion disease, we generated Tg(C1) transgenic mice expressing this fragment (PrP(Δ23-111)) in the presence and absence of endogenous PrP. In contrast to several other N-terminally deleted forms of PrP, the C1 fragment does not cause a spontaneous neurological disease in the absence of endogenous PrP. Tg(C1) mice inoculated with scrapie prions remain healthy and do not accumulate protease-resistant PrP, demonstrating that C1 is not a substrate for conversion to PrPSc (the disease-associated isoform). Interestingly, Tg(C1) mice co-expressing C1 along with wild-type PrP (either endogenous or encoded by a second transgene) become ill after scrapie inoculation, but with a dramatically delayed time course compared with mice lacking C1. In addition, accumulation of PrPSc was markedly slowed in these animals. Similar effects were produced by a shorter C-terminal fragment of PrP(Δ23-134). These results demonstrate that C1 acts as dominant-negative inhibitor of PrPSc formation and accumulation of neurotoxic forms of PrP. Thus, C1, a naturally occurring fragment of PrPC, might play a modulatory role during the course of prion diseases. In addition, enhancing production of C1, or exogenously administering this fragment, represents a potential therapeutic strategy for the treatment of prion diseases.
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http://dx.doi.org/10.1074/jbc.M111.286195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243553PMC
December 2011

The N-terminal, polybasic region is critical for prion protein neuroprotective activity.

PLoS One 2011 29;6(9):e25675. Epub 2011 Sep 29.

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.

Several lines of evidence suggest that the normal form of the prion protein, PrP(C), exerts a neuroprotective activity against cellular stress or toxicity. One of the clearest examples of such activity is the ability of wild-type PrP(C) to suppress the spontaneous neurodegenerative phenotype of transgenic mice expressing a deleted form of PrP (Δ32-134, called F35). To define domains of PrP involved in its neuroprotective activity, we have analyzed the ability of several deletion mutants of PrP (Δ23-31, Δ23-111, and Δ23-134) to rescue the phenotype of Tg(F35) mice. Surprisingly, all of these mutants displayed greatly diminished rescue activity, although Δ23-31 PrP partially suppressed neuronal loss when expressed at very high levels. Our results pinpoint the N-terminal, polybasic domain as a critical determinant of PrP(C) neuroprotective activity, and suggest that identification of molecules interacting with this region will provide important clues regarding the normal function of the protein. Small molecule ligands targeting this region may also represent useful therapeutic agents for treatment of prion diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025675PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183058PMC
January 2012

A nine amino acid domain is essential for mutant prion protein toxicity.

J Neurosci 2011 Sep;31(39):14005-17

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Transgenic mice expressing prion protein (PrP) molecules with several different internal deletions display spontaneous neurodegenerative phenotypes that can be dose-dependently suppressed by coexpression of wild-type PrP. Each of these deletions, including the largest one (Δ32-134), retains 9 aa immediately following the signal peptide cleavage site (residues 23-31; KKRPKPGGW). These residues have been implicated in several biological functions of PrP, including endocytic trafficking and binding of glycosaminoglycans. We report here on our experiments to test the role of this domain in the toxicity of deleted forms of PrP. We find that transgenic mice expressing Δ23-134 PrP display no clinical symptoms or neuropathology, in contrast to mice expressing Δ32-134 PrP, suggesting that residues 23-31 are essential for the toxic phenotype. Using a newly developed cell culture assay, we narrow the essential region to amino acids 23-26, and we show that mutant PrP toxicity is not related to the role of the N-terminal residues in endocytosis or binding to endogenous glycosaminoglycans. However, we find that mutant PrP toxicity is potently inhibited by application of exogenous glycosaminoglycans, suggesting that the latter molecules block an essential interaction between the N terminus of PrP and a membrane-associated target site. Our results demonstrate that a short segment containing positively charged amino acids at the N terminus of PrP plays an essential role in mediating PrP-related neurotoxicity. This finding identifies a protein domain that may serve as a drug target for amelioration of prion neurotoxicity.
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http://dx.doi.org/10.1523/JNEUROSCI.1243-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227396PMC
September 2011