PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-4 (4)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Ecological Modeling from Time-Series Inference: Insight into Dynamics and Stability of Intestinal Microbiota 
PLoS Computational Biology  2013;9(12):e1003388.
The intestinal microbiota is a microbial ecosystem of crucial importance to human health. Understanding how the microbiota confers resistance against enteric pathogens and how antibiotics disrupt that resistance is key to the prevention and cure of intestinal infections. We present a novel method to infer microbial community ecology directly from time-resolved metagenomics. This method extends generalized Lotka–Volterra dynamics to account for external perturbations. Data from recent experiments on antibiotic-mediated Clostridium difficile infection is analyzed to quantify microbial interactions, commensal-pathogen interactions, and the effect of the antibiotic on the community. Stability analysis reveals that the microbiota is intrinsically stable, explaining how antibiotic perturbations and C. difficile inoculation can produce catastrophic shifts that persist even after removal of the perturbations. Importantly, the analysis suggests a subnetwork of bacterial groups implicated in protection against C. difficile. Due to its generality, our method can be applied to any high-resolution ecological time-series data to infer community structure and response to external stimuli.
Author Summary
Recent advances in DNA sequencing and metagenomics are opening a window into the human microbiome revealing novel associations between certain microbial consortia and disease. However, most of these studies are cross-sectional and lack a mechanistic understanding of this ecosystem's structure and its response to external perturbations, therefore not allowing accurate temporal predictions. In this article, we develop a method to analyze temporal community data accounting also for time-dependent external perturbations. In particular, this method combines the classical Lotka–Volterra model of population dynamics with regression techniques to obtain mechanistically descriptive coefficients which can be further used to construct predictive models of ecosystem dynamics. Using then data from a mouse experiment under antibiotic perturbations, we are able to predict and recover the microbiota temporal dynamics and study the concept of alternative stable states and antibiotic-induced transitions. As a result, our method reveals a group of commensal microbes that potentially protect against infection by the pathogen Clostridium difficile and proposes a possible mechanism how the antibiotic makes the host more susceptible to infection.
doi:10.1371/journal.pcbi.1003388
PMCID: PMC3861043  PMID: 24348232
2.  Intestinal CD103+ CD11b+ lamina propria dendritic cells instruct intestinal epithelial cells to express antimicrobial proteins in response to Toll-like receptor 5 activation 
Immunity  2012;36(2):276-287.
Microbial penetration of the intestinal epithelial barrier triggers inflammatory responses that include induction of the bactericidal C-type lectin RegIIIγ. Systemic administration of flagellin, a bacterial protein that stimulates Toll-like receptor 5 (TLR5), induces epithelial expression of RegIIIγ and protects mice from intestinal colonization with antibiotic-resistant bacteria. Flagellin-induced RegIIIγ expression is IL-22-dependent, but how TLR signaling leads to IL-22 expression is incompletely defined. Using conditional depletion of lamina propria dendritic cell (LPDC) subsets, we demonstrated that CD103+ CD11b+ LPDCs, but not monocyte-derived CD103− CD11b+ LPDCs, expressed high amounts of IL-23 following bacterial flagellin administration and drove IL-22-dependent RegIIIγ production. Maximal expression of IL-23 subunits IL-23p19 and IL-12p40 occurred within 60 minutes of exposure to flagellin. IL-23 subsequently induced a burst of IL-22 followed by sustained RegIIIγ expression. Thus, CD103+ CD11b+ LPDCs, in addition to promoting long-term tolerance to ingested antigens, also rapidly produce IL-23 in response to detection of flagellin in the lamina propria.
doi:10.1016/j.immuni.2011.12.011
PMCID: PMC3288454  PMID: 22306017
3.  Profound Alterations of Intestinal Microbiota following a Single Dose of Clindamycin Results in Sustained Susceptibility to Clostridium difficile-Induced Colitis 
Infection and Immunity  2012;80(1):62-73.
Antibiotic-induced changes in the intestinal microbiota predispose mammalian hosts to infection with antibiotic-resistant pathogens. Clostridium difficile is a Gram-positive intestinal pathogen that causes colitis and diarrhea in patients following antibiotic treatment. Clindamycin predisposes patients to C. difficile colitis. Here, we have used Roche-454 16S rRNA gene pyrosequencing to longitudinally characterize the intestinal microbiota of mice following clindamycin treatment in the presence or absence of C. difficile infection. We show that a single dose of clindamycin markedly reduces the diversity of the intestinal microbiota for at least 28 days, with an enduring loss of ca. 90% of normal microbial taxa from the cecum. Loss of microbial complexity results in dramatic sequential expansion and contraction of a subset of bacterial taxa that are minor contributors to the microbial consortium prior to antibiotic treatment. Inoculation of clindamycin-treated mice with C. difficile (VPI 10463) spores results in rapid development of diarrhea and colitis, with a 4- to 5-day period of profound weight loss and an associated 40 to 50% mortality rate. Recovering mice resolve diarrhea and regain weight but remain highly infected with toxin-producing vegetative C. difficile bacteria and, in comparison to the acute stage of infection, have persistent, albeit ameliorated cecal and colonic inflammation. The microbiota of “recovered” mice remains highly restricted, and mice remain susceptible to C. difficile infection at least 10 days following clindamycin, suggesting that resolution of diarrhea and weight gain may result from the activation of mucosal immune defenses.
doi:10.1128/IAI.05496-11
PMCID: PMC3255689  PMID: 22006564
4.  Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura 
Objectives
We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
Background
The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).
Methods
Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.
Results
Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.
Conclusions
Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.
doi:10.1016/j.jacc.2007.04.093
PMCID: PMC3167088  PMID: 17868804

Results 1-4 (4)