Fecal microbiota transplant rescues mice from human pathogen mediated sepsis by restoring systemic immunity.

Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcare-associated pathogens. Here we report that sepsis in mice caused by a defined four-member pathogen community isolated from a patient with lethal sepsis is associated with the systemic suppression of key elements of the host transcriptome required for pathogen clearance and decreased butyrate expression. More specifically, these pathogens directly suppress interferon regulatory factor 3. Fecal microbiota transplant (FMT) reverses the course of otherwise lethal sepsis by enhancing pathogen clearance via the restoration of host immunity in an interferon regulatory factor 3-dependent manner. This protective effect is linked to the expansion of butyrate-producing Bacteroidetes. Taken together these results suggest that fecal microbiota transplantation may be a treatment option in sepsis associated with immunosuppression

Fecal microbiota transplant rescues mice from sepsis due to multi-drug resistant healthcare pathogens by restoring systemic immunity

Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcare-associated pathogens. Here we report that sepsis in mice caused by a defined four-member pathogen community isolated from a patient with lethal sepsis is associated with the systemic suppression of key elements of the host transcriptome required for pathogen clearance and decreased butyrate expression. More specifically, these pathogens directly suppress interferon regulatory factor 3. Fecal microbiota transplant (FMT) reverses the course of otherwise lethal sepsis by enhancing pathogen clearance via the restoration of host immunity in an interferon regulatory factor 3-dependent manner. This protective effect is linked to the expansion of butyrate-producing Bacteroidetes. Taken together these results suggest that fecal microbiota transplantation may be a treatment option in sepsis associated with immunosuppression

TET2 Regulates Homeostatic Th2 Immunity in the Small Intestine

The intestinal immune system facilitates nutrient absorption in the presence of diverse commensal microbiota while establishing a protective barrier to prevent infection. Prototypically studied microbes induce specific immune programs and these models provide insight into how the immune system is regulated in this unique environment. Tritrichomonas species are protozoan symbionts that are common in many mouse facilities. These protozoa typically induce a type-2 immune program in the small intestine characterized by interleukin-25 (IL-25) signaling and secretory cell hyperplasia that is primarily mediated through the action of GATA3+ innate lymphocytes (ILC2s). However, unlike immunity to helminths, for which the type 2 immune program is evolved, this immune response is self-limiting; a state of tolerance is developed whereby the protozoa continue to occupy the lumen without continued immune activation or adaptive memory formation. We previously identified small intestinal barrier dysfunction correlated with increased IL-25 signaling in mice deficient for the DNA methylcytosine dioxygenase TET2. In these mice, Tritrichomonas colonization induces a population of long-lived adaptive CD4 T lymphocytes expressing GATA3 (Th2 cells) that chronically propagate this IL-25 circuit. Naïve lymphocytes typically require paracrine interleukin-4 (IL-4) from various innate populations for efficient Th2 differentiation in helminth infections. Tet2-deficient naïve cells are able to make increased autocrine IL-4, which results in Th2 polarization even in the absence of helminth induced innate activation. In a model of peanut allergy, loss of TET2 predisposed mice to anaphylaxis. Collectively, our findings formally demonstrate that a cell-intrinsic checkpoint can prevent exacerbated immune responses at homeostasis in the microbe- and stimulus-rich intestinal environment

Environmental toxin acrolein alters levels of endogenous lipids, including TRP agonists: A potential mechanism for headache driven by TRPA1 activation

Exposure to airborne toxins can trigger headaches, but the mechanisms are not well understood. Some environmental toxins, such as acrolein, activate transient receptor potential ankyrin 1 (TRPA1), a receptor involved in pain sensation that is highly expressed in the trigeminovascular system. It has been shown in rat models that repeated exposure to acrolein induces trigeminovascular sensitization to both TRPA1 and TRP vanilloid 1 (TRPV1) agonists, a phenomenon linked to headache. In this study, we test the hypothesis that the sensitization of trigeminovascular responses in rats after acrolein exposure via inhalation is associated with changes in levels of endogenous lipids, including TRPV1 agonists, in the trigeminal ganglia, trigeminal nucleus, and cerebellum. Lipidomics analysis of 80 lipids was performed on each tissue after acute acrolein, chronic acrolein, or room air control. Both acute and chronic acrolein exposure drove widespread alterations in lipid levels. After chronic acrolein exposure, levels of all 6 N-acyl ethanolamines in the screening library, including the endogenous cannabinoid and TRPV1 agonist, N-arachidonoyl ethanolamine, were elevated in trigeminal tissue and in the cerebellum. This increase in TRPV1 ligands by acrolein exposure may indicate further downstream signaling, in that we also show here that a combination of these TRPV1 endogenous agonists increases the potency of the individual ligands in TRPV1-HEK cells. In addition to these TRPV1 agonists, 3 TRPV3 antagonists, 4 TRPV4 agonists, and 25 orphan lipids were up and down regulated after acrolein exposure. These data support the hypothesis that lipid signaling may represent a mechanism by which repeated exposure to the TRPA1 agonist and environmental toxin, acrolein, drives trigeminovascular sensitization

Acute periodontal lesions (periodontal abscesses and necrotizing periodontal diseases) and endo-periodontal lesions

Objective: To critically evaluate the existing literature on acute lesions occurring in the periodontium (periodontal abscesses [PA], necrotizing periodontal diseases [NPD], and endo-periodontal lesions [EPL]) to determine the weight of evidence for the existence of specific clinical conditions that may be grouped together according to common features. The ultimate goal is to support an objective classification system. Importance: Although PA, NPD, and EPL occur with relatively low frequency, these lesions are of clinical relevance, because they require immediate management and might severely compromise the prognosis of the tooth. Findings: In general, the evidence available to define these three conditions was considered limited. PA and EPL are normally associated with deep periodontal pockets, bleeding on probing, suppuration, and almost invariably, with pain. EPL are also associated with endodontic pathology. NPDs have three typical features: pain, bleeding, and ulceration of the gingival interdental papilla. The available data suggested that the prognosis of PA and EPL are worse in periodontitis than in nonperiodontitis patients. Lesions associated with root damage, such as fractures and perforations, had the worst prognosis. NPD progression, extent and severity mainly depended on host-related factors predisposing to these diseases. Conclusions: PA should be classified according to the etiological factors involved, with the most frequent being those occurring in pre-existing periodontal pockets. NPD are clearly associated with the host immune response, which should be considered in the classification system for these lesions. EPLs should be classified according to signs and symptoms that have direct impact on their prognosis and treatment, such as presence or absence of fractures and perforations, and presence or absence of periodontitis.Depto. de Especialidades Clínicas OdontológicasFac. de OdontologíaTRUEpu