Intestinal inflammation is frequently associated with an alteration of the gut microbiota, termed dysbiosis, which is characterized by a reduced abundance of obligate anaerobic bacteria and an ...expansion of facultative Proteobacteria such as commensal E. coli. The mechanisms enabling the outgrowth of Proteobacteria during inflammation are incompletely understood. Metagenomic sequencing revealed bacterial formate oxidation and aerobic respiration to be overrepresented metabolic pathways in a chemically induced murine model of colitis. Dysbiosis was accompanied by increased formate levels in the gut lumen. Formate was of microbial origin since no formate was detected in germ-free mice. Complementary studies using commensal E. coli strains as model organisms indicated that formate dehydrogenase and terminal oxidase genes provided a fitness advantage in murine models of colitis. In vivo, formate served as electron donor in conjunction with oxygen as the terminal electron acceptor. This work identifies bacterial formate oxidation and oxygen respiration as metabolic signatures for inflammation-associated dysbiosis.
Display omitted
•Genes encoding respiratory pathways are overrepresented in the dysbiotic microbiome•Utilization of microbiota-derived formate enhances E. coli fitness in the inflamed gut•Formate concentrations in the gut are elevated during inflammation-associated dysbiosis•During gut inflammation, formate utilization by E. coli requires oxygen respiration
Intestinal inflammation is associated with changes in the microbiota composition (dysbiosis), such as the expansion of the commensal Enterobacteriaceae population. Hughes and Winter et al. show that utilization of microbiota-derived formate as electron donor and oxygen as terminal electron acceptor contribute to the bloom of Enterobacteriaceae in the inflamed gut.
Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing
strains, are risk factors for the development of colorectal cancer. Here, we sought to determine ...whether precision editing of gut microbiota metabolism and composition could decrease the risk for tumor development in mouse models of colitis-associated colorectal cancer (CAC). Expansion of experimentally introduced
strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways. Oral administration of sodium tungstate inhibited
molybdoenzymes and selectively decreased gut colonization with genotoxin-producing
and other Enterobacteriaceae. Restricting the bloom of Enterobacteriaceae decreased intestinal inflammation and reduced the incidence of colonic tumors in two models of CAC, the azoxymethane/dextran sulfate sodium colitis model and azoxymethane-treated,
-deficient mice. We conclude that metabolic targeting of protumoral Enterobacteriaceae during chronic inflammation is a suitable strategy to prevent the development of malignancies arising from gut microbiota dysbiosis.
During Salmonella-induced gastroenteritis, mucosal inflammation creates a niche that favors the expansion of the pathogen population over the microbiota. Here, we show that Salmonella Typhimurium ...infection was accompanied by dysbiosis, decreased butyrate levels, and substantially elevated lactate levels in the gut lumen. Administration of a lactate dehydrogenase inhibitor blunted lactate production in germ-free mice, suggesting that lactate was predominantly of host origin. Depletion of butyrate-producing Clostridia, either through oral antibiotic treatment or as part of the pathogen-induced dysbiosis, triggered a switch in host cells from oxidative metabolism to lactate fermentation, increasing both lactate levels and Salmonella lactate utilization. Administration of tributyrin or a PPARγ agonist diminished host lactate production and abrogated the fitness advantage conferred on Salmonella by lactate utilization. We conclude that alterations of the gut microbiota, specifically a depletion of Clostridia, reprogram host metabolism to perform lactate fermentation, thus supporting Salmonella infection.
Display omitted
•Salmonella Typhimurium (S. Tm) utilizes l-lactate as a nutrient during gut infection•Lactate used by S. Tm during infection is primarily host derived•Depletion of Clostridia from the microbiota alters host metabolism to produce lactate•Oxygen is the terminal electron acceptor for l-lactate utilization by S. Tm
Intestinal infection with Salmonella Typhimurium results in inflammation-induced dysbiosis. Gillis et al. demonstrate that depletion of commensal Clostridia reduces butyrate availability and subsequently alters host metabolism to produce lactate. Lactate oxidation by Salmonella enhances fitness in the gut and allows the pathogen to outcompete the microbiota.
The mucosal inflammatory response induced by Salmonella serovar Typhimurium creates a favorable niche for this gut pathogen. Conventional wisdom holds that S. Typhimurium undergoes an incomplete ...tricarboxylic acid (TCA) cycle in the anaerobic mammalian gut. One change during S. Typhimurium-induced inflammation is the production of oxidized compounds by infiltrating neutrophils. We show that inflammation-derived electron acceptors induce a complete, oxidative TCA cycle in S. Typhimurium, allowing the bacteria to compete with the microbiota for colonization. A complete TCA cycle facilitates utilization of the microbiota-derived fermentation product succinate as a carbon source. S. Typhimurium succinate utilization genes contribute to efficient colonization in conventionally raised mice, but provide no growth advantage in germ-free mice. Mono-association of gnotobiotic mice with Bacteroides, a major succinate producer, restores succinate utilization in S. Typhimurium. Thus, oxidative central metabolism enables S. Typhimurium to utilize a variety of carbon sources, including microbiota-derived succinate.
Display omitted
•During gut colonization, S. Typhimurium performs a complete, oxidative TCA cycle•Host-derived alternative electron acceptors impact S. Tm central metabolism•Uptake of C4-dicarboxylates enhances S. Tm fitness in the inflamed intestine•Utilization of microbiota-derived succinate supports growth of S. Tm in the gut lumen
Spiga et al. show that during colonization of the intestinal lumen, the enteric pathogen S. Typhimurium performs a complete TCA cycle. This oxidative central metabolism enables S. Typhimurium to utilize the microbiota-derived fermentation product succinate as a nutrient and to compete with the microbiota for colonization of the intestinal tract.
In spite of all the research effort for developing new vaccines against brucellosis, it remains unclear whether these new vaccine technologies will in fact become widely used. The goal of this study ...was to perform a meta-analysis to identify parameters that influence vaccine efficacy as well as a descriptive analysis on how the field of Brucella vaccinology is advancing concerning type of vaccine, improvement of protection on animal models over time, and factors that may affect protection in the mouse model.
A total of 117 publications that met the criteria were selected for inclusion in this study, with a total of 782 individual experiments analyzed.
Attenuated (n = 221), inactivated (n = 66) and mutant (n = 102) vaccines provided median protection index above 2, whereas subunit (n = 287), DNA (n = 68), and vectored (n = 38) vaccines provided protection indexes lower than 2. When all categories of experimental vaccines are analyzed together, the trend line clearly demonstrates that there was no improvement of the protection indexes over the past 30 years, with a low negative and non significant linear coefficient. A meta-regression model was developed including all vaccine categories (attenuated, DNA, inactivated, mutant, subunit, and vectored) considering the protection index as a dependent variable and the other parameters (mouse strain, route of vaccination, number of vaccinations, use of adjuvant, challenge Brucella species) as independent variables. Some of these variables influenced the expected protection index of experimental vaccines against Brucella spp. in the mouse model.
In spite of the large number of publication over the past 30 years, our results indicate that there is not clear trend to improve the protective potential of these experimental vaccines.
This work reports a combination of aryl diselenides/hydrogen peroxide and carbon‐nanotube (CNT)/rhodium nanohybrids (RhCNT) for naphthol oxidation towards the synthesis of 1,4‐naphthoquinones and ...evaluation of their relevant trypanocidal activity. Under a combination of (PhSe)2/H2O2 in the presence of O2 in iPrOH/hexane, several benzenoid (A‐ring)‐substituted quinones were prepared in moderate to high yields. We also studied the contribution of RhCNT as co‐catalyst in this process and, in some cases, yields were improved. This method provides an efficient and versatile alternative for preparing A‐ring‐modified naphthoquinonoid compounds with relevant biological profile.
It's the mix that makes it! A combination of aryl diselenides/hydrogen peroxide for naphthol oxidation towards synthesis of 1,4‐naphthoquinones and evaluation of their relevant trypanocidal activity. Under a combination of PhSeSePh/H2O2 in the presence of O2 in iPrOH/Hexane, several substituted benzenoid quinones were prepared in moderate to high yields. RhCNT was also used as co‐catalyst in this process.
Evasion of host immune responses is a prerequisite for chronic bacterial diseases; however, the underlying mechanisms are not fully understood. Here, we show that the persistent intracellular ...pathogen Brucella abortus prevents immune activation of macrophages by inducing CD4(+)CD25(+) T cells to produce the anti-inflammatory cytokine interleukin-10 (IL-10) early during infection. IL-10 receptor (IL-10R) blockage in macrophages resulted in significantly higher NF-kB activation as well as decreased bacterial intracellular survival associated with an inability of B. abortus to escape the late endosome compartment in vitro. Moreover, either a lack of IL-10 production by T cells or a lack of macrophage responsiveness to this cytokine resulted in an increased ability of mice to control B. abortus infection, while inducing elevated production of pro-inflammatory cytokines, which led to severe pathology in liver and spleen of infected mice. Collectively, our results suggest that early IL-10 production by CD25(+)CD4(+) T cells modulates macrophage function and contributes to an initial balance between pro-inflammatory and anti-inflammatory cytokines that is beneficial to the pathogen, thereby promoting enhanced bacterial survival and persistent infection.
The potential use of carbon-based methodologies for drug delivery and reproductive biology in cows raises concerns about residues in milk and food safety. This study aimed to assess the potential of ...Fourier transform Raman spectroscopy and discriminant analysis using partial least squares (PLS-DA) to detect functionalized multiwalled carbon nanotubes (MWCNT) in bovine raw milk. Oxidized MWCNT were diluted in milk at different concentrations from 25.00 to 0.01 µg/mL. Raman spectroscopy measurements and PLS-DA were performed to identify low concentrations of MWCNT in milk samples. The PLS-DA model was characterized by the analysis of the variable importance in projection (VIP) scores. All the training samples were correctly classified by the model, resulting in no false-positive or false-negative classifications. For test samples, only one false-negative result was observed, for 0.01 µg/mL MWCNT dilution. The association between Raman spectroscopy and PLS-DA was able to identify MWCNT diluted in milk samples up to 0.1 µg/mL. The PLS-DA model was built and validated using a set of test samples and spectrally interpreted based on the highest VIP scores. This allowed the identification of the vibrational modes associated with the D and G bands of MWCNT, as well as the milk bands, which were the most important variables in this analysis.
Salmonella serotypes are a major cause of human morbidity and mortality worldwide. Over the past decades, a series of animal models have been developed to advance vaccine development, provide ...insights into immunity to infection, and study the pathogenesis of human Salmonella disease. The successive introduction of new animal models, each suited to interrogate previously neglected aspects of Salmonella disease, has ushered in important conceptual advances that continue to have a strong and sustained influence on the ideas driving research on Salmonella serotypes. This article reviews important milestones in the use of animal models to study human Salmonella disease and identify research needs to guide future work.
Capsular polysaccharides are common virulence factors of extracellular, but not intracellular bacterial pathogens, due to the antiphagocytic properties of these surface structures. It is therefore ...paradoxical that Salmonella enterica subspecies
serovar Typhi, an intracellular pathogen, synthesizes a virulence-associated (Vi) capsule, which exhibits antiphagocytic properties. Here, we show that the Vi capsular polysaccharide has different functions when S. Typhi interacts with distinct subsets of host phagocytes. The Vi capsular polysaccharide allowed S. Typhi to selectively evade phagocytosis by human neutrophils while promoting human macrophage phagocytosis. A screen of C-type lectin receptors identified human DC-SIGN as the receptor involved in macrophage binding and phagocytosis of capsulated S. Typhi. Consistent with the anti-inflammatory activity of DC-SIGN, purified Vi capsular polysaccharide reduced inflammatory responses in macrophages. These data suggest that binding of the human C-type lectin receptor DC-SIGN by the Vi capsular polysaccharide contributes to the pathogenesis of typhoid fever.
Salmonella enterica subspecies
serovar Typhi is the causative agent of typhoid fever. The recent emergence of S. Typhi strains which are resistant to antibiotic therapy highlights the importance of vaccination in managing typhoid fever. The virulence-associated (Vi) capsular polysaccharide is an effective vaccine against typhoid fever, but the role the capsule plays during pathogenesis remains incompletely understood. Here, we identify the human C-type lectin receptor DC-SIGN as the receptor for the Vi capsular polysaccharide. Binding of capsulated S. Typhi to DC-SIGN resulted in phagocytosis of the pathogen by macrophages and induction of an anti-inflammatory cytokine response. Thus, the interaction of the Vi capsular polysaccharide with human DC-SIGN contributes to the pathogenesis of typhoid fever and should be further investigated in the context of vaccine development.
PDF
