ABSTRACT: Polyunsaturated dietary fats decrease mortality and bacterial load during septic S. aureus infection, and improve neutrophil function in mice
Project description:Severe infections and sepsis is an increasing clinical problem that cause prolonged morbidity and substantial mortality. At present, antibiotics are essentially the only pharmacological treatment for sepsis. The incidence of antibiotic resistance is increasing and it is therefore critical to find new therapies for sepsis. Staphylococcus aureus (S. aureus) is a major cause of septic mortality. Neutrophils play a major role in defense against bacterial infections. We have recently shown that a saturated high fat diet decreases survival in septic mice, but the mechanisms behind remain elusive. The aim of the present study was to investigate how the dietary fat composition affects survival and neutrophils function after experimental septic infection in mice. We found that, after S. aureus infection, mice fed polyunsaturated high fat diet (HFD/P) for 8 weeks had increased septic survival and decreased bacterial load compared with mice fed saturated HFD (HFD/S), and similar to that of mice given low fat diet (LFD). Furthermore, uninfected mice fed HFD/P had increased number of Ly6G+ neutrophils in bone marrow. In addition, mice fed HFD/P had a higher number Ly6G+ neutrophils recruited to the site of inflammation after peritoneal injection of thioglycollate. In conclusion, polyunsaturated dietary fat increased both survival and the efficiency of the bacterial clearance during septic S. aureus infection. Moreover, this diet enhanced the number and chemotaxis of neutrophils, a key component of the immune response to S. aureus infections. Mice (non-infected) fed saturated high fat diet, low fat diet, or polyunsaturated high fat diet
Project description:Severe infections and sepsis is an increasing clinical problem that cause prolonged morbidity and substantial mortality. At present, antibiotics are essentially the only pharmacological treatment for sepsis. The incidence of antibiotic resistance is increasing and it is therefore critical to find new therapies for sepsis. Staphylococcus aureus (S. aureus) is a major cause of septic mortality. Neutrophils play a major role in defense against bacterial infections. We have recently shown that a saturated high fat diet decreases survival in septic mice, but the mechanisms behind remain elusive. The aim of the present study was to investigate how the dietary fat composition affects survival and neutrophils function after experimental septic infection in mice. We found that, after S. aureus infection, mice fed polyunsaturated high fat diet (HFD/P) for 8 weeks had increased septic survival and decreased bacterial load compared with mice fed saturated HFD (HFD/S), and similar to that of mice given low fat diet (LFD). Furthermore, uninfected mice fed HFD/P had increased number of Ly6G+ neutrophils in bone marrow. In addition, mice fed HFD/P had a higher number Ly6G+ neutrophils recruited to the site of inflammation after peritoneal injection of thioglycollate. In conclusion, polyunsaturated dietary fat increased both survival and the efficiency of the bacterial clearance during septic S. aureus infection. Moreover, this diet enhanced the number and chemotaxis of neutrophils, a key component of the immune response to S. aureus infections.
Project description:Abstract Cardiovascular disease (CVD) is closely associated with obesity through risk factors such as dyslipidemia and chronic low-grade inflammation, which may be affected by diet. Dietary fats have been extensively studied in relation to CVD risk, however these studies have not always yielded consistent results, most likely due to lack in control of experimental conditions and confounding factors. Here we studied the effects of different plant and animal fats on dyslipidemia, inflammation and atherosclerosis. Ldlr-/-.Leiden mice were fed isocaloric energy-dense diets with translational macronutrient composition for 28 weeks. The diets were identical apart from the type of fat they contained: either 1) a mixture of olive and rapeseed oil; 2) sunflower oil; 3) pork fat; 4) beef fat; or 5) milk fat. The fatty acid composition of the diets was determined and effects on circulating lipid and inflammatory risk factors and atherosclerosis were examined, complemented by adipose tissue histology and liver transcriptomics. While visceral fat mass, adipocyte size and adipose tissue inflammation were not differentially affected by the diets, atherosclerotic lesion load and severity was more pronounced with increasing dietary saturated fatty acid content and decreasing monounsaturated and polyunsaturated fatty acid content, and hence most pronounced with beef and milk fat. These differential effects were accompanied by increases in pro-atherogenic plasma lipids/lipoproteins (e.g., triglycerides, apolipoprotein B), activation of pro-atherogenic cytokine/chemokine signaling pathways in liver, and with circulating pro-atherogenic mediators of inflammation altogether providing a rationale for the differential effects of plant and animal fats.
Project description:Septic arthritis, most often caused by Staphylococcus aureus (S. aureus), is a rapidly progressive and destructive joint disease with substantial mortality and morbidity. S. aureus lipoproteins (Lpps) are known to induce arthritis and bone destruction. Here, we aimed to investigate the bone resorptive effect of S. aureus Lpps in a murine arthritis model by intra-articular injection of purified S. aureus Lpps, synthetic lipopeptides, and live S. aureus strains. Analyses of the bone mineral density of the distal femur bone were performed. Intra-articular injection of both live S. aureus and purified S. aureus Lpps were shown to significantly decrease total- and trabecular the bone mineral density. HPLC-high resolution MS/MS analyses revealed that the Lpps expressed by S. aureus SA113 strain contain both diacyl and triacyl lipid moieties. Therefore, tryptic digestion of Lpps was carried out, and the resulting lipopeptides were analyzed by HPLC-MS/MS, in which peptide fragments and neutral losses of fatty acids were used to identify the lipopeptide structures.
(doi: 10.3389/fmicb.2022.843799)
Project description:Pancreatic cancer is a rare but fatal form of cancer, the fourth highest in absolute mortality. The main reason for the high mortality is late detection, caused in part by an incomplete understanding of the initiating factors. Known risk factors include obesity, diet and type 2 diabetes, however the low incidence rate and interconnection of these factors confound the isolation of individual effects from patient data. Here we use epidemiological analysis of prospective human cohorts and parallel tracking of pancreatic cancer in mice to dissect the impacts of obesity, diet and diabetes on pancreatic cancer development, growth and lethality. Through longitudinal magnetic resonance imaging and multi-omics analysis in mice we found distinct effects of obesity and the protein, sugar and fat composition of diet, and no added impact of diabetes. Using epidemiological approaches in humans, we found that dietary plant fats reduced the risk of future pancreatic cancer development, while dietary sugars gave a genotype-dependent increased susceptibility to pancreatic cancer. An interaction between MAD2L1 and dietary glucose in pancreatic cancer pathogenesis was supported through both genetic epidemiology in human patients and molecular analysis of mouse models. These results demonstrate that both quantitative and qualitative dietary effects are at play in pancreatic cancer kinetics, in both mice and humans. Translation of these results to a clinical setting could aid identification of theat-risk population for screening and potential harness dietary modification as a therapeutic measure.
Project description:S. aureus is a deadly pathogen due to its abilities to readily develop antibiotic resistance and evade our immune system. Antibiotic resistance in S. aureus is associated with reduced levels of neutrophil recruitment, which is a vital step in triggering an immune response to resolve infection. In this work, we report enhanced antibiotic agents that act as potential dual-function antibiotic-chemoattractants, enabling augmented neutrophil recruitment to S. aureus along with direct killing. Our agents exploit formylated peptides as chemoattractants for neutrophil recruitment, which is combined with the targeted binding of vancomycin to bacteria that generates a chemoattractant gradient for neutrophil recruitment. The combination of in vitro assays, cellular assays, infection-on-a-chip and in vivo mouse models, determined that these antibiotic-chemoattractants improve the recruitment, engulfment and killing of S. aureus by neutrophils. Furthermore, optimizing the fPep sequence can play an important role in the enhancement of neutrophil activity through differential activation of formyl peptide receptors. This offers an alternate approach in antibiotic development to overcome the threat of antibiotic resistance in the clinic.
Project description:Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can cause persistent infection. Here we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite, itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and oxidative burst, which impairs survival and bacterial killing. In a murine pneumonia model, neutrophil Irg1 expression protects critical lung cell populations from oxidative stress but compromises bacterial clearance. S. aureus is thus able to evade innate immune clearance by targeting neutrophil metabolism and inducing the production of the antiinflammatory metabolite itaconate.
Project description:Abstract S. aureus is a major opportunistic pathogen infecting patients with diabetes. Increased mortality was observed following IV S. aureus infection in diabetic mice compared to non-diabetic controls, correlating with increased numbers of low density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDN development is dependent on TGFβ, which was more activated in the diabetic host. Neutralization of TGFβ, or the integrin responsible for its activation α5β8, reduced numbers of LDNs and improved survival. Comparison of high and low density neutrophils identified PTEN signaling as a central regulator of LDN NET release. Inhibition of PTEN improved survival and decreased NET production in infected diabetic mice. MEDI4893*, a monoclonal antibody that neutralizes alpha toxin (AT) in development for prevention of S. aureus infection, was able to block TGFβ activation, reduce LDNs and NETs, and significantly improve survival. Our data identify a population of neutrophils in infected diabetic mice which correlated with decreased survival and increased NET production. Targeting a single virulence factor of S. aureus prevented emergence of the LDN population and improved survival, supporting potential use of pathogen specific antibodies for treating diabetic infections.
Project description:We assessed the effect of dietary glycemic load on miRNA expression in a sample of healthy, premenopausal women participating in a 12 month intervention designed to lower dietary glycemic load.
Project description:The potential for dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) to improve reproductive efficiency in cattle has received much interest. The mechanisms by which n-3 PUFA may affect physiological and biochemical processes in key reproductive tissues are likely to be mediated by significant alterations in gene expression. We used microarrays to assess endometrial gene expression on day 17 of the estrous cycle in n-3 PUFA compared with control fed heifers.