This review describes the antimicrobial properties of nitric oxide (NO) and its application as an antimicrobial agent in different formulations and medical devices. We depict the eukaryotic biosynthesis of NO and its physiologic functions as a cell messenger and as an antimicrobial agent of the cell-mediated immune response. We analyze the antimicrobial activity of NO and the eukaryotic protective mechanisms against NO for the purpose of delineating the therapeutic NO dosage range required for an efficacious and safe antimicrobial activity. We also examine the role of NO produced by virulent bacteria in lessening the efficacy of traditional antimicrobials. In addition, we discuss the efficacy of NO in the healing of infected wounds, describing different NO-producing devices by category, analyzing therapeutic levels, duration of NO production, as well as commercial considerations. Finally, we provide current and future prospects for the design and use of NO-producing devices.

We performed an analysis to determine the importance of bile acid modification genes in the gut microbiome of inflammatory bowel disease and type 2 diabetic patients. We used publicly available metagenomic datasets from the Human Microbiome Project and the MetaHIT consortium, and determined the abundance of bile salt hydrolase gene (bsh), 7 alpha-dehydroxylase gene (adh) and 7-alpha hydroxysteroid dehydrogenase gene (hsdh) in fecal bacteria in diseased populations of Crohn's disease (CD), Ulcerative Colitis (UC) and Type 2 diabetes mellitus (T2DM). Phylum level abundance analysis showed a significant reduction in Firmicute-derived bsh in UC and T2DM patients but not in CD patients, relative to healthy controls. Reduction of adh and hsdh genes was also seen in UC and T2DM patients, while an increase was observed in the CD population as compared to healthy controls. A further analysis of the bsh genes showed significant differences in the correlations of certain Firmicutes families with disease or healthy populations. From this observation we proceeded to analyse BSH protein sequences and identified BSH proteins clusters representing the most abundant strains in our analysis of Firmicute bsh genes. The abundance of the bsh genes corresponding to one of these protein clusters was significantly reduced in all disease states relative to healthy controls. This cluster includes bsh genes derived from Lachospiraceae, Clostridiaceae, Erysipelotrichaceae and Ruminococcaceae families. This metagenomic analysis provides evidence of the importance of bile acid modifying enzymes in health and disease. It further highlights the importance of identifying gene and protein clusters, as the same gene may be associated with health or disease, depending on the strains expressing the enzyme, and differences in the enzymes themselves.

A disrupted gut microbiome, including a reduction of bile salt hydrolase (BSH)-active bacteria, can significantly impair the metabolism of BAs and may result in an inability to maintain glucose homeostasis as well as normal cholesterol breakdown and excretion. To better understand the link between dysbiosis, BA dysmetabolism and chronic degenerative disease, large-scale metagenomic sequencing studies, metatranscriptomics, metaproteomics and metabolomics should continue to catalog functional diversity in the gastrointestinal tract of both healthy and diseased populations. Further, BSH-active probiotics should continue to be explored as treatment options to help restore metabolic levels.

During the systemic inflammatory state induced by sepsis, the potential for coagulopathy exists because of up-regulation of natural procoagulants and antifibrinolytics, and down-regulation of natural anti-coagulants, with protein C (PC) being a critical example of the latter case. PC functions as an anti-coagulant, profibrinolytic, and anti-inflammatory agent, and, thus, its administration or deficiency may affect the course and outcome of sepsis in patients. In this study, a cecal ligation and puncture model of septic peritonitis was applied to wild-type mice and littermates with a targeted heterozygous deficiency of PC (PC ؉/؊ ) to characterize the importance of a PC-deficiency on polymicrobial sepsis. An enhanced mortality rate was found to accompany a PC deficiency. Plasma cytokines, as well as organ-specific expression of cytokine transcripts, were elevated in PC ؉/؊ mice. No signs of severe disseminated intravascular coagulation (DIC) were observed in wild-type or PC ؉/؊ mice, as indicated by an increase in fibrinogen levels and the invariability of platelet counts after cecal ligation and puncture. Consumption of coagulation factors was similar in both genotypes and a decrease in the PC mRNA and protein levels was more prominent in PC ؉/؊ mice. Renal and organ muscle damage was enhanced in PC ؉/؊ mice, as shown by increases in plasma blood urea nitrogen, creatinine, and creatinine kinase. Hypotension and bradycardia were more enhanced in PC ؉/؊ mice than in wild-type mice, thus provoking a more severe septic shock response. Thus, the hemodynamic role of PC during sepsis is of critical importance to the outcome of the

The size and composition of the circulating bile acid (BA) pool are important factors in regulating the human gut microbiota. Disrupted regulation of BA metabolism is implicated in several chronic diseases. Bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242, previously shown to decrease LDL-cholesterol and increase circulating BA, was investigated for its dose response effect on BA profile in a pilot clinical study. Ten otherwise healthy hypercholesterolemic adults, recruited from a clinical trial site in London, ON, were randomized to consume delayed release or standard release capsules containing L. reuteri NCIMB 30242 in escalating dose over 4 weeks. In another aspect, 4 healthy normocholesterolemic subjects with LDL-C below 3.4 mmol/l received delayed release L. reuteri NCIMB 30242 at a constant dose over 4 weeks. The primary outcome measure was the change in plasma BA profile over the intervention period. Additional outcomes included circulating fibroblast growth factor (FGF)-19, plant sterols and LDL-cholesterol as well as fecal microbiota and bsh gene presence. After one week of intervention subjects receiving delayed release L. reuteri NCIMB 30242 increased total BA by 1.13 ± 0.67 μmol/l (P = 0.02), conjugated BA by 0.67 ± 0.39 μmol/l (P = 0.02) and unconjugated BA by 0.46 ± 0.43 μmol/l (P = 0.07), which represented a greater than 2-fold change relative to baseline. Increases in BA were largely maintained post-week 1 and were generally correlated with FGF-19 and inversely correlated with plant sterols. This is the first clinical support showing that a BSH-active probiotic can significantly and rapidly influence BA metabolism and may prove useful in chronic diseases beyond hypercholesterolemia.