Current Drug Metabolism - Volume 10, Issue 1, 2009

The human microbiome contains all of the genomes or proteomes, of all the microorganisms present in or on the human body [1, 2]. With increasing interest in the understanding of the association of human microbome with diseases, this special issue is focused specifically on diseases caused by the alteration in human microbiome. The biological mechanisms and pharmacokinetics of various drugs are also included. In addition, this issue also introduces some novel modalities or concepts for treatments of human microbome-related diseases. Two papers, by Matthew E. Falagas and his colleagues, in this issue exemplify the pharmacokinetic/pharmacodynamic aspects of linezolid and tigecycline, two antibiotics for human bacterial infections including community-acquired and nosocomial pneumonia, skin and soft tissue infections, and infections due to vancomycin-resistant enterococci. The paper, by Anja Sandek and coworkers, discusses the gut and intestinal bacteria in chronic heart failure and suggest that the gut may pose a potential target for therapeutic interventions in patients with chronic heart failure. The paper, by Minoru Fukuda and his coworkers, demonstrated their recent findings of inhibition of cholesterol alphaglucosyltransferase by mucin-type O-glycans. The finding illustrates that a battery of carbohydrates expressed in the stomach is closely associated with pathogenesis and prevention of Helicobacter pylori-related diseases. The paper, by Doris M. Jacobs and coworkers, reviews the metabolomics studies with a focus on microbe-host mutualism and concludes that metabolomics holds great potential to better understand the fate of non-digestible food ingredients on gut health and immunity. Keith L. Kirkwood and Carlos Rossa, Jr. discuss the importance of the p38 MAPK pathway in periodontal disease progression and the potential therapeutic consequences of pharmacological antagonism of this pathway in the treatment of periodontal diseases. The paper, by Maria Carmen Collado and coworkers, introduces new evidences support the use of probiotics in the prevention and treatment of many human diseases including atopic diseases, immune disorders, obesity, and diabetes. Andrea M Stringer and his colleagues explore the potentially vital connection between intestinal microflora and the subsequent development of chemotherapy-induced mucositis. Benjamin J. Vesper and his colleagues summarize current advancements in the interactions between the proton pump inhibitors and the natural human microbiota. In this paper of Huang Chun-Ming Eric and his coworkers, novel modalities using vaccination and photodynamic therapies for oral microbialrelated diseases are introduced. The advantages of novel modalities are highlighted and compared with antimicrobial agents and traditional periodontal surgery. We hope you enjoy reading these papers as we did. Special thanks must go to our reviewers for this special issue. REFERENCES [1] Raoult, D. Human microbiome: take-home lesson on growth promoters? Nature, 2008, 454(7205), 690-691. [2] Whitlock, D.R. Human microbiome: hype or false modesty? Nature, 2008, 454(7205), 690.

Linezolid is the first antibiotic of a new class (oxazolidinones). It inhibits protein synthesis by binding to the bacterial 23S ribosomal RNA of the 50S subunit, thus blocking the formation of the functional 70S initiation complex, but it does not inhibit peptidyl transferase. Therefore, its mechanism of action is unique and cross resistance is unlikely to occur; however, resistant strains have already been reported, but the rate of resistance is low in surveillance programs. Linezolid has a favorable pharmacokinetic profile. It is rapidly absorbed when administered orally, and it is 100% bioavailable, thus allowing early switch from intravenous to oral administration. The maximum plasma concentration (range between 13.1±1.8 to 19.5±4.5 μg/ml according to the route of administration, studied population and dosages administered to subjects) is achieved 1-2 hours after the first dosage. It penetrates readily to most tissues of the human body at concentrations much higher than that of the minimal inhibitory concentrations of the targeted pathogens. It is metabolized by oxidation in two major inactive metabolites and is eliminated mainly through the kidneys. Linezolid is bacteriostatic for staphylococci and enterococci but bactericidal for pneumococci and kills bacteria in a time-dependent fashion. It has been studied in several randomized controlled trials and has been approved for the treatment of patients with Gram positive bacterial infections (community-acquired and nosocomial pneumonia, skin and soft tissue infections, and infections due to vancomycin-resistant enterococci) including these due to multidrug-resistant strains. Careful and judicious use is warranted to preserve the activity of this important antibiotic.

Tigecycline is a novel antibacterial agent with a wide spectrum of antimicrobial activity that includes pathogens with clinically significant resistance patterns. The clinical effectiveness of tigecycline has been evaluated in several non-inferiority, phase III, randomized, double-blind, controlled clinical trials regarding, mainly, complicated skin and skin structure infections and complicated intraabdominal infections. Clinical data regarding the effectiveness of tigecycline against infections caused by multidrug-resistant pathogens that commonly affect severely ill patients as well as community acquired pneumonia are favorable, yet limited. The consideration of the pharmacokinetic and pharmacodynamic properties of tigecycline may aid in further understanding the therapeutic role of this agent. Respectively, the utility of tigecycline in the treatment of severe infections involving the bloodstream has not been substantiated, particularly regarding pathogens with borderline susceptibility. Moreover, the fact that a relatively small proportion of the administered tigecycline dose is excreted unchanged in the urine may compromise the effectiveness of this agent in serious urinary tract infections. Increasing the dose of tigecycline to maximize effectiveness against severe infections appears as an appealing therapeutic option, considering the linear pharmacokinetics exhibited by this agent. However, gastrointestinal toxicity (nausea and vomiting) is usually dose-limiting. Further research is recommended on therapeutic strategies to optimize the effectiveness and safety of tigecycline therapy in severely ill patients.

Chronic heart failure (CHF) is now recognized as a multisystem disorder with increased sympathetic tone, hormonal derangements, an anabolic/catabolic imbalance, endothelial dysfunction, and systemic low-grade inflammation affecting various organ systems. Pro-inflammatory cytokines appear to play important roles in that context. There is increasing evidence for the gut to have a pathophysiological role for both chronic inflammation and malnutrition in CHF. Indeed, disturbed intestinal microcirculation and barrier function in CHF seem to trigger cytokine generation, thereby contributing to further impairment in cardiac function. On the other hand, myocardial dysfunction can induce microcirculatory injuries leading to a disruption in the intestinal barrier. This amplifies the inflammatory response. Furthermore, alterations of specific absorption functions of the intestinal mucosa in CHF may aggravate symptoms of cachexia. The increased number of adherent bacteria seen in patients with CHF and elevated systemic levels of anti-lipopolysaccharide immunoglobulin A underscore this fact. Therefore, the gut poses an interesting target for therapeutic interventions in patients with CHF.

Helicobacter pylori is a Gram-negative bacterium that infects over 50% of the world's population. This organism causes various gastric diseases such as chronic gastritis, peptic ulcer, and gastric cancer. H. pylori possesses lipopolysaccharide, which shares structural similarity to Lewis blood group antigens in gastric mucosa. Such antigenic mimicry could result in immune tolerance against antigens of this pathogen. On the other hand, H. pylori colonize gastric mucosa by utilizing adhesins, which bind Lewis blood group antigenrelated carbohydrates expressed on gastric epithelial cells. In chronic gastritis, lymphocytes infiltrate the lamina propria, and such infiltration is facilitated by 6-sulfo sialyl Lewis X-capped O-glycans, peripheral lymph node addressin (PNAd), on high endothelial venule (HEV)-like vessels. The number of HEV-like vessels increases as chronic inflammation progresses. Furthermore, PNAd formed on HEVlike vessels disappear once H. pylori is eradicated. These results indicate that PNAd plays an important role in H. pylori-associated inflammation. H. pylori barely colonizes gland mucous cell-derived mucin where α1,4-GlcNAc-capped O-glycans exist. In vitro experiments show that α1,4-GlcNAc-capped O-glycans function as a natural antibiotic to inhibit H. pylori growth. We recently identified cholesterol α-glucosyltransferase (CHLαGcT) using an expression cloning strategy and showed that this enzyme is specifically inhibited by mucin-type O-glycans like those present in deeper portions of the gastric mucosa. These findings show that a battery of carbohydrates expressed in the stomach is closely associated with pathogenesis and also prevention of H. pylori-related diseases.

Increasing health issues related to immune and gut function such as inflammatory disorders, resistance to infections and metabolic syndrome demand modern analytical approaches to accelerate nutritional research aimed at health promotion and disease prevention. Gut microbial-human mutualism endows the host ‘superorganism’ with a fitness advantage including nutritional, immune and intestinal health aspects. The gut microbiome enlarges our genome and enhances our metabolic potential. Dietary modulation can significantly alter the microbiota community and metabolic activity, and consequently impacts on nutrient bioavailability and host metabolism. Although in an early stage, microbial metabolites generated during colonic fermentation of food stuffs may have beneficial or deleterious effects on intestinal health and immunity, as summarized in this review. However, current evidence is largely based on in vitro and animal studies while substantiation in humans is lacking. The challenge to establish coherent links between the bioconversion of non-digestible food ingredients, their bioavailability and their downstream effects on the host metabolism may be achieved by metabolomics. In this review, metabolomics studies focusing on microbe-host mutualism have demonstrated that metabolomics is capable of detecting and tracking diverse microbial metabolites from different non-digestible food ingredients, of discriminating between phenotypes with different inherent microbiota and of potentially diagnosing infection and gastrointestinal diseases. Integrative approaches such as the combined analysis of the metabolome in different biofluids together with other -omics technologies will cover exogenous and endogenous effects and hence show promise to generate novel hypotheses for innovative functional foods impacting gut health and immunity.

Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. The innate and acquired immune systems are critical for the proper immune response. LPS, an outer membrane constituent of periodontal pathogenic bacteria, stimulates the production of inflammatory cytokines IL-1β, TNFα, IL-6 and RANKL either directly or indirectly. In LPS-stimulated cells, the induction of cytokine expression requires activation of several signaling pathways including the p38 MAPK pathway. This review will discuss the significance of the p38 MAPK pathway in periodontal disease progression and the potential therapeutic consequences of pharmacological antagonism of this pathway in the treatment of periodontal diseases.

The gastrointestinal tract (GIT) microbiota plays an important role in host health due to its involvement in nutritional, immunologic and physiological functions. Microbial imbalances have been associated with enhanced risk of specific diseases. This observation has allowed the introduction of microorganisms as probiotics which are microbes with demonstrated health benefits in humans when ingested in foods. The mechanisms of action include the inhibition of pathogen growth by competition for nutritional sources and adhesion sites, secretion of antimicrobial substances, toxin inactivation. Consequently, the primary clinical interest in the application of probiotics has been in the prevention and treatment of gastrointestinal infections and antibiotic-associated diarrhea diseases. The well-characterized immunomodulatory potential of specific probiotic strains, beyond the effect on the composition of the microbiota, has been be used as innovative tools to alleviate intestinal inflammation, normalize gut mucosal dysfunction, and down-regulate hypersensitivity reactions. Clinical efficacy of specific probiotic strains has been demonstrated in, rotavirus's diarrhea, antibiotic associated diarrhea, irritable bowel syndrome and food allergies. Further, recent clinical and nutritional studies have uncovered the function of specific strains in energy metabolism and thereby have opened up new angles on their exploitation. However, as these processes are highly specific, it is important to characterize the properties of specific probiotic strains an in order to select the best strains or strain combinations for the target in question. Advances have prompted increased the interest of researchers and industry and new applications and targets are being discovered.

Mucositis is a common side effect of chemotherapy which remains poorly understood. Despite advances in the understanding of oral and small intestinal mucositis over recent years, large intestinal mucositis, including diarrhoea, has not been well defined and the underlying mechanisms of the condition are yet to be established. The majority of the literature available concerning large intestinal mucositis is based on clinical observations, with very little basic research existing. However, from the little research conducted, it is likely that the intestinal microflora play a role in the development of chemotherapy-induced mucositis. This review will explore the potentially important relationship between intestinal microflora and the subsequent development of chemotherapy-induced mucositis.

Proton pump inhibitors (PPIs) are commonly used to treat acid-related diseases, most notably gastroesophageal reflux disease. PPIs are designed to shut down the gastric proton pump (H+/K+-ATPase) of parietal cells, thereby raising the pH of the stomach. While effective, a number of side effects have been associated with PPI use. Naturally occurring bacteria, some of which are acid-producing and contain ATPase enzymes, have also been found within the stomach, upper gastrointestinal tract, and oral cavity. Likewise, a number of fungi are known to inhabit the human body; some of these fungi contain H+-ATPase enzymes. Recent literature has suggested that PPIs may be inadvertently affecting these bacteria and fungi in two different ways: 1) PPIs may directly target the proton pumps of the bacteria and fungi, and/or 2) PPIs may indirectly affect the microenvironment of the flora via changes in pH. These unintended interactions are exasperated by the systemic distribution of PPIs throughout the body and may potentially lead to some of the side effects observed with PPI use. Herein we summarize what is currently known about the interactions between the PPIs and the natural human microbiota.

The mouth is a favorable habitat for a great variety of bacteria. Microbial composition of dental plaque is the usual cause of various oral diseases in humans, including dental caries, periodontal disease and halitosis. In general, oral antibacterial agents such as antibiotics are commonly used to treat oral bacterial infection. Traditional periodontal surgery is painful and time-consuming. In addition, bacterial resistance and toxicity of antibiotics have become a global pandemic and unavoidable. Recently, vaccines for dental caries and periodontal disease have been developed and applied. Moreover, the use of photodynamic therapy has become an alternative to antibiotic drugs. The purpose of this article is to highlight the advantages of vaccine therapy and photodynamic therapy for oral microbial-related diseases compared to treatments with antimicrobial agents and traditional periodontal surgery.