Showing papers by "Fergus Shanahan published in 2007"

Rapid and Noninvasive Metabonomic Characterization of Inflammatory Bowel Disease

Abstract: Inflammatory bowel diseases (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) have a major impact on the health of individuals and populations. Accurate diagnosis of inflammatory bowel disease (IBD) at an early stage, and correct differentiation between Crohn's disease (CD) and ulcerative colitis (UC), is important for optimum treatment and prognosis. We present here the first characterization of fecal extracts obtained from patients with CD and UC by employing a noninvasive metabonomics approach, which combines high resolution 1H NMR spectroscopy and multivariate pattern recognition techniques. The fecal extracts of both CD and UC patients were characterized by reduced levels of butyrate, acetate, methylamine, and trimethylamine in comparison with a control population, suggesting changes in the gut microbial community. Also, elevated quantities of amino acids were present in the feces from both disease groups, implying malabsorption caused by the inflammatory disease or an element of protein losing enteropathy. Metabolic differences in fecal profiles were more marked in the CD group in comparison with the control group, indicating that the inflammation caused by CD is more extensive in comparison with UC and involves the whole intestine. Furthermore, glycerol resonances were a dominant feature of fecal spectra from patients with CD but were present in much lower intensity in the control and UC groups. This work illustrates the potential of metabonomics to generate novel noninvasive diagnostics for gastrointestinal diseases and may further our understanding of disease mechanisms.

Antimicrobial activity of lacticin 3147 against clinical Clostridium difficile strains

Abstract: Clostridium difficile-associated diarrhoea (CDAD) is the most common hospital-acquired diarrhoea, and is a major type of gastroenteritis infection in nursing homes and facilities for the elderly. In this study the antimicrobial activity of the two-component lantibiotic, lacticin 3147, against a range of genetically distinct C. difficile isolates was studied. The bacteriocin exhibited an MIC50 of 3.6 μg ml−1 for 10 genetically distinct C. difficile strains isolated from healthy subjects, inflammatory bowel disease patients and culture collection strains. In time-kill studies, 106 c.f.u. ml−1 C. difficile ATCC 42593 and CDAD isolate DPC 6220 were killed within 120 or 20 min incubation, respectively, at a concentration of 6 μg lacticin ml−1. Interestingly, addition of lacticin 3147 to exponentially growing cells of C. difficile ATCC 43593 caused rapid lysis of the cells after an initial lag phase, as measured by the concomitant release of the intracellular enzyme, acetate kinase. The addition of a food-grade, milk-based lacticin containing powder to faecal fermentation demonstrated that lacticin is effective in completely eliminating 106 c.f.u. C. difficile ml−1 from a model faecal environment within 30 min when present at concentrations as low as 18 μg ml−1. While other culturable microflora such as total anaerobes, bacteroides, total non-spore-forming anaerobes and total Gram-negative anaerobes were unaffected, populations of lactobacilli and bifidobacteria were reduced by 3 log cycles at bacteriocin levels sufficient to eliminate over 106 C. difficile. In light of these findings, the potential of lacticin 3147 for treatment of CDAD is discussed.

Probiotic Effects on Inflammatory Bowel Disease

Abstract: Components of the commensal flora, including Bifidobacteria and Lactobacilli, have been associated with beneficial effects on the host. These beneficial effects include maintenance of intestinal homeostasis, competitive exclusion of pathogens, production of antimicrobial compounds, promotion of gut barrier function, and immune modulation. Probiotics currently can be administered in dairy yogurts and drinks and also in the form of sachets or capsules. Although preliminary studies are clearly promising, placebo-controlled, randomized, double-blind clinical trials are required to clarify the role of probiotic bacteria in the treatment of inflammatory bowel disease. The choice of probiotic bacteria, the optimal dose, mode of administration, and duration of therapy still need to be established. Detailed strain characterization is also required for all potential probiotic strains. As evidence accumulates to suggest a breakdown in tolerance toward ubiquitous intestinal bacteria, it appears logical to intervene by modulating the enteric flora. Increasingly, research suggests that probiotics may offer an alternative or adjuvant approach to conventional therapy by altering the intestinal microflora and modulating the host immune system.

The normal intestinal microbiota.

Abstract: Purpose of review: Long neglected and considered a difficult ecosystem to study, several developments have recently converged to renew interest in studying the normal gut microbiota. These include molecular methods of studying the microbiota, improved understanding of host–microbe interactions in health and disease, and the potential for therapeutic manipulation of the microbiota. This review focuses on the most recent work in these areas. Recent findings: Host–microbe signaling in the gut is critical for normal development and homeostasis of the gastrointestinal mucosa. The molecular basis of these interactions promises new therapeutic strategies for various disorders. Particularly noteworthy has been the emergence of evidence for the role of enteric bacterial metabolism in the pathogenesis of disorders ranging from functional and inflammatory bowel diseases to human obesity. Metagenomic and metabolomic profiling of the microbiota, although at an early stage, has demonstrated the range and complexity of the gut ecosystem and cast insights into several diseases. The molecular basis of host–microbe dialogue and the mechanisms by which the host contains enteric bacteria within the lumen has immediate relevance to infectious and chronic inflammatory bowel disease. Summary: Improved understanding of the normal gut microbiota has made the therapeutic manipulation of the gut ecosystem a valid and realistic future prospect.

Mechanisms of action of probiotics in intestinal diseases.

Abstract: Intestinal microbiota is a positive health asset that exerts a conditioning effect on intestinal homeostasis. Resident bacteria deliver regulatory signals to the epithelium and instruct mucosal immune responses. Recent research has revealed a potential therapeutic role for the manipulation of the microbiota and exploitation of host-microbial signalling pathways in the maintenance of human health and treatment of various mucosal disorders. A variety of pharmabiotic strategies, such as the use of specific members of the microbiota, their surface components, or metabolites, as well as genetically modified commensal bacteria, are being investigated for their ability to enhance the beneficial components of the microbiota. It is clear that engagement with host cells is central to pharmabiotic action, and several strain-specific mechanisms of action have been elucidated. However, the molecular details underpinning these mechanisms remain almost entirely unknown. Understanding how pharmabiotics exert their beneficial effects is critical for the establishment of definitive selection criteria for certain pharmabiotic strategies for specific clinical conditions. Scientifically accredited evidence of efficacy and studies to elucidate the molecular mechanisms of host-microbiota interactions are needed to lend credence to the use of pharmabiotic strategies in clinical medicine.

In vitro replication models for the hepatitis C virus.

Abstract: Soon after the discovery of the hepatitis C virus (HCV), attention turned to the development of models whereby replication of the virus could be investigated. Among the HCV replication models developed, the HCV RNA replicon model and the newly discovered infectious cell culture systems have had an immediate impact on the study of HCV replication, and will continue to lead to important advances in our understanding of HCV replication. The aim of this study is to deal with developments in HCV replication models in a chronological order from the early 1990s to the recent infectious HCV cell culture systems.

Intestinal tuberculosis mimicking Crohn's disease: lessons relearned in a new era.

Abstract: Over 400 000 cases of tuberculosis existed in Europe in 2002, 1% of which were intestinal tuberculosis. With population migrations on the increase, physicians may have to face an increase in intestinal tuberculosis. One of the attributes of intestinal tuberculosis is its ability to present in nonspecific ways and to mimic other disorders, in particular inflammatory bowel disease. We present a case series of intestinal tuberculosis presenting as inflammatory bowel disease and referred for management to a specialized clinic in inflammatory bowel disease, followed by a discussion of the difficulties encountered with this condition. We highlight the consequences that misdiagnosis can have, in an era where population demographics are changing in Europe and where immunomodulators and biological agents have the potential to do more harm than good.

Salmonella typhimurium stimulation combined with tumour-derived heat shock proteins induces potent dendritic cell anti-tumour responses in a murine model

Abstract: Appropriate activation of the immune system and effective targeting of tumour cells are the primary hurdles to be overcome for cancer immunotherapy to be successful and applicable to a wide range of tumour types. Our studies have examined the ability of bacterial-stimulated dendritic cells (DCs), loaded with tumour-associated antigens, to inhibit tumour growth in a murine model. Immature murine bone marrow-derived DCs were stimulated in vitro with the cytoplasmic fraction (CM) of Salmonella typhimurium in combination with heat shock proteins (hsps) from 4T1 tumours, isolated using heparin affinity chromatography. Activated DCs were administered subcutaneously. Tumours were generated by orthotopic inoculation of 4T1 cells in Balb/c mice. Primary tumour growth was measured using Vernier calipers, while lung metastases were measured using the clonogenic assay. S. typhimurium CM induced potent tumour necrosis factor (TNF)-alpha responses from DCs accompanied by significant up-regulation of CD80 and CD86 expression. When injected into mice, bacterial-stimulated DCs loaded with 4T1 hsps inhibited the formation of new 4T1 tumours and reduced the growth rate of established tumours. In addition, the number of lung metastatic nodules was reduced significantly in the DC-treated mice (1.6 +/- 0.6 versus 245.9 +/- 55.6, P = 0.0015). DCs stimulated with CM alone, exposed to tumour hsps alone or exposed to tumour hsps from an unrelated tumour cell line did not induce a protective immune response. Dendritic cells primed with a proinflammatory bacterial stimulus and tumour-associated antigens induce a protective anti-tumour immune response in this murine model.

Steroid allergy in patients with inflammatory bowel disease.

Abstract: Summary Background Contact allergy to a steroid enema leading to worsening of inflammatory bowel disease (IBD) has recently been reported. This study was designed to look for evidence of steroid allergy in patients with IBD. Objectives To look for the presence of steroid allergy in general, and steroid enema allergy in particular, in a cohort of IBD patients prepared to attend for patch testing. Methods Patients with IBD in two gastroenterology units at Dublin and Cork were asked to take part in the study. Those who agreed to take part were tested to the British Contact Dermatitis Society standard and steroid batteries. Patients with positive tests to steroids were subsequently asked to attend for intradermal testing with prednisolone, and patch testing to the two commercially available steroid enemas in Ireland and an extended battery of steroids. Reactions were read at days 2 and 4. Results In total, 44 patients from the two units were patch tested. Four patients had positive patch tests to one or more steroids in these batteries: budesonide (n = 2), triamcinolone acetonide (n = 1), tixocortol pivalate (n = 1) and prednisolone (n = 1). Of these, three underwent further testing. All three had positive reactions to intradermal prednisolone and one had a positive test to steroid enema. Conclusions Four (9%) of our patients were found to have steroid allergy. This has important implications for the local and systemic treatment of their IBD.

Probiotics, prebiotics, and inflammatory bowel disease.

Abstract: Publisher Summary Crohn's disease and ulcerative colitis, collectively known as Inflammatory Bowel Disease [“IBD”], are chronic idiopathic relapsing and remitting inflammatory disorders of the gastrointestinal tract. These disorders result in tissue-damaging inflammatory responses in the intestine that might result in much personal suffering and impaired quality of life. Traditional therapeutic strategies for IBD target only the host inflammatory response. Within the gastrointestinal tract, the resident microbiota is an essential health asset that crucially influences homeostasis and the normal structural and functional development of mucosal immunity. In susceptible individuals, some components of the microbiota might become a liability. Genetically-influenced unrestrained mucosal immune activation in response to local bacterial signals is believed to contribute to the pathogenesis of IBD. Probiotics are commensal micro-organisms, usually bacteria, which can be harnessed for health benefits. The term ‘probiotic' traditionally refers to live micro-organisms. Prebiotics are non-digestible food ingredients, usually polysaccharides or oligosaccharides, which beneficially affect the host by selectively modulating the composition of the enteric microbiota. Therefore, pharmabiotics also embrace prebiotics, as well as synbiotics and genetically modified commensal bacteria. This chapter presents an overview of the host-microbe interface within the gut, as well as the therapeutic rationale, role, and range of pharmabiotic options in IBD.

Strain bifidobacterium longum infantis for probiotic production, anti-microbial agent and preparation based on strain bifidobacterium longum infantis with immunomodulating properties

Abstract: FIELD: biotechnology, medicine ^ SUBSTANCE: strain Bifidobacterium longum infantis NCIMB 41003 is isolated from dissecated and washed human gastrointestinal tract and has immunomodulating action after peroral administering Said strain is useful in production of probiotic, anti-microbial agent and preparation with immunomodulating properties Preparation is used for prophylaxis and/or treatment of undesired inflammation activity such as inflammatory bowel disease, irritable bowel syndrome, or inflammation caused by cancer ^ EFFECT: new pharmaceutical agents ^ 46 cl, 25 dwg, 9 tbl, 9 ex

Colitis-associated cancer and dysplasia surveillance: an opposing perspective.

Abstract: Gastroenterologists have an understandable fear of missing colorectal cancer in any patient under their care. In patients with an increased risk of colorectal cancer, it is instinctive and perhaps intuitive for gastroenterologists to search the colon frequently for early markers of cancer risk. This would appear to be supported by various consensus statements and published guidelines on dysplasia surveillance. However, there are opposing viewpoints, and the practice of dysplasia surveillance in patients with ulcerative colitis has been questioned in terms of its efficacy and cost effectiveness.

Probiotics, prebiotics, and inflammatory bowel disease.

Abstract: Publisher Summary Crohn's disease and ulcerative colitis, collectively known as Inflammatory Bowel Disease [“IBD”], are chronic idiopathic relapsing and remitting inflammatory disorders of the gastrointestinal tract These disorders result in tissue-damaging inflammatory responses in the intestine that might result in much personal suffering and impaired quality of life Traditional therapeutic strategies for IBD target only the host inflammatory response Within the gastrointestinal tract, the resident microbiota is an essential health asset that crucially influences homeostasis and the normal structural and functional development of mucosal immunity In susceptible individuals, some components of the microbiota might become a liability Genetically-influenced unrestrained mucosal immune activation in response to local bacterial signals is believed to contribute to the pathogenesis of IBD Probiotics are commensal micro-organisms, usually bacteria, which can be harnessed for health benefits The term ‘probiotic' traditionally refers to live micro-organisms Prebiotics are non-digestible food ingredients, usually polysaccharides or oligosaccharides, which beneficially affect the host by selectively modulating the composition of the enteric microbiota Therefore, pharmabiotics also embrace prebiotics, as well as synbiotics and genetically modified commensal bacteria This chapter presents an overview of the host-microbe interface within the gut, as well as the therapeutic rationale, role, and range of pharmabiotic options in IBD

Exploring the link between gut microbes and obesity

Abstract: Evaluation of: Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI: An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006). In this article, the investigators show that the gut microbiota in leptin-deficient obese (ob/ob) mice are more effective at releasing calories from food during digestion than are the microbiota from nonmutant, lean littermates. This trait is transmissible to germ-free recipients, resulting in greater fat deposition.