Showing papers by "Fergus Shanahan published in 2001"

Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice.

Abstract: Background: The enteric bacterial flora has been implicated in the pathogenesis of enterocolitis and colon cancer in C57BL/6 IL-10 knockout mice. Probiotic Lactobacilli modify the enteric flora and are thought to have a beneficial effect on enterocolitis. We conducted a controlled feeding trial in IL-10 knockout mice using the probiotic Lactobacillus salivarius ssp. salivarius UCC118. Aim: To determine the effect of probiotic consumption on the gastrointestinal microflora, tumour development and colitis in IL-10 knockout mice. Methods: Twenty IL-10 knockout mice were studied (10 consumed probiotic organisms in milk and 10 consumed unmodified milk) for 16 weeks. Faecal microbial analysis was performed weekly to enumerate excretion of the probiotic UCC118, total lactobacilli, Clostridium perfringens, bacteroides, coliforms, bifidobacteria and enterococci. At sacrifice, the small and large bowel were microbiologically and histologically assessed. Results: L. salivarius UCC118 was detected in faeces from all mice in the probiotic fed group, but not the control group. Faecal coliform and enterococci levels were significantly reduced in probiotic fed animals compared to the controls (P < 0.05). At sacrifice, a significant reduction in C. perfringens numbers was observed in the test mice (P < 0.05). There were no fatalities in the test group compared to two deaths from fulminant colitis in the control group. Only one test mouse developed colonic adenocarcinoma compared to five in the control group. Test animal mucosal inflammation consistently scored lower than that of the control mice. Conclusion: In this placebo controlled trial, modification of enteric flora in IL-10 knockout mice by probiotic lactobacilli was associated with reduced prevalence of colon cancer and mucosal inflammatory activity.

Immune privilege or inflammation? Insights into the Fas ligand enigma.

Abstract: Fas ligand (FasL) has become an enigmatic molecule: some evidence indicates that it contributes to immune privilege in tissues and tumors, whereas other data demonstrates that FasL can elicit inflammation. New findings may begin to reconcile the paradoxical effects of FasL.

Tumour necrosis factor 5' promoter single nucleotide polymorphisms influence susceptibility to rheumatoid arthritis (RA) in immunogenetically defined multiplex RA families.

Abstract: Tumour necrosis factor (TNF) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA) and it has been shown that the TNF-lymphotoxin (TNF-LT) region influences susceptibility to RA. To investigate the role of the TNF-LT locus further, inheritance of TNF 5' promoter alleles was determined in multiplex RA families. Six previously defined TNF promoter single nucleotide polymorphisms (SNPs) (-238, -308, -376, -857, -863, -1031) were observed in these families and in addition, a heretofore undocumented adenine (A) to cytosine (C) substitution at position -572 relative to the transcription start site was defined. TNF 5' promoter SNPs were found to co-segregate with specific TNF microsatellite haplotypes. In particular, the SNP -308A allele was found to be inherited with the TNF a2, b3, c1, d1, e3 (H2) microsatellite haplotype (P < 0.001) which had previously been found to be associated with RA in individuals heterozygous for the HLA-DR 'shared epitope' (SE). When the data were stratified by the presence of the SE with further stratification according to SE DR subtypes and analysed by transmission disequilibrium test (TDT) for which offspring were assumed independent, the -308A and -857T alleles were found to be associated with RA in patients carrying the SE (P = 0.0076 and 0.0063 respectively). The data were further stratified to analyse for association in individuals homozygous or heterozygous for SE alleles. Results showed that the -308A allele was significantly associated with RA susceptibility in individuals heterozygous for the SE (P < 0.001) with the significance only occurring in patients carrying HLA-DR4 (P < 0.001), while the -857T allele was significant in individuals homozygous for the SE (P = 0.0039). Further analysis using the pedigree disequilibrium test (PDT) which conservatively adjusts for all sources of familial correlation except that conferred by linkage disequilibrium still indicated a significant role for the -308A and -857T alleles. These data provide evidence that TNF promoter SNPs may play an independent role in RA susceptibility in specific immunogenetically-defined groups of RA patients.

Probiotics in inflamatory bowel disease

Abstract: Probiotics are live micro-organisms that alter the enteric microflora and have a beneficial effect on health. Bacteria associated with probiotic activity have frequently been lactobacilli or bifidobacteria, but Escherichia coli and enterococcal strains have been used, as have non-bacterial organisms such as Saccharomyces boulardii . The rationale for using probiotics in inflammatory bowel disease (IBD) is based on persuasive evidence implicating intestinal bacteria in the pathogenesis of IBD.1 2 The most compelling evidence is derived from animal models; despite great diversity in genetic defects and immunopathology, a consistent feature is dependency on the presence of normal enteric flora for full expression of disease. It appears that the pathogenesis of IBD, particularly Crohn's disease, involves genetically influenced dysregulation of the mucosal immune …

Fas ligand upregulation is an early event in colonic carcinogenesis.

Abstract: Background/Aims—Fas ligand (FasL) is a mediator of apoptosis via the Fas receptor (Fas/CD95/APO-1). Normal colonic epithelium expresses Fas, and appears to be relatively sensitive to Fas mediated apoptosis. Colonic adenocarcinomas coexpress FasL and Fas without undergoing widespread apoptosis. This study investigates the expression of FasL in colonic carcinogenesis from the earliest stages of the adenoma–carcinoma sequence. Methods—FasL expression was determined in colonic adenomas (n = 38) of varying degrees of dysplasia and histological type by immunohistochemistry. Adenomas that contained areas of carcinomatous change were included (n = 12 of 38). Normal colonic epithelium (n = 10), hyperplastic polyps (n = 8), and serrated adenomas (n = 3) from patients without colonic adenocarcinomas were used for comparison. Cell death was detected in situ in adenomas using TUNEL (terminal transferase mediated dUTP nick end labelling). Results—In normal colonic epithelium and hyperplastic polyps, FasL expression was restricted to the luminal surface of the crypts, where Fas–FasL coexpression was coincident with a high frequency of TUNEL positive epithelial cells. All adenomas (n = 38) had an altered distribution of positive FasL staining; FasL expression was found in most cells (> 70% of neoplastic cells). Expression of Fas was also detected throughout the adenomas, but coexpression of FasL and Fas was not associated with TUNEL positivity in most cells. Conclusions—FasL upregulation occurs early in the adenoma–carcinoma sequence of colon carcinogenesis, and is evident at the level of mild dysplasia. The lack of pronounced apoptosis in areas of adenomas coexpressing Fas and FasL suggests that colonocytes acquire resistance to Fas mediated apoptosis early in the transformation process. Key Words: Fas (CD95/APO-1) • Fas ligand • colon • adenoma

Why is celiac disease so common in Ireland

Abstract: Celiac disease (gluten sensitive enteropathy) is a condition affecting the small bowel, characterized by permanent intolerance to dietary gluten, and giving rise to varying degrees of malabsorption and diarrhea. With the advent of sensitive screening tests, the condition is being increasingly diagnosed. Celiac disease is more common in the Irish and in those of Irish descent. Simoons (1978, 1981) hypothesized that the present-day prevalence of celiac disease across Europe is related to the interaction between genetic gradients, largely determined by the advance of agriculture, and historical patterns of cereal ingestion. This essay examines Simoons' hypothesis as it relates to Ireland, reviews the ethnic and genetic mix of those living on the island of Ireland and aspects of Irish dietary history, and considers how these factors may have combined to result in a high frequency of celiac disease.

Transplantation immunology and the gut

Abstract: The full spectrum of transplantation immunologic reactions and complications associated with immune suppression, opportunistic infections, and mucosal injury from chemoradiation induction protocols, may be observed within the gastrointestinal tract. In addition to being a site of rejection reactions (host-versus-graft) in the setting of intestinal transplantation, the gastrointestinal tract is also a major target organ in graftversus-host (GvH) reactions, in patients undergoing other forms of organ transplantation, particularly bone marrow transplantation. A comprehensive analysis of modern concepts in transplantation immunology is beyond our scope here and an overview of those aspects particularly pertinent to the gastrointestinal tract is presented.