IBD
Inflammatory bowel disease pathogenesis: therapeutic implications
Fiocchi C.
Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. cxf18@po.cwru.edu
The pathogenesis of inflammatory bowel disease (IBD) is complex, involving environmental, genetic, microbial, and immune factors. Therefore, treatment should target components that either predispose to or mediate the chronic inflammatory response of IBD. At the moment it is assumed that all components are necessary to have the typical manifestations of IBD but, in reality, it is unclear to what extent each factor contributes to the disease process, and whether some are more important than others. In addition, some factors are not practical targets; for example, environmental factors are poorly defined, too numerous, and require changes that cannot be implemented by the physician or the patient alone. The same is true for genetic factors that are still not amenable to therapeutic manipulations for technical and ethical reasons. This leaves microbial and immune factors as the two categories that can be selected for therapeutic intervention and where all current treatments are focused. The commensal gut flora can be qualitatively or quantitatively modified with antibiotics, probiotics, or diet, and a better characterization of enteric bacteria strains should help greatly in developing more effective therapies. Most current drugs are focused on inhibiting pro-inflammatory molecules produced by immune cells, including biological agents that block specific cytokines such as tumor necrosis factor-alpha. It is anticipated that combination therapies targeting multiple pathogenic components will prove more effective than those blocking single components of IBD pathogenesis.
Chin J Dig Dis. 2005;6(1):6-9
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Physiological Basis for Novel Drug Therapies Used to Treat the Inflammatory Bowel Diseases I. Pathophysiological basis and prospects for probiotic therapy in inflammatory bowel disease.
Shanahan F.
Mechanisms underlying the conditioning influence of the intestinal flora on mucosal homeostasis, including development and function of immune responses, are attracting increasing scientific scrutiny. The intestinal flora is a positive asset to host defense, but some of its components may, in genetically susceptible hosts, become a risk factor for development of inflammatory bowel disease (IBD). It follows that strategies to enhance assets or offset microbial liabilities represent a therapeutic option; therein lies the rationale for manipulation of the flora in IBD. In addition, the diversity of regulatory signalling among the flora and host epithelum, lymphoid tissue, and neuromuscular apparatus is an untapped reservoir from which novel therapeutics may be mined. Moreover, the capacity to engineer food-grade or commensal bacteria to deliver therapeutic molecules to the intestinal mucosa promises to extend the scope of microbial manipulation for the benefit of mankind.
Am J Physiol Gastrointest Liver Physiol. 2005 Mar;288(3):G417-21.
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Probiotic therapy of intestinal inflammation and infections
Sartor R.B.
PURPOSE OF REVIEW: The author presents evidence published during the past year regarding treatment of clinical and experimental intestinal inflammation and infections by probiotic agents.
RECENT FINDINGS: Normal commensal bacteria are implicated in the pathogenesis of chronic, immune-mediated intestinal inflammation, particularly Crohn disease and pouchitis, whereas viral, bacterial, fungal, and protozoan infections are increasingly important with widespread use of immunosuppressive agents and broad-spectrum antibiotics. Combinations of Lactobacilli, Bifidobacteria, and Streptococcus salivarius prevent relapse of recurrent pouchitis and perhaps decrease the initial onset of pouch inflammation, whereas Escherichia coli Nissle 1917 maintains remission in ulcerative colitis. Several agents offer promise as primary therapy of ulcerative colitis. Use of probiotics in Crohn disease remains unsubstantiated. Animal models demonstrate marked differences in responses among various probiotic bacterial species and that nonviable organisms can have therapeutic efficacy. Probiotics have multiple mechanisms of action, including prevention of pathogenic bacterial growth, binding to or penetration of pathogens to mucosal surfaces, stimulation of mucosal barrier function, or altering immunoregulation (decreasing proinflammatory and promoting protective molecules). Although multiple probiotic species block epithelial adhesion and invasion by microbial pathogens in vitro, their proven utility in clinical infections is limited to accelerating recovery from acute infectious diarrhea and preventing antibiotic-associated diarrhoea.
SUMMARY: Probiotics offer promise for physiologic, nontoxic treatment of pouchitis, ulcerative colitis, and acute infectious diarrhea, but larger, controlled clinical studies must be performed to clarify optimal agents; doses; combinations of various probiotics, prebiotics, and antibiotics; and therapeutic conditions.
Curr Opin Gastroenterol. 2005 Jan;21(1):44-50
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Probiotics, prebiotics and antibiotics in inflammatory bowel disease
Cummings J.H., Kong S.C.
Probiotics and prebiotics are the sort of therapy that most patients with inflammatory bowel disease (IBD) wish for. They are without significant side effects, except possibly an increase in gas with prebiotics, and so far, appear to be entirely safe. However, are they effective? More than a dozen studies using probiotics in IBD have now been reported, and there is dear benefit in pouchitis and possibly also in Crohn's, although there are so many clinical types of this condition that a clear indication has yet to emerge. For ulcerative colitis (UC) more studies are needed. The use of prebiotics in IBD is only just starting, although significant effects on both the luminal and mucosa-associated flora have been demonstrated in healthy subjects. Antibiotics offer more certain hope in IBD treatment, although with a much greater risk of unwanted effects. Their efficacy in clinical studies varies, with Crohn's disease and pouchitis reporting more benefit than ulcerative colitis. However, the ideal combination of antibiotics, and rationale for their use has not been determined.
Novartis Found Symp. 2004;263:99-111; discussion 111-4, 211-8
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Probiotic Lactobacillus spp. Diminish Helicobacter hepaticus-Induced Inflammatory Bowel Disease in Interleukin-10-Deficient Mice
Pena J.A., Rogers A.B., Ge Z., Ng V., Li S.Y., Fox J.G.,Versalovic J.
Clinical and experimental evidence has demonstrated the potential role of probiotics in the prevention or treatment of inflammatory bowel disease. Probiotic clones with direct immunomodulatory activity may have anti-inflammatory effects in the intestine. We investigated the roles of tumor necrosis factor alpha (TNF-alpha)-inhibitory Lactobacillus clones with a pathogen-induced murine colitis model. Murine-derived probiotic lactobacilli were selected in vitro for their ability to inhibit TNF-alpha secretion by Helicobacter hepaticus-stimulated macrophages. Interleukin-10 (IL-10)-deficient mice were treated with probiotic Lactobacillus reuteri in combination with Lactobacillus paracasei and then challenged with H. hepaticus. Ten weeks postinoculation, the severity of typhlocolitis was assessed by histologic examination of the cecocolic region. Intestinal proinflammatory cytokine responses were evaluated by real-time quantitative reverse transcriptase PCR and immunoassays, and the quantities of intestinal H. hepaticus were evaluated by real-time PCR. Intestinal colonization by TNF-alpha-inhibitory lactobacilli reduced intestinal inflammation in H. hepaticus-challenged IL-10-deficient mice despite similar quantities of H. hepaticus in cocolonized animals. Proinflammatory colonic cytokine (TNF-alpha and IL-12) levels were lowered in Lactobacillus-treated animals. In this H. hepaticus-challenged IL-10-deficient murine colitis model, lactobacilli demonstrated probiotic effects by direct modulation of mucosal inflammatory responses.
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Host-bacterial interactions in inflammatory bowel disease
Mahida Y.R., Rolfe V.E.
Large numbers of different bacterial species are resident in the lumen of the distal gastrointestinal tract. The normal intestinal host-microbial interactions are not well understood, but the relationship is generally believed to be either mutually beneficial or beneficial to one without disadvantage to the other. Animal model and clinical studies suggest that IBD (inflammatory bowel disease) may develop in a susceptible individual when the normal host-bacterial relationship is dysregulated. In addition to rodent models, this article reviews studies that have investigated the cellular and molecular mechanisms of interactions between intestinal mucosal cells and the resident luminal bacteria in healthy individuals and patients with ulcerative colitis and Crohn's disease. Mechanisms by which the intestinal mucosa is able to avoid pro-inflammatory responses to commensal bacteria (and their products) but able to respond appropriately to luminal pathogens is currently an area of active investigation. Such studies are beginning to provide important clues regarding possible alterations in the mucosa that lead to the development of pro-inflammatory responses to resident bacteria in patients with IBD. Approaches to alter the intestinal microflora for therapeutic purposes and their potential mechanisms of action are also discussed.
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Future therapies for inflammatory bowel disease
Bickston S.J., Comerford L.W., Cominelli F.
Three domains are accepted components of the etiology of inflammatory bowel disease (IBD): genetic predisposition, environmental stimuli, and abnormal immune response. The latter two are reasonable targets for medical therapies in the near future, whereas all three merit consideration for the more distant future as techniques of genetic manipulation evolve. In this review we summarize some of the fundamental concepts and offer comments on treatments for IBD that are likely and desirable in the near and distant future.
Curr Gastroenterol Rep. 2003 Dec;5(6):518-23.
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Use of complementary and alternative medicines by children and adolescents with inflammatory bowel disease
Day A., Whitten K., Bohane T.
Objectives:
The use of complementary and alternative medicines (CAM) appears increasingly prevalent in children and adolescents. Individuals with chronic illness may have patterns of greater usage. This questionnaire-based study aimed to ascertain the frequency of use by a group of children with proven inflammatory bowel disease (IBD) and to consider the reasons for their use.
Methods:
A questionnaire was sent by mail to the parents of patients currently attending a paediatric IBD clinic. Parents were asked to describe their child's usage of alternative and probiotic therapies and to comment on a number of aspects of such therapies.
Results:
Forty-six (77%) of 60 mailed questionnaires were returned. The mean age of the children was 10.9 (+/- 4.1) years and they were taking an average of 1.7 (+/- 0.8) prescribed medications. Thirty-three (72%) of the children were said by their parents to be having CAM, with four having five or more such therapies (average 2.4 +/- 1.3 agents per child). The most commonly used agents were probiotics (78%) and fish oils (56%). A minority (12%) of respondents reported that their child's CAM was very effective, although many (50%) noted partial benefits. The 13 children who had never used any CAM therapies ('non-users') did not differ from the 'users' in terms of gender, age, disease or duration of disease. As expected, non-users expressed greater concerns about use of CAM and described different attitudes towards such therapies.
Conclusion:
Complementary and alternative medicines, especially probiotic therapies, frequently are administered to children and adolescents with inflammatory bowel disease. Often this appears to be due to parental frustration with managing their child's chronic illness. Practitioners caring for children and adolescents with IBD need to be aware that their patients may be using alternative therapies and adopt an open attitude in this situation.
J Paediatr Child Health. 2004 Dec;40(12):681-4.
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