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      Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study

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          Abstract

          5-Fluorouracil (5-FU)-based chemotherapy is frequently associated with diarrhoea. We compared two 5-FU-based regimens and the effect of Lactobacillus and fibre supplementation on treatment tolerability. Patients diagnosed with colorectal cancer ( n=150) were randomly allocated to receive monthly 5-FU and leucovorin bolus injections (the Mayo regimen) or a bimonthly 5-FU bolus plus continuous infusion (the simplified de Gramont regimen) for 24 weeks as postoperative adjuvant therapy. On the basis of random allocation, the study participants did or did not receive Lactobacillus rhamnosus GG supplementation (1–2 × 10 10 per day) and fibre (11 g guar gum per day) during chemotherapy. Patients who received Lactobacillus had less grade 3 or 4 diarrhoea (22 vs 37%, P=0.027), reported less abdominal discomfort, needed less hospital care and had fewer chemotherapy dose reductions due to bowel toxicity. No Lactobacillus-related toxicity was detected. Guar gum supplementation had no influence on chemotherapy tolerability. The simplified de Gramont regimen was associated with fewer grade 3 or 4 adverse effects than the Mayo regimen (45 vs 89%), and with less diarrhoea. We conclude that Lactobacillus GG supplementation is well tolerated and may reduce the frequency of severe diarrhoea and abdominal discomfort related to 5-FU-based chemotherapy.

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          Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth.

          Increased inflammatory cytokine levels and intestinal epithelial cell apoptosis leading to disruption of epithelial integrity are major pathologic factors in inflammatory bowel diseases. The probiotic bacterium Lactobacillus rhamnosus GG (LGG) and factors recovered from LGG broth culture supernatant (LGG-s) prevent cytokine-induced apoptosis in human and mouse intestinal epithelial cells by regulating signaling pathways. Here, we purify and characterize 2 secreted LGG proteins that regulate intestinal epithelial cell antiapoptotic and proliferation responses. LGG proteins were purified from LGG-s, analyzed, and used to generate polyclonal antibodies for immunodepletion of respective proteins from LGG-conditioned cell culture media (CM). Mouse colon epithelial cells and cultured colon explants were treated with purified proteins in the absence or presence of tumor necrosis factor (TNF). Akt activation, proliferation, tissue injury, apoptosis, and caspase-3 activation were determined. We purified 2 novel proteins, p75 (75 kilodaltons) and p40 (40 kilodaltons), from LGG-s. Each of these purified protein preparations activated Akt, inhibited cytokine-induced epithelial cell apoptosis, and promoted cell growth in human and mouse colon epithelial cells and cultured mouse colon explants. TNF-induced colon epithelial damage was significantly reduced by p75 and p40. Immunodepletion of p75 and p40 from LGG-CM reversed LGG-CM activation of Akt and its inhibitory effects on cytokine-induced apoptosis and loss of intestinal epithelial cells. p75 and p40 are the first probiotic bacterial proteins demonstrated to promote intestinal epithelial homeostasis through specific signaling pathways. These findings suggest that probiotic bacterial components may be useful for preventing cytokine-mediated gastrointestinal diseases.
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            Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro.

            Mucins are large complex glycoproteins that protect intestinal mucosal surfaces by limiting access of environmental matter to their epithelial cells. Several mucin genes have been described, including MUC3 that is a membrane associated mucin of the small intestine. Increased MUC3 mRNA transcription is induced by incubation of intestinal epithelial cells with a Lactobacillus strain known to be adherent to them. To determine whether increased epithelial cell MUC3 mucin expression in response to Lactobacillus strains results in increased extracellular secretion of MUC3 mucins and the importance of epithelial cell adherence in modulation of MUC3 mucin expression. HT29 cells grown to enhance expression of MUC3 mucins were incubated with selected Lactobacillus strains. Spent cell culture medium was collected for detection of secreted MUC3 mucins using dot blot immunoassay with a generated MUC3 antibody. Post-incubation HT29 cell RNA was collected for analysis of MUC3 expression by northern blot analysis using a MUC3 cDNA probe. In vitro binding studies using Lactobacillus strains incubated alone or coincubated with enteropathogenic Escherichia coli strain E2348/69 were used for adherence and inhibition of adherence studies, respectively. Lactobacillus strains with minimal ability to adhere to HT29 cells failed to induce upregulation of mucin gene expression. There was a direct correlation between upregulation of MUC3 mucin mRNA expression and extracellular secretion of MUC3 mucin. The same Lactobacillus strains that increased extracellular secretion of MUC3 mucin led to reduced adherence of enteropathogen E coli E2348/69 during coincubation experiments. Probiotic microbes induce MUC3 mucin transcription and translation with extracellular secretion of the MUC3 mucins. Epithelial cell adherence enhances the effects of probiotics on eukaryotic mucin expression.
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              Global cancer statistics.

              Statistics are given for global patterns of cancer incidence and mortality for males and females in 23 regions of the world.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                25 September 2007
                16 October 2007
                22 October 2007
                : 97
                : 8
                : 1028-1034
                Affiliations
                [1 ]Department of Oncology, Helsinki University Central Hospital PO Box 180, 00029 HUS Helsinki, Finland
                [2 ]Institute of Biomedicine, University of Helsinki PO Box 63, FI-00014 Finland
                [3 ]Valio Ltd, R&D PO Box 30, FI-00039 VALIO, Helsinki, Finland
                [4 ]Department of Internal Medicine, Helsinki University Central Hospital PO Box 340, FI-00029 Helsinki, Finland
                [5 ]Department of Anaesthesiology, Helsinki University Central Hospital/Jorvi Hospital Turuntie 150, FI-02740 Espoo, Finland
                Author notes
                [* ]Author for correspondence: pia.osterlund@ 123456hus.fi
                Article
                6603990
                10.1038/sj.bjc.6603990
                2360429
                17895895
                e224428e-c548-417c-8232-62d064ec94df
                Copyright 2007, Cancer Research UK
                History
                : 30 May 2007
                : 23 July 2007
                : 14 August 2007
                Categories
                Clinical Studies

                Oncology & Radiotherapy
                5-fluorouracil,probiotic,chemotherapy,colorectal cancer,lactobacillus rhamnosus gg

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