Browsing by Author "Jobin, Christian"

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    The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View
    Xavier, Joao B.; Young, Vincent B.; Skufca, Joseph; Ginty, Fiona; Testerman, Traci; Pearson, Alexander T.; Macklin, Paul; Mitchell, Amir; Shmulevich, Ilya; Xie, Lei; Caporaso, J. Gregory; Crandall, Keith A.; Simone, Nicole L.; Godoy-Vitorino, Filipa; Griffin, Timothy J.; Whiteson, Katrine L.; Gustafson, Heather H.; Slade, Daniel J.; Schmidt, Thomas M.; Walther-Antonio, Marina RS S.; Korem, Tal; Webb-Robertson, Bobbie-Jo M.; Styczynski, Mark P.; Johnson, W. Evan; Jobin, Christian; Ridlon, Jason M.; Koh, Andrew Y.; Yu, Michael; Kelly, Libusha; Wargo, Jennifer A. (Cell Press, 2020-03-01)
    The collection of microbes that live in and on the human body – the human microbiome – can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell–cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology – a systems biology approach.
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    The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer
    Allen, Irving C.; TeKippe, Erin McElvania; Woodford, Rita-Marie T.; Uronis, Joshua M.; Holl, Eda K.; Rogers, Arlin B.; Herfarth, Hans H.; Jobin, Christian; Ting, Jenny P.-Y. (Rockefeller University Press, 2010-05-10)
    Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1Β and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3-l- mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3-l- mice than in Pycard-l- or Casp1-l- animals. No significant differences were observed in disease progression or outcome in Nlrc4-l- mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC.
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    Probiotic bacteria produce conjugated linoleic acid locally in the gut that targets macrophage PPAR gamma to suppress colitis
    Bassaganya-Riera, Josep; Viladomiu, Monica; Pedragosa, Mireia; De Simone, Claudio; Carbo, Adria; Shaykhutdinov, Rustem; Jobin, Christian; Arthur, Janelle C.; Corl, Benjamin A.; Vogel, Hans; Storr, Martin; Hontecillas, Raquel (Public Library of Science, 2012-02-21)
    Background: Inflammatory bowel disease (IBD) therapies are modestly successful and associated with significant side effects. Thus, the investigation of novel approaches to prevent colitis is important. Probiotic bacteria can produce immunoregulatory metabolites in vitro such as conjugated linoleic acid (CLA), a polyunsaturated fatty acid with potent anti-inflammatory effects. This study aimed to investigate the cellular and molecular mechanisms underlying the anti-inflammatory efficacy of probiotic bacteria using a mouse model of colitis. Methodology/Principal Findings: The immune modulatory mechanisms of VSL#3 probiotic bacteria and CLA were investigated in a mouse model of DSS colitis. Colonic specimens were collected for histopathology, gene expression and flow cytometry analyses. Immune cell subsets in the mesenteric lymph nodes (MLN), spleen, blood and colonic lamina propria cells were phenotypically and functionally characterized. Fecal samples and colonic contents were collected to determine the effect of VSL#3 and CLA on gut microbial diversity and CLA production. CLA and VSL#3 treatment ameliorated colitis and decreased colonic bacterial diversity, a finding that correlated with decreased gut pathology. Colonic CLA concentrations were increased in response to probiotic bacterial treatment, but without systemic distribution in blood. VSL#3 and CLA decreased macrophage accumulation in the MLN of mice with DSS colitis. The loss of PPAR γ in myeloid cells abrogated the protective effect of probiotic bacteria and CLA in mice with DSS colitis. Conclusions/Significance: Probiotic bacteria modulate gut microbial diversity and favor local production of CLA in the colon that targets myeloid cell PPAR γ to suppress colitis.