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Probiotic Bacteria Produce Conjugated Linoleic Acid Locally in the Gut That Targets Macrophage PPAR γ to Suppress Colitis

Nutritional Immunology and Molecular Medicine Laboratory, Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2012; 7(2):e31238. DOI: 10.1371/journal.pone.0031238
Source: PubMed

ABSTRACT 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.
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.
Probiotic bacteria modulate gut microbial diversity and favor local production of CLA in the colon that targets myeloid cell PPAR γ to suppress colitis.

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Available from: Janelle Arthur, Sep 04, 2015
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    • "It could be very interesting to test the hypothesis that PUFA-derived bacterial metabolites, by acting as GPR40 and/or GPR120 agonists, could thus modulate host metabolism, namely by changing incretins production. On the other hand, PPARγ is expressed at the intestinal level and activation of this receptor by CLA is associated with a decreased of inflammation in murine model of inflammatory bowel diseases [47]. So, the activation of these receptors by PUFA-derived bacterial metabolism at the intestinal level could have an effect on host metabolism or host inflammation. "
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    ABSTRACT: In vitro studies have suggested that isolated gut bacteria are able to metabolize PUFA into CLA (conjugated linoleic acids) and CLnA (conjugated linolenic acids). However, the bioavailability of fatty acid metabolites produced in vivo by the gut microbes remains to be studied. Therefore, we measured intestinal concentration and plasma accumulation of bacterial metabolites produced from dietary PUFA in mice, first injected with a lipoprotein lipase inhibitor, then force-fed with either sunflower oil (200 µl) rich in n-6 PUFA or linseed oil (200 µl) rich in n-3 PUFA. The greatest production of bacterial metabolites was observed in the caecum and colon, and at a much lesser extent in the jejunum and ileum. In the caecal content, CLA proportions were higher in sunflower oil force-fed mice whereas CLnA proportions were higher in linseed oil force-fed mice. The accumulation of the main metabolites (CLA cis-9,trans-11-18:2 and CLnA cis-9,trans-11,cis-15-18:3) in the caecal tissue was not associated with their increase in the plasma, therefore suggesting that, if endogenously produced CLA and CLnA have any biological role in host metabolism regulation, their effect would be confined at the intestinal level, where the microbiota is abundant.
    PLoS ONE 01/2014; 9(1):e87560. DOI:10.1371/journal.pone.0087560 · 3.23 Impact Factor
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    • "First, probiotic bacteria may fail to protect against tumorigenesis in an environment with established dysbiosis. Earlier studies have revealed that VSL#3 probiotic can provide protection against colitis and colitis-associated CRC when VSL#3 is administered prior to the onset of inflammation24252930324362. VSL#3 bacteria can mediate protection in part through induction of IL-1063, which is absent in our system and also in a subset of human IBD patients646566. "
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    Scientific Reports 10/2013; 3:2868. DOI:10.1038/srep02868 · 5.58 Impact Factor
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    • "Because probiotic intervention resets immunoactivation and metabolism in multiple organs, we have then investigated whether it modulate the expression of nuclear receptors involved in reciprocal regulation of immune system and metabolism. Previous studies have established a role for nuclear receptors in mediating the effects of probiotics in rodent models of inflammation [38]–[42]. Because an inverse regulation exists between several members of nuclear receptor superfamily and inflammation, we have assessed whether products of probiotic metabolism might directly regulate the activity of these regulatory factors. "
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