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

Abstract

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

RDH10, RALDH2, and CRABP2 are required components of PPARγ-directed ATRA synthesis and signaling in human dendritic cells

“…Due to potential side effects, the application of RSG in the treatment of IBD is not likely ( 61,62 ). Efforts toward the discovery of a new class of PPAR ␥ agonist that elicits therapeutic effects against IBD with limited or no adverse side effects revealed that conjugated linoleic acid (CLA) is a safer alternative to RSG in the model of spontaneous pan-enteritis and DSS-induced colitis (63)(64)(65).…”

Bacterial Neuroactive Compounds Produced by Psychobiotics

“…We have reported that the CLA-producing bacterium, B. breve NCIMB702258 converts linoleic acid to CLA in the murine gut, resulting in significantly elevated c9, t11 CLA in the liver [133]. Moreover, Bassaganya-Riera et al [134] demonstrated that administration of the probiotic mixture VSL#3 to mice with colitis resulted in high colonic concentrations of c9, t11 CLA and that this locally produced CLA improved colitis by activating peroxisome proliferator-activated receptor gamma (PPAR γ) in macrophages. Two studies have also reported the in vivo production of the CLA isomer, trans-10, cis-12 (t10, c12) CLA, by using two strains of human origin, L. rhamnosus PL60 and L. plantarum PL62.…”

Modulation of inflammation and immunity by dietary conjugated linoleic acid

“…Some of these strains are contained in a bacterial mixture known as VLS#3, a probiotic with demonstrated therapeutic efficacy in patients with UC (Bibiloni et al, 2005) and in animal models of colitis (Madsen et al, 2001). Following up on these studies, we recently published novel in vivo evidence showing how VSL#3 administration changes microbial diversity and local CLA production, which results in PPARγ-dependent anti-inflammatory effects during DSS-and IL-10-deficiency-induced experimental colitis in mice (Bassaganya-Riera et al, 2012b). PPARγ is expressed in a large population of colonic cell types including epithelial cells and lamina propria mononuclear cells such as macrophages and lymphocytes.…”