CLA-supplemented diet accelerates experimental colorectal cancer by inducing TGF-β-producing macrophages and T cells

Abstract

Conjugated linoleic acid (CLA) has been shown to activate the nuclear receptor PPAR-γ and modulate metabolic and immune functions. Despite the worldwide use of CLA dietary supplementation, strong scientific evidence for its proposed beneficial actions are missing. We found that CLA-supplemented diet reduced mucosal damage and inflammatory infiltrate in the dextran sodium sulfate (DSS)-induced colitis model. Conditional deletion of PPAR-γ in macrophages from mice supplemented with CLA diet resulted in loss of this protective effect of CLA, suggesting a PPAR-γ-dependent mechanism mediated by macrophages. However, CLA supplementation significantly worsened colorectal tumor formation induced by azoxymethane and DSS by inducing macrophage and T-cell-producing TGF-β via PPAR-γ activation. Accordingly, either macrophage-specific deletion of PPAR-γ or in vivo neutralization of latency-associated peptide (LAP, a membrane-bound TGF-β)-expressing cells abrogated the protumorigenic effect of CLA. Thus, the anti-inflammatory properties of CLA are associated with prevention of colitis but also with development of colorectal cancer.

LAP + Cells Modulate Protection Induced by Oral Vaccination with Rhesus Rotavirus in a Neonatal Mouse Model

“…RRV vaccination reduces the frequency of total memory (CD44 ؉ ) LAP ؉ cells in spleen and induces CD4 tetramer-positive LAP ؉ T cells in spleen and liver. As stated above, LAP ϩ Treg play an important role in mucosal immunity, and they can be depleted in mice by the administration of antibodies against LAP (11)(12)(13)(14)(15). First, we verified if anti-LAP antibody treatment effectively depleted total CD4 LAP ϩ T cells.…”

“…These Treg depend on TGF-␤ for their generation and mediate tolerance in a TGF-␤-dependent mechanism (10). The administration to mice of antibodies against LAP that deplete LAP-positive (LAP ϩ ) Treg has been illuminating in establishing that these cells play a role in oral tolerance, autoimmune diseases, and antitumor immunity (11)(12)(13)(14)(15). To our knowledge, the role of LAP ϩ cells in in vivo immunity to pathogens, and viruses in particular, using this strategy has not been evaluated.…”

Intervention on gut microbiota may change the strategy for management of colorectal cancer

“…Nowadays, linoleic acid (conjugated linoleic acid)‐supplemented diets are widely admired. Recent scientific study has demonstrated the role of conjugated linoleic acid dietary supplementation in decreasing the inflammatory infiltrate and mucosal damage in the mice model of DSS‐induced colitis by mediating nuclear receptor PPAR‐γ in macrophages 40 . A couple of studies have reported the chemo‐preventive effects of Aster glehni, a traditional edible herb on the animal models of CRC.…”

Dietary Components, Microbial Metabolites and Human Health: Reading between the Lines

“…Moreover, they are a mixture of positional and geometric isomers of linoleic acid belonging to conjugated fatty acids that contain one or more cis-trans non-methylene discontinuous double bonds ( Figure 1 ). Moreover, CLA can also be produced endogenously by the enzyme delta-9-desaturase [ 87 ]. The production of CLA isomers is mainly due to the rumen microbiota including the strains of Clostridium proteoclasticum , Propionibacterium acnes , Butyrivibrio fibrisolvens , Megasphaera elsdenii , and rumen protozoa [ 88 ].…”

“…Some studies have shown that dietary supplementation of CLA can activate PPAR-γ in macrophages and T cells and play anti-inflammatory and cancer-promoting roles. On the one hand, CLA can improve amyloid-induced colitis; in contrast, it can also promote the formation of colorectal cancer in mice [ 87 ]. When fed with 10-hydroxy- cis -12-octadecenoic acid, a metabolite derived from linoleic acid, NC/Nga mice had better health conditions, such as restoring skin barrier, suppressing skin inflammation, enhancing intestinal IgA production and regulating gut microbiota [ 89 ].…”