Modulation of inflammation and immunity by dietary conjugated linoleic acid

Depletion due to binding to spike protein has consequences

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The main dietary sources of CLA are dairy products and beef. According to this paper there are many benefits to ensuring that your diet provides enough of these. And by implication repeat dosing with a transfection agent that depletes your CLA may not be such a good idea.

If they had done long term randomised controlled trials we would know just how bad an idea it might be, along with possible synergistic effects caused by other confirmed pathologies. But they didn't, so until then the precautionary principle applies.

Modulation of inflammation and immunity by dietary conjugated linoleic acid (2016)

Abstract

Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of linoleic acid. This family of polyunsaturated fatty acids has drawn significant attention in the last three decades for its variety of biologically beneficial properties and health effects. CLA has been shown to exert various potent protective functions such as anti-inflammatory, anticarcinogenic, antiadipogenic, antidiabetic and antihypertensive properties in animal models of disease. Therefore, CLA represents a nutritional avenue to prevent lifestyle diseases or metabolic syndrome. Initially, the overall effects of CLA were thought to be the result of interactions between its two major isomers: cis-9, trans-11 and trans-10, cis-12. However, later evidence suggests that such physiological effects of CLA might be different between the isomers: t-10, c-12-CLA is thought to be anticarcinogenic, antiobesity and antidiabetic, whereas c-9, t-11-CLA is mainly anti-inflammatory. Although preclinical data support a benefit of CLA supplementation, human clinical findings have yet to show definitive evidence of a positive effect. The purpose of this review is to comprehensively summarize the mechanisms of action and anti-inflammatory properties of dietary CLA supplementation and evaluate the potential uses of CLA in human health and disease.

Keywords: Asthma; Conjugated linoleic acid; Diabetes; Inflammation; Inflammatory Bowel Disease; Obesity.

Excerpts:

3.1. CLA and the immune response

Beneficial effects of CLA on immune and inflammatory responses have been reported in a number of animal models (Bassaganya-Riera and Hontecillas, 2002, Bassaganya-Riera and Pogranichniy, 2003, Cook and Miller, 1993, Yu and Correll, 2002; Yang and Cook, 2003; Dilzer and Park, 2012) and human clinical trials (Albers and van der Wielen, 2003, Turpeinen and Ylonen, 2008, Peterson and O’Shea, 2009), including decreased colonic inflammation, reduced antigen-induced cytokine production by immune cells, decreased adverse effects of immune challenges, and modulation of inflammatory mediators such as cytokines, prostaglandins, leukotrienes and immunoglobulins. There is a powerful body of evidence demonstrating that CLA is able to modify the immune response and prevent immune-induced wasting by influencing the production of soluble factors and inflammatory molecules (Miller and Park, 1994, Oleszczuk and Oleszczuk, 2012).

Both c-9,t-11 and t-10,c-12 CLA isomers decrease innate immune responses by lowering the activity of monocytes, macrophages, dendritic cells and natural killer cells and diminishing the production of prostaglandins and leukotrienes (O'Shea et al., 2004). Moreover, dietary c-9,t-11 and t-10,c-12 CLA mixtures (50:50 and 80:20) improve antigen-specific adaptive immune responses to bacterial and viral antigens, making it highly beneficial in immunocompromised patients whose responses are insufficient. 50:50c-9, t-11 and t-10, c-12 CLA dietary supplementation has also been shown to enhance humoral responses by increasing the production of IgG, IgM and IgA in spleen and mesenteric lymph nodes and to decrease macrophage function by reducing the synthesis of inflammatory mediators and enzymes in rats (Bassaganya-Riera et al., 2003). Moreover, c-9, t-11 CLA is also able to reduce IgE, IL-12 and PGE2 expression, all of which play key roles during allergic reactions and airway inflammation (Sugano et al., 1998). Hence, CLA differentially regulates class-specific production of immunoglobulins. Such influence on immunoglobulin production and enhanced antibody synthesis has been attributed to the t-10c-12 CLA isomer, which elicits opposing effects depending on the cytokine environment (Yamasaki et al., 2003a).

3.2. CLA as a modulator of T cell responses

In 2001, we assessed the effects of dietary conjugated linoleic acid on growth, body composition and immune competence in nursery pigs of dirty and clean environments (Bassaganya-Riera et al., 2001a). Such study revealed an expansion of peripheral porcine CD8+ lymphocyte subsets and enhancement of lymphocyte proliferation in both clean and dirty environments during 50:50c-9, t-11 and t-10, c-12 dietary CLA supplementation. These interesting data suggested that CLA enhances cellular immunity and that could be used to control inflammation resulting from diseases in which CD8+ T cells have been identified to be critical in preventing pathogenesis.

3.3. CLA as a modulator of cytokine expression

Several cell culture studies have demonstrated that CLA, particularly the c-9t-11 isomer, is able to diminish pro-inflammatory cytokine production, mainly IL-6, TNFα, IFNγ, and IL-1β, which play an important role in the pathogenesis of many chronic inflammation-mediated diseases (O’Shea and Bassaganya-Riera, 2004, Peterson and O’Shea, 2009, Bassaganya-Riera and Hontecillas, 2010, Oleszczuk and Oleszczuk, 2012). The ability of CLA to reduce inflammation has been recently investigated in a series of detailed in vitro experiments using bovine blood. Such studies have revealed that the t-10,c-12 CLA isomer is able to reduce LPS-induced TNFα production in cultured bovine blood immune cells, whereas linoleic acid and c-9t-11 CLA treatments result in no detectable changes (Perdomo et al., 2011). Another ex vivo study showed decreased NF-κB activation and TNFα mRNA levels after adding t-10,c-12 CLA to endotoxin-stimulated pig peripheral blood mononuclear cells (PBMCs) (Kim et al., 2011). However, t-10,c-12 CLA treatment in non-stimulated PBMCs resulted in differing results as the authors report an increased NF-κB activation and TNFα production, thus suggesting that CLA is acting in a pro-inflammatory manner. These findings highlight that CLA may elicit different actions depending on the environment conditions, thus requiring further mechanistic investigations.

4.1. Obesity

Obesity is a disease characterized with a systemic low-grade chronic inflammation (Kennedy et al., 2010). Several animal studies, especially in rodents, report beneficial metabolic effects resulting in reduced fat deposition and increased lean body mass during 50:50 c-9, t-11 and t-10, c-12 CLA mixture supplementation (Miner and Cederberg, 2001, Hargrave and Li, 2002, Takahashi and Kushiro, 2002, House and Cassady, 2005, Bhattacharya and Banu, 2006, So and Tse, 2009). However, later studies have confirmed that isomer t-10, c-12 rather than c-9, t11 is responsible for CLA's role in body composition and adipogenesis (Park et al., 1999). CLA's anti-obesity properties are thought to be a result of (1) reduced energy intake by suppressing appetite, (2) inhibition of fatty acid metabolism, adipogenesis and lipogenesis, (3) increased lipolysis or delipidation, (4) decreased adipocyte size and (5) increased fat oxidation and energy expenditure in white adipose tissue, muscle and liver tissue (Wang and Jones, 2004, Kennedy and Martinez, 2010).

4.2. Type II diabetes

…The anti-diabetic effects of CLA have been examined using ob/ob mice fed a high fat diet enriched with either c-9, t-11 CLA or linoleic acid for 6 weeks. Dietary CLA administration resulted in no significant effects regarding weight loss, food intake and adipose tissue mass. However, c-9, t-11 CLA was able to reduce fasting plasma glucose, insulin and triacylglycerol concentrations, all of them indicators of insulin resistance, while it up-regulated the production of insulin signaling pathway molecules such as GLUT4 and insulin receptor IRS-1 (Moloney et al., 2007). Moreover, c-9, t-11 CLA reduced the infiltration of macrophages into the adipose tissue as well as the production of MCP-1, CD68, IL-6 and TNFα, probably as a result of reduced NF-KB signaling in adipocytes (Moloney et al., 2007). These results suggest that alerting fatty acid composition by administering CLA may reduce the inflammation in adipose tissue that predisposes to obesity-induced insulin resistance. However, such anti-diabetic effects are not translated into T2DM patients, which suffer an increased fasting glucose concentration, exaggerated oxidative stress and reduced insulin sensitivity after t-10, c-12 CLA supplementation (Riserus and Berglund, 2001, Riserus and Vessby, 2004, Wilson and Barker, 2009). Therefore, profound preventive and therapeutic effects of CLA seen in animal models of T2DM have yet to be rigorously verified in human studies.

4.3. Asthma and airway inflammation

Asthma is a chronic airway inflammatory disorder that involves a complex interplay between resident cells, such as epithelial cells and connective tissue, and infiltrating immune cells including eosinophils and activated T lymphocytes (Macredmond and Dorscheid, 2011). Recent meta-analysis of several prospective studies has demonstrated that obesity precedes the development of asthma with a relative risk for incident asthma in obese adults of almost 2 (Beuther and Sutherland, 2007). These data were confirmed in a second large study in which the ratio for asthma incidence was 1.21 (Hjellvik et al., 2010). Moreover, diet-mediated weight reduction has been shown to improve asthma symptoms (Stenius-Aarniala et al., 2000). Therefore, there is compelling available evidence supporting an association between obesity and asthma.

It is thought that changes in adipokines might affect airway inflammation and hyper-responsiveness in obese individuals (Weiss, 2005). Leptin levels increase with obesity, resulting in a subsequent upregulation of pro-inflammatory cytokine production (Sood et al., 2006). Contrarily, obesity-related decrease in adiponectin levels can negatively regulate allergic airway inflammation (Shore et al., 2006). Therefore, weight loss, and reduction of fat mass in particular, represents a potential anti-inflammatory benefit for asthma management.

Dietary CLA supplementation using variable mixtures of CLA isomers has been shown to reduce circulating plasma leptin levels, an effect that has been directly linked to fat mass reduction and food consumption (Yamasaki and Mansho, 1999, Takahashi and Kushiro, 2002). Weight loss and modulation of adipokines following CLA treatment can have a beneficial effect in respiratory inflammation and asthma. CLA treatment has already been shown to reduce airway inflammation and hyper-reactivity through a variety of PPARγ-dependent and independent mechanisms.

4.4. Inflammatory bowel disease

Inflammatory Bowel Disease (IBD) is a chronic, recurring, debilitating and widespread immuno-inflammatory illness of unknown etiology with two clinical manifestations: Ulcerative Colitis (UC) and Crohn's Disease (CD) (Camilleri, 2003, Lakatos, 2006). Even though IBD therapies have improved (Camilleri, 2003), there is still a need to develop novel immuno-nutritional interventions due to the significant side effects associated with current treatments (Maconi et al., 2005). A promising avenue for the development of such nutrition-based treatments for IBD is by targeting PPARs. As discussed above, several CLA isomers are able to activate PPARγ in the nucleus of a cell. Upon CLA stimulation, PPARγ induces the transcription of anti-inflammatory genes, which have been shown to reduce clinical symptoms in Crohn's disease patients (Scrascia et al., 2003).

CLA has been studied for the prevention and treatment of gut inflammation since 2002 (Bassaganya-Riera et al., 2002).

4.5. Inflammation-driven colorectal Cancer

Along with hereditary syndromes of familial adenomatous polyposis and hereditary nonpolyposis, IBD is among the top three high-risk conditions for the development of colorectal cancer (Xie and Itskowitz, 2008), the third most commonly diagnosed cancer in the United States (Jemal et al., 2008). The relative risk of developing colorectal cancer in UC patients correlates with the extent and duration of the disease (Eaden and Abrams, 2001, Xie and Itzkowitz, 2008). Specifically, it has been estimated that the risk increases by 0.5–1% yearly after 8–10 years of IBD initial diagnosis (Munkholm, 2003).

In 2010, we reported that dietary 50:50c-9, t-11 and t-10, c-12 CLA ameliorates inflammation-driven colorectal cancer in mice (Evans et al., 2010). Particularly, CLA upregulated the levels of regulatory CD4+ T cells in mesenteric lymph nodes of wild type mice. However, no differences were seen in immune cell-specific PPARγ null mice, suggesting that CLA is able to modulate the Treg compartment in a PPARγ-dependent fashion. These findings are in line with previous reports which demonstrated that PPARγ is required for appropriate Treg cell function (Hontecillas and Bassaganya-Riera, 2007, Wohlfert and Nichols, 2007).

In a more recent study published in 2012 (Bassaganya-Riera et al., 2012c), we showed how dietary 50:50c-9, t-11 and t-10, c-12 CLA or VSL#3 treatments resulted in a faster recovery during acute inflammation and lowered disease severity during the chronic, tumor-bearing phase of disease during chemically-induced colorectal cancer in mice. Both treatments were able to reduce colonic adenoma and adenocarcinoma formation. Whereas VSL#3 increased the mRNA levels of TNFα, angiostatin and PPARγ, CLA treatment decreased colonic COX-2 expression. However, only the probiotic VSL#3 was able to modulate adaptive T cell responses as shown by an increased IL-17 expression in MLN CD4+ T cells and accumulation of mucosal Treg cells and memory CD4+ T cells. As follow up of these ongoing studies, placebo-controlled, large-scale studies should investigate the interaction between CLA supplementation, gut microbiota and mucosal immunity.

5. Conclusions

With the emergence of inflammatory and immune-mediated diseases, there is an urgent need to search for nutrition-based interventions that address many of the risk factors. Although preclinical data support a benefit of CLA supplementation within various areas of health and well-being, human data have yet to show convincing evidence of a positive effect. To date, there is no clear consensus regarding the role of CLA in inflammation-related diseases. Moreover, data suggest there are likely to be isomer-specific effects and mechanisms which have not been completely characterized yet. Although cumulative data suggests that CLA is well-tolerated in humans, some cases of mild gastrointestinal disturbances and increased insulin resistance have been reported after long-term CLA treatment. Evidence of such adverse side effects is not conclusive. Nonetheless, additional human studies and further animal research are being conducted to unveil CLA's beneficial mechanisms, optimal dosage, long-term management and target population. Such studies, in combination with computational and animal modeling, will accelerate the development of CLA-based nutritionals and medical foods, and eventually contribute to the effort to reduce chronic disease in humans.

Full paper:

https://pubmed.ncbi.nlm.nih.gov/25987426/