Prescription n-3 FAs at the FDA-approved dose of 4 g/d are safe and generally well tolerated. At this dose, triglyceride lowering of ≥30% has been reported in clinical trials of subjects with VHTG (triglycerides ≥500 mg/dL), in whom these agents are FDA approved.
In VHTG, the goal of therapy is to reduce triglyceride levels to <500 mg/dL and to lessen the risk of pancreatitis, although this may not be achieved with n-3 FA monotherapy, so additional triglyceride-lowering pharmacological treatment may be indicated. In the context of HTG (triglycerides, 200–499 mg/dL), 4 g/d prescription n-3 FA effectively lowers triglycerides by ≈20% to 30% and does not significantly increase LDL-C.
In all patients, established recommendations for diet and lifestyle should also be followed.11 In the largest studies of 4 g/d EPA+DHA or EPA-only as adjuncts to statin therapy, non–HDL-C and apo B were modestly decreased, suggesting reductions in total atherogenic lipoproteins.
Use of n-3 FA may be accompanied by mild gastrointestinal complaints (such as “fishy burps” or nausea), but taking n-3 FA with meals may reduce gastrointestinal side effects and improve absorption of O3AEE and IPE. In clinical trials completed to date, <5% of subjects have discontinued omega-3 agents because of side effects.
The triglyceride-lowering efficacy and generally excellent safety and tolerability of n-3 FAs make them valuable tools for healthcare providers. The use of n-3 FAs (4 g/d) for improving ASCVD risk in patients with HTG is supported by a 25% reduction in major adverse cardiovascular end points in REDUCE-IT, a randomized placebo-controlled trial of EPA-only in high-risk patients on statin therapy.
Results from the STRENGTH trial, a randomized placebo-controlled cardiovascular outcomes trial of 4 g/d prescription EPA+DHA in patients with HTG and low HDL-C on statins, are anticipated in 2020. We conclude that prescription n-3 FAs, whether EPA+DHA or EPA-only, at a dose of 4 g/d, are clinically useful for reducing triglycerides, after any underlying causes are addressed and diet and lifestyle strategies are implemented, either as monotherapy or as an adjunct to other triglyceride-lowering therapies
Flaxseed (FS) is a nutritional supplement with high concentrations of (n-3) fatty acids and lignans that have anti-inflammatory and antioxidant properties. The use of FS in the prevention or treatment of acute lung disease is unknown. In this study, we evaluated diets with high FS content in experimental murine models of acute lung injury and inflammation. The kinetics of lignan accumulation in blood, following 10% FS supplementation, was determined using liquid chromatography tandem mass spectrometry. Mice were fed isocaloric control and 10% FS-supplemented diets for at least 3 wk and challenged by hyperoxia (80% oxygen), intratracheal instillation of lipopolysacharide, or acid aspiration. Bronchoalveolar lavage was evaluated for white blood cells, neutrophils, and proteins after a 24 h postintratracheal challenge of hydrochloric acid or lipopolysacharide, or after 6 d of hyperoxia. Lung lipid peroxidation was assessed by tissue malondialdehyde concentrations. The plasma concentrations of the FS lignans, enterodiol and enterolactone, were stable after mice had eaten the diets for 2 wk. Following hyperoxia and acid aspiration, bronchoalevolar lavage neutrophils decreased in FS-supplemented mice (P = 0.012 and P = 0.027, respectively), whereas overall alveolar white blood cell influx tended to be lower (P = 0.11). In contrast, neither lung injury nor inflammation was ameliorated by FS following lipopolysacharide instillation. Lung malondialdehyde levels were lower in hyperoxic mice than in unchallenged mice (P = 0.0001), and decreased with FS treatment following acid aspiration (P = 0.011). Dietary FS decreased lung inflammation and lipid peroxidation, suggesting a protective role against pro-oxidant-induced tissue damage in vivo.
Sheylla M. Felau, Lucas P. Sales, […], and Fabiana B. Benatti
Abstract
Endothelial cells are thought to play a central role in the pathogenesis of antiphospholipid syndrome (APS). Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation has been shown to improve endothelial function in a number of diseases; thus, it could be of high clinical relevance in APS. The aim of this study was to evaluate the efficacy of n-3 PUFA supplementation on endothelial function (primary outcome) of patients with primary APS (PAPS). A 16-week randomized clinical trial was conducted with 22 adult women with PAPS. Patients were randomly assigned (1:1) to receive placebo (PL, n = 11) or n-3 PUFA (ω-3, n = 11) supplementation. Before (pre) and after (post) 16 weeks of the intervention, patients were assessed for endothelial function (peripheral artery tonometry) (primary outcome). Patients were also assessed for systemic markers of endothelial cell activation, inflammatory markers, dietary intake, international normalized ratio (INR), and adverse effects. At post, ω-3 group presented significant increases in endothelial function estimates reactive hyperemia index (RHI) and logarithmic transformation of RHI (LnRHI) when compared with PL (+13 vs. −12%, p = 0.06, ES = 0.9; and +23 vs. −22%, p = 0.02, ES = 1.0). No changes were observed for e-selectin, vascular adhesion molecule-1, and fibrinogen levels (p > 0.05). In addition, ω-3 group showed decreased circulating levels of interleukin-10 (−4 vs. +45%, p = 0.04, ES = −0.9) and tumor necrosis factor (−13 vs. +0.3%, p = 0.04, ES = −0.95) and a tendency toward a lower intercellular adhesion molecule-1 response (+3 vs. +48%, p = 0.1, ES = −0.7) at post when compared with PL. No changes in dietary intake, INR, or self-reported adverse effects were observed. In conclusion, 16 weeks of n-3 PUFA supplementation improved endothelial function in patients with well-controlled PAPS. These results support a role of n-3 PUFA supplementation as an adjuvant therapy in APS. Registered at http://ClinicalTrials.gov as NCT01956188.
Research compared effects of fresh and thermally processed oil
Date : August 23, 2019
Source : University of Massachusetts at Amherst
Summary : Food scientists have shown that feeding frying oil to mice exaggerated colonic inflammation, enhanced tumor growth and worsened gut leakage, spreading bacteria or toxic bacterial products into the bloodstream.
Foods fried in vegetable oil are popular worldwide, but research about the health effects of this cooking technique has been largely inconclusive and focused on healthy people. For the first time, UMass Amherst food scientists set out to examine the impact of frying oil consumption on inflammatory bowel disease (IBD) and colon cancer, using animal models.
In their paper published Aug. 23 in Cancer Prevention Research, lead author and Ph.D. student Jianan Zhang, associate professor Guodong Zhang, and professor and department head Eric Decker showed that feeding frying oil to mice exaggerated colonic inflammation, enhanced tumor growth and worsened gut leakage, spreading bacteria or toxic bacterial products into the bloodstream.
“People with colonic inflammation or colon cancer should be aware of this research,” says Jianan Zhang.
Guodong Zhang, whose food science lab focuses on the discovery of new cellular targets in the treatment of colon cancer and how to reduce the risks of IBD, stresses that “it’s not our message that frying oil can cause cancer.”
Rather, the new research suggests that eating fried foods may exacerbate and advance conditions of the colon. “In the United States, many people have these diseases, but many of them may still eat fast food and fried food,” says Guodong Zhang. “If somebody has IBD or colon cancer and they eat this kind of food, there is a chance it will make the diseases more aggressive.”
For their experiments, the researchers used a real-world sample of canola oil, in which falafel had been cooked at 325 F in a standard commercial fryer at an eatery in Amherst, Massachusetts. “Canola oil is used widely in America for frying,” Jianan Zhang says.
Decker, an expert in lipid chemistry performed the analysis of the oil, which undergoes an array of chemical reactions during the frying process. He characterized the fatty acid profiles, the level of free fatty acids and the status of oxidation.
A combination of the frying oil and fresh oil was added to the powder diet of one group of mice. The control group was fed the powder diet with only fresh oil mixed in. “We tried to mimic the human being’s diet,” Guodong Zhang says.
Supported by grants from the U.S. Department of Agriculture, the researchers looked at the effects of the diets on colonic inflammation, colon tumor growth and gut leakage, finding that the frying oil diet worsened all the conditions. “The tumors doubled in size from the control group to the study group,” Guodong Zhang says.
To test their hypothesis that the oxidation of polyunsaturated fatty acids, which occurs when the oil is heated, is instrumental in the inflammatory effects, the researchers isolated polar compounds from the frying oil and fed them to the mice. The results were “very similar” to those from the experiment in which the mice were fed frying oil, suggesting that the polar compounds mediated the inflammatory effects.
While more research is needed, the researchers hope a better understanding of the health impacts of frying oil will lead to dietary guidelines and public health policies.
“For individuals with or prone to inflammatory bowel disease,” Guodong Zhang says, “it’s probably a good idea to eat less fried food.”
OBJECTIVE: Omega-3 polyunsaturated fatty acid (ω-3 PUFA) has been found to possess anti-cancer potential in previous studies. However, the underlying mechanism of ω-3 PUFA in protecting hepatocarcinoma has not been fully elucidated. This study aims to explore the function of ω-3 PUFA in the development of hepatocarcinoma and its potential mechanism.
PATIENTS AND METHODS: In this study, human hepatocarcinoma cell line Hep G2 was treated with ω-3 PUFA. Cell counting kit-8 (CCK-8) and cell cloning assay were applied to detect the proliferation of Hep G2 cells. In addition, flow cytometry was performed to analyze the cell cycle and apoptosis rate. At the same time, the effect of ω-3 PUFA on invasion and metastasis of hepatocarcinoma cells were analyzed by transwell assay. Moreover, protein levels of key factors in Wnt/β-catenin pathway were detected by Western blot.
RESULTS: Cell proliferation of Hep G2 cells was decreased after ω-3 PUFA treatment in a time- and dose-dependent manner. CCK-8 assay showed that the IC50 value was 12.8 ± 0.67 μmol/L, 8.8 ± 0.43 μmol/L and 4.6 ± 0.42 μmol/L after ω-3 PUFA treatment for 24 h, 48 h and 72 h, respectively. Besides, ratio of Hep G2 cells blocked at G2/M phase after ω-3 PUFA treatment (5 μmol/L, 10 μmol/L and 20 μmol/L) was increased in a dose-dependent manner (p<0.05). Meanwhile, ω-3 PUFA could increase cell apoptosis (p<0.05) and inhibit cell proliferation. In addition, ω-3 PUFA reduced protein expressions of total, cytoplasmic and nuclear β-catenin in Hep G2 cells, indicating that the Wnt/β-catenin pathway is inhibited. Decreased expression levels of Dvl-2, Dvl-3, GSK-3β (p-ser9), c-myc and survivin, and increased expression levels of GSK-3 (p-tyr216) and Axin-2 were observed in Hep G2 cells treated with ω-3 PUFA, but no significant alteration in total GSK-3β protein level was observed (p>0.05).
CONCLUSIONS: Omega-3 PUFA regulates the malignant progression of hepatocarcinoma by inhibiting proliferation and promoting apoptosis of hepatocarcinoma cells via Wnt/β-catenin signaling pathway.
ChooseLife Notes : This is overlapping data, from the studies on carcinoma apoptosis, which have been compiled here = http://chooselife.co.uk/index.php/flax/ Though this study does not make clear the form of Omega3 used.
High levels of circulating proinflammatory cytokines are characteristic of inflammaging, a term coined to describe age-related chronic systemic inflammation involved in the etiology of many age-related disorders including nonhealing wounds. Some studies have shown that supplementing diets with n-3 polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) lowers systemic levels of key proinflammatory cytokines associated with inflammaging. However, findings from the few studies that have focused exclusively on older adults are inconclusive. As such, the objective of this randomized controlled study was to test the effects of EPA+DHA therapy on circulating levels of proinflammatory cytokines in adults in middle to late adulthood.
Methods
Plasma levels of fatty acids and interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) were measured in 35 participants with chronic venous leg ulcers (mean age: 60.6 years) randomnly assigned to 8 weeks of EPA+DHA therapy (2.5 g/d) or placebo therapy.
Results
EPA+DHA therapy had a significant lowering effect on levels of IL-6, IL-1β and TNF-α after 4 weeks of therapy and an even greater lowering effect after 8 weeks of therapy. Further, after adjusting for baseline difference, the treatment group had significantly lower levels of IL-6 (p = .008), IL-1β (p < .001), and TNF-α (p < .001) at Week 4 and at Week 8 [IL-6 (p = .007), IL-1β (p < .001), and TNF-α (p < .001)] compared to the control group.
Conclusion
Adults in middle to late adulthood receiving EPA+DHA therapy demonstrated significantly greater reductions in circulating levels of proinflammatory cytokines compared with those receiving placebo therapy. EPA+DHA therapy may be an effective low-risk dietary intervention for assuaging the harmful effects of inflammaging.
Searching for potent and specific antibiotics against pathogenic Helicobacter and Campylobacter strains
Polyunsaturated fatty acids (PUFAs) and siamycin
Matsui et al. screened for specific inhibitors of the futalosine pathway in culture broth samples of 6183 microbes including 2160 fungi, 3783 actinomycetes, and 240 lactobacilli. They employed a paper disk method using two indicator microorganisms, B. halodurans C-125 (the futalosine pathway) and B. subtilis H17 (the canonical pathway). Isolation and structural elucidation of active compounds from screening hits revealed that ω-3 and ω-6 PUFAs, including α-linoleic acid, γ-linoleic acid, arachidonic acid, eicosapentaenoic acid (EPA, 20), and docosahexaenoic acid (DHA, 21), as well as, siamycin I (22), a lasso peptide natural product, specifically inhibited the futalosine pathway [28]. They next showed that compounds 20–22 suppressed the growth of H. pylori strains SS1 and TN2GF4 in a dose-dependent manner. They also evaluated the effect of these compounds using a mouse model of H. pyloriinfection. Treatment of mice with EPA (30 μg/ml), DHA (30 μg/ml), or siamycin I (5 μg/ml) in drinking water significantly reduced the colonization of H. pylori by 96, 78, and 68%, respectively. In addition, they prepared 10-hydroxy-cis-12-octadecenoic acid (HYA; C18:1 ω-6, 23) from linoleic acid by bio-conversion with Lactobacillus plantarum and showed that 23 also suppressed the in vitro growth and in vivo colonization of H. pylori by blocking the futalosine pathway. HYA was also effective against Helicobacter suis, which causes the formation of gastric lymphoid follicles [15], when 23 was added to the drinking water of a mouse model of H. suis infection.
Walnuts are rich in omega-3 fatty acids, phytochemicals and antioxidants making them unique compared to other foods. Consuming walnuts has been associated with health benefits including a reduced risk of heart disease and cancer. Dysbiosis of the gutmicrobiome has been linked to several chronic diseases. One potential mechanism by which walnuts may exert their health benefit is through modifying the gut microbiome.
This study identified the changes in the gut microbial communities that occur following the inclusion of walnuts in the diet.
The diet groups had distinct microbial communities with animals consuming walnuts displaying significantly greater species diversity. Walnuts increased the abundance of Firmicutes and reduced the abundance of Bacteriodetes.
The intestine is the largest immune organ in the body, provides the first line of defense against pathogens, and prevents excessive immune reactions to harmless or beneficial non-self-materials, such as food and intestinal bacteria. Allergic and inflammatory diseases in the intestine occur as a result of dysregulation of immunological homeostasis mediated by intestinal immunity.
Several lines of evidence suggest that gut environmental factors, including nutrition and intestinal bacteria, play important roles in controlling host immune responses and maintaining homeostasis. Among nutritional factors, ω3 and ω6 essential polyunsaturated fatty acids (PUFAs) profoundly influence the host immune system.
Recent advances in lipidomics technology have led to the identification of lipid mediators derived from ω3- and ω6-PUFAs. In particular, lipid metabolites from ω3-PUFAs (e.g., eicosapentaenoic acid and docosahexaenoic acid) have recently been shown to exert anti-allergic and anti-inflammatory responses; these metabolites include resolvins, protectins, and maresins. Furthermore, a new class of anti-allergic and anti-inflammatory lipid metabolites of 17,18-epoxyeicosatetraenoic acid has recently been identified in the control of allergic and inflammatory diseases in the gut and skin.
Although these lipid metabolites were found to be endogenously generated in the host, accumulating evidence indicates that intestinal bacteria also participate in lipid metabolism and thus generate bioactive unique lipid mediators. In this review, we discuss the production machinery of lipid metabolites in the host and intestinal bacteria and the roles of these metabolites in the regulation of host immunity.
Lipid composition in organisms differs among species, in accordance with the expression levels of metabolic enzymes and dietary habits. Marine phytoplankton and seaweeds produce a large amount of the ω3-polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (1). Although fish do not generate EPA and DHA per se, they accumulate EPA and DHA by eating phytoplankton (1). In plants, linseed and perilla contain large amounts of α-linolenic acid, a precursor of EPA and DHA. In contrast, soybean oil and sesame oil contain copious quantities of the ω6-PUFA linoleic acid. The difference in the fatty acid composition of plants depends on the expression levels and activities of metabolic enzymes such as Δ12-desaturase and Δ15-desaturase, which are involved in the generation of linoleic acid and α-linolenic acid, respectively (2, 3). Because mammals do not have either Δ12 or Δ15-desaturase, ω3- and ω6-PUFAs are categorized as essential fatty acids that must be obtained from the diet (3). Therefore, the balance of ω3 and ω6 lipids in the body largely depends on the quality of the dietary lipid consumed.
The beneficial effect of dietary ω3-PUFAs on human health was first reported in an epidemiological study in 1978 in which Greenland Eskimos, who consume high ω3-PUFA diets that include fish, were found to have a lower mortality from coronary heart disease than Danes and Americans, who eat much less ω3-PUFAs (4). Since then, accumulating evidence indicates that EPA and DHA have beneficial effects on the inhibition of various types of inflammatory and allergic diseases, including cardiovascular disease, Alzheimer’s disease, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, asthma, and food allergy (5–13). Recent developments in analytical technology, including liquid chromatography (LC) and mass spectrometry (MS), have enabled us to identify EPA- and DHA-derived pro-resolving lipid mediators (SPMs), including resolvins (Rvs), protectins (PDs), maresins (MaRs), and 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) for inhibition of inflammatory and allergic diseases (7, 14).
Dietary lipids are metabolized not only by mammalian enzymes but also by bacterial enzymes. Microorganisms can generate unique lipid metabolites such as conjugated linoleic acids, hydroxy fatty acids, and oxo fatty acids. These bacteria-produced lipid metabolites show biological activity in the context of host health and diseases (15, 16). Here, we review our current understanding of ω3- and ω6-PUFA-derived lipid mediators in the control of inflammatory and allergic diseases.Go to:
ω6 Fatty Acid Metabolites Have Opposing Roles in Pro-and Anti-Inflammation
Dietary lipids are metabolized in the body to lipid mediators, which regulate host immune systems. Arachidonic acid (AA) is a metabolite of linoleic acid, and functions as a direct precursor of bioactive lipid mediators, which are known as eicosanoids. In addition to its biosynthesis in the body from linoleic acid, AA can be obtained from dietary sources, such as meat and eggs. AA is metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP), and then converted into lipid mediators, including prostaglandins (PGs), leukotrienes (LTs), thromboxanes (TXs), and lipoxins (LXs) (Figure 1) (17). These AA-derived lipid meditators have both pro- and anti-inflammatory effects in the intestine.
Lipid mediators derived from AA, EPA, and DHA. Various kinds of lipid mediators are produced from ω6- and ω3-PUFAs. AA, EPA, and DHA are converted to bioactive lipid mediators by the enzymatic activities of COX, LOX, and CYP. Lipid mediators exert their biological effects through binding to G-protein-coupled receptors. AA-derived lipid mediators have pro- and anti-inflammatory activities, whereas EPA- and DHA-derived lipid mediators exert anti-inflammatory or pro-resolution activities or both.
AA is converted into LTB4 by LOX activity. The LTB4-BLT1 axis plays a key role in the development of inflammatory diseases including inflammatory bowel disease by stimulating the recruitment of inflammatory cells and the production of pro-inflammatory cytokines (18–20). LTB4 also activates another receptor BLT2 which is a high affinity receptor for 12-hydroxy-heptadecatrienoic acid (12-HHT). In contrast to pro-inflammatory role of BLT1, BLT2-deficient mice show transepidermal water loss, suggesting its anti-inflammatory role in the skin (21). Indeed, BLT2-mediated pathway induced the expression of claudin-4 for enhancement of epithelial barrier (21).
AA is converted into PGs by COX activity, which generate PGD2 and PGE2 as the representative lipid mediators. The PGD2-chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) pathway induces dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis (22, 23). Eosinophil infiltration into colon is inhibited by CRTH2 antagonist treatment in TNBS-induced colitis (23). In contrast to pro-inflammatory properties, the PGD2-DP axis reduces granulocyte infiltration into the colonic mucosa in the mouse model of TNBS-induced colitis and colitis-associated colorectal cancer (24, 25) These opposing roles of CRTH2 and DP in chemotaxis are explained by different usage of G proteins. CRTH2 is coupled with Gαi while DP is coupled with Gαs, which induces decreased and increased in cAMP levels, respectively (26). Consistent with these findings when PGD2 acted on neutrophils CRTH2 pathway, it induced neutrophil migration to the intestinal lamina propria in the DSS-induced colitis model (22).
PGE2 stimulates four distinct types of receptors EP1 to EP4. The PGE2-EP2 axis in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by inducing expression of inflammation- and growth-related genes, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and Wnt5A (27). In contrast to EP2-mediated carcinogenic effects, EP3-mediated signals show anti-carcinogenic effects, which are consistent with different types of G protein pathways; EP2 activates Gαs, while EP3 activates Gαi (27).
Therefore, it is suggested that the opposing roles in pro- and anti-inflammation of ω6-PUFAs derived lipid mediators are determined by target cell types and receptor types.
In addition to these factors, cellular source of PGD2 affects in its activity in pro- and anti-inflammation in croton oil-induced skin inflammation model (28). In the initial phase of the dermatitis when few inflammatory cells exist in the skin, endothelial cells show highest COX-2 activity and produce PGD2, which leads to DP activation on endothelial cells, and inhibits vascular leakage. On the other hand, in the late phase of the dermatitis, many types of hematopoietic inflammatory cells produce PGD2, which stimulate CRTH2 on inflammatory cells for infiltration to the inflamed skin, and exacerbates skin inflammation (28, 29). These findings suggest that stage of inflammatory process is a determinant of the effects of AA-derived metabolites through distinct site of the mediator production.
Dietary ω3-PUFAs Inhibit the Development of Allergic Disease
We and others have shown the anti-inflammatory and anti-allergic effects of dietary ω3-PUFAs (4, 7, 8, 12, 13, 30–34).
Fish oil is a representative ω3-PUFA-rich dietary oil which contains plenty amount of EPA and DHA. Dietary fish oil ameliorated asthma by decreasing eosinophil infiltration, mucus production, and peribronchiolar fibrosis, which was associated with inhibition of cytokine production by downregulation of nuclear factor (NF)-κB and GATA-3 (30).These anti-allergic effects may be caused by decreased amount of ω6-PUFA-derived lipid mediators such as PGD2, LTB4, and LTE4 which exacerbate airway inflammation and increasing ω3-PUFA-derived lipid mediators, for example, RvD1 is reported to decrease allergic airway responses (6, 35, 36). Further, fish oil-fed mice reduced acute allergic skin response in food allergy model sensitized by peanut and whey by reducing mucosal mast cell protease-1 and antigen specific IgE in serum (31).
Linseed oil contains large amount of α-linolenic acid, which is converted into EPA and DHA in the body. One study reported that linseed oil-fed mice alleviated pollen-induced allergic conjunctivitis by decreasing the production of ω6-PUFA-derived pro-inflammatory lipid mediators, and reducing eosinophil infiltration into the conjunctiva (13). We also found that linseed oil-fed mice reduced allergic diarrhea in ovalbumin (OVA)-induced food allergy model (7). In this model, allergic diarrhea occurs as a consequence of a dominant Th2-type environment and the presence of allergen-specific serum IgE, which induces mast cell degranulation in the gut. We found that in linseed oil-fed mice, the Th1–Th2 balance, allergen-specific IgE level, and mast cell numbers in the gut did not change compared with those in soybean oil-fed mice in the OVA-induced food allergy model. However, we found that mast cell degranulation was profoundly inhibited in linseed oil-fed mice (7).
We also assessed fatty acid composition in intestinal tissues and found that the amounts of α-linolenic acid and its metabolites of EPA and DHA were increased in linseed oil-fed mice when compared with those in soybean oil-fed mice (7). In contrast, linoleic acid and AA levels were higher in soybean oil-fed mice than linseed oil-fed mice (7). Imaging MS analysis revealed that increased amounts of α-linolenic acid, EPA and DHA were found in the lamina propria compartment where large numbers of immune cells such as T cells, plasma cells, and dendritic cells are present (7). These findings collectively demonstrated that the composition of essential fatty acids in dietary oils directly reflect the lipid composition in the gut, which, in turn, may influence the host immune system.
ω3 Fatty Acid Metabolites Have Roles in Anti-Inflammation and Pro-Resolution
EPA and DHA are representative ω3-PUFAs, which compete with AA in the AA cascade. Therefore, it has long been considered that the beneficial effects of dietary ω3-PUFAs against inflammatory diseases stem from decreased amounts of AA-derived eicosanoids. In addition, recent technology developments in LC and MS have led to the identification of trace and novel lipid mediators, including Rvs, PDs, and MaRs, which are produced from EPA and DHA in the body (37). These metabolites have anti-inflammatory or pro-resolution properties (or both) and are known as SPMs (Figure 1) (37). Although the receptors for SPMs have not been fully elucidated, some SPMs have been shown to interact with specific receptors. For example, Rvs derived from EPA and DHA use distinct types of receptors. RvE1 interacts with BLT1 and ChemR23, while RvD1 interacts with G-protein-coupled receptor (GPR) 32 and ALX (38, 39).
Examples of how SPMs affect intestinal inflammation include their involvement in the RvE1–ChemR23 axis, which actively inhibits colonic inflammation in the DSS-induced colitis model by suppressing the TNF-α-induced nuclear translocation of NF-κB and the expression of inflammatory cytokines, including TNF-α and IL-12p40, from macrophages (40). Furthermore, RvE1 and PD1 enhance the resolution of inflammation by stimulating macrophage phagocytosis of apoptotic cells in zymosan-induced peritonitis (41, 42). MaR1 is reported to attenuate both DSS- and TNBS-induced colitis by inhibiting NF-κB activation and inflammatory cytokine production (43). Thus, multiple types of SPMs exert their anti-inflammatory properties by using different mechanisms for the regulation of colitis.
17,18-Epoxyeicosatetraenoic Acid is a New Class of Anti-Allergy Lipid Mediator
As mentioned above, dietary linseed oil inhibited the development of food allergy with increased amounts of α-linolenic acid, EPA and DHA in the intestine (7), which prompted us to investigate mediator profiles by using LC-MS/MS analysis. We found that 17,18-EpETE was the metabolite whose levels increased the most in the gut of linseed oil-fed mice (7). When 17,18-EpETE was intraperitoneally injected into soybean oil-fed mice, development of allergic diarrhea and degranulation of mast cells were inhibited, which was similar to observation in linseed oil-fed mice (Figure 2) (7). Consistent with its action at the late stage of the allergic response, 17,18-EpETE was effective as a prophylactic and a therapeutic treatment for food allergy (7).
17,18-EpETE is a new class of anti-allergy and anti-inflammatory lipid mediator. 17,18-EpETE is produced by CYP from EPA. 17,18-EpETE suppresses contact hypersensitivity by reducing neutrophil infiltration into the skin by inhibiting Rac activation and migration through GPR40 signaling. 17,18-EpETE also indirectly inhibits the development of food allergy by inhibiting mast cell degranulation. Given that mast cells do not express GPR40, the detailed mechanisms responsible for this inhibition of mast cell degranulation remain unclear.
17,18-EpETE Ameliorates Contact Hypersensitivity Through GPR40-Mediated Inhibition of Neutrophil Migration
To evaluate the biological role of 17,18-EpETE in the regulation of other types of allergic inflammatory disease, we examined the effect of 17,18-EpETE on the regulation of contact hypersensitivity (CHS) in the hapten-induced CHS model. We found that 17,18-EpETE showed both prophylactic and therapeutic anti-inflammatory effects on CHS in mice and cynomolgus macaques (44). 17,18-EpETE did not affect T cell or dendritic cell functions, including inducible skin-associated lymphoid tissue formation, but it did selectively inhibit neutrophil infiltration into the skin (44). Indeed, 17,18-EpETE reduced neutrophil mobility by inhibiting Rac-activation and pseudopod formation in a GPR40-dependent fashion (44).
Consistent with this selective influence on neutrophils, GPR40 was highly expressed by neutrophils, but not T cells or other leukocytes in the skin. It is worth noting that mast cells do not express GPR40; so, given that mast cell degranulation was inhibited by 17,18-EpETE treatment in the food allergy model (7, 44), this finding suggests that 17,18-EpETE inhibits mast cell degranulation indirectly (Figure 2). Of note, the activation of GPR40 in intestinal epithelial cells has been reported to improve intestinal barrier function by enhancing occludin expression (45). Therefore, it is likely that the improvement in intestinal barrier function induced by 17,18-EpETE via GPR40 in epithelial cells led to decreased allergen penetration, which, in turn, resulted in decreased mast cell degranulation and inhibited food allergy development.
Structure-Activity Relationships Among the GPR40-Dependent Anti-Allergic and Anti-Inflammation Effects of 17,18-EpETE
17,18-EpETE is further metabolized by soluble epoxide hydrolase to 17,18-dihydroxy-eicosatetraenoic acid (17,18-diHETE). However, 17,18-diHETE has little effect on the development of food allergy, and 14,15-epoxyeicosatetraenoic acid (14,15-EpETE), which has an epoxy structure at the ω6 position, also lacks the ability to inhibit food allergy (7). In addition, 17,18-diHETE has little effect on the development of CHS (44). Although 17,18-EpETE activates GPR40, 17,18-diHETE does not activate GPR40, which is consistent with its lack of anti-allergic and anti-inflammatory properties (7, 44). These findings therefore suggest that the 17,18-epoxy ring structure at the ω3 position in EPA is important for GPR40-mediated anti-allergic and anti-inflammatory activity.
17,18-EpETE is synthesized from EPA through the enzymatic activity of CYP and has two isomers, 17(S),18(R)-EpETE and 17(R),18(S)-EpETE. Among the CYP subfamilies in mice, five CYP isoforms (Cyp1a2, 2c50, 4a12a, 4a12b, and 4f18) are known to convert EPA into 17,18-EpETE (46). Cyp1a2 displays high stereoselectivity for producing 17(R),18(S)-EpETE, whereas Cyp4f18 displays stereoselectivity for producing 17(S),18(R)-EpETE (46). In contrast, Cyp2c50, Cyp4a12a, and Cyp4a12b display less stereoselectivity and produce a mixture of 17(S),18(R)-EpETE and 17(R),18(S)-EpETE (46). 17(R),18(S)-EpETE, but not 17(S),18(R)-EpETE, is a potent vasodilator (47). Indeed, 17(R),18(S)-EpETE activates calcium-activated potassium channels, which lead to relaxation of rat cerebral artery vascular smooth muscle cells (47). Whether stereoselectivity of 17,18-EpETE contributes to the anti-allergy and anti-inflammatory effects of 17,18-EpETE have not been evaluated in food allergy and CHS, because we used racemic compounds in our studies (7, 44). The CYP isoform and polymorphisms determine the metabolic properties of CYP and stereoselectivity. Therefore, the anti-allergic and anti-inflammatory health benefits derived from ω3-PUFA intake may be influenced by the expression levels of the various types of CYP in the body.
CYP is also found in microorganisms. For example, it has been reported that bacterial CYP (e.g., BM-3 derived from Bacillus megateirum) metabolizes PUFAs and produces hydroxy and epoxy fatty acids (48). Bacillus, Streptomyces, Pseudomonas, and Mycobacterium also have CYP (49–53). These findings suggest that many types of microorganisms are involved in lipid metabolism. In addition, other metabolic enzymes, such as COX and LOX, are thought to be expressed by some bacteria, including Pseudomonas aeruginosa, Shewanella woodyi, Mytococcus fulrus, and Burkholderia thailandensis (54, 55). Some microorganisms described above are present in environment, suggesting that in addition to mammalian expression of metabolic enzymes, various microorganisms may be a determinant of the efficacy of ω3-PUFA in the context of the regulation of inflammation.
Bacterial-Conjugated Linoleic Acid has a Role in Anti-Inflammation
Intestinal bacteria have been shown to express unique unsaturated fatty acid-metabolic enzymes and to produce bioactive lipid mediators that are not generated by mammalian cells (Figure 3). Ruminal bacteria including Butyrivibrio, Lactobacillus, and Megasphaera can produce conjugated linoleic acid (CLA), which is an isomer of linoleic acid that has conjugated double bounds (56–58). It is known that CLA has some isomers such as cis-9-trans-11-octadecenoic acid (c9,t11-CLA), trans-10-cis-12-octadecenoic acid (t10,c12-CLA) and trans-9-trans-11-octadecenoic acid (t9,t11-CLA). These isomers have different activities for insulin sensitivity and atherosclerosis.
Physiological functions of CLA and HYA. CLA and HYA are produced from linoleic acid by intestinal bacteria. c9,t11-CLA ameliorates insulin sensitivity and prevents atherosclerosis, t10,c12-CLA deteriorates insulin sensitivity and promotes atherosclerosis, and t9,t11-CLA prevents atherosclerosis. HYA enhances intestinal barrier function by increasing occludin expression and inhibiting intestinal inflammation in a GPR40-dependent manner. HYA inhibits atopic dermatitis by increasing claudin-1 expression and enhancing skin barrier function. HYA also inhibits gastric Helicobacter infections by blocking the bacterial futalosine pathways.
For example,c9,t11-CLA shows beneficial effects on insulin sensitivity by enhancing glucose uptake and adipokine production such as leptin and adiponectin, and on atherosclerosis by suppressing macrophage infiltration and activation, and reducing plaque development through an increase in expression of PPARγ, while t10,c12-CLA shows adverse effects through a decrease in expression of PPARγ (59–63). In addition, t10,c12-CLA reduces expression of liver X receptor α (LXRα) which induces expression of ATP-binding cassette (ABC) transporter A1, ABCG1, and sterol regulatory element binding protein 1c which involved in reverse cholesterol transport (64, 65). Therefore, t10,c12-CLA shows pro-atherosclerosis effects (66–68). On the other hand, t9,t11-CLA is effective for the treatment of atherosclerosis by activation of LXRα (69). These results indicate that each isomers exert different bioactivities through distinct transcriptional regulation and activation of PPARγ and LXRα for the control of insulin sensitivity and atherosclerosis.
Compared with chemical production, microbial fermentation offers better ways to produce isomer-specific CLAs. The CLA isomers are produced at different ratios, depending on the type of bacteria. Lactobacillusstrains (L. acidophilus, L. plantarum, L. casei, L. reuteri, L. rhamnosus, and L. pentosus), Bifidobacteriumstrains (B. dentium, B. breve, and B. lactis), and Propionibacterium freudenreichii can convert linoleic acid to c9,t11-CLA and t10,c12-CLA, and these bacteria produce higher levels of c9,t11-CLA than of t10,c12-CLA (15, 57, 70–72). Some Lactobacillus and Bifidobacterium strains also produce t9,t11-CLA with c9,t11-CLA and/or t10,c12-CLA (57). L. paracasei and B. bifidum produce c9,t11-CLA stereoselectively, whereas Megasphaera eldsenii produces t10,c12-CLA stereoselectively (71, 73). Given that these CLAs have different biological activities which depend on their 3D-structure, it is important to select appropriate bacteria as a probiotics or producer for obtaining required beneficial effects.
Bacterial Production of Unique Hydroxy and Oxo Fatty Acids and Their Multiple Biological Activities
L. plantarum, an intestinal bacteria, produces hydroxy fatty acids (i.e., 10-hydroxy-cis-12-octadecenoic acid [HYA], 10-hydroxy-trans-11-octadecenoic acid [HYC], 10-hydroxy-octadecanoic acid [HYB]) and oxo fatty acids (10-oxo-cis-12-octadecenoic acid [KetoA], 10-oxo-trans-11-octadecenoic acid [KetoC], 10-oxo-octadecanoic acid [KetoB]) as intermediate products of CLA production (16). Recently, these metabolic intermediates have been shown to contribute to the regulation of host health and diseases. HYA is the first metabolite produced from linoleic acid by L. plantarum, and it enhances intestinal barrier function and suppresses the development of DSS-induced colitis in mice in a GPR40-dependent manner (45). Furthermore, HYA prevents Helicobacter infections by blocking their futalosine pathways, which is an alternative menaquinone biosynthetic pathway and an essential metabolic pathway for the growth of Helicobacter. Moreover, HYA treatment suppresses the formation of lymphoid follicles in the gastric mucus layer after H. suis infection, and therefore HYA treatment protects mice against the formation of gastric mucosa-associated lymphoid tissue lymphoma induced by infection with Helicobacter (74). HYA also ameliorates the pathological scores of atopic dermatitis in NC/Nga mice by decreasing plasma IgE levels and reducing mast cell infiltration into the skin (75, 76). KetoA enhances adiponectin production and glucose uptake in a proliferator-activated receptor γ (PPARγ)-dependent manner, and is effective for the prevention and amelioration of metabolic abnormalities associated with obesity (77).
The production of these hydroxy and oxo fatty acids depends on the unique bacterial enzymes CLA-HY (unsaturated fatty acid hydratase), CLA-DH (hydroxy fatty acid dehydrogenase), CLA-DC (isomerase), and CLA-ER (enone reductase) in L. plantarum AKU1009a (16, 78). The hydroxy activity is found not only in Lactobacillus but also in a broad spectrum of bacteria. Oleate hydratase belongs to the FAD-dependent myosin cross-reactive antigen (MCRA) protein family, which is found in gram-positive and -negative bacteria; it catalyzes the conversion of linoleic acid to HYA. For example, Lactobacillus, Bifidobacterium, Streptococcus, and Stenotrophomonas bacteria are reported to have MCRA, and indeed they have the ability to produce HYA (79–82).
Together, these findings indicate that intestinal bacteria metabolize dietary lipids and produce lipid metabolites that can regulate host immune systems. Therefore, to obtain beneficial lipid metabolites and regulate intestinal inflammation, we need to consider not only host enzymes but also enzymes produced by intestinal bacteria. In addition, we must consider how dietary lipid intake causes changes in the intestinal microbiota.
Conclusion
Recent technological developments in lipidomics research initiated a new era of lipid biology by helping researchers to identify novel lipid metabolites from ω3- and ω6-PUFAs, which actively regulate the host immune system and play important roles in the control of health and diseases. Given that the production of lipid metabolites is influenced by complex factors, including diet, intestinal bacteria, and enzyme expression, combined studies on nutrition, metabolomics, and the metagenomics of the microbiota, as well as informatics, may provide powerful insights to further our understanding of the lipid network in the host immune system.
Author Contributions
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
We thank laboratory members for helpful discussion. The results described in the review were obtained, at least in part, from research supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) and the Japan Society for the Promotion of Science (JSPS; KAKENHI [JP15K19142 to TN; JP15H05790, JP18H02150, JP18H02674, JP17K09604, JP26670241, and JP26293111 to JK]); the Japan Agency for Medical Research and Development (AMED; [JP17ek0410032s0102, JP17ek0210078h0002, JP17ak0101068h0001, JP17gm1010006s0101, JP18ck0106243h0003, and 19ek0410062h0001 to JK]); the Ministry of Health and Welfare of Japan (to JK); the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries, and Food Industry (to JK); grants-in-aid for Scientific Research on Innovative Areas from MEXT (JP23116506, JP16H01373, and JP25116706 to JK); Cross-ministerial Strategic Innovation Promotion Program (SIP); the Ono Medical Research Foundation; and the Canon Foundation (to JK).
Glossary
Abbreviations
12-HHT
12-hydroxy-heptadecatrienoic acid
14,15-EpETE
14,15-epoxyeicosatetraenoic acid
17,18-EpETE
17,18-epoxyeicosatetraenoic acid
17,18-diHETE
17,18-dihydroxy-eicosatetraenoic acid
AA
arachidonic acid
CHS
contact hypersensitivity
CLA
conjugated linoleic acid
COX
cyclooxygenase
CRTH2
chemoattractant receptor-homologous molecule expressed on Th2 cells
Children can see a big improvement in their breathing within six months after eating fish twice a week, say researchers at La Trobe University in Australia.
Lead researcher Maria Papamichael said the findings add to other research studies that demonstrate how asthma can be successfully treated almost exclusively with a healthy diet.
The researchers tested the diet on a group of 64 children who had mild asthma, half of whom ate at least 150 g of fatty fish twice a week, and the rest instead ate their normal diet.
By the end of the six-month trial, the children who had eaten the fatty fish diet had reduced bronchial inflammation by 14 units; a 10-unit reduction is considered ‘significant’.
The fish is rich in omega-3 fatty acids and these have anti-inflammatory effects that reduce asthma symptoms, the researchers said.
References
(Source: Journal of Human Nutrition and Dietetics, 2018; doi: 10.1111/jhn.12609)
ChooseLife Notes : Johanna Budwig said that a high Omega3 diet (such as her Flax Oil/Cottage Cheese centred protocol), would help cure dry coughing, and other similar maladies. This research backs the claim made in her book:
FLAX OIL AS A TRUE AID AGAINST ARTHRITIS, HEART INFARCTION, CANCER, AND OTHER DISEASES.
Moreless would often broach this subject, advising that he only recommended Salmon from far north, that the waters there are cleaner, plus the meat is more mineral rich (as this is a mechanism to stop freezing). He would repeatedly state that plant based diets were those where true healing may occur, however for some including fish like Arctic Salmon may be very beneficial. Moreless did talk of the Budwig Protocol positively, so I personally defer to her expertise in this regard (ie the surplus electrons of Flax make it the best Omega3/ALA source, an Electron shower, reigniting millions of cells respiratory potential).
