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Dietary arachidonic acid: Harmful, harmless or helpful?

Invited Commentary
Dietary arachidonic acid: harmful, harmless or helpful?
Mammalian cells and tissues contain substantial amounts of
the n-6 PUFA arachidonic acid, especially in their membrane
phospholipids. For example, platelets from human adults
living on a typical Western diet have about 25 % phospholipid
fatty acids as arachidonic acid
, while for human mononuclear
cells, neutrophils, erythrocytes, skeletal muscle, cardiac tissue
and liver phospholipids, arachidonic acid contents are about
and 20
% total fatty acids, respect-
ively. This arachidonic acid can have two origins: the diet
or endogenous synthesis from a precursor, particularly linoleic
acid, which is consumed in fairly high amounts in most diets.
Important dietary sources of preformed arachidonic acid are
eggs and meat; fish also contain arachidonic acid. Typical
intakes of arachidonic acid have been estimated to be between
50 and 300 mg/d for adults consuming Western-style diets
The most well-recognised functional role of cell membrane
arachidonic acid is as a cell signalling molecule, either in its
own right or after its conversion to oxidised derivatives
known as eicosanoids. The eicosanoid family of mediators
includes prostaglandins, thromboxanes, leukotrienes, lipoxins
and hydroxy- and hydroperoxy-eicosatetraenoic acids. To
form eicosanoids, arachidonic acid is first released from cell
membrane phospholipids by phospholipase enzymes. The
free arachidonic acid then acts as a substrate for cyclooxygen-
ase, lipoxygenase or cytochrome P450 enzymes, ultimately
yielding the various eicosanoid metabolites. These metabolites
have well-established roles in many pathological processes
including thrombosis, inflammation and immunosuppression.
Thus, drugs targeted at eicosanoid synthesis (aspirin, non-ster-
oidal anti-inflammatory drugs, some steroids, cyclooxygenase-
2 inhibitors) and actions (leukotriene receptor antagonists)
have been developed and in some cases are widely used
with good efficacy. The idea has developed that, since arachi-
donic acid-derived mediators are involved in so many pathol-
ogies, arachidonic acid itself must be harmful. This notion is
compounded by observations that free arachidonic acid is a
potent platelet aggregator, induces inflammatory responses
and is an immunosuppressant. Finally, the many health ben-
efits of long chain n-3 PUFA frequently involve an ‘antagon-
ism’ of arachidonic acid: long chain n-3 PUFA partly replace
arachidonic acid in cell membranes and inhibit arachidonic
acid metabolism to eicosanoids. These observations have led
to the idea that both arachidonic acid and its eicosanoid
derivatives are harmful. This idea is supported by a study
with arachidonic acid (6 g/d as an ethyl ester) in healthy
human volunteers, which was stopped early (after 3 weeks)
because of a dramatic increase in ex vivo platelet aggrega-
, which prompted concern about a potentially adverse
pro-thrombotic action of dietary arachidonic acid.
An article in the current issue of the British Journal of
Nutrition assesses the impact of increased dietary intake of
arachidonic acid in an adult population with high fish
. This is the first study of arachidonic acid intake in
such a population; previous studies in healthy adult human
subjects have been conducted in low fish consumers in the
10,12 17
and in the UK
18 20
. In this new study, approxi-
mately 840 mg arachidonic acid/d was consumed by Japanese
adults for 4 weeks. Habitual arachidonic acid intake was esti-
mated to range between 110 and 270 mg/d with an average of
about 175 mg/d. This is not unlike typical intakes reported for
adults in Western countries
7 9,18
. Habitual intakes of EPA and
DHA ranged from 42 to 691 and from 98 to 991 mg/d, respect-
ively, with average intakes of about 310 and 550 mg/d respect-
. These are much greater than long chain n-3 PUFA
intakes among those subjects involved in studies of arachido-
nic acid previously (e.g. 90 and 150 mg/d for EPA and DHA,
). In this new study, the amount of arachidonic
acid was increased in serum phospholipids (from 9·6 to
13·7 g/100 g total fatty acids) and TAG (from 1·4 to 2·3 g/
100 g total fatty acids) with maximum incorporation occurring
at 2 weeks of supplementation
. The increase in arachidonic
acid content of serum phospholipids is consistent with that
seen in plasma phospholipids in adults in the UK supplement-
ing their diet with 680 mg arachidonic acid/d (from 9·3 to
15·9 g/100 g total fatty acids), in which maximum incorpor-
ation occurred at 4 weeks (an earlier time point was not exam-
. A washout period of 4 weeks resulted in a return of
arachidonic acid in serum phospholipids and TAG to levels
seen prior to starting supplementation
. Again, this is consist-
ent with earlier observations for plasma phospholipids after a
4-week washout period
. In the study of Kusumoto et al.
there was no effect of supplemental arachidonic acid on
blood pressure, serum lipid and glucose concentrations or
serum markers of liver function
. These findings are consist-
ent with an earlier study conducted in the USA using 1·5 g ara-
chidonic acid/d, which showed no effects on blood lipid or
lipoprotein concentrations
. However, the main focus of
this new study is platelet aggregation. Given this, it is unfor-
tunate that the authors do not report the fatty acid composition
of platelet phospholipids. Studies using data across popu-
lations with different patterns of PUFA intake have reported
that platelet aggregation is highly related to the arachidonic
acid and EPA contents of platelets
. In this new study, maxi-
mal aggregation of platelets in response to ADP, collagen or
arachidonic acid and platelet sensitivity to ADP or collagen
were not affected by dietary arachidonic acid supplemen-
. Thus, the main conclusion from this new study is
that increasing arachidonic acid intake by 840 mg/d does not
British Journal of Nutrition (2007), 98, 451–453 doi: 10.1017/S0007114507761779
q The Author 2007
result in a pro-aggregatory state. One reason for this may be
that the starting platelet content of arachidonic acid was
already above that which results in a maximal aggregatory
response. Additionally, the relatively high long-chain n-3
PUFA content expected to be present in these platelets may
have prevented any pro-aggregatory effect of an increased ara-
chidonic acid content from occurring. However, without
seeing the data on platelet fatty acid composition in this
study it is not possible to assess this further. Furthermore,
no arachidonic acid-derived eicosanoids such as prostaglan-
and thromboxane-A
are reported here and so it is not
possible to properly assess the functional impact of the sup-
plement. As indicated earlier, an early study reported a
marked increase in platelet aggregation after 6 g arachidonic
acid/d for 3 weeks
. This was associated with increased ara-
chidonic acid in platelets and increased urinary appearance of
a prostaglandin-E metabolite. In another study, arachidonic
acid (1·5 g/d for 7 weeks) only slightly increased platelet ara-
chidonic acid (from 21 to 22·5 % of total fatty acids) and did
not alter platelet aggregation in response to ADP, collagen or
arachidonic acid, or prothrombin, partial thromboplastin or
bleeding times
. The limited effect of 1·5 g arachidonic
acid/d on platelet fatty acid composition probably accounts
for the lack of a functional effect. Furthermore, this study
suggests that platelet fatty acid composition in the study by
Kusumoto et al., which used 840 mg arachidonic acid/d,
may have been little affected; this would account for the
lack of functional effect on platelets. This strengthens the
need to see the data for platelet fatty acid composition.
In contrast to what might be predicted
22 24
, studies assessing
a range of immune functions and inflammatory markers in
healthy adults in response to increased intake of arachidonic
acid (up to 1·5 g/d) have not identified any major effects
16 20
Taken together with the studies on blood lipids, platelet reactiv-
ity and bleeding time
, including this latest study
, it seems
appropriate to conclude that a significant increase in arachidonic
acid intake by healthy adults, up to an intake of, say, 1·5 g/d
appears unlikely to have any adverse effect. However, the earlier
study by Seyberth et al.
suggests that higher intakes of arachi-
donic acid should be approached with caution. Furthermore,
there is no information on the impact of increased arachidonic
acid supply in disease. It is possible that inflammatory processes
that already exist within an individual could be exacerbated by
providing exogenous arachidonic acid. However, the discovery
of novel anti-inflammatory mediators produced from arachido-
nic acid
and the identification of hitherto unknown anti-inflam-
matory actions of mediators previously considered to be pro-
inflammatory in nature
indicate first, the complexity of this
system and, second, that predicting the effect that increased ara-
chidonic acid supply might have is difficult. Nevertheless, it is
important to keep in mind that, just because there is little biologi-
cal impact of an increase in arachidonic acid intake or
11 20
, there may still be significant benefit from a decrease
in its intake or status.
It is important to note that a role for arachidonic acid in
neurological development has been identified
, that arachid-
onic acid-derived eicosanoids are not confined to pathology
but have many physiological roles, that human breast milk
contains arachidonic acid
, that infant formulas, which
include arachidonic acid (and DHA), are associated with
improved growth and development
and that formula
containing arachidonic acid (and DHA) has been shown to
enable preterm infants to achieve immune development simi-
lar to that seen with breast-milk feeding
and to lower the risk
of necrotising enterocolitis in preterm boys
. These obser-
vations suggest an important role for arachidonic acid in the
normal growth and development of infants and demonstrate
that harmful actions are not seen as a consequence to its pro-
vision, at least when given in combination with DHA.
In conclusion, this new study by Katsumoto et al. adds valu-
able new information to our knowledge about the impact of
increased dietary intake of arachidonic acid
. Taken together
with earlier studies
12 20
, this study suggests that, rather than
being harmful, moderately increased arachidonic acid intake
is probably harmless in healthy adults, although the effect of
intakes above 1·5 g/d are not known and the effect of increased
intake in diseased individuals is not known. Furthermore, ara-
chidonic acid appears to be an important constituent of infant
formulas and in this setting may be helpful in growth, devel-
opment and health.
Philip C. Calder
Institute of Human Nutrition
School of Medicine
University of Southampton
Bassett Crescent East
Southampton SO16 7PX
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Dietary arachidonic acid 453
... Up to 25% of the fatty acids in the phospholipids of skeletal muscles, brain, liver, platelets, and immune cells can be attributed to AA [11]. The interaction of AA with molecular oxygen produces mediators known as eicosanoids, which include prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs) [12,13]. ...
... According to new findings, the SARS-CoV-2 spike (S) glycoprotein of SARS-CoV-2 interacts with angiotensin-converting enzyme-2 (ACE2) and cellular protease transmembrane protease serine-2 (TMPRSS-2) as internalization receptors to enter host cells during the infection cycle. Downregulation of ACE2 by SARS-CoV-2 causes a reduction in ACE2 products such as Ang- [1][2][3][4][5][6][7], Ang [1][2][3][4][5][6][7][8][9], apelin [1][2][3][4][5][6][7][8][9][10][11][12], and accumulation of substrates such as apelin [1][2][3][4][5][6][7][8][9][10][11][12][13] and Ang II [82]. ACE2 downregulation correlates with systemic RAS imbalance and facilitates the development of multiorgan damage from SARS-CoV-2 infections [83]. ...
... According to new findings, the SARS-CoV-2 spike (S) glycoprotein of SARS-CoV-2 interacts with angiotensin-converting enzyme-2 (ACE2) and cellular protease transmembrane protease serine-2 (TMPRSS-2) as internalization receptors to enter host cells during the infection cycle. Downregulation of ACE2 by SARS-CoV-2 causes a reduction in ACE2 products such as Ang- [1][2][3][4][5][6][7], Ang [1][2][3][4][5][6][7][8][9], apelin [1][2][3][4][5][6][7][8][9][10][11][12], and accumulation of substrates such as apelin [1][2][3][4][5][6][7][8][9][10][11][12][13] and Ang II [82]. ACE2 downregulation correlates with systemic RAS imbalance and facilitates the development of multiorgan damage from SARS-CoV-2 infections [83]. ...
Background Covid-19 mortality is largely associated with a severe increase in inflammatory cytokines and polyunsaturated fatty acids (PUFAs) play an important role in modulating immune pathways and inflammatory responses; so this study was done to evaluate the effect of polyunsaturated fatty acids on the prognosis of Covid-19 disease. Methods and materials A comprehensive search was conducted in PubMed, Scopus and Web of Science. For systematic identification, the search was performed based on the following keywords COVID-19, SARS-CoV-2, COVID, Coronavirus Disease 19, SARS COV- 2 Infection, SARS-CoV-2, COVID19, Coronavirus Disease, Fatty Acids, Omega-3, Omega-3 Fatty Acid, Omega-6, n 3 Fatty and Omega-9 in the mentioned databases, using OR, and AND. All searched articles were included in the study and retrieved, and End-Note X7 software was used to manage the studies. Results Findings on the relationship between omega-3 and omega-6 fatty acids and the risk of Covid-19 are various, but omega-3 supplements have been found to be 12 to 21% effective in reducing the risk of Covid-19. Most studies emphasized the increasing severity of the disease and the need for mechanical ventilation and hospitalization due to polyunsaturated fatty acid deficiency. It is also demonstrated that omega-3 fatty acid deficiency increased mortality in patients with Covid-19. However, there is also a warning that in critical cases, elevated levels of fatty acids in patients' lungs and a cytokine storm are the main reasons for mortality in Covid-19 patients. Conclusion Polyunsaturated fatty acids can reduce the risk of covid-19 which could be considered as a preventative, inexpensive and safe method. However, the risk of taking high-dose omega-3 supplements before or during SARS-COV-2 infection needs to be investigated.
... However, the role of supplementary AA in obesity is still controversial. Some studies have found that supplemental AA worsens obesity [21,22], whereas some other recommended moderate intake is safe [23]. Alongside no study has yet demonstrated the role of supplementary AA in AA cascade signaling in HFD-induced obesity. ...
Obesity is associated with low-grade chronic inflammation and has a remarkable role in the pathophysiology of metabolic complications. In triggering these inflammatory responses, the arachidonic acid (AA) cascade plays a key role. However, there is a lack of data on how supplementary AA would affect obesity, adipose tissue inflammation, and the AA cascade in obesity. This study aims to investigate how AA supplementation affects obesity, adipocyte morphology, inflammation, and AA cascade signaling. Male Swiss Albino mice were used in our experiment. The mice were fed high-fat diets to induce obesity, and these obese mice were treated with two different doses of AA for 3 weeks. A normal diet non-obese group and an untreated obese group were kept as controls. Bodyweight and daily food intake data were recorded during that period. After the treatment period, blood serum and white adipose tissue of the experimental mice were collected for colorimetric lipid profile tests, histology, and mRNA extraction. The ΔΔCT method was employed for calculating the relative mRNA expression of target genes. The findings of our study suggest that AA has no significant effects on body weight, visceral adiposity, adipose tissue morphology, and serum lipid profile. However, AA treatment has resulted in a significant down-regulation of pro-inflammatory markers as well as the COX pathway. Besides, up-regulation of 12/15-LOX has been observed, indicating the metabolism pathway of supplementary AA through the LOX pathway. Our findings indicate that AA treatment may not provide significant benefits in terms of body weight, visceral fat mass, or serum lipid profile. However, it has effectively alleviated obesity-induced adipocyte inflammation in high-fat diet-induced obese mice.
... Arachidonic acid and docosapentaenoic acid are unsaturated fatty acids. Arachidonic acid is an essential dietary fatty acid that exists in the form of esterification in structural phospholipids in cell membranes throughout the body (Calder, 2007). In humans and other mammals, different enzymes cause membrane arachidonic (ARA) oxidation, resulting in the production of many proinflammatory and anti-inflammatory breakdown mediators (Hyde and Missailidis, 2009;Hanna and Hafez, 2018). ...
Full-text available
The reproductive tract of chickens is an important organ for egg formation. The vagina is in close contact with the external environment, which may lead to the invasion of a variety of pathogenic bacteria, affect the internal and external quality of eggs, and even increase mortality and cause economic loss. In recent years, probiotics as a substitute for antibiotics have brought economic benefits in livestock and poultry production. In the present study, we investigated the effects of vaginal administration of Bacteroides fragilis on the cloacal microbiota, vaginal transcriptome and metabolomics of chickens and evaluated the beneficial potential of B. fragilis. The results showed that B. fragilis treatment could affect the microbial composition of the cloaca. Transcriptome analysis found that the immune-related genes CCN3 , HAS2 , and RICTOR were upregulated, that the inflammatory genes EDNRB , TOX , and NKX2-3 were downregulated, and that DEGs were also enriched in the regulation of the inflammatory response, cellular metabolism, and synaptic response pathways. In addition, the differential metabolites were mainly related to steroid hormone biosynthesis, unsaturated fatty acid biosynthesis, and arachidonic acid metabolism, and we identified associations between specific differential metabolites and genes. Overall, this study provides a theoretical basis for the application of B. fragilis as a potential probiotic in livestock and poultry production.
... As for the controversial C20:4n-6, it has undergone remarkable alterations similar to those in EPA. As summarized by Calder (2007), arachidonic acid is a precursor of CLA, and has important role as a cell-signaling molecule with positive effect on neurological system, growth and immune system. The author also points out that it has also adverse effects in high diet concentrations (excess intake), which is mitigated by PUFAn-3 via conversion into oxidised derivatives. ...
Full-text available
Milk provides some beneficial fatty acids which in dairy processing are subjected to pasteurization and fermentation. With the aim to assess such changes, aliquot parts of milk from 12 buffaloes were pooled and processed to germinated yoghurt and brined cheese, and to non-germinated curd – the respective samples of raw and dairy material subjected to lipid analysis. The results show that in cheese positive and negative changes are generally balanced, rumenic acid decreasing and other CLAs altered but not total CLA and PUFA; omega ratio and atherogenicity index worsened to little extent, due to adverse change in n-3, myristic and lauric acid. In yoghurt and curd CLA dramatically decreased, excluding rumenic acid; but vaccenic acid increased, though total trans isomers decreased; the worsened n-6/n-3 ratio and atherogenicity index is mostly because of the adverse effect on PUFAn-3 but also on myristic and lauric acid. In all products SFA and MUFA did not change, including palmitic, stearic, and oleic acid. It can be concluded that the decrease of CLA in yoghurt and curd is partially compensated by the increase in the vaccenic acid, while cheese making altered individual isomers but not groups of beneficial acids.
... AA can contribute up to 25% of the fatty acids in phospholipids of skeletal muscles, brain, liver, platelets, and immune cells [46]. Deacylation and reacylation of AA in cell membranes keeps the level of free AA in cells low and limits its availability for oxidation [47]. ...
Full-text available
Oxidative stress and inflammation have been recognized as important contributors to the risk of chronic non-communicable diseases. Polyunsaturated fatty acids (PUFAs) may regulate the antioxidant signaling pathway and modulate inflammatory processes. They also influence hepatic lipid metabolism and physiological responses of other organs, including the heart. Longitudinal prospective cohort studies demonstrate that there is an association between moderate intake of the omega-6 PUFA linoleic acid and lower risk of cardiovascular diseases (CVDs), most likely as a result of lower blood cholesterol concentration. Current evidence suggests that increasing intake of arachidonic acid (up to 1500 mg/day) has no adverse effect on platelet aggregation and blood clotting, immune function and markers of inflammation, but may benefit muscle and cognitive performance. Many studies show that higher intakes of omega-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a lower incidence of chronic diseases characterized by elevated inflammation, including CVDs. This is because of the multiple molecular and cellular actions of EPA and DHA. Intervention trials using EPA + DHA indicate benefit on CVD mortality and a significant inverse linear dose–response relationship has been found between EPA + DHA intake and CVD outcomes. In addition to their antioxidant and anti-inflammatory roles, omega-3 fatty acids are considered to regulate platelet homeostasis and lower risk of thrombosis, which together indicate their potential use in COVID-19 therapy. <br/
... Our results show that the AA percentage in the TFA and the 5 -desaturase activity was increased in plasma from COVID-19 patients. Several studies have associated high concentration AA with increased inflammation through increased production and secretion of TNF-α and PGE 2 (Cubero and Nieto, 2012), and through suppression of the immune system (Calder, 2007). AA is also recognized as a second messenger that affects cellular functions by modulating intracellular signal transduction (Soto et al., 2018). ...
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The kidnapping of the lipid metabolism of the host’s cells by severe acute respiratory syndrome (SARS-CoV-2) allows the virus to transform the cells into optimal machines for its assembly and replication. Here we evaluated changes in the fatty acid (FA) profile and the participation of the activity of the desaturases, in plasma of patients with severe pneumonia by SARS-CoV-2. We found that SARS-CoV-2 alters the FA metabolism in the cells of the host. Changes are characterized by variations in the desaturases that lead to a decrease in total fatty acid (TFA), phospholipids (PL) and non-esterified fatty acids (NEFAs). These alterations include a decrease in palmitic and stearic acids ( p ≤ 0.009) which could be used for the formation of the viral membranes and for the reparation of the host’s own membrane. There is also an increase in oleic acid (OA; p = 0.001) which could modulate the inflammatory process, the cytokine release, apoptosis, necrosis, oxidative stress (OS). An increase in linoleic acid (LA) in TFA ( p = 0.03) and a decreased in PL ( p = 0.001) was also present. They result from damage of the internal mitochondrial membrane. The arachidonic acid (AA) percentage was elevated ( p = 0.02) in the TFA and this can be participated in the inflammatory process. EPA was decreased ( p = 0.001) and this may decrease of pro-resolving mediators with increase in the inflammatory process. The total of NEFAs ( p = 0.03), PL ( p = 0.001), cholesterol, HDL and LDL were decreased, and triglycerides were increased in plasma of the COVID-19 patients. Therefore, SARS-CoV-2 alters the FA metabolism, the changes are characterized by alterations in the desaturases that lead to variations in the TFA, PL, and NEFAs profiles. These changes may favor the replication of the virus but, at the same time, they are part of the defense system provided by the host cell metabolism in its eagerness to repair damage caused by the virus to cell membranes.
Westernized societies ingest an unhealthy high dietary omega-6/omega-3 fatty acid ratio of 20:1 or even higher. Seafood is the primary source of omega-3 long chain polyunsaturated fatty acids (LC-PUFA) for humans, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are involved in a plethora of physiological and health-related processes. However, the production of marine organisms with aquafeed formulations based on marine ingredients leads to serious environmental impacts on global pelagic fish resources, resulting in an unsustainable activity. The present study aims to gain further insight into the metabolism of fatty acids in chicken as a potential supply for omega-3 LC-PUFA. To this purpose, lipid classes and fatty acid profiles of thighs and hepatocytes, and the modification of [1-¹⁴C]18:3n-3 by hepatocytes isolated from three dual-purpose chicken breeds adapted to free-range culture systems were determined. Arachidonic acid highly accumulated in thighs meat (7.16-8.79%) despite being barely supplied in the diet, with DHA (1.22-1.71%) and n-3 docosapentaenoic acid (DPA, 22:5n-3; 1.02-1.14%) being also relevant. Our experimental design with radiolabeled fatty acids was validated for the first time in terrestrial vertebrates. Chicken hepatocytes incubated with [1-¹⁴C]18:3n-3 produced a wide variety of C18-C24 intermediates demonstrating that the set of fatty acyl desaturases and elongases enzymes necessary to metabolize dietary C18 precursors are active for the production of LC-PUFA, including EPA, n-3 DPA and DHA.
Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been found to be modulators of immune function. Additionally, they may affect the growth of colorectal cancer (CRC). With the advent of novel treatment approaches in oncology targeting immune checkpoint inhibition and aiming to boost the immune response against tumors the exact role of n-3 and n-6 PUFA in inflammation as well as in CRC needs to be re-evaluated in order to understand potential interactions with these new treatment paradigms. Interestingly, for the cyclooxygenase (COX) inhibitor aspirin a possible synergistic effect together with a PD1-Ligand antibody has been shown. However, could n-3 PUFA be disadvantageous in the context of immune tumor therapy due to an immune suppressive effect that has been described for these fatty acids in the past, or could they also enhance the effect of immune checkpoint inhibition? In this paper, we discuss the current data regarding the immune modulatory as well as the anti-CRC effect of n-3 PUFA. Arguing towards an immune-activating effect of n-3 PUFA, we demonstrate the results of a pilot study. Here, we show that incubation of human peripheral blood mononuclear cells (PBMCs) with the n-3 PUFA docosahexaenoic acid (DHA) significantly decreases CRC-cell supernatant-triggered secretion of IL-10 and increases secretion of TNF-a, while the omega-6 polyunsaturated fatty acid (n-6 PUFA) arachidonic acid (AA) reduced TNF-a secretion. These changes in cytokine secretion upon incubation with DHA demonstrate a possible enhancing effect of n-3 PUFA on an anti-tumor immune response.
Arachidonic acid (ARA), an n-6 essential fatty acid, plays an important role in human and animal growth and development. The ARA presents in the membrane phospholipids can be released by phospholipase A2. These free arachidonic acid molecules are then used to produce eicosanoids through three different pathways. Previous studies have demonstrated that eicosanoids have a wide range of physiological functions. Although they are generally considered to be pro-inflammatory molecules, recent advances have elucidated they have an effect on innate immunity via regulating the development, and differentiation of innate immune cells and the function of the intestinal epithelial barrier. Here, we review eicosanoids generation in intestine and their role in intestinal innate immunity, focusing on intestinal epithelial barrier, innate immune cell in lamina propria (LP) and their crosstalk.
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We studied the incorporation and metabolism of eicosapentanoic (EPA) and docosahexaenoic acid in six human volunteers who supplemented their normal Western diet for 5 mo daily with 10-40 ml of cod liver oil, rich in omega-3 polyunsaturated fatty acids. EPA and docosahexaenoic acid were incorporated into the total phospholipids of plasma, platelets, and erythrocytes in a dose- and time-dependent manner. During omega-3 fatty acid ingestion serum triacylglycerols were lowered and platelet aggregation upon low doses of collagen was reduced. Concomitantly, formation and excretion of prostanoids showed a characteristic change. As measured in serum from whole clotted blood, thromboxane A3 was formed in small amounts, whereas thromboxane A2 formation was reduced to 50% of control values. Excretion of the main urinary thromboxane A metabolites was unaltered in subjects with low basal excretion rates, but decreased markedly in two subjects with high control values. As determined from the main urinary metabolite, prostaglandin I3 was formed from EPA at rates up to 50% of unaltered prostaglandin I2 formation. The biochemical and functional changes observed lasted for the entire supplementation period of 5 mo and were reversible within 12 wk after cessation of cod liver oil intake. Favorable changes induced by long-chain omega-3 fatty acids include a dose-related and sustained shift of the prostaglandin I/thromboxane A balance to a more antiaggregatory and vasodilatory state.
The fatty acid composition of inflammatory and immune cells is sensitive to change according to the fatty acid composition of the diet. In particular, the proportion of different types of polyunsaturated fatty acids (PUFA) in these cells is readily changed, and this provides a link between dietary PUFA intake, inflammation, and immunity. The n-6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds, which have important roles in inflammation and in the regulation of immunity. Fish oil contains the n-3 PUFA eicosapentaenoic acid (EPA). Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators. In addition, EPA is a substrate for cyclooxygenase and lipoxygenase and gives rise to mediators that often have different biological actions or potencies than those formed from AA. Animal studies have shown that dietary fish oil results in altered lymphocyte function and in suppressed production of proinflammatory cytokines by macrophages. Supplementation of the diet of healthy human volunteers with fish oil-derived n-3 PUFA results in decreased monocyte and neutrophil chemotaxis and decreased production of proinflammatory cytokines. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease. Clinical studies have reported that fish oil supplementation has beneficial effects in rheumatoid arthritis, inflammatory bowel disease, and among some asthmatics, supporting the idea that the n-3 PUFA in fish oil are anti-inflammatory and immunomodulatory.
Investigations of the Greenland Eskimo diet and disease patterns has led to important discoveries on the role of n-3 polyunsaturated fatty acids (PUFA) in the regulation of plasma lipid levels and the production of eicosanoids derived from the n-6 PUFA, arachidonic acid (AA). As a result of these findings, recommendations have been made for western countries to increase their dietary intake of n-3 PUFA, with the aim being to decrease the tissue level of AA and to increase that of the n-3 PUFA. Studies on traditional foods in the hunter-gatherer diet eaten by Australia Aborigines have shown that both AA and the n-3 PUFA were significant components of the dietary fatty acids and that tissue fatty acid patterns reflected dietary intake. The significance of the raised AA levels in plasma and tissue phospholipids which occurred in association with raised n-3 PUFA levels is discussed in relation to current theories. It is argued that these patty acid patterns are unlikely to have been harmful to health. The fatty acid profiles of wild animals from other countries does not differ greatly from those analysed
Although essential to host defense, neutrophils are also involved in numerous inflammatory disorders including rheumatoid arthritis. Dietary supplementation with relatively large amounts of fish oil [containing >2.6 g eicosapentaenoic acid (EPA) plus 1.4 g docosahexaenoic acid (DHA) per day] can attenuate neutrophil functions such as chemotaxis and superoxide radical production. In this study, the effects of more moderate supplementation with fish oil on neutrophil lipid composition and function were investigated. The rationale for using lower supplementary doses of fish oil was to avoid adverse gastrointestinal problems, which have been observed at high supplementary concentrations of fish oil. Healthy male volunteers aged <40 yr were randomly assigned to consume one of six dietary supplements daily for 12 wk (n=8 per treatment group). The dietary supplements included four different concentrations of fish oil (the most concentrated fish oil provided 0.58 g EPA plus 1.67 g DHA per day), linseed oil, and a placebo oil. The percentages of EPA and DHA increased (both P<0.05) in neutrophil phospholipids in a dose-dependent manner after 4 wk of supplementation with the three most concentrated fish oil supplements. No further increases in EPA or DHA levels were observed after 4 wk. The percentage of arachidonic acid in neutrophil phospholipids decreased (P<0.05) after 12 wk supplementation with the linseed oil supplement or the two most concentrated fish oil supplements. There were no significant changes in N-formyl-met-leu-phe-induced chemotaxis and superoxide radical production following the dietary supplementations. In conclusion, low-to-moderate amounts of dietary fish oil can be used to manipulate neutrophil fatty acid composition. However, this may not be accompanied by modulation of neutrophil functions such as chemotaxis and superoxide radical production.
Infants need arachidonic acid (AA; C20:4n-6) for eicosanoid synthesis and deposition in growing tissues, including brain. Human milk supplies performed AA in amounts considered to meet accretion in membrane-rich tissues, but vegetable oil-based infant formulas do not contain AA. We studied two groups of ten healthy infants, each fed human milk or formula, and analyzed plasma lipid composition. Percentage contributions of AA to plasma phospholipids were stable over two months after birth in breast-fed infants, but infants fed formula developed significantly (P<0.05) lower levels at the ages of two weeks (formula 6.9% vs. breast 9.4%, w/w), one month (6.2 vs. 9.1%), and two months (5.7 vs 8.4%). In a second trial, we randomized infants to receive (from birth to age four months) formula without or with both AA and docosahexaenoic acid (DHA; C22:6n-3) at levels typical for mature human milk. Infants fed conventional formula showed a continuous decrease of phospholipid AA over time, whereas feeding of formula supplemented with AA and DHA led to significantly higher AA levels, similar to those in breast-fed infants (two months: supplemented 9.6% vs. unsupplemented 7.1%; four months; 8.7 vs. 6.6%). In order to estimate infantile capacity for endogenous synthesis of AA, we fed four term neonates with newly diagnosed phenylketonuria (mean age 18 d) a formula with all fat contributed by corn oil, which has a higher natural13C-enrichment than European human milk or formula. Analysis of13C-enrichment in plasma fatty acids over four days allowed us to estimate infantile AA synthesis. We found an increased13C-value in plasma AA of all infants, which indicates that term neonates can synthesize AA. However, with a simplified isotope balance equation, we estimate that endogenous synthesis contributed only about 23% of total plasma arachidonic acid by day four. We conclude that full-term infants fed formula may require a dietary supply of some preformed AA if the biochemical status of breast-fed infants is to be achieved.
This study characterized the fatty acid intake pattern and the contribution of different food groups to the fatty acid intake of Americans using the U.S. Department of Agriculture's 1987–1988 Nationwide Food Consumption Survey. The fatty acid intake was estimated using three-day food consumption data for children age 6–11 and for males and females age 12–19, 20–39 and 40 and older. Palmitic acid was the predominant saturated fatty acid (SFA) in the diet for all age sex groups, contributing 52–57% of SFA intake. Oleic acid was the primary monounsaturated fatty acid (MUFA) for all age sex groups, comprising 91–95% of MUFA intake. Linoleic acid was the principle polyunsaturated fatty acid (PUFA) for all age sex groups, contributing 87–92% of PUFA intake. The Milk and Milk Products group was the major contributor of the short chain SFA and lauric and myristic acids. Meat, Poultry and Meat Mixtures were the main sources of palmitic and stearic acids. Grain Products contributed appreciably to the long chain SFA intake. Oleic acid was obtained mainly from Meat, Poultry, Fish and Mixtures. Yeast breads, rolls, cakes, cookies and pastries were the main contributors of linoleic acid intake. A variety of animal and vegetable products contributed to the linolenic acid and C18:4+20:4 intake, while fish and shellfish were the main sources of C20:5+22:6 fatty acids. The contribution of the various food groups to intake of individual fatty acids was similar for both males and females. The results of the present study indicate that a wide variety of food groups contribute to the total fat intake Americans.
This study was conducted to determine the effects of arachidonic acid (AA) supplementation on human immune response (IR) and on the secretion of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). Ten healthy men (20-38 yr) participated in the study and lived at the Metabolic Suite of the Western Human Nutrition Research Center. They were fed a basal diet (57, 27, and 16 energy percentage from carbohydrate, fat, and protein, respectively, and AA 200 mg/d) for the first 15 d of the study. Additional AA (1.5 g/d) was added to the diet of six men from day 16 to 65, while the remaining four subjects remained on the basal diet. The diets of the two groups were crossed-over from day 66 to 115. In vitro indices of IR were examined using blood drawn on days 15, 58, 65, 108, and 115. Influenza antibody titers were determined in the sera prepared from blood drawn on days 92 and 115 (23 d postimmunization). AA supplementation caused significant increases in the in vitro secretion of LTB4, and PGE2, but it did not alter the in vitro secretion of tumor necrosis factor alpha; interleukins 1 beta, 2, 6; and the receptor for interleukin 2. Nor did it change the number of circulating lymphocytes bearing markers for specific subsets (B, T, helper, suppressor, natural killer) and the serum antibody titers against influenza vaccine. The opposing effects of PGE2 and LTB4 may have led to the lack of change in immune functions tested.
Death from cardiovascular disease is rare among Eskimos. Haemostasis was investigated in twenty-one Greeland Eskimos and twenty-one age and sex matched Danish controls. Platelet lipid analysis demonstrated that a high consumption of omega-3 polyunsaturated fatty acids (such as cis 5, 8, 11, 14, 17-eicosapentaenoic acid [C20:5]) by Eskimos increased the proportion of omega-3 polyunsaturated fatty acids in the platelets. The Eskimos had a significantly longer bleeding-time due to a reduction in platelet aggregation. It is suggested that C20:5 in the platelets is converted by the vascular-wall tissue to an anti-aggregatory prostacyclin. Partial dietary substitution of arachidonic acid by eicosapentaenoic acid may reduce the incidence of thrombotic disorders, including myocardial infarction.
Ethyl arachidonate was administered orally to 4 healthy male volunteers in a dose of 6 gm daily for a 2 to 3 wk period after 10-day control period. The increased intake of this precursor of the dienoic prostaglandins resulted in significant increases in the relative and absolute amount of arachidonate in plasma triglycerides, phospholipids, and cholesteryl esters. Similar changes in lipid composition were noted in platelets. The excretion of 7alpha-hydroxy-5,11-diketotetranoprostane-1,16-dioic acid, the major urinary metabolite of E prostaglandins in man, was increased by an average of 47% in 3 of the 4 volunteers. Platelet reactivity was assessed by determining the threshold concentration of adenosine diphosphate (ADP) necessary to induce secondary, irreversible aggregation of platelet-rich plasma. This threshold concentration dropped significantly in all volunteers (10% to 60% of control values). It is concluded that the biosynthesis and function of prostaglandins can be augmented in man by oral administration of an esterified precursor fatty acid.