Trends in Food Science & Technology 120 (2022) 140–153

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Trends in Food Science & Technology

journal homepage: www.elsevier.com/locate/tifs

Futuristic food fortification with a balanced ratio of dietary ω-3/ω-6 omega

fatty acids for the prevention of lifestyle diseases
Alok Patel a, *, Sneha Sawant Desai b, Varsha Kelkar Mane b, Josefine Enman a, Ulrika Rova a,
Paul Christakopoulos a, Leonidas Matsakas a
a
Biochemical Process Engineering, Division of Chemical Engineering, Department of Civil, Environmental, and Natural Resources Engineering, Luleå University of
Technology, SE-971 87, Luleå, Sweden
b
Department of Biotechnology, University of Mumbai, Kalina, Santacruz (E), Mumbai, 400098, Maharashtra, India

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Over the last three decades, consumption of total and saturated fat has steadily declined in Western
Food fortification diets as a proportion of calories intake. At the same time, omega (ω)-6 fatty acid intake has risen at the expense of
ω-3/ω-6 fatty acid ratio ω-3 fatty acids, resulting in an ω-6/ω-3 ratio of 20:1 or higher.
Human health
Scope and approach: The observed changes in fatty acids ratio coincide with a significantly increased prevalence
Polyunsaturated fatty acids
of coronary heart disease, hypertension, cancer, diabetes, obesity, rheumatoid arthritis, and autoimmune or
neurodegenerative disorders. The low intake of ω-3 fatty acids may be attributed to their absence from the diet or
lack of awareness about suitable dietary sources.
Key findings and conclusions: A sustainable and cost-effective way of reaching a large population with essential ω-3
fatty acids is fortification of staple foods. A variety of food items enriched with ω-3 have entered the market in
recent years, including beef, fish, dairy products, cereals, cereal bars, and infant formula. The present review
discusses the role of ω-3 and ω-6 fatty acids, as well as their ratio, on human health. Additionally, it focuses on
the latest developments regarding dietary sources, innovative technologies, and challenges of food fortification
with ω-3 fatty acids.

1. Introduction disorders including Alzheimer’s and Parkinson’s disease, as well as the

Fatty acids provide a structural framework for cells, tissues, and
organs, as well as the building blocks for several bioactive ingredients.
They can be divided in omega (ω)-6 and ω-3 fatty acids based on the
position of the first double bond counting from the methyl end of the
fatty acid molecule. In the case of ω-6 fatty acids, this double bond oc­
curs between the 6th and 7th carbon atoms; whereas in ω-3 fatty acids, it
is located between the 3rd and 4th carbon atoms (Saini & Keum, 2018).
Docosahexaenoic acid (DHA; 22:6n-3) eicosapentaenoic acid (EPA;
20:5n-3), and α-linolenic acid (ALA; 18:3n-3) are the most important
members of the ω-3 family. ω − 3 fatty acids regulate lipid metabolism in
humans, reducing the risk of cardiovascular illness and neurological
progression of age-related macular degeneration and dry eye disease
(Kerdiles et al., 2017). They have been shown to exert also a broad
spectrum of anti-inflammatory effects, which makes them effective
agents against inflammation-related diseases (Giacobbe et al., 2020).
ALA is a precursor for the synhesis of long-chain ω-3 fatty acids but,
because it cannot be produced in the human body, it must be taken
through the diet, making it an essential fatty acid (Das, 2010; Patel,
Rova, et al., 2020). Vegetable oils, such as flaxseed, rapeseed or soybean,
chia seeds, and eggs represent an important source of ALA. Even though
humans can convert ALA into DHA and EPA, the rate is too low to meet
the daily requirement for these fatty acids (Burns-Whitmore et al., 2019;
Patel et al., 2021). Important sources of DHA and EPA include marine

; AA, arachidonic acid; ALA, α-linolenic acid; BDNF, brain-derived neurotrophic factor; DHA, docosahexaenoic acid; DGLA, dihomo-γ-linolenic acid; ELOVLs,
elongation of very-long-chain fatty acids; EPA, eicosapentaenoic acid; FAO, Food and Agriculture Organization; GLA, gamma linolenic acid; HDLs, high-density
lipoproteins; IL, interleukin; LA, linoleic acid; LC-PUFAs, long-chain polyunsaturated fatty acids; MAPK, mitogen-associated protein kinase; PUFAs, polyunsaturated
fatty acids; PPAR, peroxisome proliferator-activated receptor; SDA, stearidonic acid; SPMs, specialized pro-resolving mediators; WHO, World Health Organization;
TNF, tumor necrosis factor; α, alpha; β, beta; γ, gamma; Δ, delta; ω, omega.
* Corresponding author.
E-mail address: alok.kumar.patel@ltu.se (A. Patel).

https://doi.org/10.1016/j.tifs.2022.01.006
Received 15 June 2021; Received in revised form 17 December 2021; Accepted 1 January 2022
Available online 4 January 2022
0924-2244/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
A. Patel et al.
fish oils, krill oils, eggs, and seaweed or microalgae. The minimum daily
consumption of ω-3 fatty acids (EPA and DHA) is 0.5 g, but the ideal
amount is two to three times higher (Kris-Etherton et al., 2009). To fulfil
20%–35% of the required daily calorie intake (2500 Kcal), at least 0.5%–
1% of total fats should be in the form of DHA and EPA. When caloric
constraints reduce lipid intake, the proportion of ω-3 polyunsaturated
fatty acids (PUFAs) should be increased through supplementation
including with less efficient ω-3 PUFAs, such ALA and stearidonic acid
(SDA; C18:4n-3). Individuals who follow a reduced- or low-fat diet, for
example, may need up to 3–10% of their dietary lipids to be ω-3 PUFAs
(Hamilton et al., 2020; Madore et al., 2020).
Similar to ALA, linoleic acid (LA; 18:2n-6) is the parent compound for
ω-6 fatty acids and it also cannot be synthesized in the human body.
After it is absorbed through the diet, LA is converted to arachidonic acid
(AA; 20:4n-6). Generally, ω-6 fatty acids are obtained from plant sources,
such as sunflower, soybean or nut-derived oils, but also from animal
sources, such as pork, lard, and turkey (Kaliannan et al., 2019; Scan­
ferlato et al., 2019). Unhealthy diets and limited access to healthy foods
are the main reasons why people lack essential fatty acids, such as ALA,
EPA, and DHA. Whereas during the Paleolithic the ratio between ω-6
and ω-3 fatty acids was quite balanced (Simopoulos, 2016), Western
diets are associated with higher consumption of ω-6 and lower con­
sumption of ω-3 fatty acids. Ensuring a balanced ω-6:ω-3 fatty acids ratio
is crucial for a healthy lifestyle, as it allows for the progressive brain,
eyes, and heart development, while also reducing the risk of coronary
heart disease and neurodegenerative disorders (Shetty et al., 2020;
Trebatická et al., 2020). To enable proper neuronal development and
prevent most chronic disorders, a 1:1 or 2:1 ω-6:ω-3 fatty acids ratio
should be maintained. Because this ratio affects body fat metabolisms
through adipogenesis, lipid homeostasis, and adipose tissues browning,
as well as systemic inflammation (Simopoulos, 2016). Increasing ratio of
omega-6 to − 3 fatty acids has led to obesity due to increase in phos­
pholipids in RBCs membrane and AA eicosanoid metabolites (Simo­
poulos, 2016). Intake of diets rich in ω-6 PUFAs before or during
pregnancy can have adverse effects on fetal development and may
impair overall health of the offspring in adulthood (Lee et al., 2018;
Shrestha et al., 2020). There is presently little information about dietary
sources and palatability of foods fortified with ω-3 PUFAs. This is a
critical issue, as fish oils are not prevalently used as a source of dietary
lipids, therefore, a broader range of fat-containing foods must be forti­
fied to achieve the 0.5 g/day target of ω-3 PUFAs.
Since the beginning of the 20th century, food fortification has been
practiced in developed nations and has helped to eradicate deficiency-
related disorders in high-income countries. However, its progress in
low- and middle-income nations has been limited (Pinstrup-Andersen,
2013) due to absence of political will, which has led to government
under-prioritization, lack of funding for the food fortification industry,
inadequate or poor regulation and compliance, and insufficient aware­
ness by customers of the advantages of eating fortified foods (Ponied­
ziałek et al., 2020). Even where there was political will, successful
implementation and control of legislation promoting food fortification
has been beset by difficulties. To meet the daily requirements of essen­
tial PUFAs through the diet, food fortification needs better
implementation.
2. Effect of ω-3 and ω-6 PUFAs on human health
By forming primary structural constituents of phospholipids, ω-3 and
ω-6 PUFAs provide fluidity and flexibility to cell membranes. LA and
ALA are precursors of ω-6 and ω-3 PUFAs, respectively (Balić et al.,
2020). They are stored in different lipid fractions, such as triglycerides,
cholesteryl esters, and in minute quantities in phospholipids. While EPA
can be found in all three of the above lipid fractions, DHA and AA are
found preferentially in phospholipids. In humans, large amounts of DHA
are found in the cerebral cortex, retina, testis, and sperm, whereas it
represents the most abundant structural lipid in the brain (Ahmmed
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Trends in Food Science & Technology 120 (2022) 140–153
et al., 2020; Calder, 2016). In contrast, AA is found in the phospholipids
of skeletal muscle, liver, brain, spleen, and retina (Hanna & Hafez,
2018). These PUFAs affect gene expression, cell signaling, eicosanoid
metabolism, and organization of the cell membrane (Georgiadi & Ker­
sten, 2012). Fatty acid-induced changes in cell membrane organization
and the availability of the substrates involved in eicosanoid synthesis are
long-standing processes that are thought to be explained by observed
effects. More recently, effects of dietary supplementation of PUFA on
signal transduction pathways and gene expression profiles have been
identified (Kalkman et al., 2021; Kitajka et al., 2004).
2.1. ω-6 PUFAs
LA is the most abundant PUFA in the human diet and, because it
plays a significant role in brain development, it is implicated in fetal and
infant growth (Lauritzen et al., 2015; Thomas Brenna, 2016). Reports
suggest consumption of LA is inversely proportional to ischemic heart
disease, diabetes, and blood pressure (Ng & Schooling, 2020). A
reduction in blood cholesterol levels, due to a specific reduction in
low-density lipoprotein-cholesterol is a key metabolic attribute of LA
(Hooper et al., 2018). LA acts also as a precursor of AA, which is
necessary for neural development (Marangoni et al., 2020), and γ-lino­
lenic acid (GLA; C18n-6), which is an important constituent of neuronal
membrane phospholipids. Specifically, GLA plays a critical role in pre­
serving nerve blood flow by serving as a substrate for prostaglandin
synthesis (Poorani et al., 2020). It is reported to relieve the symptoms of
chronic inflammatory diseases, such as rheumatoid arthritis and atopic
dermatitis (Sergeant et al., 2016). Clinical trials have shown that GLA
enhances the treatment of heart disease, obesity, alcoholism, depression,
schizophrenia, Parkinson’s disease, and multiple sclerosis (Sathasivam
et al., 2019). Additionally, it can downregulate inflammatory responses
by reducing expression of the cytochrome-c oxidase COX-2 and
prointerleukin-1 (Silva et al., 2018).
GLA is converted to dihomo-γ-linolenic acid (DGLA; C20:3n-6) by the
ELOVL-5 fatty acid elongase before being incorporated into cellular
glycerolipids. DGLA and its metabolites strongly inhibit platelet aggre­
gation and inflammation (Sergeant et al., 2016). DGLA can be metabo­
lized into eicosanoids, prostaglandin PGE1 or 15-hydroxyeicosatrienoic
acid, which exert anti-inflammatory as well as immunoregulatory effects
(Silva et al., 2018). Moreover, it can prevent both motility and inva­
siveness of human colon cancer cells by enhancing expression of the
metastasis suppressor E-cadherin (Pang et al., 2021). Both GLA and
DGLA suppress the expression of oncogenes Her-2/neu and Bcl2, while
promoting the activity of p53 and, thereby, inducing apoptosis of tumor
cells (Wang et al., 2012).
AA is a key component of cell membranes and a regulator of mem­
brane permeability. AA and its metabolites (lipoxin A4 and epox­
yeicosatrienoic acid) modulate smooth muscle function and
proliferation, regulate voltage-gated ion channels, membrane receptors,
G-coupled receptors, peroxisome proliferator-activated receptors
(PPARs), free radical generation, nitric oxide synthesis, inflammation
and immune responses involved in the monitoring of blood pressure and
the pathogenesis of diabetes mellitus (Das, 2018). AA influences the
function of specific membrane proteins involved in cellular signaling,
thereby maintaining cellular and organellar integrity, as well as vascular
permeability. It is also involved in neuronal function, brain synaptic
elasticity, and potentiation in the hippocampus. Specifically, AA is re­
ported to modulate synaptic transmission and neuronal excitability by
acting on sodium, calcium, potassium, and chloride channels, as well as
proton pumps (Tallima & El Ridi, 2018). Dietary AA supplementation in
the elderly has been shown to improve cerebral function by increasing
neural stem/progenitor cell or newborn neuronal proliferation together
with overall hippocampal neurogenesis (Tokuda, Kontani, Kawashima,
Akimoto, et al., 2014; 2014b). Furthermore, AA affects neuromuscular
signaling and improves neurotransmitter firing by stimulating nerve
cells (Tallima & El Ridi, 2018). Owing to its beneficial effect on the
A. Patel et al.
newborn’s nervous system, the FAO and WHO have recommended AA
supplementation in infant formula. Prostaglandins derived from AA,
such as PGF2a, PGE2, and PGI2, function in skeletal muscle development
and growth by regulating proliferation, differentiation, migration,
fusion, and survival of myoblasts (Mo et al., 2019). PGE2 and PGI2, as
well as leukotrienes B4 and D4 stimulate wound healing by monitoring
the synthesis of angiogenic factors and endothelial cell function (Sonn­
weber et al., 2018). Lipoxin A4, another downstream product of AA,
participates in neutrophil infiltration, mitigates leukotriene C4-induced
bronchoconstriction in asthmatic patients, and reduces eczema severity,
thereby improving life quality by inhibiting innate lymphoid cell type 2
activity (Tallima & El Ridi, 2018). Lipoxin A4 is also reported to inhibit
interleukin (IL)-6 and tumor necrosis factor (TNF), while promoting the
release of reactive oxygen species, further testifying to its potential in
ischemic stroke treatment (Tułowiecka et al., 2021).
2.2. ω-3-PUFAs
ALA is known for its neuroprotective, anti-inflammatory, and anti-
depressant potential. Enhanced dietary ALA supplementation lowers
the risk of ischemic stroke and carotid atherosclerosis (Bork et al., 2018;
Ding et al., 2020). The cardioprotective effect of ALA stems from its
ability to decrease lipid content, maintain endothelial function, and
counteract both thrombosis and arrhythmia (Sharifi-Rad et al., 2020).
Intake of ALA has been reported to improve symptoms in children with
attention deficit hypersensitivity disorder (Spector & Kim, 2019).
Furthermore, ALA improves brain-derived neurotrophic factor (BDNF)
levels (Rahman et al., 2020), lowers the risk of type 2 diabetes due to
increased insulin sensitivity (Jovanovski et al., 2017), and slows down
cancer cell proliferation owing to its downregulation of anti-apoptotic
genes (e.g., Bcl-2 and Bcl-xl) and upregulation of pro-apoptotic genes
(e.g., BAX and BAD) (Roy et al., 2017).
SDA lowers the level of TNF, thus playing a protective role in
tumorigenesis. Additionally, it has been observed to decrease cyclo­
oxygenase transcription and translation by downregulating nuclear
kappa light chain enhancer of activated B cells and PPAR-γ (Mansour
et al., 2018). It is also reported to inhibit platelet aggregation and
arachidonate oxygenation (Baeza-Jiménez et al., 2017). It plays an
important role in rheumatoid and mild asthma through its direct
involvement in terminating the inflammatory response by blocking
5-lipooxygenase, which is responsible for catalyzing leukotriene syn­
thesis (Prasad et al., 2021). Whelan et al. (2012) have reported the
atheroprotective potential of SDA, as indicated by its ability to signifi­
cantly reduce the levels of the inflammatory biomarker C-reactive pro­
tein (Whelan et al., 2012).
DHA amounts to 15% of total fatty acids in the frontal cortex. It is
involved in regulation of the neurotransmitter pathway, synaptic
transmission, and signal transduction (Hsu et al., 2020). It functions at
synaptic terminals, mitochondria, and the endoplasmic reticulum,
where it forms complexes with phosphatidylethanolamine, phosphati­
dylserine, and phosphatidylcholine. It regulates cell membrane fluidity,
neurotransmitter release, gene expression, myelination, neuro­
inflammation, and neuronal growth (Avallone et al., 2019). It exhibits a
neuroprotective effect by inhibiting nitric oxide synthesis, caspase sig­
nalling pathways, tau hyperphosphorylation, and by regulating the
PI3K/Akt signalling pathway. Together with preventing neuronal cell
death, it promotes dopaminergic synaptic plasticity and transmission
(Jackson et al., 2019). DHA is essential for brain development as
demonstrated by demand peaking during the late gestational period
(Chianese et al., 2017). DHA has been shown to induce expression of
BDNF, a vital mediator of synaptic transmission and biomarker of
neurologic disorders, via the p38 mitogen-associated protein kinase
(MAPK) pathway (Sun et al., 2018). In infants, DHA plays a critical role
in ensuring optimal visual and cognitive growth, with improved cerebral
functioning and behaviour following DHA supplementation during
pregnancy and lactation (Garg et al., 2017). Low plasma DHA levels
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Trends in Food Science & Technology 120 (2022) 140–153
have been identified in patients with retinitis, leading to speculation that
central retinal cone defects could be associated with DHA deficiency
(Bannenberg et al., 2019). DHA is an integral component of cell mem­
brane phospholipids, altering their physical, chemical, and signalling
properties. DHA content is known to influence cellular behavior and
responses to chemical, antigenic, electrical or hormonal signals (Calder,
2016). It is reported to induce and activate PPARs, which may aid in
lowering fasting plasma triglyceride levels, enhancing insulin sensi­
tivity, and decreasing inflammation (Naeini et al., 2020; Skulas-Ray
et al., 2019; Toupchian et al., 2016). DHA affects cell and tissue physi­
ology by altering membrane structure and function, membrane protein
function, cellular signalling, and synthesis of lipid signalling mediators,
eventually lowering the risk of insulin resistance, metabolic syndrome,
hyperlipidemia, and cardiovascular disease (Calder, 2016). Higher DHA
plasma levels have been associated with slower progression of coronary
atherosclerosis in coronary artery disease patients. DHA supplementa­
tion has been observed to significantly reduce both daytime ambulatory
blood pressure and 24-h measurements, resting heart rate, triglycerides
(Nishizaki et al., 2016); and diastolic blood pressure (Lee et al., 2019). In
Alzheimer’s patients, DHA levels are substantially lower, which may not
be surprising as DHA is required for both synthesis and clearance of
β-amyloid plaques, enhanced vascular health, neuronal membrane ho­
meostasis, and inflammation. Importantly, early DHA supplementation
before the onset of Alzheimer-related dementia may delay or decrease
its incidence (Yassine et al., 2017). DHA is also implicated in reducing
dyskinesia in Parkinson’s disease and its supplementation lowers the
risk of depression associated with this disorder (Gómez-Soler et al.,
2018). DHA counteracts the inflammatory processes affecting motor
neurons in the brain stem, spinal cord, and cortex, as indicated by an
increase in glutathione levels in microglial cells, thus improving their
antioxidant capacity (Newton, 2020). Its anti-atherothrombotic poten­
tial is associated with the ability to decrease AA content in blood cells
and prevent thromboxane synthesis in platelets (Lagarde et al., 2018).
DHA is metabolized by 15-lipooxygenase to active lipid mediators (i.e.,
oxylipins), such as resolvin RvD1 and neuroprotectin D1, which resolve
neuroinflammation in the brain (Sun et al., 2018). RvD1 and RvD2, as
well as protectin D1 possess anti-inflammatory and
inflammation-resolving abilities (Calder, 2016).
EPA reduces the release of AA from phospholipids by blocking
phospholipase A2 activity. This, in turn, promotes cyclooxygenase-2-
mediated synthesis of prostaglandin PGE3 and leukotriene B5, favoring
anti-inflammatory, anti-mitotic, and anti-allergic activities (Araujo
et al., 2019). It is also reported to inhibit nuclear factor-κB, leading to a
decrease in IL-1 and TNF-α, as well as block the MAPK pathway,
resulting in lower protein-1 transcription factor activity Evidence sug­
gests the usefulness of EPA-supplemented food for the treatment of bi­
polar depression disorder (Nasir & Bloch, 2019). The regulation of
microglial activity in the brain and inhibition of chronic inflammatory
responses by these cells and/or annexed monocytes is mediated by EPA
and its derivatives. These are potent regulators of the synthesis of
pro-inflammatory cytokines by activated microglia (Bazinet et al.,
2020). EPA is known to increase presynaptic serotonin release by
inhibiting the production of PGE2 (Günther et al., 2010). Importantly,
EPA can replace AA in membrane phospholipids, thereby modifying the
physical properties of membranes (Brinton & Mason, 2017). Specif­
ically, it decreases triglyceride levels and insulin sensitivity by stimu­
lating fatty acid oxidation through increased synthesis of PPAR-α
(Delarue, 2020). Furthermore, EPA reduces the complex steps involved
in atherogenesis, protects against oxidative stress, and enhances
vascular and endothelial function. It also prevents the movement of
monocytes into early lesions, regulates inflammation, participates in
anti-inflammatory and antioxidant functions of high-density lipopro­
teins (HDLs), and stimulates HDL-mediated cholesterol efflux from
macrophages. EPA retards atherosclerotic plaque formation, develop­
ment, and susceptibility to lysis (Brinton & Mason, 2017). The anti­
atherogenic effect of EPA is attributed chiefly to its potential to regulate
A. Patel et al. Trends in Food Science & Technology 120 (2022) 140–153

inflammation, thrombosis, and membrane cholesterol metabolism
(Brinton & Mason, 2017). Its antithrombotic activity derives from
obstructing the synthesis of thromboxane A2 involved in platelet ag­
gregation and vasoconstriction (Trebatická et al., 2017). EPA supple­
mentation helps to improve endothelial function and reduce systolic
blood pressure (Borow et al., 2017; Guo et al., 2019). Importantly, EPA
stimulates the neutral sphingomyelinase-mediated pathway, thereby
promoting apoptosis of breast cancer cells (Guo et al., 2019). In general,
EPA retards the growth of cancer cells by blocking the MAPK pathway
via decreased activation of the oncogenic transcription factors Ras and
activator protein-1 (Gorjao et al., 2019). EPA is reported to improve
muscle mass and function without any adverse effects (Ochi & Tsuchiya,
2018). It also downregulates the acute phase response during inflam­
mation by decreasing C-reactive protein, TNF-α, and IL-6 (Mocellin
et al., 2016), as well as the ubiquitin-proteasome pathway (Mocellin
et al., 2016).
3. Role of omega 3 and 6 fatty acids in the synthesis of bioactive
lipid mediators
Lipid mediators are well-known for their functions in leukocyte
trafficking, which is necessary for host defense (Serhan & Chiang, 2013).
PUFA act as potent source for the synthesis of bioactive lipid mediators
such as oxylipins, pro-resolving mediators and isoprostanes. Oxylipins
are important in immunological and inflammatory responses. Eicosa­
noids, a class of bioactive lipid mediators produced from AA, are the
most prevalent oxylipins. After getting stimulation by hormones and
cytokines, PUFA attached with membrane phospholipids are released
and act as a precursor for the synthesis of eicosanoids and docosanoids
by using three families of enzymes cyclooxygenases (COX-1 a constitu­
tive enzyme, or COX-2 an inducible enzyme), lipoxygenases (5-, 12-, or
15-LOX), or cytochrome P450 monooxygenases (Russo, 2009). More
specifically, COX enzymes and peroxidases act on AA to make 2-series
prostanoids (prostaglandins E2, prostacyclin I2, and thromboxane A2),
whereas 5-LOX action on AA produces 5-HPETE (arachidonic acid 5-hy­
droperoxide), which is then utilized to produce 4-series leukotrienes
(Fig. 1).
Another important class of bioactive lipids mediators derived from
both omega 3 and 6 fatty acids are specialized pro-resolving mediators
(SPMs) (Bannenberg & Serhan, 2010; Serhan & Chiang, 2013). They are
responsible for turning off inflammatory responses during the resolution
phase of inflammation in an active fashion (Serhan, 2007). There are
two specific classes of SPMs, S series and R series. S-resolvins, S-pro­
tectins, and S-maresins are S-series SPMs that emerge from
LOX-mediated oxygenation of omega 3 fatty acids such as EPA and DHA
while R-Series is result of aspirin-dependent acetylation of COX-2 where
both omega 3 and 6 Fatty acids (AA, EPA and DHA) were used to
generate aspirin-triggered R-series SPMs. It has been clearly described
the role of omega-3 fatty acids for anti-inflammatory function through
these mediators (Calder, 2013; Nicolaou et al., 2014). Isoprotanes are
another group of mediators that are usually produced after exposure of
free radicals to oxidize triple or more double bonds of PUFA (Milne

Fig. 1. Conventional aerobic desaturase (des) and elongase (elovl) pathway for long-chain PUFA synthesis. Fatty acids composition of the cell membrane can be
altered by dietary intake, which can severely affect the production of bioactive lipid mediators. ω-3 and ω-6 fatty acids precursors give rise to a variety of molecules
with inflammatory (orange), anti-inflammatory (green), and proresolving (blue) activities. Isoprostanes (yellow) are markers of oxidative stress. (For interpretation
of the references to color in this figure legend, the reader is referred to the Web version of this article.)

143
A. Patel et al.
et al., 2011; Song et al., 2009), hence act as marker for oxidative stress
and also function as pro and anti-inflammatory mediators (Czerska
et al., 2016; Montuschi et al., 2004) (Fig. 1).
4. Role of a balanced ratio of dietary ω-6/ω-3 PUFAs
A 1:1 to 5:1 ω-6:ω3 fatty acid ratio is considered optimal for human
health (Lupette & Benning, 2020). However, a marked decline in the
consumption of ω-3 PUFAs and a concomitant increase in ω-6 PUFAs
have been observed during the past decades. This has led to an increase
in the ω-6:ω3 fatty acid ratio from 1:1 to 20:1 in the Western diet
whereas 45:1 in the South Asian diet (Singh et al., 2017). . Because ω-6
and ω-3 PUFAs depend on the same downstream digestive enzymes, a
greater ω-3 intake would lead to less ω-6 being available to produce
pro-inflammatory signaling molecules (Bhardwaj et al., 2016). Western
societies are characterized by an increased frequency of cardiovascular
diseases, asthma, and cancer, which are associated with higher levels of
pro-inflammatory signaling molecules (Lupette & Benning, 2020). In
contrast, daily intake of a diet rich in ω-3 PUFAs has been linked with a
lower prevalence of these diseases in the Icelandic population, Inuit
indigenous people, and native Americans in Alaska (Simopoulos, 2016).
The same beneficial health effects have been ascribed also to the Med­
iterranean diet, which is rich in fish, fruits, vegetables, and olive oil
(Lupette & Benning, 2020). PUFA composition is particularly important
in depressive patients, because EPA and AA are processed through the
same cyclooxygenase. The pro-inflammatory and anti-inflammatory
nature of eicosanoids derived from AA and EPA, respectively, points
to a correlation between a higher ω-6:ω-3 ratio and depression. An
elevated ω-6:ω-3 ratio could stimulate the secretion of pro-inflammatory
cytokines, thereby inducing low-grade inflammation and promoting the
hypothalamic-pituitary-adrenal axis in major depression disorders
(Husted & Bouzinova, 2016). The ω-6:ω-3 ratio modulates also matrix
attachment region binding proteins, scaffold/matrix attachment region
binding protein 1, and CCAAT-displacement protein/cut homeobox.
This, in turn, regulates an intrinsic signal transduction mechanism,
which alters cell growth. Accordingly, reducing the ω-6:ω-3 ratio in our
diets could affect cancer cell metabolism, as demonstrated by a lowered
risk of breast cancer in premenopausal women consuming a diet rich in
ω-3 but poor in ω-6 PUFAs (Huerta-Yépez et al., 2016). The link between
a high ω-3:ω-6 ratio and lowered breast cancer risk can be attributed to
the anti-carcinogenic activity of ω-3 PUFAs, which counteracts the car­
cinogenetic effect of ω-6 PUFAs and their ability to generate
pro-inflammatory eicosanoids linked to angiogenesis and mitosis (Nin­
drea et al., 2019). An increased prevalence of complex coronary lesions
has been reported in patients with a low plasma EPA:AA ratio (Taka­
hashi et al., 2017). Coronary atherosclerosis development was observed
in coronary artery disease patients treated with certain statins, who
displayed a low serum ω-3:ω-6 PUFAs ratio (Nozue et al., 2013). Animal
models with a low ω-3:ω-6 ratio have been found to display abundant
eicosanoid metabolites, which leads to a pro-thrombotic and
pro-aggregatory state with ensuing elevated blood viscosity (Mariame­
natu & Abdu, 2021), as well as vasospasm, vasoconstriction, and cell
proliferation (Simopoulos, 2016). A low ω-3:ω-6 ratio impairs the syn­
thesis of pro-thrombotic thromboxane and pro-inflammatory leukotri­
enes B4 and C4, thus explaining the increased thrombotic phenotype
(Lev et al., 2010). Grootendorst-van Mil et al. (2018) reported an asso­
ciation between maternal plasma ω-3 and ω-6 PUFA levels and fetal
health, as manifested by a faster fetal growth and greater infant birth
weight at a higher ω-3:ω-6 PUFAs ratio (Grootendorst-van Mil et al.,
2018). A 70% reduction in mortality due to secondary cardiovascular
disease was found to be associated with a 4:1 ω-6:ω-3 ratio. Similarly, a
2.5:1 ratio was observed to slow down cell growth in colorectal cancer
patients; whereas a 2:1 to 3:1 ω-6:ω-3 ratio curbed inflammation in
rheumatoid arthritis patients (Bhardwaj et al., 2016). Also a beneficial
effect of a 5:1 ω-6:ω-3 ratio on asthma whereas an adverse effect of 10:1
ω-6:ω-3 ratio is also reported (Mariamenatu & Abdu, 2021). High
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subscapular skin-fold thickness in 3-year-old children was correlated
with a high ω-6:ω-3 ratio in umbilical cord red blood cell membrane
phospholipids. Elevated adiposity in the offspring has been linked to a
higher intake of ω-6 PUFAs during the perinatal period. A diet with a
high ω-6:ω-3 ratio promotes AA-derived endocannabinoid signaling,
which favors inflammation, energy homeostasis, and mood swings
(Simopoulos, 2016). Endocannabinoids are group of lipid mediators that
activate central (CB1) and peripheral (CB2) cannabinoid receptors
usually expressed as membrane G-coupled receptors in brain and pe­
ripheral tissue (Chianese et al., 2017; D’Angelo et al., 2020). Berger
et al. (2017) have observed that elevated ω-6:ω-3 ratios in erythrocyte
membranes could trigger mood disorders in people aged <18 years
presenting with an ultrahigh risk phenotype, suggesting the possibility
of using the ω-6:ω-3 ratio as a biomarker for mood disorders. A high
ω-6:ω-3 ratio is deleterious to carriers of genetic variations in APOA5,
CD36, TCF7L2, and ALOX5 genes; while lowering it can prevent chronic
disease in these individuals (Bhardwaj et al., 2016). Additionally, a
higher ω-3:ω-6 supplementation was found to have a positive impact on
periodontal health as seen by a reduction in the levels of prostaglandin
D2, prostaglandin E2 and leukotriene levels (Navarro Hortal et al.,
2018). Muzsik et al. (2020) have observed a lower ω-3:ω-6 ratio in red
blood cells of postmenopausal women with metabolic syndrome as
compared to those without it (Muzsik et al., 2020). Additionally, acute
coronary syndrome, myocardial infarction, stroke, chronic heart failure,
CAD, PAD and vascular disease was found to be associated with lower
EPA:AA ratio (Nelson & Raskin, 2019). A low EPA:AA ratio and high
C-reactive protein sensitivity were observed in diabetes mellitus patients
with prior myocardial infarction (Nelson & Raskin, 2019). Takahashi
et al. (2017) reported that statin affected the DHA:AA ratio but not the
EPA:AA ratio, thus establishing the latter as a biomarker for cardio­
vascular events (Takahashi et al., 2017). Improved triglyceride, very
low-density lipoprotein-c, glucose, insulin, and insulin resistance were
observed in subjects with a dietary intake characterized by a low ω-6:ω-3
ratio (Torres-Castillo et al., 2018). Finally, Christian et al. (2016) noted
that a higher AA:DHA ratio in the maternal erythrocyte membrane was
associated with an enhanced risk of premature birth in
African-Americans (Christian et al., 2016).
5. Food sources of dietary ω-3/ω-6 polyunsaturated fatty acids
LA is the parent compound of ω-6 PUFAs and a precursor for the
synthesis of long-chain PUFAs, such as AA and GLA. It is the most
abundant PUFA in many plant oils, such as corn, safflower, soybean, and
sunflower, as well as in nuts, seeds, meats, and eggs (Ganesan et al.,
2014). In both terrestrial and marine ecosystems, plants are the main
source of ω-3 PUFAs. ALA is the most abundant ω-3 PUFA in various
foods of both plant (e.g., linseed/flaxseed, soybean, and rapeseed oils)
(Ganesan et al., 2014; Mardones et al., 2008) and animal origin, and
serves as the precursor for EPA and DHA. These two are produced
mainly by marine algae and further concentrated in the food chain
(Dewhurst & Moloney, 2013). Consequently, fish and fish oils are the
most prominent food sources of EPA and DHA (Ganesan et al., 2014);
their levels can range from several hundred mg to more than 1 g per 100
g of fish (Kawashima, 2019).
The lipids in beef, lamb, poultry, and pork represent a negligible
source of omega-3 PUFAs. As a result, meats display a generally high
ω-6:ω-3 ratio and low polyunsaturated: saturated fatty acids ratio
(Dewhurst & Moloney, 2013). LA is the most common ω-6 and ALA the
most common ω-3 fatty acid in meat. Ruminant and non-ruminant meats
differ in PUFA composition. While ALA is present at 0.7–1.4% of total
fatty acids for beef, pork, and lamb; LA is considerably higher in pork
(14.2%) than in beef (2.4%) and lamb (2.7%) resulting in a higher
ω-6:ω-3 ratio for pork. Poultry shows a similar fatty acid composition as
pork, i.e., a relatively high content of LA. The ω-6:ω-3 ratio in ruminant
meat is somewhat more favorable due to intake of grass rich in ALA
(Dewhurst & Moloney, 2013), but the low conversion of ALA to EPA and
A. Patel et al.
DHA limits the ω-3 fatty acid content in meat (Ganesan et al., 2014). In
ruminants, conjugated linoleic acids (CLAs) represent an important
group of fatty acids (Wood et al., 2004; Woods & Fearon, 2009). AA is
only found in moderate amounts (<200 mg per 100 g) in meat, poultry,
eggs, fish, and dairy products (Kawashima, 2019). Like meat, milk has a
relatively low PUFA content and low polyunsaturated: saturated fatty
acids ratio, with LA and ALA being the most common ω-6 (1–3% w/w)
and ω-3 (0.5–2% w/w) fatty acids in milk fat, respectively (Jensen,
2002).
6. Food fortification with ω-3 fatty acids
Food fortification is an effective strategy to counteract nutrient de­
ficiencies and has been applied for a long time, especially in industri­
alized countries, where foods have been fortified with vitamins A, B, and
D, iodine, and iron. “Designer foods” is a concept that defines regular
foods, which besides their traditional nutritional value contain some
compound that provides additional health benefits. They are also
referred to as “functional” or “fortified” foods and have a long history of
use in East Asia in traditional medicine to reduce the risk of various
diseases. The use of designer foods avoids the need for changing dietary
habits and adequate amounts of nutrients can be delivered regularly,
thereby improving the diet and preventing deficiencies (Rajasekaran &
Kalaivani, 2013). Foods fortified with ω-3 fatty acids are taking a
growing share of the market due to their accessibility, low cost, and
increased awareness of the health benefits attributed to long-chain ω-3
PUFAs. To balance the effect of ω-6 fatty acids, a sufficient intake of ω-3
fatty acids is required, particularly given the low conversion of ALA into
EPA and DHA (Mariamenatu & Abdu, 2021). This, in turn, requires an
adequate supply of food rich in these fatty acids. The elevated content of
mercury and environmental pollutants in oceanic fish has enhanced
consumer interest in alternative ω-3 sources (Ganesan et al., 2014) and
the development of a variety of foods fortified with ω-3 PUFAs.
6.1. Meat
Meat and meat products constitute a significant dietary source, but
are poor in ALA, EPA, and DHA. Meat products obtained by supple­
mentation of ω-3 PUFAs in animal feed have been developed; however,
excessive amounts of these fatty acids in feed can adversely affect rumen
activity and milk production (Woods & Fearon, 2009). A common
strategy to increase ω-3 content is to add linseed oil to lamb and beef
cattle diet (Pajor et al., 2021). Fish oil or marine algae with long-chain
ω-3 PUFAs have also been used in animal feed for this purpose
(Gómez-Cortés et al., 2021) and a mixture of these sources was shown to
allow successful incorporation of EPA and DHA in lambs (Gómez-Cortés
et al., 2021). Broiler meat with an improved ω-6:ω-3 ratio has been
produced by feeding broilers with ultrasonicated flaxseed oil nano
emulsions (Abbasi et al., 2020). Another method to enrich meat prod­
ucts with ω-3 fatty acids is to use walnuts, oils or pre-emulsified oils in
processed foods. This has led to the development of fortified fresh meat
products, such as ground beef patties with fish oil (Raeisi et al., 2021)
and fresh sausages enriched with algal oil emulsions (Lee et al., 2006) or
pre-emulsified linseed/fish oil (Valencia et al., 2008). This has resulted
in cooked sausages fortified with pre-emulsified fish oil (Cáceres et al.,
2008) and walnut paste (Ayo et al., 2007), as well as pâté, in which pork
fat has been replaced with an oleo gel based on linseed oil with elevated
LA content (Martins et al., 2020).
6.2. Eggs
Eggs are a widely used, inexpensive, and nutrient-dense food source,
which can be conveniently supplemented with additional nutrients. The
idea of eggs as a designer food arose in the 1930s by inducing changes in
fatty acid composition of egg yolk (Cruickshank, 1934). Modification of
the hens’ diet is a common strategy to enrich eggs with ω-3 fatty acids.
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Saturated fatty acids in the yolk can be replaced with ω-3 fatty acids by
feeding hens with sunflower, flaxseed or marine algal oils (Jensen, 2002;
Neijat et al., 2020). Consumption of such ω-3 enriched eggs was found to
improve the serum lipid profile and blood pressure in some patient
groups. Other designer eggs have been developed by feeding hens a diet
rich in CLA; the resulting eggs had a pronounced anti-inflammatory
effect in mice (Corrales-Retana et al., 2021; Franczyk-Zarów et al.,
2008).
6.3. Dairy
Dairy products fortified with ω-3 fatty acids are attractive to con­
sumers. Hence, various designer milks have been developed and their
effects on human health have been evaluated. A common strategy for
increasing ω-3 PUFA content in milk is supplementation of the rumi­
nants’ diet with linseeds/linseed oil, marine oils/algae or a combination
of the above (Donovan et al., 2000; Petit & Côrtes, 2010; Shingfield
et al., 2003). By supplementing the cow diet with sunflower seeds,
designer milk with increased CLA content is produced. However, the
increase in ω-3 fatty acids in milk is limited by rumen biohydrogenation
(Toral et al., 2017). Partially circumventing this limitation enabled the
production of ω-3 milk with more than 10% ALA based on linseed oil
infusion (Petit et al., 2002). Another approach for obtaining ω-3 fortified
milk products is through nutrient enrichment. Intake of milk enriched
with fish oil, oleic acid, EPA, DHA, minerals, and vitamins has shown
health benefits such as reduced cell adhesion molecules in healthy
children (Romeo et al., 2011), as well as diminished cardiovascular risk
in postmenopausal women and improved bone metabolism (Fonolla-­
Joya et al., 2016). Decreased blood lipids (Lopez-Huertas, 2010),
improved composition of red blood cell membranes, and positive effects
on inflammatory parameters have also been ascribed to ω-3 fortified
milk. Pregnant women receiving powdered milk fortified with ω-3 fatty
acids gave birth to children with greater weight and length (Mardones
et al., 2008). Fortified yogurts with microencapsulated salmon oil
(Estrada et al., 2011) and flaxseed powder have resulted in an increased
PUFA content and a decreased ω-6:ω-3 ratio. In an attempt to provide
pregnant and breastfeeding women with adequate amounts of DHA, a
yogurt fortified with microalgae oil was formulated. Finally, butter with
increased ALA content has been developed using a flaxseed oil- and
flaxseed-whey protein concentrate emulsion (Pandule et al., 2021).
Some fortification techniques such as microencapsulation and emulsi­
fication to entrap omega-3 fatty acids enhance the quality of yogurt for
its water holding-capacity, and textural attributes with a lower oxida­
tion and syneresis rate (Gumus & Gharibzahedi, 2021). The yogurt
fortification with functional omega-3 fatty acids improves bioavail­
ability while also decreasing serum lipidemic profile and obesity-related
risk factors (Gumus & Gharibzahedi, 2021).
6.4. Bakery
During bread manufacturing, fats are added to the dough, making
this type of food a convenient choice for ω-3 fatty acid fortification.
Cookies, cakes, and breads have been produced using eggs and dairy
ingredients containing ω-3 PUFAs (Ganesan et al., 2014). Breads forti­
fied with flaxseed displayed a lower ω-6:ω-3 ratio (Taglieri et al., 2020).
Microencapsulation of flaxseed oil in β-glucan or yeast cells has been
proposed as a promising strategy for making ω-3 fortified bread and
avoiding lipid oxidation (Beikzadeh et al., 2020; Kairam et al., 2021).
Similarly, enriching gluten-free cornbread with anchovy-derived ω-3
PUFAs have been proposed, and fortification with the herb purslane
resulted in pasta with a high content of LA and ALA.
6.5. Infant formula
Human milk serves as the ultimate food for proper growth and
development of infants. Its composition is therefore recreated when
A. Patel et al.
developing infant formula. Human milk has a complex and balanced
composition of nutrients including lipids, of which DHA and AA
constitute the main long-chain PUFAs. As cow milk does not contain
DHA and AA in sufficient amounts, commercial oils are added to most
infant formulas reformulated from cow milk. Common sources of fat for
infant formula include mixtures of plant oils, as well as fish and algal oils
(D’Ascenzo et al., 2014; Kuratko et al., 2013; Tai et al., 2013; Winwood,
2013; Yeiser et al., 2016). Formulas with a combination of dairy lipids
and plant oils have been shown to stimulate endogenous conversion of
precursors to long-chain ω-3 fatty acids in infants.
7. Innovative technologies for food fortification with ω-3 fatty
acids
The FAO and WHO have defined fortification as enhancing the
nutritional content of food by increasing the composition of an essential
micronutrient, thus providing health benefits with minimal health risks
to consumers (Saeid, 2018). Consumers and producers have become so
comfortable with the notion of fortified foods that promotional public
health campaigns are no longer needed. In particular, ω-3 fortified foods,
such as milk-based products, meat, eggs, juices, table spreads, salad
dressings, sauces, breakfast cereals, baked goods, and infant formula,
have been received very positively by the public. Light can oxidize ω-3
fatty acids and, hence, ω-3 fortified foods should be wrapped in an
opaque packaging. Microencapsulation delays or inhibits the oxidation
of ω-3 as well as the development of undesirable flavors and odors
(Hegde et al., 2016). Various methods, such as spray drying, freeze
drying, coacervation, extrusion, and fluidized bed coating are used for
encapsulating oils rich in ω-3 fatty acids (Chang & Nickerson, 2018). The
latter can be spray-dried into powders and mixed with starch or proteins
to protect them from oxidation. Powders are preferred in baked foods
and beverages, where ingredients require greater dispersion and sta­
bility. For liquid applications, they have to be blended with emulsifiers
to prevent their separation (Hegde et al., 2016); this can be achieved
through nanocapsules, micelles, liposomes, emulsions, microspheres,
and biopolymer matrices (Zheng & McClements, 2020).
A superior capsule design requires that a comparatively large
amount of fatty acid-rich oils is entrapped in food-grade wall material.
Such strategy ensures protection against chemical degradation, allows
the dispersion of bioactive compounds at a specific rate and site in
response to environmental factors, tunability with the neighboring food
matrix without influencing the final appearance or texture, and con­
sumer acceptability (Chang & Nickerson, 2018). Fioramonti et al., 2019
have described another strategy for encapsulating flaxseed oil by using a
mixture of whey protein concentrate, sodium alginate and maltodextrin
(Fioramonti et al., 2019). Shrimp oil nanoliposomes prepared from
cephalothorax of Pacific white shrimp by using phosphatidyl choline in
ethanol, glycerol and deionized water has been described. The freeze
dried as well as spray dried nanoliposomes made by using carboxy
methyl cellulose and fumed silica as wall material and anti-caking agent
provided advantages by masking foul odors and protecting oil against
oxidation (Gulzar & Benjakul, 2020). Microcapsules designed using pea
protein isolate and glucose syrup have been shown to successfully
encase 20% rapeseed oil (Tamm et al., 2016). Emulsion properties, such
as stability, droplet size, and viscosity are known to significantly affect
microcapsule properties (Chang & Nickerson, 2018). Chen et al. (2016)
have reported the use of transglutaminase to introduce covalent
cross-links and enhance the emulsifying activity of soy protein isolate
when entrapping DHA-rich oil with gum Arabic and maltodextrin (Chen
et al., 2016). Jiménez-Martin et al. (2016a, 2016b) reported the prep­
aration of a primary emulsion homogenizing fish oil with sodium
caseinate and lactose monohydrate, which was further combined with
olive oil containing polyglycerol polyricinoleate to synthesize a sec­
ondary emulsion. The latter was subsequently amalgamated with so­
dium caseinate and lactose monohydrate to synthesize feed emulsions
prior to spray drying. This multiple-emulsion step enhanced entrapment
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efficiency of EPA (94%) and DHA (83%) (Jiménez-Martín, Antequera
Rojas, et al., 2016). Trilaksani et al., 2020 have described the prepara­
tion of microcapsules containing tuna virgin fish oil with mangrove fruit
extract encapsulated in sodium caseinate and a mixture of arabic
gum-maltodextrin (Trilaksani et al., 2020). A single-layer emulsion was
developed by blending tuna oil with negatively charged lecithin. Later,
positively charged chitosan solution was added to produce a
double-layer solution by inducing electrostatic interaction. Finally, this
double layered solution was diluted with maltodextrin prior to spray
drying (Kwamman & Klinkesorn, 2015).
Fortified breads containing 100 mg of microencapsulated ω-3 fatty
acids per 100 g product have become hugely popular among consumers
(Agriculture and Agri-Food Canada, 2011). They serve as good vectors
for delivering EPA and DHA in adequate quantities. Tip Top Up bread
was launched as a joint endeavor of Nu-Mega Ingredients and George
Weston Foods, and was formulated to contain Nu-Mega’s micro­
encapsulated HiDHA oils (Hegde et al., 2016). Functional bread
encapsulated with flaxseed oil and garlic oil microcapsules was devel­
oped using nanoemulsions and spray drying (Kairam et al., 2021).
Ingredient compatibility as well as popularity makes dairy products apt
for omega-3 fortification. Examples of ω-3 fortified dairy products
include yoghurt, milk drinks, margarines, spreads, plus fresh and
ultra-high temperature milk (Hegde et al., 2016). Bello et al. (2015)
have described the fortification of yoghurt with ALA using flaxseed oil,
Camelina sativa, raspberry, blackcurrant oil, and Echium plantagineum.
Besides yoghurts supplemented with raspberry and E. plantagineum, the
rest were judged positively by consumers (Dal Bello et al., 2015). Goyal
et al. (2016) have described flaxseed oil microcapsules incorporation in
dahi (Indian yoghurt) as a means of delivering ω-3 fatty acids (Goyal
et al., 2016). Whole milk, yoghurt, cheese, yoghurt drinks, dairy-based
beverages, milk powder, butter and buttermilk can be fortified with
PUFAs to minimize nutrition deficiency and related disorders (Minj &
Dogra, 2020). Generally, 200 mL of fortified milk can contain 10–190
mg of EPA and DHA or 800 mg of ALA. Margarines and salad dressings
are fortified with ALA derived from flaxseed or colza oils; whereas
spreads are fortified with EPA/DHA from fish oils (Feizollahi et al.,
2017). The inclusion of ω-3 fatty acids in infant formula has expanded
their usage in fluid milk (Hegde et al., 2016). This is particularly true of
the algal DHA market, currently dominated by Martek Biosciences. Most
companies produce infant formula, whose quantities of algae-derived
DHA imitate those in human breast milk (Hegde et al., 2016). Cold
beverages have surpassed hot beverages as the preferred delivery
vehicle for ω-3 fortification. Formulation of ω-3-enriched chocolate milk
using chia oil to replenish energy in athletes following exercise has been
reported (González et al., 2021). Minute Maid’s enhanced POM blue­
berry, Tropicana pure premium health heart orange juice, and Indian
Rivers fortified grapefruit juice are some famous fortified fruit juices on
the US market (Hegde et al., 2016). Chicken meat is the fastest growing
sector of the world meat market. Fishmeal, fish oil, and linseed oil have
been used to increase the ω-3 fatty acid content of meat (Alagawany
et al., 2019). Jiménez-Martin et al. (2016a, 2016b) have described the
preparation of chicken nuggets supplemented with microcapsules of ω-3
fatty acids from fish oil. These were formulated using multilayer mi­
crocapsules prepared with lecithin-chitosan and maltodextrin, and
comprising 10% fish oil (Jiménez-Martín, Pérez-Palacios, et al., 2016).
Ainsa et al., 2021 have described the preparation of ω-3 and ω-6
enriched pasta prepared from trimmings and small pieces of sea bass
(Dicentrarchus labrax), semolina from durum and spelt wheat, bran and
rosemary extract (Ainsa et al., 2021). Anbudhasan and Surendraraj
(2014) have reported the development of ω-3 fatty acid-enriched pasta
using refined wheat flour, salt, fish meat, fish oil, and water. The protein
content of ω-3-enriched pasta was 4.84% higher than in regular pasta
and an ω-3 content of 974 mg was measured (Anbudhasan & Sure­
ndraraj, 2014). Chocolate spread formulations using soybean oil and
coconut oil in combination with commercial palm stearin has been re­
ported (Nazir & Azad, 2018). Furthermore, nutritional supplements
A. Patel et al.
containing ω-3 fatty acids as active ingredients are commercially
available in the form of fish liver oil or cod liver oil encapsulated as soft
gels (Hegde et al., 2016).
8. Drawbacks of food fortification
A significant disadvantage of food fortification is that the encapsu­
lation process can be more expensive than the ω-3 fatty acid ingredient
itself (Feizollahi et al., 2017). The weaker emulsifying property of pro­
teins makes the emulsions unstable when exposed to non-optimal tem­
perature, pH, and salt. Thinner interfacial protein films affect the ability
to protect oil droplets and control their release (Chang & Nickerson,
2018). Bread fortified with microencapsulated oils was reported to
exhibit a lower water absorption capacity and inferior baking properties
due to increased firmness, leading to unfavorable consumer accept­
ability (Serna-Saldivar et al., 2019). Another issue with the incorpora­
tion of ω-3 fatty acids in baked goods is the extended shelf life required,
in some cases over a year, which becomes challenging due to instability
of ω-3 fatty acids. The properties and distinct flavors of dairy products
make it difficult to include ingredients such as fish oil. Oxidation and the
off-putting fish flavor represent other drawbacks of incorporating ω-3
fatty acids in foods (Stamenkovic et al., 2019). To overcome these issues,
the industry has introduced novel encapsulation techniques using anti­
oxidants and protein-based emulsions; however, they add to the cost of
the final product (Chang & Nickerson, 2018). The increasing content of
mercury and pesticides in the marine environment raises further con­
cerns over the use of fish and fish oil for food fortification (Costa et al.,
2019). PUFAs in marine lipids undergo oxidation when exposed to at­
mospheric oxygen, releasing free radicals, free fatty acids, and oxidation
products, which are deleterious for cardiovascular health (Ahmed et al.,
2016). It is also possible that the target population misses out on forti­
fication, because in rural areas people who consume the poorest diets
are less likely to have access to fortified foods (Lalani et al., 2019).
Despite the risk of inadequate nutrient intake through the diet, there are
also concerns whether some individuals are consuming an excess of
nutrients. Choosing a suitable fortification vehicle, addressing target
populations, avoiding overindulgence in untargeted populations, and
examining the nutritional status are important challenges (Chadare
et al., 2019). In summary, poor understanding or lack of consumer
awareness regarding the health benefits of ω-3 fatty acids, a superior
price range of ω-3 fortified products, regulatory restrictions, and the lack
of a globally accepted reference daily intake level for a nutrient are
major market restraints for such products.
9. Fortification of food with ω-3/ω-6 PUFAs; an incomplete
agenda for low- and middle-income countries
Food systems in many low- and middle-income countries do not
provide nutritionally appropriate meals to all people, leading to
micronutrient deficiencies in women and children (Pinstrup-Andersen,
2013). Iron, iodine, folate, vitamin A, and zinc deficiencies are the most
frequent, and they contribute to poor growth, poor cognitive develop­
ment, reduced IQ, prenatal problems, and an increased risk of morbidity
and mortality at the individual level (Bailey et al., 2015). Micronutrient
deficits in such countries contribute to human capital and economic
development inefficiencies at the population level. As a result, pre­
venting them is critical for global health and economic growth.
Although large-scale food fortification (LSFF) is a cost-effective and
extensively used intervention, there is still room for improvement. We
used the Global Fortification Data Exchange (GFDx) to identify nations
that potentially benefited from new fortification projects in order to
identify gaps and possibilities (“Global Fortification Data Exchange
GFDx,” 2021). We identified 84 nations as potential LSFF program re­
cipients. According to Fortification Assessment Coverage Toolkit sta­
tistics, the potential of oil/ghee and salt fortification is not being
realized due to insufficient population coverage of adequately fortified
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foods. For regulatory agencies to monitor food fortification, mandatory
fortification imposes a legal obligation. Mandatory legislation is more
cost-effective, egalitarian, and long-term than voluntary fortification
when it is accompanied by sufficient regulatory monitoring to assure
compliance. Foods fortified on a voluntary basis may have lower pop­
ulation coverage, inconsistent manufacturing, and higher costs than
those fortified under mandated laws. However, if adequate nutritional
levels and compounds are specified, food standards that enable volun­
tary fortification also give information to food manufacturers on how to
fortify foods safely and efficiently. GFDx populates its database through
a bi-annual survey, aiming to reach 196 countries. In between survey
cycles, the GFDx database is updated when new information is received
directly from fortification partners and/or national stakeholders. Ac­
cording to GFDx, only 27 countries could legally mandate fortification of
a food with oil (Fig. 2). Among these, only three have collected data
showing the proportion of the population that eats the fortified food
vehicle in question (Fig. 3). Ideally, the amount of fortified food
consumed is comparable in the entire population (all households). In
practice, the percentage of families who do not consume a food must be
taken into account, as they cannot be regarded prospective beneficiaries.
For example, if they eat predominantly cassava, fortification of wheat
flour may not be beneficial to them. When these families are included in
the denominator, the projected population coverage is reduced, altering
the manager’s perception of the program’s utility.
10. Microbial production of omega 3 fatty acids
Due to declining fish supplies and contamination of marine ecosys­
tems, the worldwide demand for omega-3 and 6 PUFAs cannot be
satisfied only by fish oils, which has sparked research in alternate sus­
tainable sources. Some vegetable oils and genetically engineered plant
oilseeds such as Brassica juncea, Arabidopsis thaliana, and Camelina sativa
are a good alternative sources of omega-3 PUFAs in the commodities
(Gill & Valivety, 1997). Despite the various benefits of transgenic plants,
their production is limited by seasonal and climatic circumstances, as
well as the availability of arable land. Furthermore, there are public
concerns about transgenic agricultural production in open environ­
ments. These factors, along with regulatory concerns, limit the pro­
duction of genetically modified crops on a wide scale. Now, microbial
oils for PUFA production getting more attention these days due to
similar fatty acids profile to those obtained from plants and animals and
a possible source of nutritionally important omega-3 & 6 PUFAs (Ward
& Singh, 2005). Some oleaginous microbes such as microalgae and
thraustochytrids has high amount of DHA and EPA in their total lipids
content (Patel et al., 2021). Microalgae are mostly autotrophic in nature
and the productivity of theses fatty acids are lower than those obtained
with heterotrophic cultivation (Patel et al., 2018). Only few microalgae
like Crypthecodinium cohnii are good example of heterotrophic micro­
algae that can produce high amount of DHA (Patel, Karageorgou, et al.,
2020). However, among several oleaginous microbes thraustochytrids
are natural producer of omega-3 fatty acids heterotrophically.
11. Conclusions
Our forefathers ate a diet that had an almost equal proportion of ω-6
and ω-3 fatty acids. Since then, the ω-6:ω-3 ratio has changed to 15–20:1
through the development of modern agriculture and new dietary habits.
This switch has become problematic because of the low interconversion
between ω-6 and ω-3 fatty acids. Changes in tissue ω-3 fatty acid profiles
may have important health consequences because these fatty acids
control essential cell properties and activities, such as membrane
fluidity, cell signaling, gene expression, and eicosanoid metabolism. As a
result, a shift in the fatty acid ratio is expected to have significant clinical
implications for the health of newborns and cardiovascular disease.
Humans require only small amounts of ω-6 fatty acids, which are found
in a variety of meals. As a result, people exposed to a Western diet may
A. Patel et al. Trends in Food Science & Technology 120 (2022) 140–153

Fig. 2. Low-income, middle-income, and upper-middle income countries that do not have mandatory programs in place and have the potential to benefit from new
LSFF programs or from making voluntary programs mandatory (Global Fortification Data Exchange. Accessed May 23, 2021 [http://www.fortificationdata.org.].).

Fig. 3. Population coverage in low-income, middle-income, and upper-middle income countries towards fortified foods (Global Fortification Data Exchange.
Accessed May 23, 2021 [http://www.fortificationdata.org.].).

be already consuming excessive amounts of these foods. While popular,
a combination of ω-3-6-9 pills does not offer any significant benefits
besides those brought by supplementation with ω-3 fatty acids alone.
The health advantages of ω-3 PUFAs are widely recognized. Ultimately,
dietary intake of ω-3 PUFAs through incorporation into foods is the most
effective way of delivering them to the average consumer. While ω-3
PUFAs themselves do not contribute to the off-putting fishy flavor of
many ω-3 fortified foods, it is important to identify the origin of such
fishy taste and attempt its removal to make the end-products more
palatable to the public.
CRediT authorship contribution statement
Alok Patel: Conceptualization, Methodology, Data curation, Writing
– original draft. Sneha Sawant Desai: Writing – original draft. Varsha
Kelkar Mane: Writing – review & editing, Visualization. Josefine
Enman: Writing – review & editing. Ulrika Rova: Writing – review &
editing, Visualization, Supervision. Paul Christakopoulos: Formal
analysis, Visualization, Supervision. Leonidas Matsakas: Validation,
Visualization.
Acknowledgement
Alok Patel, Ulrika Rova, Paul Christakopoulos and Leonidas Matsa­
kas would like to thank the Swedish Research Council (FORMAS) and
Kempestiftelserna, Sweden for supporting this work as part of the pro­
jects ‘Green and sustainable approach to valorise high saline and oily
fish processing effluents for the production of nutraceuticals’ (INVEN­
TION; 2020-01028), Boosting the squalene content in thraustochytrids
by genetic engineering using CRISPR–Cas9 System to replace the shark-

148
A. Patel et al.
based squalene as an adjuvant for COVID 2019 vaccine (JCK-2115) and
‘Tuned volatile fatty acids production from organic waste for biorefinery
platforms (VFA biorefinery; reference number 2018–00818).
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