HARAMAYA UNIVERSITY,

COLLEGE OF HEALTH AND MEDICAL SCIENECES

SCHOOL OF PUBLIC HEALTH

THE EFFECT OF NUTRITION ON THE DEVELOPMENT OF HUMAN

IMMUNE SYSTEM- A SYSTEMATIC REVIEW.

Individual Assignment 2

Fowzi Salih

College: HEALTH AND MEDICAL SVIENCES

School/Department: Public Health
Program: Public Health Nutrition

Course Lecturer: Dr. Kedir Teji (PhD)

March 2023
Harar, Ethiopia
Introduction: A well-functioning immune system is critical for survival. The immune system
must be constantly alert, monitoring for signs of invasion or danger. Energy and nutrients
obtained through food play an important role in the development and preservation of the immune
system therefore any nutritional imbalance affects its competence and integrity. This review
describes the effect of nutrition on the development of human immune system.

Method: We performed a comprehensive systematic review on PubMed/MEDLINE and Web of

from 2017 until April 2023.

Result :

Discussion:
Introduction
The immune system is concerned with defense of the host against pathogenic organisms. It
consists of a complex network of molecules and cells that have precise roles. The immune
response may be divided into innate (sometimes called natural) and adaptive (sometimes called
acquired) components.(Morse and High, 2015; Wani et al., 2019)

The innate immune response is rapid and nonspecific; it uses receptors encoded in the germ line.
In contrast, the adaptive immune response is slower to react and specific; it uses receptors that
are generated by somatic DNA rearrangement. Cells involved in the innate response include
various phagocytic cells (neutrophils, monocytes, and macrophages), inflammatory cells
(basophils, mast cells, and eosinophils), and natural killer (NK) cells. Molecules involved in
innate immunity include complement, acute-phase proteins, and cytokines. The barrier function
is also part of the innate immune response.(Nunez et al., 2018). The adaptive response involves
the binding of antigen to surface receptors of antigen-specific B- and T-lymphocytes (also called
B- and T-cells) via an antigen presenting cell (APC) and the subsequent activation and
proliferation of the B- or T-cell. In response to the activation, B-cells secrete antibodies; these
are antigen-specific immunoglobulins (Ig). The key role of antibodies is to identify and aid in the
destruction of extracellular microorganisms. T-cells help B-cells to produce antibodies, therefore
participating in adaptive immune defense against extracellular microorganisms. T-cells also play
a key role in adaptive immune defense against intracellular microorganisms either directly, for
example by killing virally infected cells, or indirectly, through activation of macrophages. The
innate and adaptive immune responses work together in an integrated way to effectively
eliminate organisms, toxins, and allergens.(Calder and Kulkarni, 2018)

The diversity of immune responses during infections and repair mechanisms following injuries
might be influenced differently by the host's physiology and nutrition. Energy and nutrients
obtained through food play an important role in the development and preservation of the immune
system therefore any nutritional imbalance affects its competence and integrity.(Lopez Plaza and
Bermejo Lopez, 2017). Of the micronutrients, zinc, selenium, iron, copper, vitamins A, C, E and
B6, and folic acid have important influences on immune responses. Overnutrition and obesity
also reduce immunity.
The effect of Nutrition on the Development of Human Immune System
Adequate and appropriate nutrition is required for all cells to function optimally and this includes
the cells in the immune system. An “activated” immune system further increases the demand for
energy during periods of infection, with greater basal energy expenditure during fever for
example. Thus, optimal nutrition for the best immunological outcomes would be nutrition, which
supports the functions of immune cells allowing them to initiate effective responses against
pathogens but also to resolve the response rapidly when necessary and to avoid any underlying
chronic inflammation. The immune system’s demands for energy and nutrients can be met from
exogenous sources i.e., the diet, or if dietary sources are inadequate, from endogenous sources
such as body stores. Some micronutrients and dietary components have very specific roles in the
development and maintenance of an effective immune system throughout the life course or in
reducing chronic inflammation. For example, the amino acid arginine is essential for the
generation of nitric oxide by macrophages, and the micronutrients vitamin A and zinc regulate
cell division and so are essential for a successful proliferative response within the immune
system.(Childs et al., 2019)

Undernutrition is well understood to impair immune function, whether as a result of food

shortages or famines in developing countries, or as a result of malnutrition arising from periods
of hospitalisation in developed countries. The extent of impairment that results will depend upon
the severity of the deficiency, whether there are nutrient interactions to consider, the presence of
infection, and the age of the subject. A single nutrient can also exert multiple diverse
immunological effects, such as in the case of vitamin E, where it has a role as both antioxidant,
inhibitor of protein kinase C activity, and potentially interacting with enzymes and transport
proteins. For some micronutrients, excessive intake can also be associated with impaired immune
responses. For example, supplementation with iron can increase morbidity and mortality of those
in malaria endemic regions. As well as nutrition having the potential to effectively treat immune
deficiencies related to poor intake, there is a great deal of research interest in whether specific
nutrient interventions can further enhance immune function in sub-clinical situations, and so
prevent the onset of infections or chronic inflammatory diseases.
Effect of Nutrients on Human Immune System
The immune system and nutrients interact in four steps. Steps 1 and 2 do not play a role in
providing essential nutrients to the immune system, so these two steps are called inactive. Steps
3 and 4 play a role in regulating the immune response, for example, through gastrointestinal
receptors, so these two steps are called “active methods” in increasing the immune system. Step
1 includes nutrients such as protein, vitamins (vitamins A, E, and C), and minerals (Fe and Zn)
that are provided to improve the function of the immune system. Step 2 involves the supply of
glutamine, which is a common fuel for immune cells and the body, especially during strenuous
exercise. This step plays a role in providing more nutrients than the first stage in the performance
and better response of the immune system against invading factors(Hamidianshirazi et al., 2022).

The goal is to communicate with the immune system in order to control how it works. Step 3
allows dynamic communication with the body’s defense system to control its function to the
desired goal. For example, probiotic bacteria and bovine colostrum are effective in improving
functioning of Th1 and the immune system. Also, docosahexaenoic acid )DHA) and omega-3
fatty acids that can reduce the damaging effects of inflammation. Step 4 surveys the relationship
between diet, environment, and genome; thus, a good diet can be effective in eliminating disease
and improving quality of life.

Effect of Micro-Nutrients on Human Immune System

VITAMIN A
Vitamin A and its metabolites are capable of controlling both endogenous and adaptive immune
response strength, enhancing the secretion of IL-2 and modulating proliferation, differentiation
and signaling as well as the development of cytokines in both T, B and antigen-presenting cells.
Metabolites of vitamin A also modulate more complex functional features of the immune
response, such as TH1–TH2-cell balance and TReg cell differentiation and TH17 cells. Vitamin
A is capable of activating the IFN-type intracellular network conducting antiviral activities.
(Huang et al., 2018)

VITAMIN B
Vitamin B complex was historically supposed to be the single vitamin but later it was found that
it consists of several different compounds that can be grouped into different categories according
to their functional distinctions, members of B complex include thiamine (B1), riboflavin (B2),
niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folic acid (B9) and cobalamins
(B12). Several members of the vitamin B complex are used in our body to promote the defensive
role for better health and prevention of diseases by boosting-up the immune system.(Mishra et
al., 2020)

Vitamin forms falling under this group of vitamin B complex plays a vital role by functioning as
antioxidants in the body, thus improving the efficacy of the immune response. Members of the
vitamin B complex that have such roles in immune response efficacy include vitamin B6, B9,
and B12 .

Folic acid, which is a synthetic source of folate, is a water-soluble vitamin that plays an essential
role in cell division and helps in the bone marrow and cell growth. The body transforms folic
acid into tetrahydrofolic acid and is, in effect, an essential part of nucleic acid (DNA and RNA)
and protein synthesis. Enlarged red blood cells are found in deficiency of folic acid as well as
defects of white and red blood cells due to macrocytic anemia.

Vitamin B12 also plays an important role in the development of the immune system as it is
responsible for cell division and production. White blood cells can't grow and expand while B12
is in short supply. Healthy older immunocompetent adults with low serum concentration of
vitamin B12 had impaired antibody responses to the pneumococcal polysaccharide vaccine [10].

VITAMIN C
Often recognized as an antioxidant and/or enzyme cofactor, Vit C had been developed as an
efficient reducing agent. The effect of Vit C on lymphocytes is not fully evident, however, it was
observed that Vit C controls genes that are responsible for the production of B cells and T cells,
and promotes their differentiation similar to their proliferation. Impaired immunity and decreased
susceptibility to infection had also been documented after Vit C deficiency, and vitamin C
supplementation proved to be useful in the prevention and/or treatment of serious respiratory and
systemic infections.

When sepsis happens, the immune cells such as the cytokine are activated, and neutrophils
accumulate in the lungs, destroying alveolar capillaries. Vitamin C may help to prevent the
excess activation and accumulation of neutrophils, and decrease alveolar epithelial water channel
damage. A controlled, randomized trial found that 200 mg/day of vitamin C improved
respiratory symptoms and lowered the mortality rate in severely ill elderly patients

VITAMIN D
Vitamin D is unique: it is a pro-hormone released in the skin during sunlight exposure (UVB
radiation at 290–315 nm), typically with lower quantities obtained from food. Many people,
especially those living in the northern latitudes (such as the United Kingdom, Ireland, Northern
Europe, Canada and the northern parts of the United States, Northern India and China) have low
vitamin D status, particularly in winter.

The sternness of vitamin D lack is separated into mild (25-hydroxyvitamin D less than 20
ng/mL), moderate (25-hydroxyvitamin D less than 10 ng/mL), and severe (25-hydroxyvitamin D
less than 5 ng/mL).

Vitamin D receptors (VDRs) are extensively distributed in respiratory epithelial cells and
immune cells (B cell, T cell, macrophages, and monocytes). 25-hydroxyvitamin D (25OHD), the
major circulating form of vitamin D can be converted to the active form (1,25- dihydroxyvitamin
D) in the bronchial epithelium and immune cells. The enzyme, 1α-Hydroxylase (CYP27B1),
required for vitamin D activation, is induced by diverse stimuli, including cytokines and toll-like
receptor ligands in the respiratory tract. However, adequate serum levels of 25(OH) Dare
required to increase levels of 1,25- dihydroxyvitamin D and consequently improve the immune
response to respiratory virus infections.

VITAMIN E
Vitamin E is essential to preserving older people's physical well-being and their immunity.
Vitamin E is an effective antioxidant able to provide protection against various pathogens,
bacteria and viruses. To get the daily dosage of vitamin E, soaked almonds, peanut butter,
sunflower seeds, and even hazelnuts should be eaten. Vitamin E has been shown to have a
beneficial impact in enhancing the production of T-cell immune synapse and activating signs of
T-cell activation.

Vitamin E supplementation has restored interleukin-2 (IL-2) development when administered to

humans, which increases the overall functioning of T cell proliferation and the immune system.
Thus, increasing dietary sources of vitamin E in the diet of the elderly may be advantageous for
their immune function, may provide resistance to infection, and may decrease morbidity because
of infections.

Vitamin K.
Vitamin K is a fat-soluble vitamin required for synthesis of certain proteins involved in blood
coagulation and is linked to calcium pathways and calcification. VitK1 can be obtained from,
e.g., meats, cheeses, and eggs or synthetized (VitK2) by the microbiota of the colon de novo or
from VitK1. VitK deficiency has been associated with both adult and pediatric CD patients . A
protective role of VitK was shown in a model of DSS-induced colitis associated with a reduction
in IL-6 production from B cells .

Trace Metals
Zinc
Zinc (Zn2+) is a dietary trace mineral that plays a critical role in the structure of cell membranes
and in the function of cells of the immune system. Zinc is required for the activity of hundreds of
enzymes associated with carbohydrate and energy metabolism, protein synthesis and
degradation, nucleic acid synthesis, heme biosynthesis, and carbon dioxide transport.

Zinc deficiency occurs most commonly in association with starvation, PEM, and malabsorption
syndromes. In the developed world, zinc deficiency is seen primarily in children and the elderly,
although it is estimated that a larger proportion of North Americans may be at risk. Zinc
deficiency has been documented in association with numerous conditions of relative
immunocompromise, including pregnancy, alcoholism, kidney disease, burns, inflammatory
bowel disease, and HIV infection.

Clinical manifestations of zinc deficiency include growth impairment, delayed sexual

maturation, hypogonadism, impotence, oligospermia, alopecia, dysgeusia, night blindness,
impaired wound healing, skin abnormalities, and impaired immunity.

Clinical trials have examined the role of zinc in immune system modulation during infection and
other illnesses. For children living in developing nations, zinc supplementation limited growth
stunting and reduced the duration and intensity of diarrheal illness, acute lower respiratory tract
infections, and pneumonia. Children receiving zinc supplements had higher CD3+ and CD4+
lymphocyte counts and higher CD4+/CD8+ ratios in peripheral blood and improved cellmediated
immunity when compared with control subjects. Zinc supplementation also reduced the
incidence of clinical disease caused by Plasmodium falciparum.34 In patients with sickle cell
disease, zinc supplementation increased IL-2 production and decreased microbiologically
confirmed infections and hospitalizations.

A number of studies have evaluated the role of zinc in protecting against the common cold.
Postulated mechanisms include zinc mediated interference with rhino viral protein cleavage and
assembly of viral particles and protection of plasma membranes against lysis by cytotoxic agents
such as microbial toxins and complement; some of these effects may be due to correction of
subclinical zinc deficiency. It has also been suggested that common cold symptoms—sneezing
and nasal discharge—may be reduced in intensity by elevations in intranasal zinc salts through
production of a “chemical clamp” on trigeminal and facial nerve endings. However, other trials
have cast doubt on the validity of these findings. The anti rhino viral effect of zinc is weak, and
serum zinc concentrations are well below those required for a direct antiviral effect. A meta-
analysis of eight published randomized trials found no clear benefit for the use of zinc lozenges
in the treatment of the common cold, and there are mixed/inconclusive data on theefficacy of
zinc to prevent otitis media or as adjunctive treatment for pneumonia in children.

Selenium
Selenium is essential for the function of selenium-dependent proteins, which play critical roles in
the redox regulation of key enzymes, transcription factors, and receptors. Beyond its role as an
antioxidant, selenium may have additional immune properties that contribute to the maintenance
of normal immune function. Selenium is ubiquitous in the soil and enters the diet through both
plant and animal sources.

Dietary intake varies depending on geographic region. Overt selenium deficiency is rare and is
limited to certain regions of China. However, the effects of relative selenium deficiency on
disease susceptibility and disease progression remain only partially characterized and are a
subject of intense ongoing studies of both hosts and pathogen (see “Host Nutritional Status and
Pathogen Virulence”).

Selenium deficiency has been shown to decrease the production of free radicals and killing by
neutrophils, IL-2 receptor affinity and expression on T cells, T-cell proliferation and
differentiation, and lymphocyte cytotoxicity. In vitro, selenium deficiency results in enhanced
neutrophil adherence to endothelial cells, an early event in the inflammatory response. In both
mice and humans, supplementation with selenium has been shown to increase lymphocyte
proliferative responses, IL-2 receptor expression, and macrophage and cytolytic T-lymphocyte–
dependent tumor cytotoxicity. Even at plasma selenium levels associated with normal dietary
intake in the United States, supplementation with 200 μg selenium per day has considerable
immunoenhancing effects, although an upper limit is likely, because “megadose” therapy may be
associated with reduced immunity.

Iron
Iron deficiency is the most common trace element deficiency worldwide. It is estimated to affect
20% to 50% of the world’s population, including infants, children, and women of childbearing
age in tropical regions.40 The effects of iron deficiency are seen in multiple systems of the
human body, including the immune system. In animal and human studies, iron deficiency has
been associated with impairments in cell-mediated immunity, reductions in neutrophil activity
with decreased myeloperoxidase activity and bactericidal activity, and diminished NK-cell
activity. Iron deficiency has been shown to impair lymphocyte and neutrophil functions in
children, although no resultant increase in susceptibility to infection has been described.

Whereas iron deficiency and infection often coexist in developing nations, no cause-and-effect
relationship has been established, except for the well-documented association between
gastrointestinal blood loss and heavy infestations of hookworms.

Many of the immune abnormalities associated with iron deficiency appear to be reversible with
iron replacement, but this has been difficult to demonstrate in human studies. Studies in
laboratory animals have demonstrated reversible, deleterious effects of iron deficiency on
measures of functional immunity, even in mildly iron-deficient animals.

Most clinicians routinely replace iron in documented iron deficiency to avoid anemia and
associated morbidities. However, controversy exists regarding possible deleterious effects of iron
supplementation in some settings. Many microorganisms require trace elements such as iron and
zinc for survival and replication in the host and may increase in pathogenicity with
supplementation. Iron deficiency appears to protect against severe malaria,and oral iron
supplementation has been associated with increased infection rates.Further, parenteral iron
supplementation has been shown in human and animal studies to be harmful when administered
during infection. Therefore, administration of iron, particularly intravenous iron, or iron-
chelating agents such as deferoxamine should be delayed in subjects with active infection.

Fatty Acids
Three major groups of dietary fatty acids—oleic acid, linoleic acid, and linolenic acid—serve as
precursors for the biosynthesis of polyunsaturated fatty acids (PUFAs). Metabolic competition
exists among these groups of fatty acids, and modification of dietary fatty acid intake canlead to
alterations in the fatty acid composition of tissue lipids and, in turn, changes in cellular
responses.

PUFAs, including arachidonic acid and eicosapentaenoic acid (EPA), can be enzymatically
converted to eicosanoids. Extensive data suggest a strong modulatory role for fatty acids in
various cellular responses, including inflammation and immune function and there is growing
evidence that they also act as second messengers or regulators of signal-transducing
molecules.46 Among the fatty acids, it is the omega-3 (ω-3) PUFAs that possess the most potent
immunomodulatory activities; and among them, those found concentrated in fish oil, EPA, and
docosahexaenoic acid (DHA) are more biologically potent than α-linolenic acid (ALA).

A number of clinical trials have assessed the benefits of dietary supplementation with fish oils in
several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis,
Crohn’s disease, ulcerative colitis, psoriasis, lupus erythematosus, and multiple sclerosis. Animal
and clinical studies of acute respiratory distresssyndrome (ARDS) and sepsis suggest that a high-
fat diet containing

EPA (fish oil), γ-linolenic acid (GLA; borage oil), and antioxidants can improve lung
microvascular permeability, oxygenation, and cardiopulmonary function, reduce
proinflammatory eicosanoid synthesis and lung inflammation, and improve survival (see
“Surgical and Critically Ill Patients”).47,48
Effect of Macro- Nutrients on Human Immune System
Saturated Fatty Acids
Fatty acids belonging to SFAs and containing 12 or less carbon (CX) atoms, include carprylic
acid (C8:0), capric acid (C10:0), and lauric acid (C12:0), are found in vegetable oils, cocoa
butter, palm oil. SFAs containing more than 12 carbon atoms include myristic (C14:0), palmitic
acid (C16:0), stearic acid (C18:0) which can be found in lard, butter, beef, pork, chicken fats,
eggs, and vegetable oils (147).

Evidence exists that SFA can act as pro-inflammatory mediators, e.g., as ligands for TLR4 (148,
149). Potential mechanisms by which SFAs elicit a TLR4-induced inflammatory response have
been recently reviewed (12). Briefly, it is proposed that similar to lipopolysaccharide (LPS), the
SFA lauric acid can trigger TLR4 via CD14/MD2 activation thereby promoting the expression of
the transcription factor NF-κB, which plays a crucial role in the induction of the pro-
inflammatory mediators COX2, TNFα, IL-1β, IL-6, CXCL8, IL-12, and IFNγ (150)

Comparably, palmitic acid and stearate can induce pro-inflammatory cytokine production from
macrophages via degranulation of Ikappa B alpha (IκBα) and phosphorylation of c-Jun N-
terminal kinases, MAPKs, and extracellular signal-regulated kinases (ERK). LPS together with
palmitate activate reactive oxygen species and the NLRP3 inflammasome leading to IL-1β
maturation in macrophages (95) (Figure 4). Moreover, a high intake of SFA, i.e., given in
western diet, leads to the modification of the gut microbiota raising the proportion of Gram-
negative bacteria and thereby the natural ligand for TLR4, LPS, as well as an increase in
intestinal permeability, which in itself induces a state of metabolic endotoxemia (151) (Figure 4).
Intake of SFAs can also increase plasma low-density lipoprotein cholesterol by inducing the
formation of low-density Lipoprotein (LDL) and by reducing LDL turn-over leading to the
generation of oxidized LDL (152). Both oxidized LDL and phospholipids are damage-
associated molecular patterns, which are also recognized by TLR4 and can trigger a CD36–
TLR4–TLR6-mediated inflammatory response (153). These findings support a pro-inflammatory
effect of SFA on the microbiota on innate responses in macrophages. To date, mechanistic
studies on saturated fats in human IBD are scarce and, therefore, much of our knowledge on
SFAs and intestinal inflammation emanates from studies in experimental models. TNFΔARE
mice fed a palm oil-based high-fat diet for up to 12 weeks resulted in an initial acceleration of
ileitis followed by worsening of proximal colitis associated with loss of TJ protein occludin in
the distal ileum, endotoxin translocation, and increased infiltration of DCs and Th17 cells into
the lamina associated metabolic features (154). Similarly, Mdr1a−/− mice fed a lard-based high-
fat diet for 12 weeks led to an exacerbation of spontaneous colitis associated with elongated
crypts, loss of goblet cells, and infiltration of immune cells. Contrary to TNFΔARE mice,
Mdr1a−/− mice developed obesity as characterized by increased adiposity and presence of foamy
macrophages, while WT mice did not (155). Rats fed a diet containing capric and lauric acid
followed by DSS-induced colitis, developed worse colitis associated with a higher colonic
myeloperoxidase activity and a pro-inflammatory cytokine profile as well as a reduction in
goblet cells (156). Overall, these findings indicate that the type of SFA diet, microbiota status,
diet regimen, and/or the genetic background of the animals determine the development of
intestinal inflammation and obesity, suggesting that different dietary-induced mechanisms
regulate these two conditions. In asthma, SFA have been shown to effect symptoms and immune
activation, e.g., by inducing a neutrophilic inflammation and suppressing bronchodilator
recovery in asthmatic patients (11,27) .

Monounsaturated Fatty Acids and Derived Oils

Monounsaturated fatty acids, including palmitoleic acid (C16:1) and oleic acid (C18:1, OA) are
normally found in macadamia nuts, blue-green algae, olive oil, canola oil, beef tallow, lard, and
avocado. Diets rich in MUFA appear to reduce LDL cholesterol and potentially increase high-
density lipoprotein (HDL) cholesterol (157), and palmitoleate treatment of M1 macrophages
induce an anti-inflammatory M2 profile (158) indicating an anti-inflammatory capacity of
MUFAs. The specific role of MUFAs in IBD and asthma remains inconclusive. For example, a
prospective study by de Silva and colleagues showed that a dietary oleic acid was inversely
associated with UC development (114), while palmitoleic and oleic acid treatment of polarized
intestinal epithelial cells impaired epithelial barrier function (159). MUFA and oleic acid intake
indicated an increased risk of wheeze and non-atopic asthma, respectively (160). Extra virgin
olive oil, high in MUFAs, contains highly bioactive components which are present in the
unsaponifiable fraction (UF). Beneficial effects of UF and olive oil were demonstrated in an
acute DSS model of colitis and in mice with C. rodentium induced colitis. Disease amelioration
included alleviation of oxidative stress, reduction of pro-inflammatory proteins and increased
levels of intestinal alkaline phosphatase, which can de-phosphorylate bacterial LPS (161–163).
In line with these findings, isolated blood and intestinal T cells from UC patients treated with UF
resulted in a reduction in T cell activation, β7 integrin expression and IFNγ production as well as
induction of apoptosis (164). Findings from these studies indicate MUFA exert both pro- and
anti-inflammatory activities in these mucosal conditions.

Polyunsaturated Fatty Acids

Polyunsaturated fatty acids are FAs containing more than one double carbon bonds. Therefore,
naturally, they are more prone to oxidation and oxidized LDL synthesis. Long chain PUFAs are
divided in two main groups; omega-3 (n-3) PUFAs including—alpha-linolenic acid (ALA,
C18:2), docosahexaenoic acid (DHA, C22:6), and EPA (C20:5); and omega-6 (n-6) PUFAs
including—linoleic acid (LA, C18:3), and arachidonic acid (ARA, 20:4). LA and ALA are
referred to as essential FAs as they are the precursors of ARA, EPA, and DHA. DHA and EPA
compete for the enzymes and products of ARA metabolism whereby they can antagonize the
formation of inflammation related eicosanoid mediators (165, 166).

Arachidonic acid is the primary n-6 PUFA found in inflammatory cells and is important for the
production of inflammatory eicosanoids. ARA is formed out of LA which is further converted to
prostaglandins [e.g., prostaglandin E2 (PGE2), leukotrienes (LTBD4), and other lipoxygenase or
cyclooxygenase products (COX1/-2)], the so-called eicosanoids, all of which have pro- and anti-
inflammatory in addition to atherogenic and pro-thrombotic effects (166). PGE2 is one of the
key prostaglandins produced in the intestine where it has dual functions: (1) a pro-inflammatory
role, e.g., it is produced by macrophages and neutrophils as a response to inflammatory stimuli
and (2) a regulatory role, by inducing immune tolerance, independent of IL-10 or Tregs (167). n-
3 PUFAs are primarily sourced from the human diet, with DHA and EPA especially sourced
from fish (e.g., salmon) and ALA from seed oils (e.g., walnut, linseed oil). Several reports have
highlighted their effect in preventing and/or treatment of different inflammatory diseases in
animals and humans, including IBD and asthma. n-3 PUFAs can inhibit TLR4 signaling and the
subsequent gene transcription of pro-inflammatory mediators (168), a process partly mediated
via GPR120 (169). n-3 PUFAs can also activate the anti-inflammatory transcription factor
PPAR-γ and inhibit NF-κB and the subsequent pro-inflammatory cytokine production including
TNFα, activity which is highly expressed in the mucosa of patients with IBD and asthma
subtypes (13, 170, 171). DHA can also improve epithelial barrier integrity by increasing the
expression of the TJ proteins occludin and claudin-1 (172), as the integrity of the epithelium is
critical in preventing paracellular translocation of LPS into systemic circulation. PUFA
supplementation in particular those related to fish oils can also modulate asthma symptoms (173,
174), with reduction of wheeze, improved pulmonary function and reduced pro-inflammatory
mediators in sputum. However, it should be noted that many trials are designed to measure
different outcomes which can deliver conflicting findings (27, 175). With the evolution in food
technology and modern agriculture in the last 100 years the amount of n-6 FAs, e.g., LA present
in our food has increased due to change in animal feed from grass to grains (176, 177).

Therefore, the ratio of n-6/n-3 PUFAs present in the food has changed from 1:1 to 16:1 in
USA/Europe (177) (Figure 2). This ratio has increased dramatically due to food processing, less
fish and fiber consumption, and the dietary habits of farm animals. In line with this, a recent
study identified a higher ARA:EPA ratio in the inflamed mucosa of UC patients, which
correlated with the severity of the disease (178). No association of n-6/n-3 ratio was found in
individuals with hay fever or allergic sensitization (179). The relevance of a lack of n-6/n-3 ratio
association to asthma is still to be uncovered.

Carbohydrates
Carbohydrates are divided into four groups: monosaccharides, disaccharides, oligosaccharides
and polysaccharides. Generally, monosaccharides and disaccharides are referred to as sugar. In
the western diet a large amount of calories are ingested in form of refined carbohydrates, i.e.,
sucrose, starch, fructose syrup, etc.—obtained from soft drinks, pastries and desserts, and white
bread. This energy-dense but nutrient-poor diet is a risk factor for obesity, type 2 diabetes,
cardiovascular diseases and more.

Therefore, the biological plausibility exists that it has impact on intestinal inflammation and
asthma. Moreover, related to the carbohydrates that can be metabolically used by gut microbes,
the term “microbiota-accessible carbohydrate” has been proposed. The term refers to the ability
of microbial carbohydrates to modify the composition of the microbiota, and dictate the
functionality and metabolic output (180).
Fibers
Dietary fiber is a plant-based nutrient and a type of carbohydrate, which due to its biochemical
structures resists digestion by intestinal and pancreatic enzymes in the human GI tract.
Therefore, the fiber passes through the GI tract relatively intact.

Fermentable carbohydrate substrates such as non-starch polysaccharides, resistant starch and

oligosaccharides serve as important substrates for the gut microbiota. The microbes located in
the human colon use fermentation to produce SCFAs, lactate and gas (181). These fermentation
products selectively promote the growth of beneficial Bifidobacteria and Lactobacilli and exert
anti-inflammatory (inhibition of NFκB transcription via GPR41) and anti-carcinogenic functions
(182). Short-Chain Fatty Acids. Upon fermentation of dietary fiber, bacterial metabolites such as
SCFAs are produced in the colon. SCFA mediates the communication between the commensal
microbiota and the immune system affecting the balance between pro- and anti-inflammatory
responses. The beneficial effects of butyrate on colonic health are particularly well established
(183). Microbial-derived butyrate and to a lesser extent acetate and propionate, can facilitate the
generation of extrathymic Foxp3+ Tregs which are crucial for limiting intestinal inflammation
(17, 184, 185) (Figure 3). Presence of butyrate during human DC maturation results in a
tolerogenic phenotype, with an increased expression of IL-10 (186, 187), further supporting the
regulatory potential of SCFAs (Figure 3). SCFA can signal through the activation of specific G-
protein coupled receptors (GPCRs), GPR41, GPR43, GPR109, which are particularly expressed
in immune cells, e.g., polymorphonuclear leukocytes, and are suggested to participate in immune
surveillance of the colonic mucosa affecting the balance between pro- and anti-inflammatory
responses (188). GPR43 is additionally expressed in the colonic epithelium where it can mediate
SCFA-regulated effects on epithelial barrier and proliferation (Figure 3). Butyrate is also a
natural ligand for PPARγ, which is expressed in colonic epithelial cells, macrophages and
lymphocytes. Colonic PPARγ expression is linked to host–microbe interactions with natural
(e.g., SCFA— butyrate, conjugated LA) and synthetic (e.g., 5-aminosalicylic acid) PPARγ
ligands preventing inflammation in experimental colitis (189).

A significant decrease in the number of butyrate-producing bacteria including Eubacterium

rectale/Roseburia spp (which belong to Clostridium coccoides) and F. prausnitzii (which belong
to Clostridium leptum cluster), both within the Firmicutes phylum was revealed in patients with
UC and CD (190, 191). In patients with UC, colonic irrigation with butyrate is able to limit
inflammation and in experimental models it ameliorates inflammation and modifies microbial
composition (183, 192).

In the Canadian CHILD study the SCFA acetate was reduced in the feces of infants with atopy
and wheeze (83). Feeding a high fiber diet to mice has resulted in gut microbiota alteration
which concomitantly leads to increased serum SCFAs, such as acetate and propionate, and
alleviates allergic asthma symptoms. These SCFAs induced an enhanced DC and macrophage
phagocytosis and reduced Th2 responses in the murine lung (17, 23, 193). Furthermore, binding
of propionate to GPR41 and acetate and propionate to GPR43 also supported the reduction in
airway inflammation (17, 23, 194, 195). These microbiota- mediated effects are also linked to
maternal influences of asthma risk, where high serum acetate concentrations, but not propionate,
in pregnant mothers’ correlate with reduced asthma risk and are thought to modulate Tregs
biology of the fetus (17). These findings clearly point to a crosstalk between the gut and the lung
via SCFA in asthma and between the microbiota and the intestine in IBD, indicating that
treatments aiming to increase SCFAs and SCFA producing bacteria should be further
investigated.

Proteins
Proteins consist of carbon, hydrogen, oxygen, and nitrogen elements. They are essential nutrients
and are involved in virtually all physiological functions. High protein intake, especially animal
derived protein, is associated with an increased risk of CD (196). In asthmatics high ingestion of
cured meats is linked with worsening of symptoms (24).

Carnitine is an amino acid derivative synthesized primarily in the liver and kidneys from lysine
and methionine and is involved in lipid metabolism in eukaryotic cells (197). In humans, the
main source of carnitine is red meat. Humans with an omnivorous diet following ingestion of l-
carnitine, presented increased plasma trimethylamine-N-oxide (TMAO) levels, which was
dependent on microbiota mechanisms, when compared to vegans or vegetarians. Elevated
plasma levels of TMAO are positively correlated with an increased risk for major adverse
cardiovascular events (198). However, TMAO has also protective functions, e.g., by protecting
cells from osmotic and hydrostatic damage, and therefore, is essential for all organisms (25). A
recent study proposed plasma TMAO as a non-invasive biomarker for IBD, as decreased TMAO
levels are seen in these patients (199). The reduced TMAO was likely related to alterations in the
gut microbiome (the abundance of anaerobes or facultative anaerobes) in these patients. TMAO
is also an oxidation product of trimethylamine which can be found in seafood, fish, etc.
Consumption of TMAO-containing food, e.g., oily fish can lead to accumulation of TMAO and
protection against asthma in childhood (200). Further studies are necessary to shed a light into
mechanisms that underlie the association of high intake of animal protein in these conditions.

Other studies have also shown how dietary peptides and amino acids can modulate intestinal
immune functions and influence inflammatory responses. Supplementation with the dipeptide
alanine-glutamine, led to decreased expression of inflammatory mediators and increased
expression of mucin 2 (MUC2) promoting mucosal recovery in the DSS-induced colitis mouse
model (26). Moreover, lower serum tryptophan is associated to active CD (201). Supplementing
tryptophan presented beneficial effects in the DSS-induced porcine IBD model, by inducing T
cell apoptosis and thereby inhibiting Th1-mediated immune responses and subsequently reducing
inflammation.(Morse and High, 2015)

Impact of Early Life Nutrition on Immune System Development

A growing body of evidence highlights the importance of a mother’s nutrition from
preconception through lactation in programming the emerging organ systems and homeostatic
pathways of her offspring. The developing immune system may be particularly vulnerable.

Evidence from human studies, both experimental and epidemiological, suggests that early-life
nutritional exposures may influence the developing immune system, with consequences
extending even into adulthood.

Intra-uterine growth retardation.

Although intra-uterine growth retardation has multiple etiologies, maternal malnutrition is a
major determinant of poor fetal growth. Substantial epidemiological evidence links LBW, a
rough indicator of intra-uterine growth retardation, with increased risk of infectious morbidity
and mortality later in life. Often-cited studies using data from the United States have highlighted

LBWand even moderately LBWas strong determinants of infant mortality and morbidity during
infancy and childhood (264–266). However, LBW in developed countries is predominantly due
to preterm delivery rather than intra-uterine growth retardation. In Scandinavia, researchers have
noted more frequent hospitalization for infectious morbidity throughout childhood and mortality
through 15 y of age among children born LBW, even after controlling for gestational age
(267,268). Data from the Dutch Famine also suggest a link between early- and mid-gestation
exposure to famine, resulting in lower birth weight and excess mortality up to the age of 18 y
(15).

Work in Brazil confirms the association between LBW and both neonatal and post-neonatal
mortality (269). Preterm infants had a 2.5-fold higher mortality risk than small-for-gestational
age infants during the neonatal period, although these differences were less pronounced
afterwards.

Further analysis also revealed that infants with both low birth length and low ponderal index
were at greatest risk of hospitalization and mortality in the first year of life regardless of
gestational age (270). Using datasets from multiple countries, Ashworth (271) found increased
risk of neonatal and postneonatal morality among infants born LBW due to intra-uterine growth
retardation. Even though RR for small–for-gestational age infants were less consistent across
studies than for preterm infants, their mortality risk was elevated even beyond infancy. Similar
findings emerged from analysis of long-standing demographic surveillance in the

Gambia. Moore et al. (12) reported increased infectious mortality among adults born during the
hungry season, characterized by an elevated incidence of nutritionally mediated

LBW. This seasonal pattern was not apparent in adult mortality trends from Bangladesh (13),
Senegal (16), or Burkina Faso (17). Neither was mortality after the age of 18 y affected by in
utero exposure to the Dutch Famine (15). Yet the authors of this latter work stressed the small
number of deaths in this cohort, to date, and their limited power to detect survival differences.

Findings from the case-control study byMoore et al. (12) led to the exploration of immune
function in Gambian primary school children. Participants were challenged with human diploid
cell rabies and 23 valent pneumococcal capsular polysaccharide vaccines, and both a delayed-
type hypersensitivity skin reaction and mucosal antibodies were measured(5). This study found
no differences between children born in the hungry compared to harvest seasons. Addressing
these same questions in an older Pakistani population for whom birth weights were available,
researchers reported a less robust response to the Vi polysaccharide typhoid vaccine among those
born at a LBW(7). A typhoid vaccine challenge yielded similar results among LBWinfants in the
Philippines in their teenage years at the time of the study (8). This lack of effect among Gambian
individuals compared to study participants in both Pakistan and Bangladesh may be due to their
younger age, i.e. differences may not become apparent until later in life (272). Although
differential response to predominantly T cellindependent vaccine responses would suggest
otherwise, subsequent work has focused on altered thymic development.

In the Gambian children, researchers noted significant seasonal variation in thymic size and
function; hungry season babies had a lower thymic index and impaired thymic function,
indicated by lower serum TCR excision circles (6).

Similar work in Bangladesh confirmed this seasonal pattern and further demonstrated a direct
association between thymic size and infant weight (273). In the Philippines, researchers noted
that serum thymopoietin concentrations were indeed lower among those who had been born
small for gestational age compared to their appropriate for gestational age peers (9). If these
differences in the smaller thymus were not due to nutrient restriction in early pregnancy, it has
been suggested that they could be mediated by seasonal variations in breast milk IL-7 (274).
Subsequent explorations of T lymphocyte kinetics in these populations have yielded conflicting
results (275,276).

Maternal micronutrient deficiencies.

The impact of maternal micronutrient deficiencies on the emerging immune system is a
relatively new area of inquiry. Trials of single or multiple micronutrient deficiencies conducted
in developing countries have focused primarily on outcomes of infectious morbidity and
mortality. In rural Nepal, maternal supplementation with either vitamin A or b-carotene failed to
improve fetal or infant survival (277). However, after restricting the analysis to infants whose
mothers reported night blindness during pregnancy, supplementation substantially reduced, but
did not eliminate, the increased risk of early infant mortality (278). Subsequent work in the same
population demonstrated that maternal folic acid supplementation, delivered alone or with iron,
reduced early infant mortality among those delivered preterm (279). Similar findings were
recently reported from China, where early neonatal deaths were reduced by 54% in the iron-folic
acid arm of the trial compared to folic acid alone (280). Trials of antenatal zinc supplementation
have also documented significant reductions in infectious morbidity among infants (281–283).

To date, only the antenatal zinc supplementation trials have directly assessed any aspects of
infant immune function. The trial conducted in Bangladesh reported fewer anergic delayed-type
hypersensitivity responses to purified protein derivative among LBW infants born to
supplemented mothers (284). No similar effect was apparent among normal birth weight infants.
The authors found no impact on immune response to Haemophilus influenza type b vaccine,
although they noted that high natural infection rates may have masked any beneficial effect. Data
from a separate trial in Indonesia showed an impact of antenatal zinc supplementation on ex vivo
cytokine response among infants (282). Taken together, the findings of maternal
supplementation trials with regard to infant mortality, morbidity, and immune function are
suggestive of immune programming. However, any effects may be modified by the severity of
maternal deficiency, size at birth, and/or gestational age at delivery.

In addition to studies in developing countries, there is an increasing focus on the importance of

maternal micronutrient status in the literature on allergic and atopic diseases (285). Much of this
work has concentrated on vitamin E, which is important for promoting a tolerogenic response
upon initial allergen exposure (286). Although no randomized trials are yet available, evidence
from prospective cohort studies links low maternal vitamin E intake during pregnancy with
increased peripheral blood mononuclear cell responsiveness, wheezing/asthma, and markers of
airway inflammation (287–290). Vitamin D also plays a role in tolerance induction and the
promotion of a regulatory phenotype (291). The impact of vitamin D status during pregnancy on
development of immune-mediated diseases is thus a growing area of investigation (292). For
example, investigators from a multi-country prospective cohort study reported that vitamin D
supplement use during pregnancy increased tolerogenic antigen-presenting cells in cord blood
(293). Additional research is needed to expand these findings, both to clarify mechanisms of
action and to test prophylactic efficacy in randomized trials (285).

Infant feeding.
Infants exposed to human milk are characterized by an antiinflammatory and tolerance-inducing
gut environment (49) as well as immunophenotypic differences in lymphocyte populations (294).
Improved mucosal (295) and systemic immune function (296) have also been reported after
exposure to breast milk, although the latter may be modified by gestational age (297).
Furthermore, breast-fed infants have a larger thymic size than formulafed infants (298,299),
which correlates well both with thymic function (300) and infant survival (301).

To assess changes in immune function related to breastmilk exposure, many groups have relied
on vaccine response as an accepted indicator of immune function (302). There have been reports
of improved antibody response to the Hemophilus influenzae B conjugate (303,304), oral polio
(305,306), diphtheria (305), and tetanus toxoid vaccines (305). However, most studies have
found little difference in antibody responses between breast- and formula-fed infants for
common vaccine antigens (307–312). Findings regarding cellular responses are similarly
inconclusive. Although Pabst et al. (313,314) noted an increased T cell proliferative response to
BCG vaccination in breastfed infants (313), they also reported lower responses for bothmeasles
hemagglutinin (314) and a recall tetanus toxoid challenge (313).

The longer term effects of breastfeeding are also widely debated (315). Several studies have
reported a reduced incidence of allergic diseases (316–318), presumably through an early
influence on regulatory mechanisms. Similar work has emerged for other diseases of the immune
system including rheumatoid arthritis (319,320), Type 1 diabetes mellitus (321,322), Crohn’s
disease (323,324), and certain lymphomas (325). However, these findings are countered by a
number of studies showing little to no effect (326–334).Whether assessing the response to
vaccination or long-term effects on immune-mediated disease, the observational evidence thus
far is open to doubt. An impact of infant feeding on the developing immune system is
biologically plausible and likely to remain an active area of research (335). However, an
experimental design, such as long-term follow-up of participants from the Promotion of
Breastfeeding Intervention Trial (336), is needed to further guide this debate.

Colostrum and strengthening the immunity of infants

First, Colostrum is the breast secretion that follows the release of mature milk, which is different
in form and nutritional properties, it is a yellow liquid water, but it forms a high degree of
immunity to infants by affecting it on the digestive tract more than its absorption in the blood
later. The colostrum is exposed from 5-10 days after birth for changes in the chemical
composition and its natural properties until it reaches at the tenth day to its natural properties of
mature milk (7, 8). It is worth mentioning that the materials responsible for the anti-infection
properties in the mother's milk are the colostrum particles which are stable in the acidic
environment of the stomach and resistant to digestive enzymes (9), including lysozymes, which
has a concentration of 300 times compare to what is found in cow's milk, which attacks and
destroys the cell membranes of bacteria after inhibition it with peroxides found in breast milk,
infant saliva and vitamin C found in colostrum (10), in addition, lactoperoxidase which kills
Streptococcus bacteria (11). Another group of cells that have a protective role which are
macrophages, these molecules are not absorbed but they improve the immune system of infants
by protecting them from pathogenic bacteria and viruses such as influenza, diphtheria, and
poliomyelitis (12), these cells also create complements, which are a protein that enters a series of
reactions that produce immunity against infectious organisms (13).

Lactoferrin is a protein containing iron that has immunological properties, it is found in

colostrum and mature mother's milk, this substance inhibits the growth of E. coli and
Staphylococcus bacteria by binding the iron that necessary for the growth of these bacteria, in
case of addition of iron to the meal food, the lactoferrin becomes saturated and any additional
iron in a free state supports the growth of infectious organisms, so children who take iron
supplementation are then exposed to infection (14, 15). On the other hand, there is a
carbohydrate-containing nitrogen found in breast milk is the Lactobacillus bifidus factor and this
substance creates an encouraging environment in the digestive tract activates the growth of
Lactobacillus bifidus bacteria, and these bacteria produce acetic acid or lactic acid from lactose,
which inhibits the growth of pathogenic microbes, which reduces the infant's susceptibility to
infectious diseases and inhibits the growth of E. coli (16, 17). Lactulose exists in large quantities
in mother’s milk, which is derived from lactose, it is found in larger quantities in heat-treated
cow’s milk comparing to non-heat-treated cow’s milk. It is worth mentioning that Lactobacillus
bifidus grows when eating a rich meal of high lactose and low protein, and the ratio of
lactose/protein in breast milk is 1:7 compared to bovine milk 1:4. (18). In addition, a group of
proteins (Immunoglobulins) in breast milk play an important role in protecting the body against
infectious diseases such as lgA, which are present at high concentrations in the early days of the
infant's life, because they contain many antibodies that act as anti-viral, antibacterial against
pathogens, which are particularly effective against the diseases which mother is exposed to, such
as viral diseases, Streptococcus infection, and pneumonia, as well as its resistance to enzyme
activity, and it is stable in the high acidic medium of stomach (19, 20,).
Human milk (HM) is a complex mixture of macronutrients and bioactive compounds that
provide optimal nutrition to infants (1–5). HM has been shown to impact infant’s gastro-
intestinal tract, immune system, microbiota composition, metabolism and also may have long-
term effects on the development of infectious and non-communicable diseases (3, 6–8). The aim
of this editorial is to provide a summary of the original research, reviews and opinions regarding
key factors affecting human milk composition, and the role of bioactive components of human
milk on infants’ health. Maternal obesity and maternal atopy are highly prevalent states that may
have an effect on HM composition and infants’ health outcomes (9–14). Few studies, however,
have attempted to evaluate associations between HM metabolome composition and measures of
infants’ health and development. For instance, Bardanzellu et al. reviewed different studies for
HM metabolite profile from mothers with overweight and obesity in an attempt to determine the
milk metabolome composition with respect to obesity. However, the small sample size and large
variability of the measures precluded the investigators from drawing conclusions which
underscores the necessity of large sample size studies in this area of research. The authors,
however, found that the fatty acid profile of human milk was associated with the maternal
obesity status. Specifically, higher levels of saturated fatty acids and lower levels of
monounsaturated and n-3 long-chain polyunsaturated fatty acids were found in milk of women
with obesity compared to milk of women with normal weight. These changes in milk
composition may influence long-term weight gain and glucose tolerance, in infants. Allergic
diseases are of a major concern and a significant burden to healthcare. It has been previously
shown that HM composition may differ in allergic and non-allergic mothers (15). Recent
research from Stinson et al. demonstrated that human milk from atopic mothers had lower levels
of short-chain fatty acids (SCFA). Importantly, reduced levels of SCFA during early life may
program the gut, microbiota, and obesity in infants. Nutritional interventions during pregnancy
and lactation could serve as strategies to mitigate maternal atopy and potentially improve HM
composition. For instance, Kao et al. showed that maternal consumption of goat milk during
pregnancy and lactation associated with reduced airway inflammation and allergy outcomes in
the offspring compared to cow’s milk consumption.

The goat milk feeding had increased immunoglobulin levels, Th1 cytokine production, and
improved NK cell activity in comparison to cow’milk feeding in the offspring. In addition, in an
animal study by Adel-Patient et al. showed that altering maternal immune status by sensitizing to
different antigens protects offspring by modulating the antibody composition of human milk to
specific antigens. In summary, obesity and prenatal antigen exposure of mothers were associated
with HM composition and may affect infant health and development, but relationships should be
confirmed in methodologically rigorous studies with a large sample size.

Human milk feeding likely protects from pathogens, thereby reducing/preventing negative
outcomes associated with infection via different bioactives of milk such as human milk
oligosaccharides (HMOs) and free amino acids (FAAs) (1, 16– 19). Indeed, Carr et al. review
highlighted the antipathogenic and immunomodulatory properties of HMOs and Zuurveld et al.
reviewed the potential role of HMOs in preventing allergic diseases. In their article Sadelhoff et
al., discuss the potential role of amino acids (particularly glutamine and glutamate) in HM to
protect against neonatal allergies and infection. Further, using a HM-fed piglet model, Rosa et al.
demonstrated the appearance of HM metabolites’ in the gut, serum, and urine of HM-fed piglets.
Importantly, glutamic acid and glutamate levels were higher in the HM-fed animals relative to
the formula fed group suggesting potential benefits of HM FAAs. Also, Rosa et al., study
discussed human metabolites such as polyamines and tryptophan impact on immune response.

Human milk has been shown to promote gut microbiota development and function (20–25). In
reviewing the literature, Carr et al. comprehensively overviewed the role of HM microbiota on
gut microbiota colonization and immune function.

This article also discussed the role of human milk components such as HMOs, and IgA impact
on gut microbiota. Peroni et al. reviewed the literature regarding microbiome composition and its
impact on the development of allergic diseases. Drall et al. demonstrated an association of
microbiota composition in exclusively breastfed infants to C. difficile colonization. In summary,
dietary intake and both pre- and post-natal factors appear to be associated with the gut
microbiota composition and its association to pathogens colonization. This may be a focus for
the future intervention strategies aiming at improving infants health.

Previous studies suggest antipathogenic effects of HM components and that the addition of these
bioactive molecules (i.e., HMOs, lactoferrin, immunoglobulins, and milk fat globule membrane
FGM, extracellular vesicles) to infant formulas may benefit child health (20, 26–36), although
the studies usually lack methodological rigor and outcomes were based on a small sample size.
The studies on recombinant immunoglobulins and bioactivity in the digestive tract are limited.
Research from Sah et al. provided some evidence that recombinant antibody towards respiratory
syncytial virus (RSV) may impact growth and have neutralization activity against the virus
across the GI tract. In another study, Nederend et al. demonstrated that bovine immunoglobulin
antiviral activity and T cell response may prevent RSV infection. Interestingly, Adel-Patient et
al. found no protection to protein present in cow’s milk by feeding the hydrolysates of caseins
and Lactobacillus rhamnosus GG protobiotic. Thus, future studies are needed to fully understand
the protective effects of immunoglobulins, as well as pre and probiotics, before adding these
components to infant formula. The combined effect of different bioactive molecules within the
formula on infant health and development also requires further investigation. Human milk may
impart benefits through epigenetic programming influencing long-term health by various
mechanisms. van Esch et al. provided an overview on the evidence of maternal nutrition,
environmental factors impact on milk composition, and how the different components of milk
epigenetically program infants’ health and dictate allergy and asthma outcomes in later life.
Human milk contains extracellular vesicles with microRNAs (miRNAs) as one of the epigenetic
molecules (35). Furthermore, Carr et al. provided evidence that miRNAs known to modulate
gene expression were associated with immune function in the human milk-fed group compared
to formula diet-fed group in the piglet model. Also, the review by Carr and associates
highlighted that miRNAs present in human milk may be associated with a beneficial effect for
infants’ health and immune system.

Finally, Bilsen and colleagues elegantly show how a networkbased approach that includes
evidence from studies to determine the windows of opportunity to shape lifelong health of
infants. This can be used to predict the key candidate markers of early life immune development.
Human milk is a complex mixture with several bioactive components providing short and long-
term health benefits to infants. We sincerely hope that the article’s compilation of the Research
Topic on human milk will be useful and interesting to the readers and hope that the knowledge
gaps highlighted will be considered for future state-of the art research findings.
Discussion

7. Conclusions

In our review, the collected works provide a breadth of reviews and research indicating the effect
of nutrients on the development of human immune system responses. Nutrients may impact
directly or indirectly upon immune cells causing changes in their function or may exert effects
via changes in the gut microbiome.

Perhaps the most important elements that maintain our immune system is a healthy balanced
diet, which contains all the nutrients of proteins, carbohydrates, fats, vitamins and minerals in a
balanced proportions with the adoption of healthy eating habits, such as the increasing of eating
vegetables and fresh fruits of all kinds because they contain many useful nutrients, nuts for their
content of proteins and magnesium, fish because they contain zinc which works to produce blood
cells that fight infection, yogurt, fiber, mushrooms, garlic and olive oil, which contain
antioxidants. It is necessary to avoid intake of hydrogenated oils, saturated fats and starches in
large proportions, especially fries’ potato, chips, fast foods, high fat meats, fat dairy products,
desserts such as cacao, cake and oriental sweets as they are rich in saturated fat, and reducing
consuming of sugars, drinking carbonated water and juices as they have been shown to slow the
activity of white blood cells in attacking microbes and reduce the efficiency of the immune
system for the elderly, and reducing the intake of refined foods (White sugar, white salt, and
white flour) and using the whole flour instead of the white flour and instead of the alternative salt
of potassium salts. It is necessary to refrain from smoking since it produces free radicals to crash
the immune cells in the body, cigarette smoke contains thousands of chemical substances and the
most influential one is nicotine as it affects the central nervous system, increasing adrenaline
secretion and blood pressure, faster heartbeat and metabolic processes, and affects the immune
system because cigarette smoke contains high concentrations of the nitrogen dioxide ozone
compound, which oxidizes antioxidant vitamins and causes DNA breakdown, which in turn
accelerates aging and weakens immunity. Eating balanced healthy food accompanied by a simple
exercise, especially walking 20-30 minutes a day with exposure to indirect sunlight that works to
form vitamin D, while listening to quiet, non-loud music for half an hour a day helps to enhance
and improve immune system efficiency.
A better understanding of the role of nutrients in immune function will facilitate the use of
bespoke nutrition to improve human health.

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