JOURNAL OF MEDICINAL FOOD

J Med Food 25 (4) 2022, 341–354

REVIEW
# Mary Ann Liebert, Inc., and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2021.0012

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Omega-3 Fatty Acids and Balanced Gut Microbiota on Chronic

Inflammatory Diseases:
A Close Look at Ulcerative Colitis and Rheumatoid Arthritis Pathogenesis
Verônica Assalin Zorgetto-Pinheiro,1 David Johane Machate,2 Priscila Silva Figueiredo,1
Gabriela Marcelino,1 Priscila Aiko Hiane,1 Arnildo Pott,3
Rita de Cássia Avellaneda Guimarães1 and Danielle Bogo1
1
Graduate Program in Health and Development in the Central-West Region, Federal University of Mato Grosso do Sul,
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Campo Grande, Mato Grosso do Sul, Brazil.

2
Group of Spectroscopy and Bioinformatics Applied Biodiversity and Health (GEBABS), Graduate Program in Science
of Materials, Federal University of Mato Grosso do Sul, Mato Grosso do Sul, Brazil.
3
Graduate Program in Biotechnology and Biodiversity in the Central-West Region of Brazil, Federal University
of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.

ABSTRACT The aim of this article was to review experimental and clinical studies regarding the use of omega-3 fatty acids
on the prevention and control of chronic inflammatory diseases with autoimmune background through the gut microbiota
modulation. For this, natural omega-3 sources are presented emphasizing the importance of a healthy diet for the body’s
homeostasis and the enzymatic processes that these fatty acids go through once inside the body. The pathogenesis of ulcerative
colitis and rheumatoid arthritis are revisited under the light of the gut microbiota dysbiosis approach and how those fatty acids
are able to prevent and control these two pathological conditions that are responsible for the global chronic burden and functional
disability and life-threatening comorbidities if not treated properly. As a matter of reflection, as we are living a pandemic crisis
owing to COVID-19 infection, we present the potential of omega-3 in preventing a poor prognosis once they contribute to
balancing the immune system modulation the inflammatory process.

KEYWORDS:  autoimmunity  chronic inflammatory diseases  docosahexaenoic acid  eicosapentaenoic acid

 gut microbiota  healthy diet  linolenic acid  omega-3 fatty acids  rheumatoid arthritis  ulcerative colitis

INTRODUCTION countries and, according to the last WHO report, 74% of

deaths globally were owing to some NCD in 2019.

A growing number of people are affected by chronic

inflammatory diseases (CID) also classified as noncom-
municable diseases (NCD) by the World Health Organization
(WHO). The NCDs are characterized by high morbidity
index and they are the consequence of genetic, physiologi-
cal, environmental, and behavioral factors. Poverty and
malnutrition are closely linked to NCDs and 75% of the
NCD-related deaths happen in low- and middle-income
Manuscript received 20 January 2021. Revision accepted 22 January 2022.
Address correspondence to: Verônica Assalin Zorgetto-Pinheiro, BSc, MSc, PhD can-
didate, Graduate Program in Health and Development in the Central-West Region
(PPGSD), ‘‘Dr. Hélio Mandetta’’ Medical School (FAMED), Federal University of Mato
Grosso do Sul (UFMS), Av. Costa e Silva, s/n/-Cidade Universitária, Campo Grande,
Mato Grosso do Sul 79079-900, Brazil, E-mail: veronica.azp@outlook.com
The most classic and notable examples of NCDs are is-
chemic heart disease, stroke, and diabetes, but cancer and
obesity are also important conditions related to chronic in-
flammation. People who are already bearing CID such as
ulcerative colitis (UC) and rheumatoid arthritis (RA) are at
high risk to develop them.1,2
As recent studies have shown both CIDs are closely
related to gut dysbiosis triggering low-grade systemic
inflammation, also known as metabolic endotoxemia, and
autoimmunity processes, our aim in this literature review
was to gather information about the use of purified or food-
stuffed omega-3 polyunsaturated fatty acids (n-3 PUFAs),
including a-linolenic (ALA), eicosapentaenoic (EPA), and
docosahexaenoic (DHA) acids on the prevention or adjuvant
therapy of RA and/or UC, because UC patients are at high
risk to develop RA, mainly caused also by gut dysbiosis and
gut barrier impairment.3–5

341
 342 ZORGETTO-PINHEIRO ET AL.

The benefits of n-3 PUFAs-rich diets are correlated with
the gut microbiota balance, which is correlated to metabolic
disease prevention and health promotion for the consumers
(Figure 1).
This review was conducted following the gastrointesti-
nal tract natural flow, starting from the class of molecules
(omega-3 fatty acids) intake (oral) to the direct effects of
these acids on UC and/or RA by their anti-inflammatory
properties (local effects on joints and or intestinal mucosae)
or indirect effects on both chronic inflammatory conditions
through gut microbiota modulation. Finally, we present a link
on how microbiota imbalance acts as a trigger on both
chronic inflammatory conditions beyond hereditariness and
how omega-3 fatty acids ingestion could prevent the occur-
rence and/or a poor prognosis by keeping gut homeostasis.
OMEGA-3 SOURCES
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ing humans and are exclusively obtained from dietary
intake), chemically present 3 to 6 double bonds in their mol-
ecules, the first double bond of which is found in position 3
from methyl-end; thus, ALA, EPA, and DHA are physio-
logically the most important.
The primary sources of omega-3 PUFAs comprise crop
leaf green vegetables, marine algae and microalgae, seeds
and nuts, vegetable oils, fish and fish oils, as summarized in
Table 1.
The n-3 PUFAs are abundant in vegetables and fish origin
sources. Thus, ALA is the highly found in vegetable food-
stuff, vegetable oil (19–55%) followed by nuts and seeds
(3–23%).6–13 Likewise, ALA, EPA, and DHA are highly
found in microalgae species (42–60%, 13–31%, and 2–
14%, respectively).14 In addition, these three fatty acids are
found in macroalgae species (EPA, 3–27% and DHA, 1–
5%) and freshwater fishes (ALA, 1–4%; EPA, 0.4–3%; and
DHA, 2–8%).15–17 EPA and DHA are found in marine

Omega-3 (x-3 or n-3) fatty acids are essential PUFAs fish and fish oil (3–6% and 13–33%; 6–13% and 4–18%,
(cannot be biosynthesized by the mammalian body, includ- respectively).11,18,19

FIG. 1. The role of the omega-3 PUFAs sources consumption in gut microbiota homeostasis, which are correlated with health improvement and
metabolic diseases prevention. AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; PUFAs, polyunsaturated fatty
acids; SCFAs, short-chain fatty acids.
 OMEGA-3 ON ULCERATIVE COLITIS AND RHEUMATOID ARTHRITIS 343

Table 1. Sources of Omega-3 Polyunsaturated Fatty Acids and Their Contents

Omega-3 (%)
Origin Foodstuff ALA EPA DHA References
6
Vegetable Spinasia oleracea (Spinash) 44.0 0 0
6
Nasturtium officinale (watercress) 48.0 0 0
6
Petroselinum crispum (Parsley) 30.0 0 0
6
Brassica rapa subsp. pekinensis (Chinese cabbage) 51.0 0 0
6
Brassica oleracea var. gemmifera (Brussels sprouts) 39.0 0 0
6
Brassica oleracea var. italica (Broccoli) 40.0 0 0
7
Moringa oleifera (flower, pod, leaf) 19.0–54.0 0 0
8
Brassica spp. 7.0–20.0 0 0
9
Lactuca sativa (baby-leaf) 44.0–55.0 0 0
10
Solanum spp. (leaf) 50.0–54 0 0 0
11
Nuts and seeds Black walnut 2.7 0 0
11
Walnuts 9.0 0 0
11
Butternuts 8.7 0 0
11
Flax and chia seeds 22.8 0 0
11,12
Vegetable oil Linum usitatissimum (seed) 53–58 0 0
11,13
Brassica spp. (seed) 6.8–20 0 0
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11
Glycine max (seed) 6.0–16 0 0
14
Microalgae Chroomonas mesostigmatica 60.3 30.5 1.7
14
Guillardia theta 56.7 14.9 3
14
Hemiselmis sp. 53.2 21.2 5.1
14
Proteomonas sulcata 58.5 12.7 12.6
14
Rhodomonas salina 48.8 17.2 11.2
14
Storeatula major 41.9 16.0 10
14
Teleaulax acuta 46.2 26.0 14.3
14
Taleaulax amphioxeia 43.3 23.6 12.7
15
Macroalgae (Phaeophyta) Halopteris scoparia 0 14.4 1
15
Dictyota dichotoma 0 6.6 0
15
Toania atomaria 0 13.6 0.8
15
Sargassum vulgare 0 8.6 1.5
15
Cladostephus spongiosus 0 11.5 0
15
Macroalgae (Rhodophyta) Jania sp. 0 25.5 0
15
Pterocladiella capillacea 1.0 15.3 0
15
Asparagopsis armata 0 2.9 0
15
Peyssonnelia sp. 0 18.5 4.9
15
Bornetia secundiflora 0 27.3 0
16
Fresh-water fish Pimelodus spp. 1.3–3.9 0.4–1.3 1.9–8.2
16
Ageneiosus brevifilis (Palmito) 1.0 0.7 8.7
17
Aspius aspius (Asp) 2.2 2.6 5.2
17
Barbus barbus (Common brarbel) 3.4 2.9 5.6
17
Acipenser ruthenus (Sterlet) 4.3 2.9 3.8
17
Esox lucius (Northern pike) 2.6 1.6 7.6
18
Marine water fish Caranx hippos (Crevalle jack) 0 3.1 17.6
18
Thunnus thynnus (AB tuna) 0 4.8 32.5
18
Scomberomorus maculatus (AS mackerel) 0 5.6 12.6
11
Fish oil Sardina pilchardus (sardine) 0 10.1 10.7
11
Brevoortia tyrannus (menhaden) 0 13.2 8.6
11
Salmon spp. (salmon) 0 13.0 18.2
11
Gadus morhua (cod liver) 0 6.9 11.0
11
Clupea harengus (herring) 0 6.3 4.2

ALA, a-linolenic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; PUFAs, polyunsaturated fatty acids.

The n-3 PUFAs quantities of all reviewed vegetables, nuts
and seeds, vegetable oils, micro and macroalgae, freshwater
and marine fishes and fish oil given in Table 1 are summa-
rized in Figure 2.
Green leaf vegetables, pods, nuts, fruits, microalgae,
including their oils are natural sources of ALA. Therefore,
the recommended daily intake of ALA is 1 and 2 g/day for
women and men, respectively, and *1–4 g/day of EPA and
DHA (abundant in microalgae, fish, and fish oil) are needed
to maintain the gut microbiota balance and host health.20–23
In the organism, through the serial desaturation and elon-
gation of biochemical reactions, ALA from the diet is
converted to EPA and DHA, which are carried into the
bloodstream, promoting several health benefits, including
prevention, managing, and control of different types of dis-
eases including autoimmune diseases.24–29
 344 ZORGETTO-PINHEIRO ET AL.

The bioconversion processes of ALA to long-chain

FIG. 2. The mean percentage of a-linolenic, eicosapentaenoic,
and docosahexaenoic acids found in vegetable, algae, and fish origin
sources. ALA, a-linolenic acid.
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PUFAs as EPA and very-long-chain fatty acids as DHA are
given in Figure 3.
Previous clinical studies reported the benefits of n-3
PUFAs (‡4 g), individual EPA (*2 g) or mixed EPA (0.05–
2 g), and DHA (0.03–1 g) daily ingestion or supplementation
decreased the effects of UC and RA in human subjects
significantly.30–36 High intake of n-3 PUFAs is associated
with an abundance of short-chain fatty acids (SCFAs) gut
microbiota producers and intestinal health improvement,
reducing inflammatory diseases.23,29,37,38 Conversely, the
increase of beneficial gut microbiota directly reduces the
occurrence of harmful microbiota characterized by the pres-
ence of lipopolysaccharides (LPS) in the cell surface of
Gram-negative bacteria that act as an inflammatory trigger
when interacting with cell surface receptors of the macro-
phage and neutrophils of host’s immune system.38
Furthermore, the abundance of EPA and DHA (n-3

PUFAs) with anti-inflammatory effects (resolvins, pro-

tectins, and maresins) competes with arachidonic acid
(n-6 PUFAs), which is a pro-inflammatory precursor of

FIG. 3. Biosynthesis pathway conversion of ALA to LC-PUFAs and VLCFAs in the human body. Among the LC-PUFAs, EPA and DHA to
VLCFAs are the most important. These two acids are associated with human health promotion and preventing several diseases. The VLCFAs
bioconversion process takes place in hepatic cell mitochondria and peroxisome. These acids enter the bloodstream, which are conducted to
different body parts for health benefits, including prevention, control, and cure of various autoimmune diseases. LC-PUFAs, long-chain poly-
unsaturated fatty acids; VLCFAs, very long-chain fatty acids.
 OMEGA-3 ON ULCERATIVE COLITIS AND RHEUMATOID ARTHRITIS
prostaglandin (PG) and leukotriene (LT) synthesis at the
cyclooxygenase (COX) and lipoxygenase (LOX) level,
which modifies cell membrane phospholipid fatty acid pat-
tern, disruption of lipid rafts for healthy physiology condi-
tions by inhibition of the proinflammatory cytokines, as
tumor necrosis factor-a (TNF-a), interleukins (ILs): IL-1,
IL-6, IL-8, and IL-12, nuclear factor kappa B (NF-jB),
COX-2, LOX, cytochrome P450, nitric oxide, G protein-
coupled receptor 120, LTs, and peroxisome proliferator-
activated receptor-c regulation.39
In addition, EPA and DHA are related to the decrease in
the production of cytokines, T cell reactivity, PGE2 metab-
olites, thromboxane A2 (linked to platelet aggregation and
vasoconstriction), leukotriene B4 (inflammation and potent
inducer of leukocytes, lymphocytes, macrophages, endo-
thelial cells chemotaxis, and adherence) and IL-6 and the
increase of thromboxane A3 (weak platelet aggregation and
vasoconstrictor), prostacyclin PGI3 and PGI2 (vasodilators
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and inhibitors of platelet aggregation), leukotriene B5 (low
inflammation and chemotactic agent).40–44 Thus, EPA and
DHA-rich diets or supplement intake have central role cor-
related with decreasing and preventing incidence of RA and
UC effects on human subjects.44–50
UC AND RA PATHOGENESIS: THEN AND NOW
In the past, UC and RA were identified mainly through
the observation of the symptoms, and both had in common
the prerogative of genetic background and a chronic in-
flammation status at the committed sites, rectum/colon and
joints, respectively. The symptoms of UC are abdominal
pain, diarrhea, and hematochezia (passage of fresh blood
through the anus) but not all cases of colitis present blood
in stools, for example, microscopic colitis. Anemia, high
erythrocyte sedimentation rate (ESR), or C-protein level
may be present on blood tests; however, it is not a rule, the
endoscopic biopsy confirming the clinical diagnosis.51
The main affected sites in UC are the rectum and colon
and it is characterized by an impaired intestinal lining owing
Table 2. Most Frequent Extraintestinal Manifestation in Patients With Ulcerative Colitis on Different Populations
Population Period of study
British (Bristol) 1952–1965
North Americans (mainly 2001–2002
midwestern and southern regions)
Swiss 2006–2008
Central and East Europe and Middle 2002–2008
Eastern countries
Italian 2000–2011
Brazilian (Salvador, State of Bahia) 2011–2012
a
EIMs observed only in UC patients.
b
Type 1 arthritis: commitment of < 5 joints/it can be asymmetrical; type 2 arthritis: commitment of 5 or more joints symmetrically (RA).
EIMs, extraintestinal manifestations; IBD, inflammatory bowel disease; RA, rheumatoid arthritis; UC, ulcerative colitis.
345
to chronic inflammation and the presence of ulcerative le-
sions; if not treated, it can lead to dangerous conditions such
as toxic megacolon or colorectal cancer.52
Of interest, several studies published since the 1960s until
now from different populations, that is, different genetic
backgrounds, point to arthritis/polyarthritis as the most
common extraintestinal manifestation of UC, corroborat-
ing a common etiology in both diseases (Table 2). Those
observations showed that there were shared environmental
factors, regardless of genetic inheritance, triggering the
onset of UC and/or RA in genetically predisposed people,
such as food habits.53–58
Another CID with an autoimmune background is RA. Its
symptoms are primarily swollen and painful joints, especi-
ally the smaller ones such as those from fingers, hands, feet,
wrists, and temporomandibular; however, it is also common
in the bigger ones like knees, hips, and shoulders. Another
characteristic of RA is morning stiffness when joints’ swell-
ing is greater before getting up with motion impairment and
tends to be ameliorated throughout the day. If not adequately
treated, the host’s autoimmune response tends to promote
extracellular matrix degradation and osteoclasts’ activity
leading to cartilage, ligaments, tendons and bones weaken-
ing, and destruction leading to functional impairment.59
A recent study demonstrated that this is a distinct path-
ophysiologic phenomenon characterized by fibrin clots as-
sociated with neutrophils deposited along the synovial
lining, and it was found to be associated with DAS28 score
and duration of ‡1 h of morning stiffness.60
Beyond joint inflammation, RA can also present some extra-
articular consequences such as subcutaneous or lung rheuma-
toid nodules, interstitial lung disease, dry eye syndrome (ker-
atoconjunctivitis sicca), vasculitis, and consequently a higher
risk of cardiovascular diseases, hematologic abnormalities
(ESR, C-protein level, anemia, and plasma viscosity im-
provement), and consequently a higher risk of stroke.59
In this way, RA has to be considered a syndrome cau-
sed by genetic, epigenetic, and environmental factors. This
multifactorial behavior allows opportunities for searching
n (IBD) n (UC), n (%) Most frequent EIMsa Reference
53
243 198 (81.48) Eczema, polyarthritis, and hay fever
54
16,139 10,104 (62.6) Ankylosing spondylitis, RA, and
multiple sclerosis
55
950 370 (39) Arthritis, aphthous stomatitis, uveitis,
sclerosing cholangitis, and erythema
nodosum
56
357 237 (66.4) Symmetrical arthritis, erythema
nodosum, pyoderma gangrenosum,
and aphthous stomatitis
811 595 (73.4) Arthritis type 1 and 2,b ankylosing 57
spondylitis, and uveitis
58
267 267 (100) Arthritis, erythema nodosum,
sclerosing cholangitis, and dry eye
 346 ZORGETTO-PINHEIRO ET AL.
what environmental factor could be changed or modulated
to prevent epigenetic processes (DNA methylation or his-
tones acetylation) or to control the disease activity leading
to a remission state. The genetic background is mainly rela-
ted to DNA loci associated with immune mechanisms,
shared with other CIDs, generating autoantibodies (rheuma-
toid factor, anti-cyclic citrullinated peptide, among others);
however, they are absent in 30–50% of patients at diagnosis,
known as seronegative RA patients.61,62
Environmentally speaking, once the low socioeconomic
status is also considered a risk factor, the nutritional quality
of food intake could also be considered a risk factor. A poor
nutritional status with a lack of fibers, vegetables and fruits,
considered prebiotics, could favor a gut dysbiosis promoting
epithelial barrier impairment, inflammatory processes, and
metabolic endotoxemia.63
OMEGA-3 ON UC AND RA
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UC is a CID characterized by a gut disorder of the large
gut, which is marked by the destruction of the bowel mucosa
and intractable ulcers.63–65 In contrast, RA is an autoimmune
disease and systemic inflammatory disorder characterized
by chronic synovitis and cellular infiltration, often leading
to bone joint erosion, cartilage destruction, and disability, if
not treated.66,67
Thus, these two dysbiosis-related inflammatory condi-
tions could be managed by n-3 PUFAs, including EPA and
DHA administration in diet or supplementations.40,47,49,68,69
The beneficial effects of n-3 PUFAs diet and supplementa-
tion on UC and RA subjects are given in Table 3.
Several studies have reported the positive effects of
n-3 PUFAs, including EPA and DHA, on controlling and
decreasing the activity of various CID, especially UC and
RA (Table 4). The results of some studies demonstrated
lowering UC and RA effects on animal models and human
subjects with the administration of n-3 PUFAs (EPA + DHA),
seafood, fish, and fish oil on a short-term (1–4 weeks) to
measure the disease activity and in a long-term (6 months to
26 years) as lifestyle educational diet.35,48,73,81,82 Therefore,
it is the most important to highlight that decreasing of UC
and RA activity may be associated with the balance of
gut microbiota, especially Bacteroidetes-to-Firmicutes ratio,
Actinobacteria, Proteobacteria species, and SCFAs pro-
ducers, which are related to host health.23,26,29,64,72,83,84
OMEGA-3 ON CID AND GUT MICROBIOTA
The gut is a complex tract through which food and its
metabolites pass during the lifetime. Furthermore, it is
the home to *100 trillion dynamic microorganisms with
35,000 strains of bacteria, of which 107–108 cells/mL are
located in the small intestine, and 1010–1011 cells/mL are
present in the large intestine.83,85,86 This microbiota is con-
stituted mainly by anaerobic strains with *98% formed
by Bacteroidetes Phyla (9–42%, Porpyromonas and Pro-
votella), Firmicutes (30–52%, Ruminococcus, Clostridium,
and Eubacteria), and Actinobacteria (1–13%, Bifidobacter-
ium), whereas another 2% is composed of Lactobacilli (2%),
Streptococci (2%), and Enterobacteria (1%) Phyla.29,87–90
Furthermore, this gut microbiota composition varies
among human subjects, and it may be determined by ethnic/
tribal/racial, geographical location, dietary habits, and
environmental conditions.92–95 Thus, a high diversity com-
position of Bacteroidetes/Firmicutes, Actinobacteria, Pro-
teobacteria, and Verrucomicrobia strains are correlated with
healthy human subjects.29,93–95
However, adverse conditions such as inflammatory chro-
nic disease environment are correlated with different kinds
of cancer, inflammatory bowel disease, diabetes, neurode-
generative syndromes, cardiovascular disease, multiple
sclerosis, obesity, central nervous system syndromes (stress,
anxiety, and depression), and others, resulting in gut micro-
biota imbalanced system caused by the diet profile.29,90,93–98
In addition, several studies have shown that long-term intake
of n-3 PUFA-rich foodstuffs are correlated with several dis-
eases prevention or health improvement, avoiding the preva-
lence of gut dysbiosis on animal models and human
subjects.29,96,99–101 The first benefit of n-3 PUFAs-rich food-
stuffs is linked to gut microbiota harmony balance, creating an
efficient barrier, which manages the harvesting energy in the
body and controls several associated diseases.29,103–107 Thus,
the benefit of an n-3 PUFA-rich diet, including ALA, EPA, and
DHA, is related to decreasing or managing CID, and the bal-
ance of gut microbiota on animal models is given in Table 4.
The increased Bacteroidetes-to-Firmicutes ratio, includ-
ing Actinobacteria and Proteobacteria strains, was demon-
strated with feeding n-3 PUFAs (ALA, EPA + DHA),
maternal, flaxseed, fish, and algae oils in high-fat diet and
n-6/n-3 proportion (1/2) on animal models (Table 2). The
results showed the decreased effects of obesity, type 2 dia-
betes mellitus, inflammatory bowel diseases (IBDs), body
weight, nonalcoholic steatohepatitis, adipose tissue, and
insulin resistance.109,112–116
In addition, the balance of the Bacteroidetes-to-
Firmicutes ratio is the most important, linked to the in-
creasing SCFA (acetate, propionate, and butyrate acids)
production in the gut, which is the leading biofuel used
by several colonocytes that promote the healthy environ-
mental hemostasis among the systems in the body, pro-
tecting against pathogenic agents’ entrance and,
consequently, various CID.23,26,29,83,84,91,106,117–122
On the contrary, the unchanged body weight was reported
in n-3 PUFAs (EPA = 40% plus DHA = 27%) administrated
to healthy models for 2 weeks, which may be explained by
the short study time. Likewise, with human subject studies,
the same results were reported as found in animal models
(Table 5).
GUT MICROBIOTA AUTOIMMUNITY AXIS
The gut microbiome is built from the very first day of
birth. The composition may change according to the mode
of delivery; when naturally delivered, the newborn will
acquire bacteria mainly from the mother’s vaginal tract and
when through C-section, mainly from the mother’s skin
 OMEGA-3 ON ULCERATIVE COLITIS AND RHEUMATOID ARTHRITIS
Table 3. Effect of Omega-3 Polyunsaturated Fatty Acids Diet and Supplementation Administrated
to Ulcerative Colitis and Rheumatoid Arthritis Subjects and Their Outcomes
Disease Host
UC Mice C57BL/6 (8–10 weeks old) male70
Men and women (45–74 years old)34
Women (30–55 years old)48
Rats Wistar (8–10 weeks old) male71
Men and women (18–70 years old)72
Men (‡18 years old)73
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RA Men and women (30–68 years old)74
Men and women75
Female (38–60 years old) with RA76
Mice male DBA/1OlaHsd (Harlan,
Indianapolis, IN)77
Women (54–89 years old) with RA35
ICR mice male arthritis induced78
Rats Lewis (10 weeks old) arthritis
induced79
Female (30–72 years old) with early RA80
Mice male C57/B6 fat-1 transgenic
induced arthritis81
Female (35–69 years old) with RA82
Y, significant decrease; [, significant increase; 4, unchanged; COX-2, cyclooxygenase 2; FFA, free fatty acid; ICR mice, albino mice originating in SWISS from
the Institute of Cancer Research (USA); IL, interleukin; MAG, monoglyceride; NSAID, nonsteroidal anti-inflammatory drug; TNF-a, tumor necrosis factor-a.
surface. Another variant is, if the baby was breastfed, the
quality of its immunoglobulin and neutrophils in the
colostrum/milk. Later, in childhood, other factors may in-
terfere in the gut microbiome, such as environment, diet,
and rate of infections the child could develop, and also the
genetics interferes with the gut microbiome.124
Recent studies have shown that gut dysbiosis could be an
early event, previous to the clinical onset of CIDs such as
UC and RA, triggering the autoimmunity on genetically
predisposed people. A balanced gut microbiome is the
coexistence of beneficial (commensal and symbiotic) and
harmful (pathogenic) microorganisms being supported by
the ingestion of food considered prebiotics, whereas the
347
Diet Main outcomes
n-3 PUFAs for 28 days ColitisY
AdiponectinY
Mucosal inflammationY
Inflammatory cytokines (TNF-a)[
InflammationY
AdiponectinY
n-3 PUFAs (0.86–3.07 g/day) EPA (0.03– Colitis effectsY
0.05) + DHA (0.03–0.05 g/day) for 7 days
n-3 PUFA (EPA + DHA) for 26 years Colitis effectsY
Inflammatory effectsY
EPA (791 mg) + DHA (527 mg) for 2 weeks Colitis effectsY
Supplementation of EPA-FFA (capsule Fecal calprotectinY
2 · 500 mg/day) for 3 months Mucosal inflammationY
Intestinal microbiota modulation[
Supplementation of EPA-FFA (capsule Fecal calprotectinY
2 · 500 mg/day) for 6 months Mucosal inflammationY
n-3 PUFAs of fish oil (3 g/day) for 6 months Joint pain intensityY
Morning stiffnessY
Onset handgripY
n-3 PUFAs (>2.7 g/day) for 3 months NSAID consumptionY
Supplementation n-3 PUFAs (capsule EPA RAY
(2.09 g) + DHA (1.165 g) for 16 weeks
DHA (1000 and 2000 mg/kg) prophylactic ArthritisY
treatment for 45 days InflammationY
Joint destructionY
n-3 PUFAs (>0.21 g/day) for 7.5 years RAY
1. DHA (30 and 100 mg/kg) for 25 days InflammationY
Knee edemaY
2. DHA (25 and 50 lg/joint/twice weekly) InflammationY
25 days Spontaneous pain behaviorY
InflammationY
Diameter of the ipsilateral knee jointY
MAG-EPA (318 mg/kg/day) for 15 days Inflammation (COX-2, IL-17A, TNF-a,
IL-6, IL-1b, MMP-2, and MMP-9)Y
Pro-resolving[
Fish oil (n-3 PUFAs rich) for 12 months RAY
n-3 PUFAs for 9 days Inflammation in joint tissue (IL-17,
IL-6 and IL-23 cytokines)Y
Bone and cartilage damageY
CD4+ Foxp3+ Treg in splenocyte[
Tregs, and IL-174
Marine n-3 PUFAs (EPA + DHA) from RAY
seafood, fish and fish oil for 1–5 per week
consumption of high-fat and refined carbohydrate, and low-
fiber and resistance nutrients diet or the crescent use
of antibiotics could promote an imbalance into this highly
complex system of bacterial community.3,29,125,126
In fact, a decreased bacterial diversity in gut microbiota
was found in new-onset untreated RA and psoriatic arthritis
patients, which resembles the same dysbiosis also found in
IBDs. Indeed, a predominance of Prevotella copri is cor-
related with the reduction of the other beneficial Bacter-
oidetes strains. In addition, when P. copri is transplanted to
an in vivo model of chemically induced colitis, it can spread
and dominate the gut microbiome, increasing the sensitivity
to the chemical.127–129
 Table 4. Effects of Omega-3 Polyunsaturated Fatty Acids, Including a-Linolenic, Eicosapentaenoic, and Docosahexaenoic
Intake and Related Outcomes in Managing Inflammatory Chronic Diseases and Gut Microbiota in Animal Models

Main outcome
Host Diet Gut microbiota Metabolic dysbiosis
ICR Swiss mice Supplementation with n-3 Bifidobacterium spp. (Actinobacteria)[ IBDY
(8 weeks old) obese PUFAs (EPA + DHA) for 19 Bacteroidetes[ ObesityY
female107 weeks Lactobacillus spp. (Firmicutes)[
Enterobacteriales (Proteobacteria)[
Clostridial cluster XIVa (Firmicutes)Y
Mice BALB/c HFD n-6/n-3 PUFAs (1/2) with Blautia, Oscillibacter, Clostridales, Robinsoniella, IBDY
(3 weeks old) male 40% energy for 2 weeks Lactococcus, and Eubacterium (Firmicutes)[
and female pups Porphyromonadaceae (Bacteroidetes)Y
colonic Lachnospiraceae and Rosebeuria, Enterococcus
inflammation108 (Firmicutes)Y
Mice C57BL/6J n-3 PUFAs with 37% energy for Lactobacillus, Allobaculum, Clostridium, and Body weightY
(6 weeks old) obese 8 weeks Turicibacter (Firmicutes)Y Adipose tissueY
female109 Bifidobacterium (Actinobacteria)[ Bamesella Insulin resistanceY
(Bacteroidetes)Y Bilophila (Proteobacteria)Y
Akkemansia (Verrucomicrobia)Y
Downloaded by 201.231.230.61 from www.liebertpub.com at 07/19/22. For personal use only.

Rats (5 weeks old) n-3 PUFAs (1 g EPA 80% + Butyrivibrio, Jeotgalicoccus, and Peptococcus IBDY
early life stressed DHA 20%) for 17 weeks (Firmicutes)[
(weaned) inflamed Caldicoprobacter (Terrabacteria)[ Bifidobacteria
gut female cubs110 and Aerococcus (Actinobacteria)[ Undibacterium
(Proteobacteria)Y
Mice C57BL/6J (4–5 Supplementation of n-3 PUFAs Bacteroidetes[ IBDY
weeks old) and (1 g EPA + DHA/100 g diet) Verrucomicrobia and Bifidobacterium
adulthood (11–13 for 8 weeks (Actinobacteria)[ FirmicutesY
weeks old) male Tenercutes and Enterobacteria (Proteobacteria)Y
inflamed gut111
Mice C57BL/6WT Maternal n-3 PUFA for 4 weeks Helicobacter (Proteobacteria)[ ObesityY
(4 weeks old) obese plus HFD 60% energy Bacteroides (Bacteroidetes)[ Epsilonproteobacteria IBDY
male and female112 (PUFA, 32% and n-3 PUFA, (Proteobacteria)[
2.1%) for 6 weeks Lachnospiraceae and Ruminococcaceae
(Firmicutes)[
Akkermansia (Verrucomicrobia)[
Rats (7 weeks old) n-3 PUFAs (11.11% and Proteobacteria[ Body weightY
male and female 33.33%) Allobaculum (Firmicutes)[ IBDY
T2DM113 ActinobacteriaY Insulin resistanceY
Firmicutes/BacteroidetesY T2DMY
Mice C57BL/6 Supplementation with fish oil or Butyricimonas[ HyperlipidemiaY
(7 weeks old) male algae oil for 12 weeks Lachnospiraceae[
hyperlipidemic116

HFD, high-fat diet; T2DM, type 2 diabetes mellitus.

Table 5. Effects of Omega-3 Polyunsaturated Fatty Acids, Including a-Linolenic, Eicosapentaenoic and Docosahexaenoic
Intake and Related Outcomes in Managing Inflammatory Chronic Diseases and Gut Microbiota in Human Subjects

Main outcome
Host Diet Gut microbiota Metabolic dysbiosis
Men and women (58–62 100 g of sardine with EPA + Escherichia coli (Proteobacteria)Y Gut inflammationY
years old) T2DM123 DHA (3.0 g) during 5 days a Bacteroides and Prevotella (Bacteroidetes)[ Gut microbiota[
week for 6 months
Men and women (‡65 Supplementation with n-3 Bacteroidetes[ Body weightY
years old) prediabetic, PUFAs fish oil (EPA + DHA) Firmicutes[ IBDY
obese and T2DM116 for 7 weeks ProteobacteriaY T2DMY

348
 OMEGA-3 ON ULCERATIVE COLITIS AND RHEUMATOID ARTHRITIS
An imbalanced gut microbiota promotes local inflamma-
tory processes activating the local innate immunity, such
as macrophages and dendritic cells that under the action of
cytokines are differentiated into antigen-presenting cells
(APCs), disrupting the epithelial barrier, promoting intesti-
nal permeability, and favoring the influx of bacterial
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DNA and/or LPS to the bloodstream.5,130
This local process may allow the failure of tolerance
mechanisms by epitope spreading caused by a change of
proteins structure owing to citrullination, molecular mim-
icry when some pathogens share the same sequence or
structure also found on the host’s organism, bystanders ac-
tivation caused by bacteria stimulation of Toll-like receptors
on APCs leading to a production of proinflammatory cyto-
kines and tissue damage, and under prolonged infection,
causing constant activation of T cells, overproduction of
antibodies, and immune complexes.124
Once in the bloodstream or the lymphatic vessels, acti-
vated immune cells or bacterial antigens (LPS and or DNA)
are directed to the joints, and local cytokines activate resi-
dent dendritic cells, B cells, T cells, and natural killer (NK)
cells, leading to activation of a complement system en-
FIG. 5. Summary on how omega-3 fatty acids can act improving gut health and switching the organism to an anti-inflammatory profile
by modulation the gut microbiome and/or by immune cells membrane composition. COX, cyclooxygenase; IL, interleukin; LOX, lipoxygenase;
NF-jB, nuclear factor-kappa B; TNF-a, tumor necrosis factor alpha.
349
FIG. 4. Theoretical scheme of the link
between UC and RA pathogenesis having in
common the gut dysbiosis. RA, rheumatoid
arthritis; SCAFs, short-chain fatty acids; UC,
ulcerative colitis.
hancing synovial inflammation.130 Corroborating the gut
dysbiosis/loss of immune tolerance hypothesis, Kempsell
et al.131 were able to identify several bacterial ribosomal
RNA in arthritis synovial tissue and controls; however,
some strains were unique to arthritic synovial tissue indi-
cating living bacteria in the joints. The link between the
genetic background and environmental factors leading to
gut dysbiosis and collaborating with UC and RA patho-
genesis is given in Figure 4.
Another dysbiosis-prone site is the mouth, specifically
Porphyromonas gingivalis, the leading cause of periodontal
disease. This strain is well studied and correlated with RA
and the citrullination mechanism generating post-translation
protein modifications through bacterial enzymatic activity
and later producing anticitrullinated protein/peptides anti-
bodies.132 Besides the citrullination process, P. gingivalis
could also promote an aggressive type of RA in an animal
model by induction of NETosis (when neutrophil aggregate
emits thin evaginations of their cell membrane forming a
kind of network to contain pathogens and which also pro-
motes platelet entrapment), osteoclastogenesis, and Th17
proinflammatory response.133
 350 ZORGETTO-PINHEIRO ET AL.
The idea to modulate the gut microbiota for prevention or
as adjuvant therapy in CIDs such as UC and RA is not new.
Fasting studies in RA patients followed by a vegetarian diet,
which is rich in prebiotics, demonstrated that the change
of diet could improve the outcome of the disease, having a
long-term effect both clinically and statistically.134
Prebiotics are considered food products or by-products
that promote the growth and maintenance of a healthy and
diverse gut microbiome capable of producing higher levels
of SCFAs metabolites, especially butyrate, which has the
capacity of inhibiting inflammatory pathways by suppres-
sing NF-jB activity and the expression of IL-1, IL-12, and
TNF-a (proinflammatory cytokines), inducing mucin syn-
thesis and in this way protecting the intestinal mucosa, and
decreasing the bacterial influx from the intestinal lumen to
the bloodstream by improving the tight junctions on intes-
tine epithelial cells.29,44,132–138
One of the prebiotics we highlight is omega-3 fatty acids,
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well-studied by several researchers in several experimental
and clinical studies. Results have shown their gut microbiota
modulation property favoring butyrate producers and anti-
inflammatory properties for being precursors of EPA and
DHA-derived eicosanoids, resolvins, and protectins, driving
the inflammatory process to its control and resolution and
avoiding tissue damage.29,138
It is proposed that switching the immune cell membrane
composition of a higher proportion of arachidonic acid,
caused by high intake of omega-6 foodstuffs, into a higher
EPA and DHA proportion, owing to an intake of omega-3
foodstuffs, may favor the production of less potent eicosa-
noids, by COX- and LOX-mediated enzymatic reactions,
generating an anti-inflammatory profile driving to control
and resolution of the inflammatory process in the gut, in the
case of UC or in the joints, in the case of RA. Indeed, it was
already observed that consumption of omega-3 ameliorates
the rates of RA remissions and improves the maintenance of
remission on IBD patients (Fig. 5).44,45,52,96,139
CONCLUSIONS
The CID social and economic burden is a concerning
issue once its prevalence keeps increasing throughout the
decades, lowering the quality of life, and overloading gov-
ernment budgets and health systems.140 Malnutrition, that is,
lack of vegetables, fruits, and fibers intake and high con-
sumption of meat and high-fat diets, drives to gut microbiota
dysbiosis and a subclinical inflammatory status, not initially
detectable on routine exams but in the long-term leading
to several chronic diseases, including UC and RA, among
them.141 Omega-3 fatty acids have been widely tested in
clinical and experimental studies, and its anti-inflammatory
action has always been corroborated in various diseases,
including the aim of our review, UC and RA, through
inflammatory factors suppression or modulation of the gut
microbiota as previously described.
Besides the benefits of preventing or as an adjuvant
treatment for UC, RA, and many other chronic pathogenic
conditions, researchers are already calling attention to the
benefits that omega-3 fatty acid supplementation could pro-
vide on COVID-19 treatment and recovery once the lead-
ing cause of death is related to an inflammatory cytokine
storm/cascade in the lungs causing respiratory failure
because most comorbidities are associated with NCDs,
CIDs, and autoimmune diseases. However, an official treat-
ment recommendation just may be made after randomized
and controlled clinical trials.142–144
Finally, it is considered most important to have a healthy
diet based on functional foods or, if it is not possible, car-
rying out a nutrient supplementation under prescription,
which can contribute to gut microbiota balance and, as a
consequence, on a controlled immune system, especially
under a double pandemic scenario humanity is facing: the
inflammatory chronic disease pandemic and the COVID-19
pandemic at the same time.145 Further preclinical and clin-
ical trials are demanded in this field of research, engaging a
multidisciplinary team with a holistic view of pathological
processes.
ACKNOWLEDGMENTS
The authors thank the Graduate Program in Biotechnol-
ogy and Biodiversity and the Graduate Program in Health
and Development in the Central-West Region, Federal
University of Mato Grosso do Sul-UFMS, for support. The
authors also thank the Coordination for the Improvement of
Higher Education Personel (Coordenação de Aperfeiçoa-
mento de Pessoal de Nı́vel Superior—CAPES) and the
National Council for Scientific and Technological Devel-
opment (Conselho Nacional de Desenvolvimento Cientı́fico
e Tecnológico—CNPq) for research grants.
AUTHOR DISCLOSURE STATEMENT
The authors declare no conflict of interest.
FUNDING INFORMATION
This research was funded by the Federal University of
Mato Grosso do Sul (UFMS) and Coordination for the
Improvement of Higher Education Personel (CAPES)—
Portaria 2016/2018. This study was financed in part by the
CAPES—finance code 001.
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