Special Article

Extra-virgin olive oil and the gut-brain axis: influence on
gut microbiota, mucosal immunity, and cardiometabolicand cognitive health

Extra-virgin olive oil (EVOO), a popular functional food and major source of fat in
the Mediterranean diet, pos sesses a variety of healthful components, including
monounsaturated fatty acids and bioactive phenolic compounds that, individuallyand collectively, exert beneficial effects on cardiometabolic markers of health andact as neuroprotective agents through their anti-inflammatory and antioxidant activities. The gut microbiota and health of the intestinal environment are now considered important factors in the development of obesity, metabolic disease, andeven certain neurodegenerative conditions via the gut-brain axis. Recently, data are
emerging which demonstrate that the health-promoting benefits of EVOO may also
extend to the gut microbiota. In this review, we aimed to examine findings from recent studies regarding the impact of EVOO on gut microbiota and intestinal healthand explore how modulations in composition of gut microbiota, production of
microbially produced products, and activity and functioning of the mucosal immune system may lead to favorable outcomes in cardiovascular, metabolic, andcognitive health.

INTRODUCTION
The Mediterranean diet, rich in plant-based foods andincorporating moderate intake of fish and wine and low
intake of red meat and processed foods, has been associated with a reduced risk of development of chronic

diseases and increased life expectancy, as evidenced
from a number of randomized clinical trials.1–3 An integral component of the Mediterranean diet, extra-virgin
olive oil (EVOO), obtained via the mechanical extraction of the olive fruit, without the use of heat or solvents, and required to possess no greater that 0.8% freeAffiliation: J.F. Millman, S. Okamoto, T. Taiki, T. Uema, and H. Masuzaki are with the Division of Endocrinology, Diabetes and Metabolism,
Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Okinawa,
Japan. S. Ikematsu is with the Department of Bioresources Engineering, National Institute of Technology, Okinawa College, Okinawa,
Japan. M. Shimabukuro is with the Department of Diabetes, Endocrinology and Metabolism, Fukushima Medical University, Fukushima,
Japan.
Correspondence: H. Masuzaki, Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department ofInternal Medicine), Graduate School of Medicine, University of the Ryukyus, 207 Uehara Nishihara, Okinawa 903-0215, Japan. Email:hiroaki@med.u-ryukyu.ac.jp. Co-correspondence: S. Okamoto, Division of Endocrinology, Diabetes and Metabolism, Hematology,
Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, 207 Uehara Nishihara,
Okinawa, 903-0215, Japan. Email: shiki@med.u-ryukyu.ac.jp.
Key words: Alzheimer disease, extra-virgin olive oil, gut microbiota, metabolic health, mucosal immunity.
C The Author(s) 2021. Published by Oxford University Press on behalf of the International Life Sciences Institute.
V

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doi: 10.1093/nutrit/nuaa148
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Jasmine F. Millman, Shiki Okamoto , Taiki Teruya, Tsugumi Uema, Shinya Ikematsu,
Michio Shimabukuro, and Hiroaki Masuzaki

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as was the possible role EVOO-modulated gut microbiota play in regulating intestinal immunity and preventing cardiovascular, metabolic, and cognitive
dysfunction and disease. Most reviews to date summarize the health benefits of EVOO on a particular aspectof health, namely cardiovascular, metabolic, and cognitive health (with EVOO included as part of theMediterranean diet). However, few reviews have been
devoted to exploring the impact of EVOO and its constituents on the gut microbiota. Therefore, unlike otherrecent review publications, in this review, we focusedon the impact of EVOO, as well as its constituents, on
the gut microbiota and intestinal immunity, with a special emphasis on the role of the gut-brain axis, and explored the potential mechanisms of how EVOOinduced modulations in gut microbiota and intestinal
health can lead to therapeutic outcomes in cardiovascular, metabolic, and cognitive health.
We searched the PubMed database for articles inEnglish, using the following terms: extra-virgin olive
oil, polyphenols, gut microbiota, immune system, cardiovascular health, metabolic health and cognition(from 2010 to April 2020). Figure 1 outlines a summaryof the widespread health benefits of EVOO.
NUTRITIONAL PROPERTIES OF EVOO
Extra-virgin olive oil mainly comprises fatty acids(98%–99% by weight)4 with monounsaturated fatty
acids such as oleic acid (18:1 x9) representing between 55% and 83% of the total fatty acids.33 Other
minor, yet valuable, components like phytosterols,
tocopherols, squalene, and phenolics make up theremaining (1%–2%) weight of EVOO.4 There are> 100 different phenolic compounds in olive-derived
products; the main phenolics are found in EVOO, including the simple phenols, hydroxytyrosol and tyrosol, and the secoiridoids, oleuropein, oleocanthal, andligstroside, all of which possess potent antioxidant activity and prolong the shelf life of EVOO.5,37 The concentration of phenolic compounds in EVOO canrange from 50 to 940 mg/kg, with concentration dependent on a variety of factors, including olive cultivar, growing conditions, and oil extraction processes
and techniques.37 Tables 1 and 2 display the major
fatty acid and major phenolic compositions, respectively, of selected olive varieties used in EVOO.
Italian olive cultivars such as Coratina and Leccino
have moderate amounts of oleic acid (78.8% 6 3.9%
and 76.7% 6 4.1%, respectively) (expressed as mean 6SD), as well as total phenolic concentration (116 mg/
kg and 125 mg/kg, respectively).38 Interestingly, theSpanish Picual and Greek Koroneiki cultivars possess
higher amounts of oleic acid (80.7% 6 2.0% andNutrition ReviewsV Vol. 00(0):1–13
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acidity, is well known for its organoleptic and nutritional properties as well as its beneficial effects on anumber of markers of cardiometabolic health andchronic disease risk.4 The health-promoting properties
of EVOO have been largely attributed to the high concentration of monounsaturated fatty acids, as well as
the presence of a variety of phenolic compounds.4,5 The
mechanisms by which EVOO exerts positive outcomeson cardiovascular and metabolic health are numerous
and include lipid- and blood glucose–lowering-effects
as well as polyphenol-influenced anti-inflammatory andantioxidant effects via inhibition of cyclooxygenase-2,
suppression of nitric oxide synthase expression and activation of nuclear factor erythroid-2–related factor.6–10
Extra-virgin olive oil and its phenolic compounds
are promising for prevention and treatment of certain
neurodegenerative diseases, such as Alzheimer disease(AD).11,12 Studies in humans have indicated that an
EVOO-rich Mediterranean diet can significantly reduce
the risk of AD.13,14 Rodent studies also support thesefindings, revealing that oral administration of EVOO
and specific EVOO phenolic compounds, in particular,
can reduce the accumulation of b-amyloid (Ab) deposits and tau neuropathologies in mouse models of AD,
resulting in improved memory and cognition.15–19
Accumulating evidence supports the notion that
consumption of an EVOO-rich Mediterranean diet canalso promote favorable outcomes on gut microbiota
and associated microbial metabolites, supporting thehealth of the intestinal environment.20–23 In parallel,
positive effects on gut microbiota and intestinal immunity have been observed with consumption of EVOO inanimals and humans.24–31 Extra-virgin olive oil affects
the gut microbiota by reducing the abundance of pathogenic bacteria, stimulating the growth of beneficial bacteria, and increasing the production of microbially
produced short-chain fatty acids (SCFAs), which exert awide range of anti-inflammatory effects and can modulate the expression of a variety of genes via epigenetic
mechanisms.32–34 Administration of EVOO influences
the health of the intestinal mucosa and supports gut
microbiota homeostasis by encouraging intestinal immunoglobulin A (IgA) production, as quantified byenzyme-linked immunosorbent assays using fecal
homogenates; dampening down inflammatory cytokine
production35; supporting production and expression ofcytokines and transcription factors involved in reducing
inflammation and promoting immune tolerance in theintestine27; and protecting against intestinal oxidative
injury through the potent antioxidant activity of EVOO
phenolic extracts.36
In this review, we highlight recent scientific progress in humans and rodents in which the impact of
EVOO consumption on gut microbiota was explored,

Table 1 Major fatty acid composition of selected varieties of extra-virgin olive oil
Olive cultivara
Fuentes et al. (2018)38
Reference

Coratina

Fatty acid methyl ester composition (%)
C16:0
13.60 6 0.6
Palmitic acidC16:1
1.2 6 0.3
Palmitoleic acidC18:0
1.91 6 0.30
Stearic acidC18:1
78.8 6 3.9
Oleic acidC18:2
4.8 6 0.3
Linoleic acidC18:3
0.6 6 0.1
a-Linolenic acida
Data are expressed as mean 6 SD.

R

Di Lecce et al. (2020)40

LeccinoArbequina

PicualKalamata

Koroneiki

13.7 6 0.7

15.3 6 1.4

11.6 6 1.2

15.660.1

10.660.0

1.3 6 0.2

1.6 6 0.2

1.0 6 0.2

2.2 60.1

0.660.0

1.7 6 0.2

1.3 6 0.5

2.0 6 0.9

2.2 60.1

2.5 60.00

76.7 6 4.1

67.3 6 4.3

80.7 6 2.0

68.7 60.1

79.260.1

6.0 6 0.4

12.7 6 2.6

3.1 6 0.5

10.060.1

5.360.0

0.7 6 0.1

0.6 6 0.1

0.7 6 0.1

0.10 60.1

Not detected

79.2% 6 0.1%, respectively) in comparison with other
Spanish commercial varieties such as Arbequina(67.3% 6 4.3%)
andKalamata(68.7% 6 0.1%)(expressed as mean 6 SD).39,40 In contrast, Kalamata
olives contain greater amounts of individual phenolic
compounds as well as total concentration of phenolics(371.0 mg/kg) compared with varieties such as theArbequina (85.0 mg/kg).38,39 Although there are nodata to date, to our knowledge, comparing the different varietals of olives used in EVOO and their associated impact on the gut microbiota, given the intimate
relationship between polyphenols and the microbiota,
Nutrition ReviewsV Vol. 00(0):1–13

Monta~no et al. (2016)39

EVOOs with higher concentrations of phenolic compounds would likely exert the most striking effects on
the gut microbiota.
Accumulating evidence regarding the health benefits of EVOO has also influenced a number of healthand nutrition policies, particularly in Europe.5
Specifically, the European Food Safety Authority recommends healthy unsaturated fats like EVOO should
be used in place of saturated and trans fats, and the organization also recognizes the particularly beneficial
effects of EVOO phenolic compounds on blood
low-density lipoprotein cholesterol (LDL-C) and3

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Figure 1 Schematic overview of the numerous health benefits of extra-virgin olive oil.

Table 2 Major classes of phenolic compounds and total phenolic concentration in selected varieties of Extra virgin olive
oilOlive cultivar
Arbequina

PicualReference

Coratina

LeccinoFuentes et al. (2018)

Kalamata

Koroneiki38ahigh-density lipoprotein (HDL) cholesterol and associated cardiovascular risk.41,42
METABOLIC HEALTH AND CARDIOVASCULAR DISEASE
Greater than one-third of the world’s adult population
is now classified as overweight or obese and approximately 25% meets criteria for the metabolic syndrome—aclusteringofdifferent
metabolicabnormalities including abdominal obesity, dyslipidemia, hyperglycemia, and hypertension.43,44 Obesity andthe metabolic syndrome are associated with an increased risk of cardiovascular disease, diabetes mellitus,
and all-cause mortality and, worldwide, represent a major public health burden, with safe and effective therapies urgently required.43
The therapeutic effects of EVOO consumption on
cardiovascular outcomes and cardiometabolic risk factors have been demonstrated in a number of randomized trials and epidemiological studies.45–47 Most
notable of these was the Prevencion con Dieta
Mediterranea (PREDIMED) trial, a large randomized
trial consisting of 7447 participants at high cardiovascular risk with type 2 diabetes mellitus or  3 major risk
factors, including smoking, hypertension, elevated
LDL-C level, low HDL cholesterol level, overweight orobesity, or a family history of premature coronary heartdisease. Results from the trial showed that consumptionof a Mediterranean diet plus either EVOO (participants
were provided 1 L/week per household and advised toconsume  4 tablespoons/day per person) or nuts (30 g/day) was associated with a 30% lower risk of development of major cardiovascular events, including myocardial infarction, stroke, or death from cardiovascularcauses, compared with a group eating a low-fat diet(participants were provided with professional dietaryadvice to reduce dietary fat) after a median of 4.8 years’
follow-up.1 In a subset of the PREDIMED study, participants allocated to a Mediterranean diet supplemented
with EVOO (as defined in the previous sentence) or
nuts (30 g/day) had significantly reduced 24-hour
4

97.0
87.0
9.1
16.6
210.0

ambulatory blood pressure as well as a total cholesteroland fasting blood glucose levels compared with the control participants after 1 year.45
In another subset of the PREDIMED study, involving participants (n ¼ 3541) with the risk factors listed in
the previous paragraph, researchers observed rates of
16.0, 18.7, and 23.6 of new-onset diabetes cases per1000 person-years for the Mediterranean diet groupsupplemented with EVOO, Mediterranean diet groupplus nuts, and the control diet group, respectively.46 A
40% significant relative risk reduction in diabetes risk
for the Mediterranean diet group supplemented with
EVOO and a nonsignificant 18% risk reduction in diabetes risk in the Mediterranean diet group supplemented with mixed nuts were observed in comparison
with the reduced-fat control diet.46 In addition, in the
ATTICA study, a large, population-based study consisting of 3042 Greek men and women with no history of
cardiovascular disease over 1 year, overweight/obese
participants with a greater adherence (as measured by avalidated food-frequency questionnaire) to theMediterranean diet, including EVOO had significantly
greater insulin sensitivity, as assessed by the homeostasis model assessment, 3% lower total cholesterol level,
and a 3 mmHg reduction in systolic blood pressure vs
overweight/obese participants with low adherence tothe Mediterranean diet.47
Acute consumption of EVOO specifically has also
proven beneficial in terms of several cardiometabolic
markers of health. Findings from a randomized control
trial of 30 participants with impaired fasting glucose
levels showed that 10 g of EVOO added to meals was associated with a reduction in blood glucose, triglyceride,apolipoprotein B-48, and dipeptidyl peptidase-4 activity
levels and a significant increase in insulin andglucagon-like peptide 1 (GLP-1) levels in the peripheral
blood.7
Moreover, in another randomized, cross-over studyof 25 participants, the addition of 10 g of EVOO to a
Mediterranean-type meal significantly reduced 2-hour
postprandial glucose, LDL-C, and dipeptidyl peptidaseNutrition ReviewsV Vol. 00(0):1–13
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Concentration (mg/kg)
Simple phenols
62.0
64.0
62.2
42.8
102.6
Oleuropein ligstroside derivatives
8.5
156.4
40.0
66.5
216.7
Lignans
0.0
5.9
6.9
3.1
14.4
Flavanoids
14.1
13.4
5.06
12.8
32.1
Total phenols
85.0
240.0
116.0
125.0
371.0
a
Quantification and sum of phenolic compounds was determined by high-performance liquid chromatography.

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Rliver and adipose tissue.62 Also, oleic acid derived fromolive oil can result in increased mRNA expression of
fatty acid transport protein 4 receptor and promote subsequent GLP-1 secretion from intestinal L cells.63
Moreover, SCFAs, produced by a number of bacteria,such as Bacteroides and Lactobacillus, which are often
elevated with EVOO consumption, are also potent activators for GPR43, playing an important role in blood
glucose regulation, with GPR43 knock-out mice exhibiting reduced levels of GLP-1, GIP, and peptide YY
secretion.64
COGNITIVE HEALTH
Alzheimer disease (AD), the most common form of dementia and neurodegenerative disorder, is estimated toaffect between 40 million and 50 million people worldwide.65 Alzheimer disease is characterized by progressive memory loss and cognitive decline and,pathologically, by the deposition of Ab plaques and accumulation of hyperphosphorylated tau proteins.66 To
date, there are no effective disease-modifying treatments for AD. However, evidence suggests that earlylifestyle modifications, such healthy dietary changes,
can potentially prevent and reduce the number of people living with dementia and AD.65
In the PREDIMED-NAVARRA randomized trial(n ¼ 522 participants) intake of the Mediterranean dietsupplemented with either EVOO (as defined in the previous section) or nuts (30 g/day) resulted in improved
cognition in comparison to a low-fat diet (as defined in
the previous section) after 6.5 years of the intervention.67 Specifically, participants allocated to a
Mediterranean diet supplemented with EVOO or nuts
had significantly higher mean Mini-Mental State
Examination scores (þ0.62; 95%CI, þ0.18 to þ1.05)
and Clock Drawing Test (þ0.51; 95%CI, þ0.20 toþ0.82) scores compared with participants eating the
low-fat control diet.67 Also, in another PREDIMED
substudy in which several neuropsychological tests wereused to assess cognitive health, researchers found thatafter 4.1-years of follow-up, participants who consumed
a Mediterranean diet supplemented with either EVOO
or nuts had improved cognitive function comparedwith those that consumed a low-fat diet.68 In addition,in the Three-City study, a French multicenter cohort
study, researchers followed 6947 participants and monitored their olive oil intake and cognitive health using
the Mini-Mental State Examination, Benton Visual
Retention Test, and Isaacs Set Tests. They found thatparticipants with moderate or intensive olive oil consumption had reduced odds of cognitive deficit for verbal fluency (odds ratio ¼ 0.88; 95%CI, 0.72–1.08) and5

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4 levels, significantly increased GLP-1 and gastric inhibitory peptide (GIP) levels in circulating blood.6
Although high-fat diet (HDF)–induced secretion of GIP
increases lipoprotein lipase activity in adipocytes, leading to potential fat accumulation and obesity,48 it is unlikely that GIP secretion induced by EVOO
consumption would cause any significant changes inadiposity. First, increases in GLP-1, which assist inbody weight reduction and fat accumulation as well as
in delaying gastric emptying and increasing satiety inhumans,48–50 have been proposed to increase the therapeutic efficacy of GIP.51 Interestingly, a feedback loop
has been established between GLP-1 and GIP, with GIP
promoting an increase GLP-1 levels and dipeptidyl
peptidase-4 inhibitors increasing both GLP-1 and GIPlevels.52 In support of this, mice fed an HFD and administered both GIP and GLP-1 had greater reductionsin appetite and body weight gain than did mice that received individual administration of these incretins.53 In
addition, it has been proposed that GIP may exert someof its beneficial effects on metabolic health via the central nervous system; increased expression of GIP in the
hypothalamus in mice resulted in regulation of food intake, and played an important role in memory, with
GIP-receptor–deficient mice exhibiting impairments inlearning, synaptic plasticity, and hippocampal neurogenesis.54,55 Unfortunately, little is known about the impact of long-term EVOO consumption on GIP levels inhumans or animals. However, in a couple of studies inrodents, elevations in GLP-1 and associated therapeutic
effects on glucose homeostasis and adiposity were observed with long-term EVOO consumption.56,57
A variety of molecular mechanisms have been implicated regarding EVOO’s positive effects on cardiovascular and metabolic health. In particular, some of
EVOO’s lipid-lowering effects can be ascribed to theability of EVOO to increase the capacity of HDL andpromote cholesterol efflux as well as increase expressionof the ATP-binding cassette transporters ABCA1 andABCG1 in macrophages.58,59 In addition, olive oil phenolic compounds demonstrate cholesterol binding activity and can impair cholesterol absorption in theintestine, as well as reduce oxidation of LDL via theirantioxidant effects.2,60,61 Interestingly, these effects were
demonstrated in a randomized crossover, controlled
trail with polyphenol-rich olive oil exerting superior
effects on LDL oxidation and proatherogenic CD40L
gene expression in comparison to olive oil with low
polyphenol content.61
The major fatty acid in EVOO, oleic acid, assists inmaintaining glucose homeostasis by activating the Gprotein–coupled receptors GPR-120 and GPR-40, leading to intestinal GLP-1 release and widespread antinflammatory effects in a variety of tissues, including

visual memory (odds ratio ¼ 0.82; 95%CI, 0.68–0.99) vsthose who never used olive oil.69
In several rodent studies, EVOO, especially the
EVOO secoiridoid oleocanthal, aided the prevention
and halted the progression of AD.15–19 Researchers
assessing the effect of chronic supplementation of
EVOO on tau metabolism and synaptic function intransgenic mice overexpressing human tau found an increase in complexin 1, a presynaptic neuronal protein,
and a notable decrease in tau oligomers in mice fed
EVOO, resulting in enhanced short-term plasticity andmemory.17 In an earlier study by the same authors, a 6month EVOO diet administered to triple transgenic
mice, which possess 3 mutant disease genes associatedwith AD (PS1M146V, tauP301L, and APPSwe) and inwhich amyloid plaques and neurofibrillary tangles develop, resulted in a significant reduction in Ab peptides
and a decrease in tau neuropathology as a result of activation of autophagy mechanisms.18 In a study of the effect of 4-week intraperitoneal injection of oleocanthal
in TgSwDI mice (transgenic mice that express the human amyloid-b precursor protein gene under themouse Thy-1 promoter, with Swedish (K670N/M671L),
Dutch (E693Q), and Iowa (D694N) mutations that enhance Ab peptide deposition)70 researchers found a significant reduction of Ab in the hippocampal
parenchyma and microvessels, higher expression of Ab
clearance proteins across a human model of the blood6

brain barrier, and decreased astrocyte activation (likely
as a result of reduced Ab burden and inflammatory cytokine production) and IL-1b levels in the brain.16 The
same authors showed in a previous study that 6-monthconsumption of EVOO by TgSwDI mice resulted inlower levels of Ab, due to beneficial changes in Ab precursor protein processing.15 Furthermore, oleocanthalrich EVOO given to TgSwDI mice at an advanced stageof AD resulted in significantly reduced NLRP3 inflammasome activation and increased Ab clearance by stimulating autophagy through the AMPK Unc-51-likekinase 1 (ULK1) pathway.19 Figure 2 mechanisticallyoutlines the potential therapeutic effects of EVOO in relation to AD.
GUT MICROBIOTA AND MUCOSAL IMMUNITY
To analyze the composition and structure of the gut
microbiota, its associated functions, and, in turn, its relationship with diet, culture-independent methods, using high-throughput and rapid computation, arebecoming increasingly popular and widely available.
Briefly, some of the most common approaches forstudying the microbiota include polymerase chain reaction–based DNA profiling techniques, DNA microarray, and next-generation DNA sequencing using 16SrRNA genes as the target.71 In addition, the omics technologies,
includingmetagenomics,
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Figure 2 Potential therapeutic effects of extra-virgin olive oil (EVOO) on Alzheimer disease. Extra-virgin olive oil may help prevent andeven halt the progression of Alzheimer disease by reducing b-amyloid (Ab) deposits and tau neuropathologies by enhancing autophagy andclearance mechanisms across the blood-brain barrier. Extra-virgin olive oil reduces astrocyte and microglial cell activation by reducing inflammatory cytokine production. Extra-virgin olive oil’s widespread antioxidant effects may also lead to enhancement of brain antioxidant
enzymes and a reduction in reactive oxygen species (ROS).

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thyme) significantly increased levels of Bifidobacteria
compared to levels in study participants who consumed
only 80 mg phenolic compounds/kg from virgin olive
oil.31In rodents, consumption of EVOO increased a-diversity, a measure of species richness, as well as b-diversity, a measure of the differences in composition
between samples, compared with controls.24,27 These
results are associated with favorable effects on metabolic
health, because reduced microbial diversity is associatedwith increased chronic inflammation and subsequentdevelopment of metabolic diseases.73 Extra-virgin olive
oil ingestion in rodents also can promote the growth ofcertain types of beneficial bacteria including species of
Lactobacillus,
Bifidobacterium,
Bacteroides,
and
24–31
Clostridium, and members of the Erysipelotrichaeae.
In additionally, EVOO has demonstrated antibacterial
and bacteriostatic effects against bacteria such as those in
the Desulfovibrionaceae,26,28,30 a family of opportunistic
pathogens associated with obesity and inflammation,74
and Blautia spp.,24 which positively correlates with visceral fat accumulation in Japanese men and women.75
The ability of EVOO to act as both a prebiotic,
stimulating the growth of beneficial bacteria, and an
antibacterial, suppressing the growth of pathogenic bacteria, is likely attributable to the array of phenolic compounds EVOO contains. Approximately 90%–95% ofingested phenolic compounds escape digestion in thesmall intestine and reach the colon, where they are catabolized into bioactive secondary structures—metabolites of their respective parent phenolic compounds thathave been transformed by resident microbiota and canmodify the composition of the gut microbiota.76
Specifically, Martinez et al28 showed that administrationof a diet high in EVOO (vs refined olive oil, which is devoid of polyphenols) to Swiss Webster mice resulted in
reduced levels of species in the Desulfovibrionaceae.
The authors concluded the observed antibacterial effects
against these pathogenic species likely were involvement of phenolic compounds in the EVOO. In supportof this, C57BL6/J mice that were administered a gavageof hydroxytyrosol at 50 mg/kg/day were rescued from
HFD-induced gut microbiota dysbiosis, showing reduced levels of pathogenic Proteobacteria andFerribacter as well as restored bacterial diversity and intestinal barrier integrity, as exhibited by the reduction
in lipopolysaccharide-binding protein in the plasma.77
In another study examining the bactericidal effects of
selected Turkish EVOOs on cultured bacterial strains,notable antibacterial activity was found against the
foodborne pathogens Escherichia coli O157: H7, Listeria
monocytogenes, and Salmonella enteritidis, with refinedolive, canola, and hazelnut oils (all with similar fatty
acid composition), by comparison, unable to7

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metatranscriptomics, metaproteomics, and metabolomics, use analysis of DNA, messenger RNA, proteins,and metabolites to ascertain biological functions of thegut microbiota.71
The crucial role the gut microbiota play in shaping
the mucosal immune system and its influence on overall
inflammatory status and cardiovascular, metabolic, andbrain health are becoming increasingly apparent.
Western-style diets, low in dietary fiber and high inhigh pro-inflammatory fats, are associated with gut dysbiosis, increased gut permeability, systemic inflammation, and a variety of chronic diseases.72 Conversely,
healthier dietary patterns like the Mediterranean diet,which is rich in dietary fiber, beneficial fatty acids, andpolyphenolic compounds, are associated with greatergut microbial diversity, increased abundance of beneficial bacteria, and reduced levels of inflammation andrisk of chronic diseases.20–23 Notably, Ghosh et al23 investigated the effect of a Mediterranean diet on gut
microbiota in 612 elderly European people over
12 months and found that adherence to the diet caused
an increased abundance in several bacteria associatedwith improved cognition and was inversely associatedwith pro-inflammatory markers including C-reactive
protein and IL-17.23 Interestingly, using 16S recombinant DNA operational taxonomic unit baseline data to
generate principle coordinate analysis plots, a specificpattern of clustering was seen across different ethnicities, with Italian people possessing a distinct microbiota
composition from that of people from the United
Kingdom and France and from Poland and theNetherlands, which showed more similarities.23
Moreover, Procrustes analyses also showed countryspecific patterns in dietary habits, which were reflectedin the microbiota composition of the people studied.23
Consumption of EVOO has exhibited positiveeffects on gut microbiota and intestinal health in human and rodent studies (Table 3). Specifically, inhumans, EVOO has prebiotic effects, promoting the
growth of beneficial bacteria such as Lactobacillus andBifidobacterium. Specifically, a Mediterranean diet supplemented with 40 g/day EVOO for 3 months administered to 18 overweight/obese participants resulted insignificantly increased levels of lactic acid bacteria compared to baseline.25 Moreover, a study of 32 patientswith HIV, aged 50 years with undetectable viral load,
who consumed 50 g/day EVOO for 12 weeks indicated asignificant elevation in abundance of Bifidobacteriaceae
species in patients without antiretroviral treatment.26 In
addition, in a randomized, controlled, double-blind,cross-over trial including 12 patients with hypercholesterolemia, researchers found that 25 mL/day virgin olive
oil for 3 weeks containing 500 mg of phenolic compounds/kg (from a mixture of virgin olive oil andTable 3 Effect of extra-virgin olive oil on gut microbiota
Reference

Study characteristics

Luisi et al (2019)25

Zhao et al (2019)

Olalla et al (2019)26

Millman et al (2020)27

Martinez et al (2019)28

Methodology

Effect of EVOO gut microbiota

Male, SD rats (n ¼ 48)
Normal chow diet with ordinary
drinking water, high-fat dietwith fructose drinking water,
diet high in oleic peanut oilwith fructose drinking wateror EVOO diet with fructose
drinking water for 12 weeks

16S rRNA sequencing

Overweight and obese adults(n ¼ 18) and normal-weightcontrol participants (n ¼ 18)
Mediterranean diet enrichedwith 40 g/day EVOO for
3 months
Patients with HIV, aged
50 years with undetectableviral load (n ¼ 32)
50 g/day EVOO for 12 weeks

qPCR" b-diversity index (comparedto high-fat diet with fructose drinking water)" Bifidobacterium (compared tohigh-fat diet with fructose
drinking water)# Blautia (compared to high-fat
diet with fructose drinking
water)" in lactic acid bacteria (compared to baseline)

Male, C57BL/6 J mice (n ¼ 20)
Low-fat purified diet, lard purified diet, high-fat EVOO dietor high-fat flaxseed oil dietfor 10 weeks

16S rRNA sequencing

16S rRNA sequencing" a-diversity (males)" Lachnospiraceae,
Ruminococcus, andAkkermansia (females)" Bifidobacteriaceae (in patients
without antiretroviraltreatment)" Gardnerella (compared tobaseline)# Dethiosulfovibrionaceae (compared to baseline)" a-diversity (compared tolard, purified diet)" Mucispirillum, "Lachnospiraceae, "Bacteroides (compared with
low-fat, purified diet)" Erysipelotrichaeae, "Sutterellaceae (compared tostandard diet)# Desulfovibrionaceae (compared to high-fat dietenriched with refined olive
oil)Male, Swiss Webster ICR (CD-1)
16S rRNA sequencing
mice (n ¼ 35)
Standard diet, high-fat dietenriched with EVOO, high-fat
diet enriched with refined olive oil, or high-fat dietenriched with butter for
12 weeksMale, spontaneously hypertenPCR-denaturing gradient gel" Lactobacillus, " Clostridium
Hidalgo et al (2018)29
sive rats (n ¼ 16)electrophoresis analysis
in cluster XIV (compared toStandard diet or diet enriched
standard diet)with EVOO for 12 weeks
Male, Swiss Webster ICR (CD-1)
Prieto et al (2018)30
16S rRNA sequencing" Erysipelotrichaeae, "mice (n ¼ 26)
Sutterellaceae (compared toStandard diet, high-fat dietstandard diet)enriched with butter or high# Desulfovibrionaceae (comfat diet enriched with EVOO
pared to high-fat dietfor 12 weeks
enriched with butter)
Randomized, controlled, douFluorescence in situ hybridiza" Bifidobacterium (virgin olive
Martin-Pelaez (2017)31
ble-blind, cross-over trial withtion combined with flow
oil containing 500 mg PCs/
adults with hypercholesterolcytometry
kg compared to 80 mg PCs/
emia (n ¼ 12)
kg from virgin olive oil and
25 mL/day virgin olive oil conthyme)
taining either 80 mg PCs/kg,
or 500 mg PCs/kg from virgin
olive oil and thyme for
3 weeks
Abbreviations: EVOO, extra-virgin olive oil; PC, polyphenolic compound; PCR, polymerase chain reaction; qPCR, quantitative polymerase
chain reaction; SD, Sprague-Dawley.

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associated with significantly greater abundance of members of the Bacteroidaceae in comparison to mice fed
diets high in palm oil, flaxseed or fish oil, and high levels of sucrose.83
Short-chain fatty acids such as acetate, butyrate,
and propionate, produced by bacteria, not only exert
therapeutic effects on colonic cells and are an importantsource of energy but also have a profound impact andinfluence on the mucosal immune system.84,85 Shortchain fatty acids can increase anti-inflammatory andimmunotolerogenic T-regulatory cells (Tregs) via induction of dendritic cells, activating innate lymphoidcells to produce Treg-inducing cytokines such as IL-10
and TGF-b, and can promote the development of Tregs
by inhibiting histone deacetylases at the FoxP3 locus.86,87 Moreover, SCFAs can assist in strengthening
the gut barrier and preventing bacterial and lipopolysaccharide (LPS) infiltration and subsequent inflammation by upregulating the expression of tight-junction
proteins.88,89 Extra-virgin olive oil phenolics can also
provide barrier protection and prevent pathogen invasion via effects on mucosal immunity. In a randomized
control trial including 10 patients with hypercholesterolemia (total cholesterol, > 200 mg/dL), ingestion of a
500 mg/kg polyphenol-rich EVOO increased intestinal
IgA, which has an important role in the homeostasis of
the microbiota community and provides protection
against pathogenic bacteria.35 In addition, in anotherstudy of the effects of EVOO and EVOO phenolics for
30 days in mice with dextran sodium sulphate–induced
colitis, EVOO and EVOO polyphenols significantly reduced inflammation by lowering MCP-1, TNF-a,cyclooxygenase-2, and nitric oxide synthase expression
levels.90 Figure 3 summarizes the impact of EVOO on
microbiota observed in studies and the potential effects
on the mucosal immune system.
IMPACT ON GUT-BRAIN AXIS AND MODULATION OF
METABOLIC HEALTH
A number of EVOO’s favorable effects on cardiometabolic and cognitive health as well as mucosal immunity
can be linked to the gut microbiota. Presence of the genus Bacteroides, which has been found to be elevatedwith EVOO consumption,27 correlates negatively withplasma triglyceride levels in mice and humans.27,91 In
addition, presence of members of the Lachnospiraceae,
known to increase with EVOO consumption,26,27 positively correlated with plasma HDL cholesterol inhumans.91 Lactobacillus, also elevated with EVOO consumption25,29 when administered in probiotic form,
promoted a significant reduction in plasma total cholesterol levels in mice as well as human patients with hypercholesterolemia (LDL-C, 3.35–4.91mmol/L and total
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significantly reduce microbial growth.78 Moreover, inthe same study, individual phenolic compounds in the
EVOO, including tyrosol, vanillin, vanillic, and cinnamic acids, also exhibited slight antimicrobial activity.
Authors Karaosmanoglu et al78 pointed out a synergistic
interaction between the phenolic compounds and, inturn, an enhanced antimicrobial effect when they werecombined. Importantly, it should be highlighted that inhumans, phenolic compounds in EVOO are not consumed in isolation; they are eaten as part of a food matrix and can synergistically function together, as well aswith other components in EVOO, such as fatty acids,
which can enhance the availability of a variety ofpolyphenols.79
In addition to phenolic compounds and their wellestablished interaction and influence on the microbiota,
other minor components in EVOO such as sterols andtocopherols may influence gut microbiota composition,although studies are limited. In a study of dietary intakeof 28 nutrients, assessed by food frequency questionnaires completed by 60 pregnant women in the
Norwegian Microbiota Study cohort, dietary intake ofthe tocopherol, vitamin E, was associated with a decrease in pathogenic Proteobacteria.80 Moreover, highdose phytosterol esters intragastrically administered torats daily for 12 weeks restored HFD-induced dysbiosis,
modulating levels of Firmicutes, Proteobacteria,
Actinobacteria, and Verrucomicrobia similar to levelsof the control group.81 In addition, the study also
showed that administration of high-dose phytosterolesters significantly increased mRNA expression level ofClaudin-1 and Occludin in the colon, in comparison to
the HFD group, likely enhancing intestinal barrier
integrity.81
Regarding the possible impact on gut microbiotia
of oleic acid in EVOO, results of several rodent studies
point to a positive effect. A study comparing the effects
of diets enriched with peanut oil high in oleic acid,
EVOO, and chow supplemented with drinking watercontaining high levels of fructose drinking water in
Swiss Webster rats, researchers found that both the peanut oil and EVOO significantly increased the relative
abundance of Bifidobacterium and reduced Blautia levels and also had favorable effects on body weight, cholesterol levels, and insulin sensitivity.24 Moreover, when
researchers exposed ICR outbred mice to HFD or a
HFD supplemented with either an oleic acid–derived
compound (1500 mg/kg/day) or a combination of n-3
fatty acids (EPA and DHA, 3000 mg/kg/day), theyfound that mice supplemented with the oleic acid compound had greater gut microbial diversity as well as
lower body weight compared with HFD-fed mice.82
Moreover, a similar study showed that diets high inoleic acid–rich olive oil fed to C57BL6/J mice werecholesterol, 5.16–7.64mmol/L).92–94 Demonstrated abilities of Lactobacillus to lower plasma cholesterol levels
may be due partly to the enhanced bile salt hydrolase
activity this genus exhibits, as well as the ability to convert cholesterol to coprostanol, both leading to an impairment of cholesterol absorption in the intestine.95,96
Short-chain fatty acids, produced by a number ofbacteria whose populations are often elevated with
EVOO consumption, can exert therapeutic effects on
blood glucose homeostasis. Specifically, the SCFA acetate activates GPR43, promoting GLP-1 release from colonic L cells.97 In addition, activation of GPR41 bypropionate or butyrate can induce both GLP-1 and peptide YY secretion from L cells in the small intestine.98
In regards to gut microbiota–mediated effects on
cognitive health via EVOO, certain commensals, including Lactobacilli and Bifidobacterium are often
greatly reduced in patients with AD.99,100 Both of thesebacterial types, populations of which are elevated with
EVOO consumption, can produce c-aminobutyric acid
(GABA), the main inhibitory neurotransmitter, likely
influencing GABAergic firing in the brain via the enteric and vagal nervous systems.99 Specifically, oral administration of a strain of Lactobacillus to micemodulated GABAAa2, GABAAa1, and GABAB1b receptor
10mRNA expression in the brain of mice, reducing anxiety and depressive-like symptoms and behaviors, withthe same effects not observed in vagotomized mice.101
However, the exact mechanisms of how “gut GABA”
may modulate the central nervous system and elicit specific regulatory effects in the brain remain largely unknown.102 In addition, EVOO may exert protective
effects on cognitive health via its antibacterial activity
toward certain pathogenic species of bacteria that havebeen considered a risk factor for AD in the pathogens
interaction hypothesis.103 This hypothesis suggests that
Ab originally functioned as an antimicrobial peptide,
controlling the population of pathogenic microbes.104
However, chronic infection by microbial pathogens
may act as a trigger for development of sporadic AD bycausing increased and prolonged levels of inflammation, microglial senescence, and microbial biofilm formation, all of which may potentially aggregate with Ab,
leading to plaque formation.104,105
Short-chain fatty acids may also assist in reducing
inflammation in the intestine by upregulating tightjunction protein expression in the intestine, reinforcing
barrier integrity, and preventing infiltration of bacterial
products like lipopolysaccharide and subsequent inflammatory signaling. In a study of the impact of
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Figure 3 Impact of extra-virgin olive oil (EVOO) on gut microbiota and mucosal immunity. Extra-virgin olive oil modulates the gut
microbiota by acting as both a prebiotic (encouraging the growth of beneficial bacteria) and antibacterial (reducing the growth of pathogenic
bacteria). Extra-virgin olive oil promotes the growth of certain bacteria that are capable of producing microbial metabolites such as shortchain fatty acids (SCFAs). Short-chain fatty acids and other gut microbiota-generated metabolites can positively influence the mucosal immune system by increasing T-regulatory (Treg) cells as well as the production of anti-inflammatory cytokines such as IL-10 and TGF-b, whichassist in reducing local inflammation and promoting immune tolerance to commensals and other harmless dietary antigens. Extra-virgin olive
oil may also promote an increase in intestinal IgA, providing further protection against pathogenic bacteria and promoting homeostasis of
the gut microbiota.

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excretion via the kidneys vary greatly depending on thetype of phenolic compound.79
CONCLUSION
Consumption of EVOO clearly demonstrates widespread beneficial effects on a variety of aspects of healthand disease and also shows great therapeutic potential
in positively modifying the gut microbiota as well as theactivity and functioning of the mucosal immune system.
Investigation of the mechanisms whereby EVOOinduced modulations in gut microbiota and microbially
produced products influence cardiovascular, metabolic,mucosal, and cognitive health outcomes still remains a
relatively unexplored area of research with excitingprospects.
Acknowledgments
The authors thank Yuko Murayama, Chie Horiguchi,
Ikumi Nomura, and Tomoko Ikematsu for technical assistance. They also thank Mamiko Hirata and Chikako
Noguchi for secretarial assistance.
Author contributions. J.F.M. wrote the manuscript under the assistance and supervision of S.O. T.U., S.I.,
M.S., and H.M. read and provided comments about themanuscript. All authors approved the final manuscript.
Funding. This work was supported in part by Grantsin-Aid from Japan Society for the Promotion of Science(KAKENHI grant 20K08912); Council for Science,
Technology and Innovation, Cross-ministerial Strategic
Innovation Promotion Program, “Technologies for
Creating Next-generation Agriculture, Forestry and
Fisheries,” Uehara Memorial Foundation, Japan Agency
for Medical Research and Development, and Rotary
Yoneyama Memorial Foundation Fellowships.
Declaration of interest. The authors have no relevantinterests to declare.

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