Unveiling the neuroprotective impact of virgin olive oil ingestion via the microbiota–gut–brain axis

Abstract

The gut–brain axis, a complex system of two-way communication between both organs, plays a key role in overall health. This comprehensive review explores the possible neuromodulatory effects upon consumption of virgin olive oil (VOO) via changes in the gut microbiota. The components found in VOO, such as polyphenols and monounsaturated fatty acids, and their function in influencing the composition of the gut microbiota, focusing on those known to possess neuroactive characteristics, based on a thorough analysis of the literature were investigated. Studies suggest that these compounds, such as hydroxytyrosol and ferulic acid, may protect against neuronal death and inhibit amyloid-β plaques (Aβ) formation. Furthermore, preclinical and clinical research indicates that VOO may promote the growth of beneficial bacteria, such as Lactobacillus and Bifidobacterium, and increase the production of short-chain fatty acids (SCFAs). These changes could be related to improved cognitive function, mood regulation, and neuroprotection. However, limitations of these studies (short duration of studies, the variability in VOO composition and the lack of standardized methodologies) need to be overcome. Furthermore, the limited number of human trials and incomplete understanding of the gut–brain axis make it difficult to establish causality and clinical application of the findings. For this reason, future research should focus on long-term clinical trials with larger cohorts, standardised characterisation of VOO and on exploring the synergistic effects with other dietary components. Furthermore, mechanistic studies should aim to uncover the molecular pathways involved in the gut–brain axis to develop specific dietary interventions for neurological and neurodegenerative disorders.

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1. Introduction

1.1. Virgin olive oil: definition and phytochemical composition

Virgin olive oil (VOO) is the juice extracted from the mesocarp of the drupe from the fruit of the olive tree (Olea europaea L.), obtained by mechanical procedures under low thermal conditions. VOO consists of at least 65% of fatty acids that vary with the different maturation stages of the olives, the tree variety, and the growing and storage conditions. Oleic acid (18:1n-9) is the major dietary monounsaturated fatty acid and represents 55 to 83% of the total fatty acids in VOO. The concentrations of saturated fatty acids (palmitic and stearic acids) and polyunsaturated fatty acids (α-linolenic and linoleic acids) in VOO range from 8 to 25% and from 3 to 21% of the total fatty acids, respectively.¹ The composition of VOO also includes minor compounds (>200 constituents) that could range from 1 to 3% of the oil.² These constituents are responsible for specific characteristics of VOO, such as its oxidative stability and its special flavour (aroma and taste) as well as its colour. Among the several minor compounds of VOO (Fig. 1–3), the most abundant fraction is hydrocarbons (squalene and, in smaller amounts, the carotenoids β-carotene and lutein). Other minor compounds of VOO include phytosterols, such as β-sitosterol, Δ5-avenasterol, and campesterol; triterpenic compounds in the form of dialcohols (erythrodiol and uvaol) or acids (oleanolic and maslinic acids); and the phenolic compounds. The main classes of phenolic compounds in VOO are secoiridoids, as ester derivatives of elenolic acid in either its aglyconic form or glycosylated with hydroxytyrosol (oleuropein) or tyrosol (ligustroside); simple phenols (p-coumaric, o-coumaric, caffeic, ferulic, sinapic, gallic, gentisic, syringic, vanillic, protocathecuic, and p-hydroxybenzoic acids); hydroxyisochromans formed by the reaction between hydroxytyrosol and benzaldehyde or vanillin; flavonoids (luteolin, apigenin, and quercetin); and pinoresinol-derived lignans. Finally, lipophilic phenols include tocopherols and tocotrienols, with α-tocopherol as the predominant constituent in VOO.

Fig. 1 Chemical structures of squalene, carotenoids, sterols, triterpenic dialcohols, and triterpenic acids in VOO.¹

Fig. 2 Chemical structures of secoiridoids, phenyl-alcohols, and phenyl-acids in VOO.¹

Fig. 3 Chemical structures of hydroxyisochromans, flavonoids, lignans, tocopherols, and tocotrienols in VOO.¹

VOO plays a pivotal role as the main source of fat in the Mediterranean diet, declared by the United Nations Educational, Scientific and Cultural Organization (UNESCO), as an Intangible Cultural Heritage since 2013. This diet has traditionally been linked to longevity in Mediterranean populations and is associated with a significant improvement in the health status, as measured by reduced mortality from several chronic diseases.³ Spain is by far the largest producer of VOO in the world, accounting for approximately 45% of total global production (3418 thousand tonnes) in 2022 (https://agriculture.ec.europa.eu/data-and-analysis/markets/price-data/price-monitoring-sector/olive-oil_en).⁴

The dietary intake of VOO in Mediterranean countries has been estimated to be 25–50 mL, corresponding to around 9 mg of phenols.⁵ During the digestive process, important losses and transformations of these compounds with the rise in compounds with different structures and chemical properties may occur leading to differences in the amount and forms available in the intestinal tract for potential uptake. Absorption of lipid molecules, such as oleic acid, takes place along the epithelial cells of the small intestine, mainly in the proximal jejunum. It is estimated that only from 10 to 15% of phenolic compounds are absorbed in the small intestine. Therefore, most phenols reach the large intestine and, consequently, will suffer high exposure to colonic metabolism,⁶ producing a wide number of metabolite compounds. Therefore, most of the observed bioactivity of phenols may result from the gut microbiota metabolism rather than the original dietary phenols.

Virgin olive oils are olive oils that have been obtained by purely mechanical processes and that do not present organoleptic defects, such as extra virgin olive oil (EVOO) or, if they do, they are of low intensity, such as VOO.⁷ The distinctions between EVOO and VOO are primarily organoleptic in nature, due to the differences in the quality of the olive and the processing in terms of harvesting, transport, storage and cleaning of the equipment. Regarding the content of minority components, among which phenols stand out, the differences between one virgin oil and another do not depend on whether it is extra or not, but on the variety of the olive, degree of maturity, agronomic conditions and water and solar stress. In other words, whether a virgin oil is extra or not only indicates an organoleptic and not a functional difference, since its fat composition and minority components depend on other factors already mentioned.

1.2. Neuroinflammation and neurodegenerative diseases

Neurodegenerative diseases are a type of disease in which the cells of the central nervous system (CNS) stop functioning or die. In this line, these disorders are a class of ailments that are typically brought on by a progressive degeneration of the neural structures, accelerated by aging. These disorders usually worsen over time and have no cure and are overall caused by genetic or environmental factors. Some of the most known diseases in this group are Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) affecting several million people around the world.⁸ Neuroinflammation, referred to the inflammation of the nervous system, is generally described as a response involving different cells within the CNS, including neurons and glial cells, and is currently understood to be a hallmark of almost all neurological illnesses. These disorders are a group of chronic degenerative diseases marked by the progressive and specific loss of neurons in the central or peripheral nervous system. These disorders can result in dementia, which is a major public health concern with rising healthcare costs and is a leading cause of disability globally.⁹ On the other hand, the neuroimmune reaction plays a relevant role in the proper maintenance of the CNS's physiological activities and function in the course of aging as well as the prevention of neurodegenerative diseases.

The currently used strategies to treat these pathologies are based on pharmacotherapy but have the drawback of also implying the development of undesirable side effects in humans. In addition to these adverse effects, usually the target of these approaches relies on reducing the clinical symptoms, which translates into relief for patients, but not providing a solution for the progression of the disease. It must be noted that a long-term consumption of drugs poses a huge risk for patients, and for this reason, ideally neurodegenerative diseases morbidity should be tackled at the preventative level for the risk factors, which are promoting the development of these diseases.¹⁰

New disease-modulating strategies that could be able to prevent neurodegeneration and have no or few adverse effects must be researched. In this line, scientists are starting to contemplate nutrition as a form of protection, and researchers are looking at the neuroprotective effects of certain diet patterns and specific nutrients.¹¹ Generally, a Mediterranean diet is recommended for brain health,¹² whereas diets low in dietary fiber content are associated with cognitive impairments.¹³ However, scarce diet interventions investigations designed to demonstrate that have been completed. In fact, the interest of patients in using dietary strategies to improve their wellness has been reported, with approximately half reporting modifying their diets.¹⁴ However, clinicians are reluctant to provide dietary information to their patients due, in part, to this lack of evidence for the effect of diet on neurodegenerative disease. It has been demonstrated that people diagnosed with neurodegenerative disease change their diet not only because of uncertainty and fear of disease progression, but also that support from health care professionals is of high relevance, to increase engagement, practicality, and credibility. In this line, consumption of VOO influences microbiota composition. The intestinal microbiota can impact the health status of humans, and it is plausible that the intestinal microbiota (through the microbiota–gut–brain axis, MGBA) influences neurodegenerative disease-associated symptoms, progression, and treatment success.

2. Microbiota–gut–brain axis

One of the most exciting and rapidly evolving fields of immunonutrition is the MGBA, which explores the mutual influences and communications between the gut, its commensal microbes, and brain function. While much remains to be understood about how microbiota influences the brain and systemic physiology, significant progress in the last decade has provided some insight into the functional role that microbiota plays in brain health and disease.¹⁵ The composition of the gut microbiome is highly dynamic and gradually increases in stability with the development of the adaptive immune system, transition to a solid food diet and standardization of lifestyle factors in early adulthood. While the composition of the gut microbiome is relatively stable during early- to mid-adulthood if unperturbed, as an individual grows older, the gut microbiota enters a period of increased volatility and distinct shifts occur in the diversity of genera and functional capacity.¹⁶ The MGBA has been implicated in the pathogenesis of a wide range of neurological and psychiatric disorders. Dysbiosis of the gut microbiota, which refers to an imbalance in the composition or function of the microbiota, has been associated with various neurodegenerative disorders, including AD, PD, and MS.¹⁷

Several bidirectional routes of communication have been identified. Principally, these include interactions with the nervous system, in particular the vagus nerve, modulation of the host immune system, and the metabolism and production of small molecules including short-chain fatty acids (SCFAs – acetate, propionate, and butyrate) and neuroactive compounds, as discussed below. These molecules may act locally on enteric neurons or on vagal and sympathetic afferent nerve terminals, or indirectly by reaching the brain via systemic circulation. Most of these signalling molecules can be classified into food-derived metabolites, metabolites of endogenously produced molecules and signals formed by microbial components of the gut.¹⁸

SCFAs act on enteroendocrine L cells secreting glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). These anorexigenic peptides act on hypothalamic centers to control feeding behavior and energy balance.¹⁹ Additionally, bacteria-derived secondary bile acids and bacterial lipopolysaccharide (LPS) can enhance GLP-1 secretion in L cells. SCFAs also have immune functions, for example, by promoting host intestinal barrier integrity (e.g., stimulation of mucus production and tight junction assembly). Other actions of SCFAs include regulating the suppression of cytokine production from myeloid cells and differentiating T regulatory and T helper cell differentiation.²⁰

Gut microbiota synthesizes key neuroactive molecules such as catecholamines (noradrenaline, norepinephrine, dopamine), γ-aminobutyric acid (GABA), serotonin (5-HT) and tryptophan metabolites and precursors. Microbiota can convert neurotransmitter precursors into active forms, such as the amino acid glutamate to GABA by Escherichia spp., while Lactobacillus spp. can stimulate the conversion of dietary tryptophan into 5-HT by enterochromaffin cells.²⁰Fig. 4 shows a visual representation of how VOO components affect the intestinal microbiota and act at the neuronal level through the gut–brain axis.

Fig. 4 Impact of virgin olive oil (VOO) on the gut–brain axis. VOO modulates the gut microbiota by acting as a prebiotic (encouraging the growth of beneficial bacteria and reducing the growth of pro-inflammatory bacteria). The picture shows the major components of the VOO. These components promote the growth of certain bacteria that are capable of producing microbial metabolites such as short-chain fatty acids (SCFAs). SCFAs and other gut microbiota-generated neuroactive metabolites (e.g. polyphenol metabolites) can act locally on enteric neurons or vagal and sympathetic afferent nerve terminals, or indirectly reach the brain through the systemic circulation. SCFAs can positively influence the mucosal immune system by increasing T cells (T-regulatory and T-helper) as well as regulating the suppression of pro-inflammatory cytokines, which help reduce local inflammation. In addition, they can control feeding behavior while acting on enteroendocrine L-cells, by secreting glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), which will reach the brain via the hypothalamic-pituitary-adrenal (HPA) axis.

It has been reported that different dietary patterns have an impact on gut microbiota. For example, a healthy diet with varied sources of phytochemicals²¹ or dietary fiber²² can promote increased microbial diversity and production of SCFAs and other bioactive compounds with beneficial physiological effects from metabolic health to brain processes.^23,24 In contrast, a western-like pattern comprising processed foods lacking the recommended quantity of dietary fiber and with a higher content of saturated fats, salt, and sugars can result in suboptimal gut microbiota composition and a low-grade systemic inflammation associated, for example, with mental illness, gastrointestinal pathology, metabolic disorders and obesity.²⁵ Studies aiming to assess diet–microbiome–neurological effects face several levels of complexity, from intra-individual variability in the microbiome to limitations inherent in diet studies (e.g., difficulty in assessing dietary intake and adherence to diet). One major challenge is the lack of standardized protocols for dietary assessment or interventions in microbiome studies.²⁶

In the next section, studies evaluating how virgin olive oil and its components might have a neuromodulatory effect on humans upon consumption are described, from in vitro studies to human interventions.

3. Virgin olive oil as the neuromodulatory mediator

3.1. In vitro studies

In vitro studies are usually carried out to screen the potential of several compounds as potential bioactive agents or to test their toxicity towards different cell lines, among other uses. In the context of the gut–brain axis, in vitro studies are essential for gaining mechanistic insights into the complex interactions that might occur. Their shortcomings, however, stem from their incapacity to accurately mimic the intricate and dynamic aspects of the in vivo gut environment, which makes supplementary in vivo research necessary for a thorough comprehension of the complex interactions between the host and microbiota. As the focus of this review is in vivo studies, only some relevant in vitro recent examples will be described.

In relation to phenolic compounds, it has been reported that hydroxytyrosol (HT), one of the most studied polyphenols in VOO, is a key component of olive-derived products that might be involved in preventing neuronal cell death.²⁷ On top of that, recent studies also evaluated the impact of its metabolites in relation to neuroinflammation. In this line, Gallardo-Fernández et al. (2023)²⁸ recently reported that the metabolite 3,4-dihydroxyphenylacetaldehyde prevented aggregation and α-synuclein-induced neurotoxicity in vitro, and although no studies were done in relation to gut modulation, considering the bioavailability of HT, which is highly affected by phase I and II metabolism in the gut and liver, it could be expected that these metabolites are correlated with the modulation at the brain level which might occur.²⁹ The same occurs with a metabolite of cinnamic acids, 4-hydroxy-3-methoxycinnamic acid (commonly known as ferulic acid (FA)). Mugundhan et al. (2024) indicated that FA could act as an AChE inhibitor in vitro, contributing to blocking the activity of this enzyme and decreasing the formation of amyloid-β plaques (Aβ). Likewise, the compound showed remarkable antioxidant activity, evidenced by its ability to inhibit the enzyme xanthine oxidase.³⁰

In relation to effects on microbiota, it was also reported that phenolic leaf extracts, which were in vitro faecal fermented, led to a reduction of oleuropein content, while also leading to an increase in HT, which was also observed in the control sample, which was VOO. The metagenomic sequencing analyses showed an increase of Coriobacteriaceae following the extract fermentation, the most affected by fermentation, a family of bacteria with a relevant role in the conversion of bile salts and steroids as well as the activation of dietary polyphenols.³¹ These authors did not correlate these findings with outcomes related to brain development, but Coretti et al. (2018)³² reported a decrease in this bacterium in a group of patients with autism spectrum disorder, and other reports have highlighted the relationship of these bacteria with improved cognitive performance;³³ thus, it might be of relevance to investigate the relationship between the changes in a bidirectional way.

HT helps to decrease the persistent activation of microglia. Research indicates that HT can lessen the activation of microglia brought on by lipopolysaccharide (LPS) and α-synuclein. It can also lessen the activation of mitogen-activated protein kinases (MAPKs) and the production of reactive oxygen species (ROS) via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.³⁴

Recently, Salvesi et al. (2024) studied the prebiotic properties of extra VOO, by monitoring the selective stimulation of gut bacterial species and SCFA production, using an in vitro fermentation system. According to the authors, all the samples analyzed were capable of stimulating Lactobacillus spp. and the bifidobacteria population. In addition, SCFAs (mostly acetic and propionic acids) increased after 24 h in all EVOO fermentations than in the control.³⁵

Overall, in vitro studies have shown the potential of VOO in relation to modulation of parameters that are related to neuromodulation and neuroinflammation, but the relevance of these studies is scarce and does not prove whether these can actually be beneficial for human health.

3.2. Animal studies

Animal studies are generally and should be used to demonstrate the mechanisms by which specific food components might have a biological effect in vivo, but they cannot be used as evidence to state health benefits in humans. The relevance of animal studies employing mice, rats, or dogs is useful but not extrapolable. In addition, there are also studies aiming to demonstrate whether components not currently used as feed could also be added to diets without implying any health risk, and sometimes, to prove whether the supplementation might have benefits in terms of performance, oxidative status, etc. Different effects of different types of fatty acids on the microbiota have been noted, but the specific processes behind these effects are yet to be understood. It has been demonstrated that eating lipids affects the proportion of the phyla Firmicutes/Bacteroidetes among the many bacterial groups present, although some polyphenols, such as HT, had no effect on this as an indicator of dysbiosis.³⁶ In relation to the use of VOO, due to the presence of monounsaturated fats and phenolic chemicals, which have significant antioxidant, anti-inflammatory, and immune-modulating properties, its ingestion has positive health effects.³⁷ In the scope of this review, the effect of VOO on gut microbiota and/or effects on cognitive function will be addressed, although not always both results were reported in the published literature. Fig. 4 shows a visual representation of how VOO affects gut microbiota.

In the evaluation of specific compounds, or the underlying mechanisms by which the consumption of VOO exerts bioactive properties, De la Cruz et al. (2015)³⁸ evaluated the relevance of the catechol group in the antioxidant and neuroprotective effects in rat brain tissue. For this purpose, three compounds with different numbers of –OH groups were evaluated, and the authors reported that lipid peroxidation was inhibited in direct proportion to the number of –OH groups, and also that the compounds could inhibit peroxynitrite formation (3-nitrotyrosine) and inflammatory mediators (prostaglandin E2 and interleukin 1β). However, no effects in relation to the microbiota were reported. In the same line in order to evaluate the contribution of HT in understanding AD development, APP/PS1mice, an animal model of AD, were administered for 6 months with 5 mg per kg per day of the test item. It was shown that the treatment enhanced electroencephalography activity and improved the cognitive behavior of the animals. It was also reported that a decrease of the levels of brain inflammatory markers, but no effect on brain amyloid-β (Aβ) accumulation occurred.³⁹ Similarly, the beneficial effects of oleuropein aglycone in reducing Aβ₄₂ deposits in the brain of young and middle-aged TgCRND8 mice have also been reported.⁴⁰ In addition to these specific studies assessing phenols as components, for instance, the neuroprotective effect of tyrosol was investigated in vivo in rat models of cerebral ischemia as well as in vitro on cell lines and brain slices. Specifically, in a rat model of temporary middle cerebral artery occlusion, this compound demonstrated a dose-dependent neuroprotective effect, as it decreased the treated group's infarct area relative to the untreated control group.⁴¹ However, these studies did not provide any information about the gut microbiota of the animals, and consequently, hinder the possibility to link the effects at the brain level with potential changes in the gut microbiota.

In relation to cognitive performance, it was reported that elderly mice's cognitive and motor deficits significantly improved after a long-term diet high in polyphenol-rich VOO,⁴² but no gut microbiota analyses were carried out. In the same line, the effects of VOO on learning and memory in SAMP8 mice, an age-related learning/memory impairment model associated with increased Aβ protein and brain oxidative damage, were evaluated by Farr et al. (2012).⁴³ The authors reported that the animals who ingested VOO had improved acquisition in the T-maze and spent more time with the novel object in one-trial novel object recognition versus mice ingesting phenol-free fats. In addition to that, the VOO group had improved T-maze retention, and the analyses showed an increase of brain glutathione levels. Although no gut microbiota analyses were carried out, this report also suggests beneficial effects on neuromodulation by VOO, in relation to reversing oxidative damage in the brain.

Al Rihani et al. (2019)⁴⁴ aimed to evaluate why VOO enriched in oleocanthal has a positive impact at early AD stages before the onset of pathology in TgSwDI mice, an AD mouse model, in a treatment of three months with the oil 0.714 g per kg per day (containing 680 mg kg⁻¹ oleocanthal). According to the authors, although no microbiota analyses were performed, the blood–brain barrier function was restored and neuroinflammation was reduced through inhibition of NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes. Further studies aiming to evaluate how oleocanthal and the other minor components impact the gut microbiota are needed.⁴⁵ In the same line, Qosa et al. (2015)⁴⁶ assessed whether the ingestion for six months of a VOO-enriched diet could have a biologically relevant effect on amyloid- and tau-related pathological alterations in TgSwDI mice. According to the authors, mice fed a VOO-enriched diet for six months, starting at an age before the onset of Aβ deposits, showed a considerable improvement in their cognitive function along with a significant reduction in the overall amount of Aβ and tau in their brains. The decrease in brain Aβ was accounted for by improved Aβ clearance pathways and decreased brain Aβ generation through altered processing of Aβ precursor protein. Additionally, it was noted that there was a notable decrease in Aβ levels and an enhanced blood–brain barrier clearance; nevertheless, it had no effect on tau levels or enhanced the cognitive abilities of TgSwDI mice. Furthermore, Lauretti et al. (2017)⁴⁷ reported that treating a 3x-transgenic mouse model of AD with VOO (ingestion of the chow diet with supplementation of the oil) for 6 months resulted in substantial reductions in levels and deposition of insoluble Aβ peptide, which was linked to autophagy activation and enhanced memory function. The same authors, in addition, reported the improvement in synaptic activity, short-term plasticity, memory, and neuropathology in a tauopathy model. The key presynaptic protein complexin 1 was upregulated as well as a notable decrease in tau oligomers and phosphorylated tau at particular epitopes was found.⁴⁸ As reported by the authors, the content of minor components was high (253 mg polyphenols per kg, 381 mg α-tocopherol per kg, and 23 mg γ-tocopherol per kg), which could be increasing the beneficial effects of this sample of VOO employed in the studies. In these studies, no microbiota analyses were performed but are indicative of how the VOO-derived components could have a beneficial effect on neuromodulation.

Polyphenol metabolites resulting from flavonoid catabolism by the intestinal microbiota or from enterohepatic metabolic conversions of phases I and II have been studied in rodent models of neurodegenerative diseases. Kho et al. (2018) explored the neuroprotective effects of 3,4-dihydroxybenzoic acid (also known as protocatechuic acid (PCA)), a polyphenol metabolite, on neuronal death induced by global cerebral ischemia. Oral administration of PCA (30 mg per kg per day) for one week in rats subjected to ischemia showed significant results. A decrease in the number of degenerative neurons in the hippocampus was observed, along with a reduction in oxidative stress, microglial and astrocyte activation, as well as decreased blood–brain barrier (BBB) disruption. Furthermore, PCA restored the levels of glutathione (GSH), a key antioxidant, in hippocampal neurons affected by ischemia.⁴⁹ 30 mg kg⁻¹ of 4-hydroxy-3-methoxybenzoic acid (also called vanillic acid (VA)) by i.p. for 3 weeks demonstrated, like PCA, the decrease of the number of activated microglia and astrocytes in C57BL/6N mice with intracerebroventricular injection of Aβ_1–42. It also improved glutathione (GSH) levels and abolished the generation of reactive oxygen species (ROS).⁵⁰ Oral administration (30 mg per kg per day) of 3,4,5-trihydroxybenzoic acid (known as gallic acid (GA)) for 30 days was shown to be effective in reducing APP deposition in the hippocampus of APP/PS1 mice.⁵¹ In another study, the authors reduced the administration concentration of GA to 20 mg per kg per day and increased the administration time to 4 months, obtaining similar results: tau phosphorylation⁵² and β-amyloid concentration were reduced, in addition to increasing synaptic protein levels. Ding et al. (2024) found that GA promoted neurogenesis through the GSK-3β-Nrf2 signaling pathway in the dentate gyrus area of the hippocampus, resulting in improved spatial memory in APP/PS1 mice.⁵³ However, in these studies on polyphenol metabolites, no effects on the microbiota were reported.

One of the primary stringent anaerobic groups of the colon, Clostridium XIVa has been found to proliferate in relation to VOO intake in male spontaneously hypertensive rats. It is in charge of producing butyrate, one of the primary metabolites produced by the gut microbiota and SCFAs that helps lower total cholesterol and has anti-inflammatory properties.⁵⁴ It has also been demonstrated that VOO intake is linked to a decrease in Lactobacillus, particularly L. animalis, L. taiwanensis, and Lactococcus, which are bacteria linked to weight loss in Swiss Webster mice, although no correlation was again done with neuromodulation.⁵⁵ These authors also concluded that VOO consumption was associated with an increase of Desulfovibrio, Sutterellaceae, Marispirillum and Mucilaginibacter dageonensis. Millman et al. (2020)⁵⁶ carried out a comparison of VOO (containing around 6000 mg kg⁻¹ of phenols) and flaxseed oils with respect to the composition of gut microbiota in mice, aiming to evaluate the benefits at metabolic and immunological levels. For that purpose, C57BL/6J mice followed different diets (low fat, lard, VOO, or flaxseed oil for 10 weeks, having free access to the food). According to the authors, the mice ingesting these diets showed higher diversity in microbiota, highlighting the reduced relative amount of Firmicutes, compared to the mice ingesting lard. In addition to that, the gene expression of FoxP3 and IL-10 was also higher in those groups in the intestines, suggesting health benefits in terms of gut microbiota and immunity, although no parameters in relation to brain were examined. Similarly, Olid et al. (2023)⁵⁷ recently showed that intestinal microbial alterations were found in mice after six weeks of ingesting VOO (containing 527 mg of polyphenols per kg) compared to refined olive oil (ROO), which lacks phenols, and Swiss Webster mice were fed a standard or a high-fat diet enriched with VOO, ROO, or butter (20%) that after twelve weeks, physiological parameters such as a decrease of Desulfovibrionaceae, Spiroplasmataceae, and Helicobacteraceae, together with an increase of Erysipelotrichaceae and Sutterellaceae in the EVOO group.⁵⁸

In a recent report, aiming to understand the neuroprotective effect of different oils, Chen et al. (2022) compared the effect of oleic acid-rich camellia oil and olive oil against AlCl₃-induced mild cognitive impairment in rats. For this purpose, a treatment with the different test items was done by intragastric gavage for 49 consecutive days, with a dose of 3.0 mL kg⁻¹ (no phenols evaluated but other minor components) and several analyses were carried out. Camellia oil treatment gave better results than olive oil treatment in improving the learning and memory skills of AlCl₃-induced rats, as demonstrated by the results of Morris water maze tests. Furthermore, the results demonstrated a significant reduction in oxidative stress and inflammatory cytokines in the AlCl₃-induced rat groups treated with camellia and olive oils. In the olive oil group, the lowest community richness was observed, with an increase in the abundance of Alistipes, Odoribacter, and Parabacteroides and a decrease in Prevotellaceae,⁵⁹ which are microorganisms which have been correlated with improvements in the gut–brain axis in other studies as well.⁶⁰ These results suggest that the effect that minor components of VOO have on inflammation response in the brain is because of the effects on microbiota and because of direct effects of the phenolic compounds in the tissue.

Vitamin E (VE) is a fat-soluble nutrient found mainly in EVOO, with α-tocopherol (150 to 250 mg kg⁻¹ of EVOO)⁷ being the isomer with the highest antioxidant capacity. Animal and human studies on the impact of VE consumption on the gut microbiota have shown that increased intake alters immune and inflammatory responses, where gut microbiota may play an important role. Choi et al. (2019) suggested that low VE intake increases the spleen size and body weight while altering the gut microbiota composition, in male C57BL/6 mice supplemented with DL-α-tocopherol at 0.06 mg per 20 g and 0.18 mg per 20 g body weight per day, respectively, for 34 days.⁶¹In addition, a study in male BALB/c mice, in which colitis was induced by dextran sulphate sodium (DSS), showed that α-tocopherol (αT) and γ-tocopherol-rich tocopherols (γTmT) (both included in the AIN93G diet by 0.05%) alleviated colitis symptoms and reduced IL-6 levels. They also mitigated the loss of the tight junction protein occludin caused by colitis and decreased plasma levels of LPS-binding protein, suggesting increased intestinal barrier integrity. Analysis of faecal DNA by 16S rRNA gene sequencing revealed that tocopherols restored the abundance of Roseburia (butyrate-producing bacteria) and improved intestinal microbial uniformity. Furthermore, in an in vitro study with Caco-2 cells, tocopherols attenuated cytokine-induced impairment of transepithelial electrical resistance.⁶²

Tung et al. (2019)⁶³ assessed the impact of fish oil and VOO in improving dysbiosis and depressive-like symptoms, in a 14-weeks study with male rats, in which the test item represented 2% of the diet. The rats were induced to suffer from chronic mild stress and using the sucrose preference test and forced swimming test, as indicative of depressive-like behavior, the VOO group exhibited significantly reduced sucrose intake from week 8. In addition, next generation sequencing results showed that the animals ingesting oil showed an increase in the abundance of Akkermansia, but no improvement of depressive-like symptoms was reported. In an independent study, however, it was reported that the administration by gavage for 10 days of pasteurized Akkermansia muciniphila in mouse models had a beneficial effect on anxiety-like behavior and memory defects in the C. rodentium infection model, together with a neuroinhibitory effect on neuronal cells stimulated with allogenic substances, thus indicating that this bacterium could have a beneficial effect.⁶⁴ As per other studies, correlation studies would be needed to validate if VOO consumption could have similar effects.

Conde et al. (2020)⁶⁵ aimed to elucidate the effect of VOO and two of their most relevant components (oleic acid and HT) in an induced rat model of MS which is a disease related to the CNS through experimental autoimmune encephalomyelitis (EAE), for 51 days. VOO was given as 10% of the calorie intake, whereas oleic acid corresponded to 4%. The other group received a dose of 2.5 mg of HT per kg. After the intervention, the microbiota's LPS and LPS-binding protein (LBP) products in the brain, spinal cord, and blood were assessed together with the glutathione redox system. In all cases, there was a reduction of lipid and protein oxidation and the activation of glutathione peroxidase and a decrease in the levels of LPS and LBP, which were shown to be elevated in the EAE and were associated with the oxidative stress caused by the illness. These results are in line with those obtained by Gutiérrez-Miranda et al. (2023),⁶⁶ who evaluated whether oleacein might protect the intestinal barrier dysfunction using MOG35-55-induced EAE in C57BL/6 mice. Reduced inflammation and oxidase stress were reported, together with a decrease in colonic IL-1 and TNF-α levels. However, no significant differences were found at the gut microbiota level, except for an increase of Akkermansiaceae family.

Andújar-Tenorio et al. (2023)⁶⁷ carried out a comparison of the intestinal enterococci population changes following an ingestion of different fat diets. The test items were butter, ROO and VOO, ingested by mice for 12 weeks. These Enterococcus were genetically and phenotypically characterized in search of virulence factors, biogenic amine production and antibiotic resistance. In addition, these strains were evaluated for the susceptibility in vitro to oleuropein and HT, showing no remarkable effects. Nonetheless, in the strains isolated from the feces of the animals, significant differences were found, including less resistance to antibiotics and a more beneficial profile overall, suggesting that these phenols could be exerting a prebiotic role. Regarding specific components, the daily ingestion of 50 mg kg⁻¹ of HT was associated with an increase of the concentration of Lactobacillus, especially L. johnsonii, in high-fat diet-induced obese mice.⁶⁸ In this line, another report showed that L. johnsonii improved the mRNA levels of tight junction proteins in the intestines, protecting animals subjected to have memory disfunction from disruption to the gut barrier and having a positive impact on the anti-inflammatory cytokine levels that had decreased.⁶⁹ Studies correlating ingestion of phenols, changes in microbiota and effects on affected animals are needed to unravel the mechanisms. In fact, Lactobacillus and Bifidobacterium have been reported to regulate gut microbiota which improves physiological function and cognitive ability in aged mice.⁷⁰

A study using APP/PS1 transgenic mice evaluated the bidirectional impact of curcumin on AD. Administration of this polyphenol improved learning, memory, and reduced Aβ plaques in the hippocampus. It also caused significant changes in gut microbiota, including a reduction in the abundance of the Prevotellaceae family and the Bacteroides genus, as well as a decrease in the abundance of the Escherichia/Shigella bacteria, all associated with improvements in AD symptoms. Furthermore, eight metabolites of curcumin, identified via HPLC-Q-TOF/MS after gut microbial biotransformation, exhibited neuroprotective properties. Notably, two metabolites, demethylcurcumin (M1) and bisdemethoxycurcumin, previously identified in humans, enhanced neprilysin activity, an enzyme involved in Aβ-degradation, an effect not observed with parent curcumin.⁷¹

In conclusion, animal studies investigating the modulation of the gut–brain axis following the ingestion of VOO or the minor components provide valuable insights into the potential mechanisms underlying its beneficial effects on overall health and well-being. Through examining various physiological and behavioral outcomes, these studies illuminate the complex interplay between dietary factors, gut microbiota, and brain function, although not always the correlation was done within the same study. Nonetheless, further research, particularly in human subjects, is warranted to fully elucidate the translational implications and optimize the use of VOO as a dietary intervention for modulating the gut–brain axis.

3.3. Human studies

Demonstrating a health-promoting effect caused by the ingestion of specific nutrients is a challenge, as it is difficult to establish a cause–effect relationship, taking into consideration the parameters involved in the physiology of humans (e.g., health condition, sex, genetics, dietary habitudes, etc.). On top of that, the gut–brain axis research field is still in an early stage, thus determining the biological relevance of results in relation to development of diseases or the effect on risk factors is still to be investigated. In relation to the effects of VOO consumption on cognitive performance, a systematic review was recently published,⁷² and the conclusions based on eleven studies were that the consumption of VOO was found to enhance cognitive functioning and to reduce cognitive decline. However, not all these studies were necessarily conducted in order to demonstrate a cause–effect relationship.

Berr et al. (2009)⁷³ aimed to explore the association between VOO use, cognitive deficit and cognitive decline in a large elderly population by following 6947 subjects with a food frequency questionnaire and repeated cognitive tests. VOO intake was categorized as none, moderate and intensive, and it was shown that these groups ingesting more VOO had lower chances of cognitive shortage for verbal fluency and visual memory. In multivariate analysis, the connection between intensive consumption of VOO and cognitive deterioration throughout the 4-year follow-up was significant for visual memory but not for verbal fluency. However, in this study, no microbiota analyses were carried out.

Furthermore, recent research has reported the effect that VOO might have on humans, in relation to the gut microbiota and the brain. In this regard, Thoma et al. (2023)⁷⁴ employed the autism treatment evaluation checklist to assess differences in behavior in individuals diagnosed with autism spectrum disorder (n = 6, aged from 4 to 11 years old) who ingested high-phenolic VOO (doses depending on the individuals and increasing over time) together with a diet aiming to diminish inflammation during six weeks. According to the authors, the results showed benefits in mental health and soothe symptoms of neurodevelopmental disorders in the group ingesting the test item, compared to the control, although no microbiota analyses were carried out. In addition, some of the limitations of this study must be noted (few parameters assessed, a small population, short duration), which should be addressed in future studies.

Martín-Peláez et al. (2017)⁷⁵ reported that VOO phenolic compounds ingested by hypercholesterolemic humans could have an impact on gut microbiota. In a randomized, controlled, double-blind, crossover human trial (n = 12), where subjects were administered 25 mL per day for 3 weeks, preceded by 2-week washout periods, it was shown that an enriched VOO containing a mixture of 500 mg phenolic compounds per kg from VOO and thyme increased the number of bifidobacteria and the levels of the phenolic metabolite protocatechuic acid compared to VOO; thus, the effect could not be associated with specific phenolic compounds or food items. In the same line, Olalla et al. (2019)⁷⁶ evaluated the effect of ingesting 50 g of EVOO for 3 months on the intestinal microbiota of human immunodeficiency virus-infected patients over 50 years of age. According to the authors, there was a significant increase in alpha diversity after the intervention in men and a decrease in proinflammatory genera such as Dethiosulfovibrionaceae. Even when these studies, it must be noted for instance that the alpha diversity of gut microbiota could be a promising predictor for AD, schizophrenia, and MS according to Li et al. (2022),⁷⁷ whereas the decrease of Dethiosulfovibrionaceae was previously reported in animals as well, but further studies investigating whether this could have an impact at the neurological level are needed. Although the results vary widely, the majority of bacteria that increased in abundance in the human investigations were those that produced SCFAs, specifically butyrate. None of the research measuring SCFAs in feces found variations in the SCFAs. It is noteworthy that, despite its known ability to produce SCFAs, no changes in SCFAs were shown to be associated with the rise in Bifidobacterium spp.⁷⁸

Recent studies have reported the effect that VE could have in humans, in relation to the intestinal microbiota. In a recent clinical study, Kim et al. (2018) evaluated 10 patients who received 400 IU of VE twice daily for 8 weeks. Metabolomic and metagenomic analyses performed showed that VE supplementation reduced the abundance of Bacteroidetes and Lactobacillaceae, as well as the Bacteroidetes/Firmicutes ratio.⁷⁹ On the other hand, Pham et al. (2021) administered 12 patients with colon-targeted VE supplementation (α-tocopherol, 100 mg kg⁻¹) for 4 weeks, in a double-blind, randomized, placebo-controlled study, where an increase in SCFA production and relative abundance of beneficial microorganisms was observed, such as Akkermansia, Lactobacillus, Bifidobacterium, and Faecalibacterium.⁸⁰

In the context of PREDIMED-Plus trial, Nishi et al. (2021)⁸¹ assessed the relationship between three different dietary patterns (Mediterranean, dietary approaches to stop hypertension (DASH), and Mediterranean-DASH intervention for neurodegenerative delay diet (MIND) diets) with 2-year changes in cognitive performance in older adults with overweight or obesity and high cardiovascular disease risk. According to the authors, adherence to the Mediterranean diet at the baseline was associated with 2-year changes in the general cognitive screening mini-mental state examination and two executive function-related assessments, whereas adherence to the MIND diet was associated with the backward recall digit span test assessment of working memory. Although these results do not show the potential health benefits of VOO or the phenol components, it must be noted that one of the main characteristics of the Mediterranean diet is the use of VOO; thus, it is still a piece of evidence supporting how this food might be associated with better cognitive performance. Similar results published in the scope of the same PREDIMED studied showed also similar outcomes.^82,83

To sum up, while human studies on the modulation of the gut–brain axis through the ingestion of VOO present intriguing findings, it is important to acknowledge the current limitations in the available evidence. Despite the suggestive associations between VOO consumption and potential improvements in cognitive function, mood regulation, and overall mental well-being, the existing research is characterized by its scarcity and inconclusiveness. The observed alterations in gut microbiota composition and metabolic markers add complexity to our understanding but fall short of providing definitive conclusions. Moving forward, it is crucial for future investigations to address these gaps in knowledge through rigorous study designs and larger sample sizes.

4. Gaps and future perspectives

The research in the following years is expected to elucidate whether VOO has an impact on the gut–brain axis, and until to what extent it would be biologically relevant, and in this case, unravel the underlying mechanisms. Clinical trials are already registered, expecting to demonstrate in healthy adults the effect of the intake of VOO on the microbiota–gut–brain axis (e.g., NCT05898113). However, scarce information to the authors’ knowledge could be found aiming to correlate changes in gut microbiota and improvements in cognitive performance. Despite that, correlation could be found linking the ingestion of VOO with gut microbiota changes on one hand, while independent students have shown that these changes in microbiota could be associated with neuromodulation, thus indicating that there is a huge field of research to investigate in.

Among the different challenges to be addressed when studying VOO as the test item in clinical trials or animal studies is the adequate and proper characterization of the sample, especially concerning the minor compounds. The wide variety of phenolic compounds and the varying concentrations depending on the cultivar, the year, the time of fruit harvest, etc., hinder the possibility of having a standard product over time in which the real concentration of each component is known.⁸⁴

Regarding the gut microbiota analyses, many scientists agree that it is hard to make diagnosis and accurately interpret the parameters of the microbiota. In fact, it is considered that current scientific knowledge does not allow defining what is healthy microbiota, and in fact, there is no evidence correlating changes in microbiota with improvements in health, at least not properly described and considered as agreement for physicians. On top of that, while there is growing evidence suggesting a strong connection between the gut and the brain, the precise mechanisms underlying neuromodulation through the gut microbiota are still not fully understood. Researchers may aim to delve deeper into the specific pathways and molecular mechanisms involved.

In this line, the majority of research in this field has been conducted in animal models. More human studies are needed to validate findings and understand the translational implications for human health. In this regard, it must be noted that human diet is a complex variety of macro and micronutrients; thus, the overall role of various dietary factors in modulating the gut–brain axis is a complex area. The interplay between different components of the diet, including fiber, polyphenols, and fats, should be considered.

In addition to that, it is still to be agreed how long a dietary intervention needs to last in order to change the gut microbiota and neuromodulate the organism; thus, it is highly likely that short-term studies are not enough to report solid evidence of information in relation to the topic. This includes assessing whether observed changes are sustained over time and exploring potential cumulative effects. In relation to this, it is also needed to explore the clinical implications of neuromodulation through the gut–brain axis. This could include investigating potential therapeutic applications for conditions such as neurodegenerative diseases, mood disorders, or cognitive decline, at the same time as the study of the interaction with existing conditions (e.g., how might the effects of VOO ingestion via the gut–brain axis differ in individuals with neurodegenerative diseases or metabolic disorders?).^85,86

In addition, understanding the effect of other oils would be also helpful in the unravelling of which components most likely exert the bioactivity. For instance, walnut, camelia or fish oils^59,63,87 have been reported to also provide beneficial effects in neuromodulation through the gut–brain axis. In this regard, a recent study reported how the degree of lipid saturation affects depressive-like behavior and gut microbiota in mice,⁸⁸ although it must be noted that on top of the different fatty acid profiles, different oils have other minor components.

Concerning the methodologies employed both for analysis of biological samples and dietary interventions (characterization of VOO), there is always room for improvements. Standardization of experimental methodologies across studies can help in comparing results and drawing more robust conclusions. This includes consistency in study designs, sample sizes, and measurement techniques.¹¹

Finally, exploring the ethical and societal implications of interventions that target the gut–brain axis is crucial. This includes considerations of accessibility, affordability, and potential unintended consequences. Consequently, this novel research field has still a long way to go, and researchers and policymakers must be aware of it and put efforts in developing it, as its socio-economic and positive health-related outcomes could be of interest for the whole population.

5. Conclusions

VOO is one of the most consumed products in the framework of a Mediterranean diet. The health benefits associated with its consumption are related both to monounsaturated fatty acids (especially oleic acid) and minor components, phenolic compounds (phenolic acids, flavonoids, lignans, and secoiridoids), tocopherols (vitamin E), phytosterols, carotenoids, squalene, and chlorophyll. This review paper elaborates on the emerging field of neuromodulation through the gut microbiota, specifically focusing on the impact of VOO ingestion. The comprehensive analysis of existing literature reveals the intricate relationship between the gut microbiota and neurological functions, highlighting the potential therapeutic implications of dietary interventions.

On the one hand, studies were reviewed showing how VOO and its main components promote the growth of certain bacteria producing microbial metabolites, such as SCFAs. In vitro studies have shown that VOO stimulates the populations of Lactobacillus spp. and Bifidobacterium and increases the production of SCFAs. In vivo studies in mice showed that Clostridium XIVa, an important group in the production of butyrate, proliferates in relation to the intake of VOO.

In addition, it has been reported that consumption of VOO improves the function of the blood–brain barrier, reduces neuroinflammation and inhibits the formation of Aβ plaques and tau in the brain. Furthermore, when studying individually the phenolic compounds present in VOO, such as hydroxytyrosol, oleuropein and tyrosol, they have shown neuroprotective and antioxidant effects in animal models, improving cognitive and motor behavior and reducing oxidative damage in the brain. These compounds inhibit lipid peroxidation and the formation of inflammatory mediators, such as prostaglandin E2 and interleukin 1β. In addition, flavonoid metabolites produced by the intestinal microbiota, such as protocatechuic acid and gallic acid, have shown neuroprotective effects by reducing oxidative stress and microglial activation. However, these studies did not analyze the impact on the intestinal microbiota. Although evidence supports the effects of VOO on microbial composition and diversity, there is little information directly linking these changes to effects on the brain, making it difficult to establish solid causal relationships, although the changes allow hypotheses of connections. The intricate interaction between the gut and the brain, influenced by VOO intake, opens avenues for future research and therapeutic applications in neurological disorders.

Finally, several studies have reported evidence on the effects of VOO on intestinal microbial composition and diversity, suggesting its potential as a modulator of the gut–brain axis. VOO consumption was associated with a higher richness of the microbial community, with an increase in Alistipes, Odoribacter and Parabacteroides and a decrease in Prevotellaceae, which have been linked to improvements in the gut–brain axis. Vitamin E mainly present in EVOO has also been shown to alter immune and inflammatory responses through modulation of the intestinal microbiota in animal and human studies. Other studies have also shown that the consumption of olive oil or its key components, such as hydroxytyrosol, improves intestinal balance and reduces oxidative stress and inflammation in models of diseases related to the central nervous system, such as multiple sclerosis.

In summary, the published data suggest that changes in the gut microbiota elicited by the consumption of virgin olive oil may benefit cognitive function and neuroprotection, but several limitations persist, such as the short duration of the study, variability in oil composition, and lack of standardized methodologies. Furthermore, the limited number of human trials and incomplete knowledge of the gut–brain axis make it difficult to draw definitive conclusions or apply these findings clinically. Future research should therefore prioritize long-term clinical trials with larger cohorts, a standardized characterization of virgin olive oil, and the exploration of its synergistic effects with other dietary components. On top of that, mechanistic studies should focus on identifying molecular pathways involved in the gut–brain axis to develop specific dietary interventions for neurological and neurodegenerative diseases.

Disclaimer

The author F. Rivero-Pino is carrying out a temporal secondment at European Food Safety Authority – EFSA – from June 1st, 2024 to May 31st, 2025. The work described in this article is not related to his current work at EFSA, it is published under the sole responsibility of the author and may not be considered as an EFSA scientific output. The views and opinions expressed in this manuscript do not represent those of EFSA.

Author contributions

L. B.-C., A. F.-P., C. M. C.-C., J. L. d.-R., F. R.-P. and S. M.-d. l. P. writing – original draft. F. R.-P. and S. M.-d. l. P.: writing – review & editing. All authors participated in the production of the final version of the manuscript.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This study was supported by the research grant TED2021-130521A-I00 (Ministry of Science and Innovation, Government of Spain) into the Recovery, Transformation and Resilience Plan funding by NextGenerationEU.

L. B.-C. has the benefit of a doctoral fellowship supported by the VII Program of Inner Initiative for Research and Transfer of University of Seville (VII-PPIT-US). A. F.-P. and F. R.-P. have the benefit of a Juan de la Cierva postdoctoral fellowship (FJC2021-047485-I and FJC2022-050043-I, respectively) from the Spanish Ministry of Science and Innovation.

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