Abstract

In recent years, there has been growing interest in the study of gut microbiota and its relationship with multiple diseases, ranging from digestive problems to cognitive disorders. The composition of this microbiota is determined by external and internal factors—such as psychosocial or environmental aspects—and is closely linked to diet, since the foods we consume provide nutrients and establish the conditions of the intestinal environment. The gut–brain axis describes how the intestinal microbial flora and the compounds it produces generate and transmit signals that act on our nervous system and regulate multiple processes in the body. This systematic review aims to explore the impact of the Mediterranean Diet on the composition of the gut microbiota and to analyze its effects on various cognitive conditions, such as memory. Based on a review of 20 articles, we examined how the Mediterranean Diet—characterized by high consumption of olive oil, fruits, vegetables, legumes, and fish—modulates the microbiota in the human gut. The results showed that adherence to the Mediterranean Diet is associated with an increase in beneficial bacteria such as Faecalibacterium prausnitzii and Bifidobacterium, and with greater production of short-chain fatty acids (SCFAs), especially butyrate. The Mediterranean Diet appears to exert a neuroprotective role in disorders such as mild cognitive impairment, schizophrenia, Parkinson’s disease, and metabolic diseases. This protective function, derived from changes in the gut microbiota, leads to improvements in cognitive function. Overall, the findings underscore the direct relationship between nutrition and mental health and reinforce the value of the Mediterranean Diet as a preventive strategy and a modulator of cognition through the gut–brain axis, promoting brain health across the lifespan.

Systematic review registration:

https://www.crd.york.ac.uk/prospero/, identifier CRD420251273990.

1 Introduction

The Mediterranean diet, originating in ancient Greece (Radd-Vagenas et al., 2017), is distinguished as a predominantly plant-based eating pattern composed of fruits, vegetables, legumes, nuts, and seeds. It also includes moderate amounts of fish and only small portions of red and processed meat. The primary fat used for cooking and as a dressing is extra-virgin olive oil (EVOO), and together with wine consumed in small quantities during meals these are hallmark features of the diet (Bach-Faig et al., 2011). It is important to emphasize that the Mediterranean diet is not defined by geographic location but by its constituent foods; thus, people living outside the Mediterranean basin may also follow this dietary pattern (Varela, 1994). The Mediterranean diet was introduced as a healthy diet by Ancel Keys through his innovative “Seven Countries Study” in the 1950s, which examined the role of the Mediterranean diet in cardiovascular disease (Keys, 1980). In that work, Keys described the link between the eating practices of certain Mediterranean communities and a lower incidence of cardiovascular disease. In 2006, Scarmeas and colleagues reported an association between adherence to the Mediterranean diet and a decreased risk of developing Alzheimer’s disease (Scarmeas et al., 2006). Compounds found in EVOO have been shown to hold substantial potential for the prevention and treatment of some neurodegenerative diseases, such as Alzheimer’s disease (Alkhalifa et al., 2024), and, more generally, adherence to the Mediterranean diet reduces the risk of chronic disease and increases life expectancy (Estruch et al., 2018). In recent decades, changes in the Mediterranean diet have been observed both in European Mediterranean countries and in regions south of the Mediterranean (Vilarnau et al., 2019). These shifts in food preferences, together with rising food costs and the industrialization of food production, have contributed to a decline in the traditional Mediterranean pattern (Russo et al., 2021), which will likely have repercussions for the health of populations that previously adhered to this diet. In the neurological sphere, a 2024 systematic review suggests that greater adherence to the Mediterranean diet may be associated with better cognitive performance and gastrointestinal symptoms in Parkinson’s disease, accompanied by variations in gut microbial composition (Seelarbokus et al., 2024).

The human intestine harbors a microbial community comprising fungi, bacteria, archaea, and viruses that can reach 1013 cells, forming a complex ecosystem known as the gut microbiota, which remains in constant communication with host cells and systems and thereby contributes to our health. Bacteria are the principal constituents of the human microbiota; to date, more than 1,000 different species have been identified, of which each person harbors roughly 500 (Leviatan et al., 2022). These bacteria establish a symbiotic relationship with the host, obtaining nutrients from the gastrointestinal tract and contributing to immunological, structural, and metabolic functions that benefit the host (Bäckhed et al., 2005; O’Hara and Shanahan, 2006). However, the composition of the microbiota is not stable: it can change as a consequence of environmental factors and host-related alterations such as the consumption of different foods, medication use, age, or even excessive personal and environmental hygiene. Among these factors, diet appears to be the most decisive, due to microorganisms’ differing capacities to metabolize specific substrates and to tolerate the intestinal milieu generated by various foods (De Filippo et al., 2017). For example, studies on extra-virgin olive oil report that this oil helps reduce pathogenic bacteria in the intestine and promotes the growth of beneficial bacteria, which is crucial for maintaining microbial balance. Moreover, EVOO consumption increases the production of short-chain fatty acids (SCFAs) synthesized by bacteria, which exert anti-inflammatory effects and can also influence host gene expression (Millman et al., 2021). Contemporary diets rich in proteins, sugars, and fats and including non-food chemicals such as preservatives, pesticides, additives, and emulsifiers provoke shifts in microbiota composition and, consequently, in host–microbe relationships (Sonnenburg and Sonnenburg, 2019). These alterations can contribute to pathologies such as inflammatory bowel disease, cardiovascular disease, diabetes, obesity, allergies, and metabolic syndromes, among others (Dapa and Xavier, 2024). The microbiota has also been shown to affect drug treatments, enhancing, inhibiting, or modifying their activity (Manrique et al., 2024). All of this has fueled scientific interest in the microbiota and in the mechanisms underlying host–microbe interactions, as well as in the role of diet in reshaping the microbiota to benefit health. At present, numerous studies analyze the microbiota of humans with diverse pathologies—from intestinal to neurological conditions—comparing findings with healthy individuals to elucidate key relationships; many other studies likewise assess the impact of diet on the microbiota. Traditional culture-based techniques have been used to study the microbiota; however, many bacteria that compose it cannot be grown outside the intestine or are present at very low abundance, preventing their isolation and identification. To address this issue, new culture methods such as microfluidics are being developed; nevertheless, identification is currently carried out primarily using molecular methods. Total DNA is extracted from fecal samples from the individuals under study and, through sequencing of the 16S rRNA gene or shotgun metagenomic sequencing of the extracted DNA, the bacterial species present and their relative abundances in the sample are determined (Xu et al., 2024).

For years it has been recognized that there is a connection between the gut and the brain known as the gut–brain axis, which constitutes a bidirectional communication route essential for maintaining homeostasis. This axis is composed of the microbiota, the enteric nervous system, the autonomic nervous system, the neuroendocrine system, the neuroimmune system, and the central nervous system (Barrio et al., 2022; Felice et al., 2016). Neurochemical signaling and the vagus nerve are among the mechanisms that transmit signals along this axis (O’Mahony et al., 2015; O’Riordan et al., 2025). As expected, dysfunction of this complex system has important pathophysiological consequences, and numerous brain disorders have been linked to alterations in microbiota composition, with dysbiosis and disease-related molecular changes detected in affected patients (Mayer, 2011). One communication mechanism within the gut–brain axis is the immune system, both through the production of immunomodulators by the resident microflora and via direct interactions between these bacteria and intestinal immune cells, given that the gut constitutes a major immune niche (Shekarabi et al., 2024). Among the major microbiota-derived mediators that modulate immunity and neuro-immune signaling are SCFAs, secondary bile acids, neuromodulators/neurotransmitters (e.g., GABA, serotonin/5-HT and their precursors), and choline-derived metabolites (TMA/TMAO) (Connell et al., 2022; Park et al., 2025). Of these, SCFAs are among the most studied: they are generated when gut microbes ferment dietary fibers that escape human digestion and act on immune, endocrine, and neuronal cells (Dalile et al., 2019). Adhering to a healthy diet can increase microbial diversity in the gut and enhance the production of these fatty acids and other bioactive compounds. In this regard, a reduction in the relative abundance of SCFA-producing bacterial genera has been linked to cognitive pathologies (Ribeiro et al., 2022). Regarding neuromodulators, some components of the microbiota can produce GABA, the principal inhibitory neurotransmitter in the nervous system (Strandwitz et al., 2019). In parallel, direct interactions between intestinal bacteria and gut immune cells trigger the release of cytokines and chemokines that enter the circulatory and lymphatic systems and influence immune signaling throughout the body, including the brain (Erny et al., 2015). Recent updates underscore the immune system as a central pathway of the microbiota–gut–brain axis: the microbiota “educates” innate and adaptive immune responses, shapes microglial function and neuroinflammation, and opens therapeutic opportunities in neurological disorders (O’Riordan et al., 2025). Another signaling route within the axis operates through intrinsic enteric neurons, which relay signals to the sympathetic ganglia, and through the vagus nerve, which expresses a variety of receptors along the gut–vagus–brain pathway and informs complex behaviors such as food preference, motivation, and reward (Shekarabi et al., 2024). Taken together with current clinical evidence, these mechanisms help explain why adherence to the Mediterranean diet may translate into more favorable microbial profiles and the cognitive benefits observed in recent cohorts and systematic reviews (Seelarbokus et al., 2024; Tessier et al., 2024). Given these considerations, the objective of this systematic review is to examine the relationship between adherence to the Mediterranean diet and gut microbiota composition within the context of the gut–brain axis, and to evaluate its impact on memory and other cognitive functions, with particular attention to microbiome-related changes.

2 Methods2.1 Search strategy

A systematic review of the scientific literature was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Liberti et al., 2009; Moher et al., 2009) to identify the effect of the Mediterranean diet on memory and other cognitive processes, the microbiota population influenced by it, and how these bacteria influence the memory system. Details of the protocol for this systematic review were registered in the PROSPERO database (CRD420251273990). The search strategy was built around the three core concepts defining our research question: “Mediterranean diet,” “Memory,” and “Microbiota.” These key terms were combined using the Boolean operator “AND” to ensure precise retrieval of studies investigating their intersection. The specific syntax was adapted for each database. The study selection process followed four distinct stages: (1) Identification: Records obtained from databases were imported into reference management software, and duplicates were removed. (2) Screening: Titles and abstracts of all unique records were screened against pre-defined eligibility criteria. (3) Eligibility: The full texts of potentially relevant studies were retrieved and assessed in detail for inclusion. (4) Inclusion: Studies meeting all criteria were finally included in the qualitative synthesis. This process was performed independently by two reviewers, with any discrepancies resolved through discussion or consultation with a third reviewer. The complete flow of information through these stages, including the number of records at each point, is presented in the PRISMA flow diagram (Figure 1).

PRISMA flow diagram of the study selection.

2.2 Study selection

Specific exclusion criteria were established to focus the search on relevant articles. First, systematic reviews were excluded, as well as studies based on research using animal models, including only empirical studies. This was done to ensure that the results could be directly applied to the human population, which is crucial both for clinical use and for advancing the understanding of neuroscience in relation to humans. Likewise, studies that did not explicitly focus on changes in the microbiota, memory, or the gut-brain axis were discarded, in order to accurately address the research objective proposed in this paper. Finally, articles published before 2014 were excluded to ensure that the selected studies reflected the current level of knowledge in the field of neuroscience. With regard to publication characteristics, no conference abstracts, preprints, or non-English publications met the inclusion criteria at the title and abstract screening stage; therefore, no studies were excluded on the basis of publication type or language.

A total of 258 articles were located (81 from PubMed and 188 from Web of Science). After eliminating duplicates, an initial screening was performed, and 29 articles were selected for full reading. During this second phase, relevant methodological aspects were verified, such as sample characteristics, cognitive tools used, and microbiota analysis techniques. Finally, new studies were excluded for not meeting the eligibility criteria, leaving a total of 20 studies included in the review (Table 1). The selection process is summarized in Figure 1.

CodeFirst author and yearJournalCitesMediterranean diet adherence measureQuality assessmentToolScore/Judgment1(Cupisti et al., 2017)Nutrients53NANANA2(Nagpal et al., 2020)PLOS ONE46NRNOS5/93(Godos et al., 2021)Nutrients36MEDI-LITENOS6/94(Berding et al., 2023)Microbiome63ModiMedDietRoB 2Some concerns5(Haskell-Ramsay et al., 2022)Psychopharmacology4NARoB 2Some concerns6(Pellegrini et al., 2020)Food Chemistry48IMIRoB 2High risk/Some concerns7(Domínguez-López et al., 2024)Frontiers in Nutrition0MEDAS-14NOS6/98(Domínguez-López et al., 2023)Molecular Nutrition and Food Research1MEDAS-17NOS6/99(Kowalski et al., 2023)Clinical Nutrition8aMEDNOS7/910(McLeod, 2021)Nutrients0aMEDRoB 2Some concerns11(Paknahad et al., 2020)Nutrients62NRRoB 2Some concerns12(van Soest et al., 2020)Nutrients51NRNOS6/913(Santoro et al., 2014)Mechanisms of Ageing and Development67NRNANA14(Cardelo et al., 2022)Frontiers in Nutrition3MEDAS-14RoB 2Some concerns15(Kamer et al., 2023)Gut Microbes4NRRoB 2Low risk/Some concerns16(McLeod et al., 2023)Nutrients1MDSRoB 2Some concerns17(O’Mahony et al., 2023)Frontiers in Nutrition1NANANA18(Nagpal et al., 2020)Trends in Endocrinology and Metabolism5NARoB 2Some concerns19(Galié et al., 2021)Journal of Clinical Medicine5MEDAS-17RoB 2Some concerns20(Choo et al., 2023)Nutrients5MEDAS-14; MDSRoB 2Some concerns

Articles included in the systematic review.

1aMED, Alternate Mediterranean Diet score; IMI: Italian Mediterranean Index; MDS, Mediterranean Diet Score; MEDAS-14, Mediterranean Diet Adherence Screener, 14-item; MEDAS-17, Mediterranean Diet Adherence Screener, 17-item; ModiMedDiet: Modified Mediterranean Diet Score; NA, Not applicable; NOS, Newcastle–Ottawa Scale; NR, Not reported.

2Observational studies were appraised with the Newcastle–Ottawa Scale (NOS; 0–9 stars). Randomized controlled trials were assessed with RoB 2 (overall judgment: low risk/some concerns/high risk). Non-primary articles (e.g., protocols/reviews) were not assessed (NA).

2.3 Quality assessment and risk of bias

The methodological quality of the included studies was assessed according to study design. Observational studies were evaluated using the Newcastle-Ottawa Scale, while randomized controlled trials were assessed using the Cochrane Risk of Bias tool. Quality scores were considered in the interpretation of findings to account for methodological heterogeneity across studies.

3 Results

Tables 2–4 summarize the studies reviewed in the context of gut microbiota, the Mediterranean diet, and cognitive processes. The results presented in Table 2 show that, in both observational studies and controlled interventions, adherence to the Mediterranean diet is associated with beneficial changes in the gut microbiota and improved cognitive function. These effects are especially notable in populations with mild cognitive impairment, obesity, or aging. The Mediterranean diet favors the increase of bacteria such as Faecalibacterium prausnitzii, Akkermansia muciniphila, Bifidobacterium, and Lactobacillus, which increase the production of short-chain fatty acids (butyrate, propionate, and acetate) with anti-inflammatory and neuroprotective effects. The presence of these metabolites has been linked to improved performance in verbal memory, executive functions, and frontal cognition (Domínguez-López et al., 2024; van Soest et al., 2020). Furthermore, bioactive components of the Mediterranean diet, such as polyphenols present in fruits, vegetables, nuts, and extra virgin olive oil, could enhance these benefits by modulating the gut microbiota (Godos et al., 2021).

CodenAgeProcedurePathologyControl/comparison groupMain results1618570MD intervention with weight lossObesity and advanced ageComparison MD, MD + weight loss, and habitual dietImproved memory; ↑ SCFAs118058.9Controlled MD trialParkinsonControl group with standard dietCognitive improvement (verbal memory)144760MD + probiotics interventionMild cognitive impairmentComparison with group without probioticsImproved executive functions and memory; ↑ Bifidobacterium720066Observational––SCFAs and phenols associated with better frontal cognition1225272MD Intervention–Control group↑ Faecalibacterium cognitive improvement634267Clinical trial with MDMild cognitive impairmentControl groupMicrobiota changes associated with improved verbal memory3204434Observational--Phenols correlated with better cognitive status

Mediterranean diet, microbiota and cognition.

In alphabetical order: ↑, increase; MD, Mediterranean diet; SCFAs, Short Chain Fatty Acids.

CodenAgeProcedurePathologyControl/comparison groupMain results193842.5MD InterventionCardiometabolic risk factorsControl group↑ Lactobacillus
↑ Bifidobacterium203460MD + nuts intervention-Comparison with low-fat diet↑ Microbial diversity;, Akkermansia muciniphila1––Dietary interventionOverweightStandard dietMicrobiota composition changes13125072Dietary intervention–Control groupImproved microbiota composition158252Intervención dietaOverweightStandard diet↑ SCFAs

Mediterranean diet and microbiota.

In alphabetical order: ↑: increase; MD, Mediterranean diet; SCFAs, Short Chain Fatty Acids.

CodenAgeProcedurePathologyComparison/control
groupMain results915541.5ObservationalSQZComparison of microbial profiles↓ SCFAs associated with poorer cognitive performance.840067.5ObservationalOverweight-Phenols correlated with better frontal lobe function.57933.5Nuts intervention-PlaceboMicrobiota changes; slight improvement in working memory.44538.5Probiotic interventionAutismControl groupImproved attention and memory.174764.5Red fruits intervention-Control groupMicrobiota changes; mild memory improvement.181764.6Dietary intervention-Control groupMicrobiota changes associated with better cognitive function.21539.2Fermented diet intervention-Control groupImproved microbiota and verbal memory.1018570Probiotic interventionObesityPlacebo groupImprovement in working memory and sustained attention.

Microbiota and cognition.

In alphabetical order: ↓: decrease; SCFAs, Short Chain Fatty Acids; SQZ, schizophrenia.

Table 3 includes studies in which DM modulates the microbiota without directly assessing cognitive functions. An increase in Butyricicoccus and a reduction in Colinsella and Veillonella observed. These changes reflect an anti-inflammatory profile that could explain the indirect cognitive benefits reported (Choo et al., 2023; Galié et al., 2021).

Table 4 details that an unbalanced microbiota with low SCFA production and lower bacterial diversity is associated with worse cognitive performance and higher risk of decline. In contrast, interventions involving MD, probiotics or polyphenols have been shown to improve cognition (Berding et al., 2023; Nagpal et al., 2020).

The assessment methods used across studies included neuropsychological scales such as the Mini-Mental State Examination (MMSE), the Trail Making Test (TMT), and the Montreal Cognitive Assessment (MoCA), with more consistent results being in long-term interventions combined with probiotics or polyphenolic compounds. Overall, the evidence supports that MD acts as a key modulator of the gut-brain axis, promoting an anti-inflammatory microbiota that contributes to cognitive health in different populations (Table 5).

Area of impactMain findingsRelevant studiesGut microbiotaIncreased abundance of beneficial bacteria such as Faecalibacterium, Bifidobacterium, Akkermansia, Lactobacillus.(van Soest et al., 2020; Choo et al., 2023)Microbial metabolites↑ SCFAs –butyrate, propionate, acetate — involved in inflammation regulation and synaptic plasticity.(Domínguez-López et al., 2024; Joseph et al., 2017)Cognitive functionImprovement in verbal memory, attention, and executive functions.(Paknahad et al., 2020; Berding et al., 2023)PathologyPositive effects observed in mild cognitive impairment, Parkinson’s disease, autism, cardiovascular disorders, and schizophrenia.(Pellegrini et al., 2020; Kowalski et al., 2023)Type of interventionMediterranean diet alone or combined with probiotics/nuts improves microbial composition and cognition.(Galié et al., 2021; Godos et al., 2021)

Summary of findings according to the analyzed.

In alphabetical order: ↑: increase; SCFAs, Short Chain Fatty Acids.

4 Discussion

In the present work, a systematic review of studies published over the past decade was conducted to examine the influence of the Mediterranean diet on memory and other cognitive processes through its effects on the gut microbiota. The evidence indicates that adherence to this dietary pattern is associated with favorable modifications in gut microbial composition, characterized by an increase in beneficial bacteria with anti-inflammatory and neuroprotective properties. These microbiota-related changes appear to contribute to improved cognitive performance and a lower risk of cognitive decline across diverse populations.

When we examined the gut–brain axis, we observed associations between specific bacterial populations and the metabolites they produce and the presence or absence of cognitive pathologies. Finally, analysis of the Mediterranean diet’s impact on cognitive processes indicates that people adhering to this diet are less likely to experience such di