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The role of a Mediterranean diet and physical activity in decreasing age-related inflammation through modulation of the gut microbiota composition

Published online by Cambridge University Press:  23 August 2021

Jessie S. Clark
Affiliation:
University of South Australia, Clinical and Health Sciences, GPO Box 2471, Adelaide 5001, Australia Alliance for Research in Exercise, Nutrition and Activity, University of South Australia, GPO Box 2471, Adelaide 5001, Australia
Bradley S. Simpson
Affiliation:
University of South Australia, Clinical and Health Sciences, GPO Box 2471, Adelaide 5001, Australia
Karen J. Murphy*
Affiliation:
University of South Australia, Clinical and Health Sciences, GPO Box 2471, Adelaide 5001, Australia Alliance for Research in Exercise, Nutrition and Activity, University of South Australia, GPO Box 2471, Adelaide 5001, Australia
*
*Corresponding author: Karen J. Murphy, email karen.murphy@unisa.edu.au
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Abstract

Chronic inflammation is known to be a predominant factor in the development of many age-related conditions including CVD, type II diabetes and neurodegenerative diseases. Previous studies have demonstrated that during the ageing process there is an increase in inflammatory biomarkers, which may be partially brought about by detrimental changes in the gut microbiota. The Mediterranean diet (MedDiet) and physical activity (PA) are protective against inflammation and chronic disease, and emerging evidence has shown that these effects may be partially mediated through favourable changes in the gut microbiota. In this review, we have evaluated the published literature on the effect of a MedDiet and PA on the gut microbiota. We also discuss the relationship between the gut microbiota and inflammation with a focus on healthy ageing. While inconsistent study designs make forming definitive conclusions challenging, the current evidence suggests that both a MedDiet and PA are capable of modifying the gut microbiota in a way that is beneficial to host health. For example, the increases in the relative abundance of SCFA producing bacteria that are considered to possess anti-inflammatory properties. Modification of the gut microbiota through a MedDiet and PA presents as a potential method to attenuate age-related increases in inflammation, and additional studies utilising older individuals are needed to fill the knowledge gaps existing in current literature.

Type
Research Article
Copyright
© The Author(s), 2021. Published by Cambridge University Press on behalf of The Nutrition Society

With current projections placing 1·5 billion people globally over the age of 65 by the year 2050, it has never been more important to identify strategies that promote the maintenance of health, well-being and functionality through a person’s older years. Chronic inflammation has been identified as a predominant factor contributing to the onset and progression of many age-related diseases(Reference Michaud, Balardy and Moulis1). The acute inflammatory response is an essential function of a healthy immune system that is triggered in response to chemical or physical stimuli. This process is tightly regulated as inadequate resolution of inflammation or a prolonged exposure to the inflammatory trigger may lead to a state of chronic inflammation that may contribute to the aetiology of diseases such as cancers, type 2 diabetes, atherosclerosis and cardiovascular and neurodegenerative diseases(Reference Chen, Deng and Cui2,Reference Medzhitov3) .

As humans age, there is a notable dysregulation of the immune system which involves a marked decline in the adaptive responses and mild increases in innate activity. This process, called immunosenescence, can impair a person’s ability to fight infection, weaken vaccination response and lead to higher levels of adiposity, and changes in the gut microbiota composition. These outcomes can lead to a state of chronic low-grade inflammation termed inflammageing(Reference Franceschi, Bonafe and Valensin4). This immune dysregulation is accompanied by increased levels of pro-inflammatory cytokines, such as IL-6, TNF-α and C-reactive protein, particularly in older people(Reference Forsey, Thompson and Ernerudh5,Reference Wei, Xu and Davies6) . Increased inflammation, specifically levels of C-reactive protein, IL-6 and TNF-α, has been associated with many age-related diseases including sarcopenia, osteoporosis and fracture, malnutrition, cognitive decline, increased risk of frailty and increased all-cause mortality(Reference Michaud, Balardy and Moulis1,Reference Rea, Gibson and McGilligan7) .

There are many common lifestyle factors that can contribute to chronic inflammation, for instance smoking, alcohol consumption, chronic stress and importantly, poor diet and lack of physical activity (PA). The Mediterranean Diet (MedDiet), a centuries-old dietary pattern evolving from the traditional eating patterns of the countries surrounding the Mediterranean basin, has long been touted as one of the most favourable dietary patterns for promoting good health and longevity(Reference Sofi, Abbate and Gensini8). The diet is predominantly plant based containing high amounts of fruits and vegetables, extra virgin olive oil (EVOO), wholegrains and legumes with moderate consumption of poultry, dairy foods and wine, and low intakes of discretionary foods and red and processed meats(Reference Davis, Bryan and Hodgson9). Early research by Ancel Keys and the Seven Countries Study highlighted the protective effect of the MedDiet against CVD(Reference Menotti and Puddu10,Reference Hatzis, Papandreou and Patelarou11) , and follow-up studies have continued to show the protective effects of a MedDiet across a range of other chronic diseases and overall mortality(Reference Kromhout, Menotti and Alberti-Fidanza12,Reference Fidanza, Alberti and Lanti13) . While this strong evidence exists, some mechanisms supporting these outcomes are not completely understood. One proposed mechanism of action is via the gut microbiota and the reduction of chronic inflammation, a state which underpins many chronic diseases(Reference Tosti, Bertozzi and Fontana14,Reference Thorburn Alison, Macia and Mackay Charles15) .

The aim of this narrative review is to provide an overview of the MedDiet diet and lifestyle, summarise the current evidence on how both a MedDiet and PA influence the human gut microbiota and discuss the relationship between the gut microbiota and healthy ageing, with a focus on inflammation.

Mediterranean diet and lifestyle

The MedDiet has existed for centuries, evolving from the traditional eating patterns of people native to countries surrounding the Mediterranean basin. It is not just one pattern, but rather numerous variations of a similar way of eating, determined by local food availability and cultural and religious practices(Reference Trichopoulou and Lagiou16). Despite these differences, the region’s dietary pattern consists of the same core principles and a focus on fresh wholefoods with limited processing. The diet is predominantly plant based with high intakes of fruits and vegetables, wholegrains, legumes, nuts and seeds and includes a moderate to high consumption of high-quality dietary fats, primarily from EVOO. There is a preference for fish over red meat, limited sweets and a moderate consumption of red wine around mealtimes and social settings(Reference Davis, Bryan and Hodgson9). However, the MedDiet is more than just the food consumed in these regions; the dietary pattern is heavily underpinned with physical activity, adequate rest, culinary activities, frugality and a high degree of socialisation and community(Reference Bach-Faig, Berry and Lairon17).

Research focusing on the MedDiet began in the 1950s when Ancel Keys and the team of the Seven Countries Study investigated the relationship between CVD and various lifestyle factors after noticing the differences in CVD between American businessmen and those living in post-war Europe(Reference Menotti and Puddu10). Multiple follow-up studies have demonstrated the association between dietary patterns, like those seen in the cohorts from Italy and Greece, and a reduced risk of CHD(Reference Menotti and Puddu10,Reference Hatzis, Papandreou and Patelarou11) . Interest in the MedDiet’s effects on health outcomes has only grown in the past few decades. A recent umbrella review by Dinu et al.(Reference Dinu, Pagliai and Casini18) meta-analysed sixteen randomised controlled trials and thirteen meta-analyses of observational studies, involving 12·8 million participants, investigating the relationship between the adherence to a MedDiet and health outcomes. The review provides strong evidence for the protective nature of the MedDiet with an 11 % reduced risk in overall mortality (95 % CI 0·89, 0·93), 33 % reduced risk of CVD (95 % CI 0·58, 0·77) and a 21 % reduced risk of neurodegenerative diseases (95 % CI 0·70, 0·90)(Reference Dinu, Pagliai and Casini18). An increasing number of studies are also focusing on the MedDiet’s impact in maintaining the physical functioning of older people demonstrating an association between higher adherence to a MedDiet and reduced risk of frailty, sarcopenia and development of a mobility disabilities and increased skeletal muscle retention and handgrip strength(Reference Barrea, Muscogiuri and Di Somma19Reference Milaneschi, Bandinelli and Corsi21).

Traditionally, the populations of the Mediterranean region had high incidental levels of PA due to the laborious nature of their occupational status. For instance, in 1960’s Crete, many inhabitants were shepherds or farmers who would travel up to 20 and 8 km on foot per day, respectively, often on uneven or rugged terrain(Reference Christakis, Severinghaus and Maldonado22). This is a stark contrast to the current lifestyles of those living in developed nations where sedentary behaviours have been increasing for decades due to technological advances and the rise of less active occupations(Reference Owen, Sparling and Healy23). The health benefits of PA are widely accepted in the literature, and it has been associated with reducing the risk of premature mortality and multiple chronic health conditions including some forms of cancer, CVD, metabolic conditions and risk of stroke(Reference Warburton and Bredin24).

Human gut microbiota through life

The gut microbiota consists of approximately 100 trillion microbial cells that form a symbiotic relationship with its human host, exerting many beneficial physiological effects that are protective of disease including maintaining the integrity of the intestinal epithelium, energy extraction from undigestible material, prevention of colonisation by pathogenic microbes and involvement in immune system development and regulation(Reference Turnbaugh, Ley and Hamady25,Reference Huttenhower, Gevers and Knight26) . It is comprised of several bacterial phyla, with Firmicutes and Bacteroidetes being identified as the two most dominant. The relative abundance of these two phyla appears to be an important determinant of human health(Reference Huttenhower, Gevers and Knight26). However, many members of these phyla are capable of exerting different effects through the individual genes they carry, and therefore their ability to produce metabolites like SCFA and bioactive compounds(Reference Wang and Zhao27), suggesting that microbiota diversity and relative abundance of particular taxa, along with their functional capability, may be more important(Reference Claesson, Jeffery and Conde28).

Microbiota colonisation begins at birth and continues to transform rapidly during the early years of life, stabilising at approximately 2–5 years of age where its composition resembles that of an adult microbiota(Reference Rodríguez, Murphy and Stanton29). From this point, the stability and resilience of an individual’s core microbiota increase and temporary external factors, like short-term dietary changes or the use of antibiotics, generate only transient changes in composition. As humans age, there is a gradual and continual shift in lifestyle that includes decreases in nutritional quality and PA, increased intestinal transit time and higher use of medications, which produce a compounding effect on the gut microbiota, and composition begins to alter(Reference Vemuri, Gundamaraju and Shastri30). These alterations present as a loss of microbial diversity, increased inter-individual variability and shifts in the relative abundance of numerous species(Reference Biagi, Nylund and Candela31,Reference Claesson, Cusack and Sullivan32) . Specific changes that have been reported are decreases in Clostridium cluster IV, Faecalibacterium prausnitzii and bifidobacterial members, which are all known for their ability to produce SCFA through the fermentation of fibre(Reference Biagi, Nylund and Candela31,Reference Zwielehner, Liszt and Handschur33Reference Mueller, Saunier and Hanisch35) . One of the largest studies conducted in an elderly cohort analysed the microbiota composition of participants who were living in different circumstances/environments. The authors reported significant decreases in the microbiota diversity of the elderly participants in long-stay care compared with that of community-dwelling participants, and that this loss of diversity was significantly associated with an increase in frailty. Further investigation found the microbiota shift found in these populations was primarily driven by dietary intake(Reference Claesson, Jeffery and Conde28). Recently, research has investigated the microbiota composition on centenarians, individuals who demonstrate healthy ageing and longevity. Numerous studies have reported a decrease in the core taxa and increases in sub-dominant species including opportunistic pathogens and usually transient bacteria including Methanobrevibacter and Escherichia (Reference Wu, Zeng and Zinellu36,Reference Kim, Choi and Shin37) . Similar to elderly cohorts, decreases in the relative abundance of SCFA producing Faecalibacterium have been reported in centenarians; however, the relative abundance of health promoting bacteria Akkermansia, Bifidobacterium and Christensellaceae is also commonly reported, perhaps promoting health benefits through functional redundancy(Reference Kim, Choi and Shin37,Reference Biagi, Franceschi and Rampelli38) . Wu et al. also reported that the functional profile of a centenarian gut microbiota was distinctly different than that of elderly and young adult participants, including increased SCFA pathways and altered amino acid metabolism(Reference Wu, Zeng and Zinellu36). Similar shifts in taxonomic and functional profiles were reported in a 2021 study in an elderly population(Reference Wilmanski, Diener and Rappaport39). The authors reported an increasingly unique microbiota composition with age, with a decrease in the relative abundance of Bacteroides, and increases in Christensellaceae, Methanobrevibacter and Desulfibrio in healthy participants, with these changes correlating with a decreased risk of mortality in participants over 85 years of age. Further, genus level uniqueness was associated with altered amino acid metabolism, with increases in phenylalanine/tyrosine and tryptophan metabolism(Reference Wilmanski, Diener and Rappaport39). Unfortunately, the cross-sectional nature of studies investigating the gut microbiota of elderly individuals and centenarians makes it impossible to ascertain if the certain taxa seen in healthy ageing are present in the earlier years of life and contribute to the longevity observed, or if the microbiota itself is a consequence of reaching extreme ageing.

Dietary intake and the gut microbiota

As research into the gut microbiota has developed, it has been widely accepted that an individual’s diet and lifestyle is one of the strongest modifiable factors that influences microbial richness, diversity and composition(Reference Singh, Chang and Yan40,Reference Conlon and Bird41) . The influence of diet has been studied over the past two decades, providing an understanding of how nutrition can promote the growth of certain microbial taxa by providing their preferred substrate, but many studies have focused on particular foods or select nutrients(Reference Creedon, Hung and Berry42,Reference So, Whelan and Rossi43) . There is an abundance of research identifying dietary fibre as a key modifier of gut microbiota composition by increasing the relative abundance of beneficial SCFA producers(Reference So, Whelan and Rossi43). As research continues to strengthen the role of the microbiota in host health and disease, additional foods and food components have begun to be investigated. Dietary fats have become of interest due to their ability to traverse the large intestine and colon intact, where they are metabolised by the local gut bacteria and potentially influence microbial composition. Until recently, the effects of high dietary fat intakes on the gut microbiota have failed to differentiate between the fatty acid profiles of meat-based Westernised diets and a plant-centred diet like the MedDiet, which includes high intakes of EVOO, n-3 fatty acids and nuts. While human studies have been scarce thus far, there is emerging evidence that due to its high concentration of phenolic compounds, EVOO can exert both prebiotic and antibacterial effects on the gut microbiota, resulting in increases in beneficial Lactobacillus and Bifidobacterium and decreases in the potentially pathogenic Staphylococcus (Reference Rodríguez-García, Sánchez-Quesada and Algarra44Reference Luisi, Lucarini and Biffi46). Recent intervention studies have also highlighted the beneficial impacts of n-3 fatty acids on the gut microbiota, showing that they are capable of increasing the relative abundance of SCFA producers in a similar fashion to that of fibre(Reference Watson, Mitra and Croden47,Reference Vijay, Astbury and Le Roy48) . Further, multiple studies investigating the effect of nuts on the gut microbiota have shown that almonds, pistachios and walnuts are all capable of exerting effects on the relative abundance of various gut bacteria. While differences in fatty acid composition between the three types of nuts present difficulties in providing conclusive results, the intake of high PUFA containing walnuts produced significant shifts in β-diversity in all three studies(Reference Bamberger, Rossmeier and Lechner49Reference Holscher, Guetterman and Swanson51). Additional foods that constitute a MedDiet that have been shown to modulate gut microbiota are dairy foods like milk and yogurt, and polyphenol-rich fruits, vegetables and red wine(Reference Aslam, Marx and Rocks52Reference Nash, Ranadheera and Georgousopoulou55). A sample of studies detailing the impacts of these foods on the gut microbiota can be found in Table 1.

Table 1. Summary of studies assessing the impact of Mediterranean diet component and a whole Mediterranean diet intervention on the human gut microbiota

MD, Mediterranean diet; MetS, metabolic syndrome.

Recently, there has been a shift towards investigating the role that whole dietary patterns and other lifestyle factors, including PA, play in establishing and modifying the human microbiota. So far, a number of studies have shown PA to be a novel influencer of microbiota composition; however, the mechanisms are not well understood(Reference Mailing, Allen and Buford56).

Effects of a Mediterranean diet and lifestyle on the gut microbiota

Research into the effect of a MedDiet and the microbiota is still in its infancy, with only a limited amount studies being published in the last 5 years. With its emphasis on wholegrains, fruits, vegetables and legumes, the MedDiet is an excellent source of complex carbohydrates and non-digestible fibre, preferentially used by certain microbes as a substrate to produce SCFA (e.g. butyrate) that are beneficial to host health(Reference Chambers, Preston and Frost57). In one of the earliest studies, De Filippis et al. compared the habitual diet of Italian vegans, vegetarians and omnivores regarding their MedDiet adherence and microbiota composition. While they found no significant difference in diversity across diet groups or adherence levels, those who showed higher adherence to a MedDiet reported higher levels of faecal SCFA(Reference De Filippis, Pellegrini and Vannini58). The relationship between MedDiet adherence and faecal SCFA has been corroborated in three subsequent cohort studies where researchers also found changes in the relative abundance of certain microbes(Reference Gutierrez-Diaz, Fernandez-Navarro and Sanchez59Reference Garcia-Mantrana, Selma-Royo and Alcantara61). These changes included an increase in F. prausnitzii, a known butyrate producer considered to have anti-inflammatory properties(Reference Li, van Esch and Henricks62), and lower levels of Escherichia coli, a well-known gut coloniser with pathogenic and inflammatory potential(Reference Kittana, Gomes-Neto and Heck63).

A recent observational study by Gallè and colleagues collected the habitual dietary habits, PA levels and microbiota composition of 140 Italian university students. A higher adherence to a MedDiet was associated with higher relative abundance of lactic acid bacteria(Reference Galle, Valeriani and Cattaruzza64), which have been previously demonstrated to be beneficial to human health through their ability to enhance metabolism, protect against infections in the gastrointestinal tract and the ability to modulate both allergy and inflammatory responses(Reference Pessione65). This relationship was also demonstrated in a 3-month intervention study where participants followed a MedDiet supplemented with 40 g of EVOO per day showed an increase in the relative abundance of lactic acid bacteria. The magnitude of this effect demonstrated greater significance in overweight and obese participants(Reference Luisi, Lucarini and Biffi46). Additional studies have highlighted the impact that participant obesity classification and metabolic status have on the gut microbiota’s response to a MedDiet. A 2019 study in elderly obese women following a hypoenergetic MedDiet for 15 d showed a significant increase in α-diversity in participants with obesity class II (35–39·9 kg/m2)(Reference Cancello, Turroni and Rampelli66), and in a subset of patients from the CORDIOPREV Study, where Haro and colleagues reported increases in the relative abundance of a number of species including F. prausnitzii and Bifidobacterium longum in the participants with the metabolic syndrome exclusively(Reference Haro, Garcia-Carpintero and Alcala-Diaz67).

Recently, a large intervention study by Ghosh et al. was part of the NU-AGE 12-month randomised clinical trial and investigated the effects of a tailored MedDiet in relation to the gut microbiota and frailty in elderly participants (n 612) across five European countries(Reference Ghosh, Rampelli and Jeffery68). While the authors reported no change in microbial diversity, there were changes in microbial composition that were positively associated with improved cognition and reduced frailty markers and negatively associated with inflammatory biomarkers C-reactive protein and IL-17. Many of the bacterial taxa associated with both adherence and inflammatory biomarkers were known SCFA producers. Similarly, the CARDIVEG study compared the gut microbiotas of participants after 3 months of either a Mediterranean or vegetarian diet and found significant changes in the relative abundance of several taxa in both groups. Interestingly, changes in the SCFA profile of the gut were observed exclusively in the MedDiet group(Reference Pagliai, Russo and Niccolai69). These changes were also negatively associated with levels of pro-inflammatory biomarkers (IL-17 and IL-12)(Reference Pagliai, Russo and Niccolai69), again highlighting the relationship between the gut microbiota, SCFA production and inflammation.

Smaller, more short-term intervention studies have highlighted that beneficial changes in the gut microbiota can even be achieved over a short period of time. Messiler et al. found changes in microbiota composition, and increases in gene richness and faecal SCFA levels within the first 4 weeks on the MedDiet intervention(Reference Meslier, Laiola and Roager70), while Zhu and colleagues reported an increase in bacteria capable of producing SCFA in just 4 d of a MedDiet(Reference Zhu, Sawrey-Kubicek and Beals71). While these studies give evidence that alterations in the relative abundance of certain species of bacteria can be achieved in a limited time frame, these changes are likely transient in nature. Dietary studies with a cross-over design or those including follow-up analyses have shown that the microbiota reverts to pre-study composition a few weeks after the cessation of the dietary intervention(Reference Burton, Rosikiewicz and Pimentel72Reference Shin, Jung and Kim74). A summary of the relevant studies can be found in Table 1.

Physical activity and the gut microbiota

Although there are numerous studies in murine models, research into the effects of PA on the gut microbiota of humans is limited to within the last decade. In the earliest study, Clarke et al. compared the gut microbiota of elite rugby players with that of healthy and high BMI control groups and the authors found increased microbiota diversity within the individual samples (α-diversity) of the rugby players, along with an increase in the relative abundance of several bacterial taxa, notably Akkermansia muciniphila (Reference Clarke, Murphy and O’Sullivan75), a mucin degrading bacteria from the Verrucomicrobia phylum involved in maintaining the integrity of the intestinal barrier, is negatively associated with impaired metabolic function and inflammation(Reference Derrien, Belzer and de Vos76). A. muciniphila abundance was also increased in the active participants of a 2017 study in premenopausal women, along with known butyrate producers F. prausnitzii and Roseburia hominis (Reference Bressa, Bailén-Andrino and Pérez-Santiago77). Other observational studies have also found correlations between levels of cardiovascular fitness and microbiota composition. Estaki et al. found increased α-diversity in participants with greater VO2 max (Reference Estaki, Pither and Baumeister78), while Durk et al. reported significant correlation between VO2 max and changes in the ratio of the two dominant phyla, Firmicutes and Bacteroidetes in a comparable population(Reference Durk, Castillo and Márquez-Magaña79). It should be noted that two of these studies reported significant dietary differences between groups, with the active participants having higher protein and fibre intakes than that of the controls. Consequently, the contribution of PA to the changes in the microbiota cannot be completely ascertained.

The small number of longitudinal studies on the topic so far have reported varying results. In a study conducted by Manukka and colleagues previously sedentary and overweight female participants (n 17) underwent 6 weeks of endurance exercise resulting in shifts in microbiota composition, including an increase in the relative abundance of the Akkermansia genus, but also noted that not all participants responded equally to the intervention(Reference Munukka, Ahtiainen and Puigbó80). A similarly designed study by Allen et al. that included lean and obese participants also reported changes in composition after the 6-week exercise period in the lean participants, with authors noting that changes were dependent on obesity status(Reference Allen, Mailing and Niemiro81). Contradictory evidence was found in another study looking at the effects of exercise and whey protein on the gut microbiota in overweight and obese participants (n 90), where no significant changes in composition were reported, potentially due to the varied obesity status of participants(Reference Cronin, Barton and Skuse82). More recent and shorter longitudinal studies have also failed to provide definitive evidence on the subject. Motaini et al. investigated the effect that 2 weeks of sprint interval training or moderate-intensity continuous training had on the microbiota of twenty-six previously sedentary participants and reported a decreased Firmicutes: Bacteroidetes ratio by an increase of the relative abundance of that both training modalities of Bacteroidetes. Interestingly, the two methods of training had distinctive effects on the relative abundance of certain species, with sprint interval training and moderate-intensity continuous training resulting in an increase in Lachnospira and F. prausnitzii, respectively(Reference Motiani, Collado and Eskelinen83). Conflicting results were reported in a 2020 study that found no significant changes in microbiota diversity or composition after 3 weeks of high intensity interval training in thirty-two male participants(Reference Rettedal, Cree and Adams84).

While there are several observational and longitudinal studies investigating the effects of PA on the microbiota, there is a paucity of evidence from randomised controlled trials outside of animal models. In one of the only randomised controlled trials conducted, Kern et al. implemented a 6-month trial comparing habitual PA and three exercise interventions: commute to work by bike, leisure time moderate exercise and leisure time vigorous exercise (n 88)(Reference Kern, Blond and Hansen85). While all three exercise groups had proportionate exercise-induced energy expenditure, increases in cardiorespiratory fitness and decreases in fat mass, only the vigorous exercise group showed a significant increase in α-diversity independent to fat mass and cardiorespiratory fitness. However, a potential limitation of this study as reported by the authors is that a change in dietary intake due to increased exercise cannot be ruled out as a contributing factor to microbiota composition changes.

Currently, there is limited research investigating the effects of PA on the elderly microbiota and studies so far have yielded varying results. In a 2017 cross-sectional study utilising data from the American Gut Project, Zhu et al. discovered a significant association between higher levels of self-reported PA and a decrease in microbiota α-diversity in overweight elderly (BMI > 25 kg/m) participants(Reference Zhu, Jiang and Du86). Interestingly, the authors also reported a positive association between α-diversity and increasing age, which contradicts numerous studies in the area(Reference Claesson, Jeffery and Conde28,Reference Biagi, Nylund and Candela31,Reference Claesson, Cusack and Sullivan32) . In contrast, a smaller cross-sectional study (n 373) of elderly men found no association between α-diversity and PA levels; however, changes in microbial composition were reported(Reference Langsetmo, Johnson and Demmer87) and Morita and colleagues compared 12 weeks of daily core muscle training or aerobic exercise on the gut microbiota of thirty-two elderly Japanese women, reporting a no change in α-diversity. However, significant increase in the relative abundance of Bacteroides was observed in the aerobic exercise group(Reference Morita, Yokoyama and Imai88). Studies detailing the impact of PA can be found in Table 2.

Table 2. Summary studies assessing the impact of physical activity status or an exercise intervention on the human gut microbiota

Gut microbiota in immune regulation and inflammation

The gut microbiota plays a crucial role in the development, maturation and regulation of the immune system. This intricate relationship begins at birth, where the immature immune system allows for the colonisation and expansion of the microbiota without inflammatory consequence, and immunological sensing of microbial molecules and metabolites allows for the development of food antigen tolerance and protective defences against pathogens concomitantly(Reference Belkaid and Hand Timothy89,Reference Penders, Stobberingh and Brandt90) . Perturbations in the development of the early relationship can have detrimental impacts on long-term health(Reference Arrieta, Stiemsma and Amenyogbe91). Given this interdependent relationship, age-related modifications of the gut microbiota may play a crucial role in the inflammation of ageing.

Studies directly investigating the effect of microbiota composition on inflammatory status have mostly been limited to animal models but have provided evidence that the aged microbiota can increase intestinal inflammation and permeability, and promote infiltration of microbes and microbial products into systemic circulation, which in turn can elevate pro-inflammatory biomarkers such as TNF-α and IL-6(Reference Spychala, Venna and Jandzinski92Reference Thevaranjan, Puchta and Schulz94). A human study analysing the gut microbiota of three age groups of Italian individuals reported major changes in the centenarian microbiota. Compared with younger cohorts, centenarians showed increases in the phyla Proteobacteria, which have been linked to increased inflammation and the onset of human disease and decreased relative abundance of F. prausnitzii and other SCFA producers. These changes were associated with increases in pro-inflammatory cytokines IL-6 and IL-8(Reference Biagi, Nylund and Candela31,Reference Rizzatti, Lopetuso and Gibiino95) .

While the 2020 study by Ghosh and colleagues focused on the impact of a MedDiet on the gut microbiota, frailty and health outcomes, it also highlights the relationship between the microbial composition of elderly participants and their inflammatory status. The diet positive taxa identified were negatively associated with the levels of C-reactive protein and IL-17(Reference Ghosh, Rampelli and Jeffery68). These results strengthen the theory that gut microbiota composition has an impact on inflammatory outcomes and demonstrate the ability of a MedDiet to induce favourable changes in the ageing gut microbiota.

Microbiota-mediated impacts on inflammation can occur in multiple pathways through various systems, molecules, receptors and cells. The high dietary fibre content of the MedDiet gives rise to an increase in SCFA, the most investigated microbial metabolites, which are capable of acting both locally and systemically. In the gut, they play a critical role in maintaining the integrity of the intestinal barrier as they provide an energy source for colonocytes and have a regulatory role in the expression of tight junction proteins(Reference Peng, Li and Green96). As seen in murine models, if the intestinal barrier is compromised, potentially harmful microbes and microbial products can infiltrate systemic circulation, inducing the inflammatory response and contributing to immune dysregulation(Reference Fransen, van Beek and Borghuis93,Reference Thevaranjan, Puchta and Schulz94) . Further, SCFA also promote the conversion of naïve T cells into forkhead box P3 (Foxp3+) and IL-10 secreting regulatory T cells (Tregs) and interact with intestinal and peripheral innate immune cells via inhibitory effects on histone deacetylase and NF-κB, leading to down-regulation of gene expression for pro-inflammatory cytokines like TNF-α, IL-6 and IL-1(Reference Li, van Esch and Henricks62,Reference Vinolo, Rodrigues and Nachbar97) . Recent work has begun to investigate the microbial metabolites of additional substrates including dietary polyphenols and amino acids. The majority of dietary polyphenols, known for their antioxidant and anti-inflammatory potential, reach the large intestine intact where they undergo transformation into bioavailable compounds by the gut microbiota(Reference Man, Zhou and Xia98,Reference Pandey and Rizvi99) . These compounds, including protocatechuic acid and urolithins, are able to enter circulation and influence the inflammatory response through mitogen-activated protein kinase and NF-κB pathways(Reference González-Sarrías, Larrosa and Tomás-Barberán100,Reference Zheng, Li and He101) . Additionally, the gut microbiota plays a central role in the metabolism of the amino acid tryptophan into various catabolites including kynurenine, indolic compounds, tryptamine and serotonin(Reference Bosi, Banfi and Bistoletti102). The majority of dietary tryptophan is fed into the kynurenine pathway, leading to the creation of various end products that are involved in a host of physiological responses including neurotransmission, and immune system and inflammatory regulation(Reference Bosi, Banfi and Bistoletti102,Reference Agus, Planchais and Sokol103) . One mechanism by which this is achieved is through the activation of the aryl hydrocarbon receptors that are highly expressed in immune cells. The activation of aryl hydrocarbon receptors plays an essential role in T cell differentiation into immunomodulatory Tregs, leading to the down-regulation of inflammation(Reference Man, Zhou and Xia98,Reference Mezrich, Fechner and Zhang104) . The relationship between the kynurenine pathway, gut microbiota and the immune system is complex, with inflammatory mediator and microbiota signalling impacting the production of kynurenine pathway end products(Reference Kennedy, Cryan and Dinan105,Reference Dehhaghi, Kazemi Shariat Panahi and Guillemin106) . This tri-directional communication warrants further research to fully elucidate clinical implications.

In addition to the direct interaction with immune cells, the gut microbiota also engages in bidirectional communication with the brain via the gut–brain axis that is comprised of neural, endocrine, immune and metabolic pathways. Initial research focused on the role of the gut–brain axis in hunger and satiety signalling but has now expanded to exploring its role in conditions including irritable bowel syndrome, depression and anxiety, autism spectrum disorder and neurodegenerative diseases(Reference Dinan and Cryan107Reference Meguid, Yang and Gleason109). One way in which the gut–brain axis can influence inflammation is through the cholinergic anti-inflammatory pathway(Reference Pavlov and Tracey110). The vagus nerve, which is comprised of both afferent and efferent nerve fibres, has fibres that innervate the intestinal wall. While these fibres do not extend into the intestinal lumen, microbial compounds and metabolites can diffuse across the gut barrier where they can activate the vagus nerve, with the resulting signal is processed by the central nervous system(Reference Bonaz, Bazin and Pellissier111). The proceeding efferent signalling of the vagus nerve results in decreased cytokine secretion by immune cells, including macrophages, dendritic cells and T-cells, through the binding of the neurotransmitter acetylcholine to their nicotinic receptors, heavily influencing intestinal homoeostasis and immune responses(Reference Bonaz, Bazin and Pellissier111,Reference Breit, Kupferberg and Rogler112) .

Knowledge gaps and future directions

The current breath of evidence suggests that both a MedDiet and PA may modulate the gut microbiota composition in a way that is beneficial to host health. However, the majority of studies have been cross-sectional or longitudinal in design and have had wide variation in duration, participant characteristics and outcome measurements, making conclusions regarding causality challenging. There is a definitive need for further well-designed RTC to elucidate a sufficient understanding of the topic. There is also a current gap in the literature investigating the combined effect of these interventions, and to identify any synergistic effects this combination may have on microbiota composition.

Changes in the composition and function of the ageing microbiota have been well demonstrated in the literature so far, and further investigation into the association of these perturbations and the chronic inflammation seen in ageing is warranted. So far, only the NU-AGE project has evaluated the effect of the MedDiet, microbiota and healthy ageing outcomes and additional studies are required to build a body of knowledge capable of influencing healthy ageing strategies.

Conclusion

There is an abundance of literature demonstrating the health benefits of a MedDiet and lifestyle through various stages of life. Comprised of high intakes of fibre, polyphenols and beneficial fatty acids, it is plausible that some of these benefits can be attributed to gut microbiota modulation. As research continues, the role of the gut microbiota in human health is being further elucidated and the intricate relationship between the gut microbiota and the immune system has been brought to the forefront. Although the aetiology of age-related diseases is multi-factorial in nature, involving a multitude of molecular mechanisms, we propose that the beneficial modification of the ageing gut microbiota by utilising a combination of a MedDiet and PA may be a powerful strategy in attenuating age-related inflammation and improving health during a person’s later years of life.

Acknowledgements

We would like to thank the team at APC Microbiome, University College Cork, Ireland for their advice and guidance regarding the microbiome content of this review. This research received no external funding but was completed as part of a Research Training Program (RTP) and postgraduate degree at the University of South Australia.

J. S. C., K. J. M. and B. S. S. contributed to the concept of the review, J. S. C. performed the review and J. S. C., K. J. M. and B. S. S. edited draft and approved the final version.

The authors declare no conflicts of interest.

References

Michaud, M, Balardy, L, Moulis, G, et al. (2013) Proinflammatory cytokines, aging, and age-related diseases. J Am Med Director Assoc 14, 877882.CrossRefGoogle ScholarPubMed
Chen, L, Deng, H, Cui, H, et al. (2017) Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9, 72047218.CrossRefGoogle ScholarPubMed
Medzhitov, R (2010) Inflammation 2010: new adventures of an old flame. Cell 140, 771776.CrossRefGoogle ScholarPubMed
Franceschi, C, Bonafe, M, Valensin, S, et al. (2000) Inflamm-aging: an evolutionary perspective on immunosenescence. Ann NY Acad Sci 908, 244254.CrossRefGoogle ScholarPubMed
Forsey, RJ, Thompson, JM, Ernerudh, J, et al. (2003) Plasma cytokine profiles in elderly humans. Mech Ageing Dev 124, 487493.CrossRefGoogle ScholarPubMed
Wei, J, Xu, H, Davies, JL, et al. (1992) Increase of plasma IL-6 concentration with age in healthy subjects. Life Sci 51, 19531956.CrossRefGoogle ScholarPubMed
Rea, IM, Gibson, DS, McGilligan, V, et al. (2018) Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol 9, 586.CrossRefGoogle Scholar
Sofi, F, Abbate, R, Gensini, GF, et al. (2010) Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr 92, 11891196.CrossRefGoogle Scholar
Davis, C, Bryan, J, Hodgson, J, et al. (2015) Definition of the Mediterranean diet; a literature review. Nutrients 7, 91399153.CrossRefGoogle ScholarPubMed
Menotti, A & Puddu, PE (2015) How the Seven Countries Study contributed to the definition and development of the Mediterranean diet concept: a 50-year journey. Nutr Metab Cardiovasv Dis: NMCD 25, 245252.CrossRefGoogle Scholar
Hatzis, CM, Papandreou, C, Patelarou, E, et al. (2013) A 50-year follow-up of the Seven Countries Study: prevalence of cardiovascular risk factors, food and nutrient intakes among Cretans. Hormones 12, 379385.CrossRefGoogle ScholarPubMed
Kromhout, D, Menotti, A, Alberti-Fidanza, A, et al. (2018) Comparative ecologic relationships of saturated fat, sucrose, food groups, and a Mediterranean food pattern score to 50-year coronary heart disease mortality rates among 16 cohorts of the Seven Countries Study. Eur J Clin Nutr 72, 11031110.CrossRefGoogle Scholar
Fidanza, F, Alberti, A, Lanti, M, et al. (2004) Mediterranean Adequacy Index: correlation with 25-year mortality from coronary heart disease in the Seven Countries Study. Nutr Metab Cardiovasc Dis: NMCD 14, 254258.CrossRefGoogle ScholarPubMed
Tosti, V, Bertozzi, B & Fontana, L (2018) Health benefits of the Mediterranean diet: metabolic and molecular mechanisms. J Gerontol: Series A 73, 318326.CrossRefGoogle ScholarPubMed
Thorburn Alison, N, Macia, L & Mackay Charles, R (2014) Diet, metabolites, and ‘western-lifestyle’ inflammatory diseases. Immunity 40, 833842.CrossRefGoogle ScholarPubMed
Trichopoulou, A & Lagiou, P (1997) Healthy traditional Mediterranean diet: an expression of culture, history, and lifestyle. Nutr Rev 55, 383389.CrossRefGoogle ScholarPubMed
Bach-Faig, A, Berry, EM, Lairon, D, et al. (2011) Mediterranean diet pyramid today. Science and cultural updates. Public Health Nutr 14, 22742284.CrossRefGoogle ScholarPubMed
Dinu, M, Pagliai, G, Casini, A, et al. (2018) Mediterranean diet and multiple health outcomes: an umbrella review of meta-analyses of observational studies and randomised trials. Eur J Clin Nutr 72, 3043.CrossRefGoogle ScholarPubMed
Barrea, L, Muscogiuri, G, Di Somma, C, et al. (2019) Association between Mediterranean diet and hand grip strength in older adult women. Clin Nutr 38, 721729.CrossRefGoogle ScholarPubMed
Kelaiditi, E, Jennings, A, Steves, CJ, et al. (2016) Measurements of skeletal muscle mass and power are positively related to a Mediterranean dietary pattern in women. Osteoporos Int 27, 32513260.CrossRefGoogle ScholarPubMed
Milaneschi, Y, Bandinelli, S, Corsi, AM, et al. (2011) Mediterranean diet and mobility decline in older persons. Exp Gerontol 46, 303308.CrossRefGoogle ScholarPubMed
Christakis, G, Severinghaus, EL, Maldonado, Z, et al. (1965) Crete: a study in the metabolic epidemiology of coronary heart disease. Am J Cardiol 15, 320332.CrossRefGoogle Scholar
Owen, N, Sparling, PB, Healy, GN, et al. (2010) Sedentary behavior: emerging evidence for a new health risk. Mayo Clin Proc 85, 11381141.CrossRefGoogle ScholarPubMed
Warburton, DER & Bredin, SSD (2017) Health benefits of physical activity: a systematic review of current systematic reviews. Curr Opin Cardiol 32, 541556.CrossRefGoogle ScholarPubMed
Turnbaugh, PJ, Ley, RE, Hamady, M, et al. (2007) The human microbiome project. Nature 449, 804810.CrossRefGoogle ScholarPubMed
Huttenhower, C, Gevers, D, Knight, R, et al. (2012) Structure, function and diversity of the healthy human microbiome. Nature 486, 207214.Google Scholar
Wang, Z & Zhao, Y (2018) Gut microbiota derived metabolites in cardiovascular health and disease. Protein Cell 9, 416431.CrossRefGoogle ScholarPubMed
Claesson, MJ, Jeffery, IB, Conde, S, et al. (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178184.CrossRefGoogle ScholarPubMed
Rodríguez, JM, Murphy, K, Stanton, C, et al. (2015) The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis 26, 26050.Google ScholarPubMed
Vemuri, R, Gundamaraju, R, Shastri, MD, et al. (2018) Gut microbial changes, interactions, and their implications on human lifecycle: an ageing perspective. Biomed Res Int 2018, 4178607.CrossRefGoogle ScholarPubMed
Biagi, E, Nylund, L, Candela, M, et al. (2010) Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 5, e10667.CrossRefGoogle ScholarPubMed
Claesson, MJ, Cusack, S, Sullivan, O, et al. (2011) Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci 108, 4586.CrossRefGoogle ScholarPubMed
Zwielehner, J, Liszt, K, Handschur, M, et al. (2009) Combined PCR-DGGE fingerprinting and quantitative-PCR indicates shifts in fecal population sizes and diversity of Bacteroides, bifidobacteria and Clostridium cluster IV in institutionalized elderly. Exp Gerontol 44, 440446.CrossRefGoogle ScholarPubMed
Rampelli, S, Candela, M, Turroni, S, et al. (2013) Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging 5, 902912.CrossRefGoogle ScholarPubMed
Mueller, S, Saunier, K, Hanisch, C, et al. (2006) Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study. Appl Environ Microbiol 72, 1027.CrossRefGoogle ScholarPubMed
Wu, L, Zeng, T, Zinellu, A, et al. (2019) A cross-sectional study of compositional and functional profiles of gut microbiota in Sardinian Centenarians. mSystems 4, e00325.CrossRefGoogle ScholarPubMed
Kim, BS, Choi, CW, Shin, H, et al. (2019) Comparison of the gut microbiota of centenarians in longevity villages of South Korea with those of other age groups. J Microbiol Biotechnol 29, 429440.CrossRefGoogle ScholarPubMed
Biagi, E, Franceschi, C, Rampelli, S, et al. (2016) Gut microbiota and extreme longevity. Curr Biol 26, 14801485.CrossRefGoogle ScholarPubMed
Wilmanski, T, Diener, C, Rappaport, N, et al. (2021) Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab 3, 274286.CrossRefGoogle ScholarPubMed
Singh, RK, Chang, H-W, Yan, D, et al. (2017) Influence of diet on the gut microbiome and implications for human health. J Transl Med 15, 73.CrossRefGoogle ScholarPubMed
Conlon, MA & Bird, AR (2014) The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7, 1744.CrossRefGoogle ScholarPubMed
Creedon, AC, Hung, ES, Berry, SE, et al. (2020) Nuts and their effect on gut microbiota, gut function and symptoms in adults: a systematic review and meta-analysis of randomised controlled trials. Nutrients 12, 2347.CrossRefGoogle ScholarPubMed
So, D, Whelan, K, Rossi, M, et al. (2018) Dietary fiber intervention on gut microbiota composition in healthy adults: a systematic review and meta-analysis. Am J Clin Nutr 107, 965983.CrossRefGoogle ScholarPubMed
Rodríguez-García, C, Sánchez-Quesada, C, Algarra, I, et al. (2020) The high-fat diet based on extra-virgin olive oil causes dysbiosis linked to colorectal cancer prevention. Nutrients 12, 1705.CrossRefGoogle ScholarPubMed
Farràs, M, Martinez-Gili, L, Portune, K, et al. (2020) Modulation of the gut microbiota by olive oil phenolic compounds: implications for lipid metabolism, immune system, and obesity. Nutrients 12, 2200.CrossRefGoogle ScholarPubMed
Luisi, MLE, Lucarini, L, Biffi, B, et al. (2019) Effect of Mediterranean diet enriched in high quality extra virgin olive oil on oxidative stress, inflammation and gut microbiota in obese and normal weight adult subjects. Front Pharmacol 10, 1366.CrossRefGoogle ScholarPubMed
Watson, H, Mitra, S, Croden, FC, et al. (2018) A randomised trial of the effect of n-3 polyunsaturated fatty acid supplements on the human intestinal microbiota. Gut 67, 1974.CrossRefGoogle ScholarPubMed
Vijay, A, Astbury, S, Le Roy, C, et al. (2021) The prebiotic effects of n-3 fatty acid supplementation: a six-week randomised intervention trial. Gut Microbes 13, 111.CrossRefGoogle ScholarPubMed
Bamberger, C, Rossmeier, A, Lechner, K, et al. (2018) A walnut-enriched diet affects gut microbiome in healthy Caucasian subjects: a randomized, controlled trial. Nutrients 10, 244.CrossRefGoogle ScholarPubMed
García-Mantrana, I, Calatayud, M, Romo-Vaquero, M, et al. (2019) Urolithin metabotypes can determine the modulation of gut microbiota in healthy individuals by tracking walnuts consumption over three days. Nutrients 11, 2483.CrossRefGoogle ScholarPubMed
Holscher, HD, Guetterman, HM, Swanson, KS, et al. (2018) Walnut consumption alters the gastrointestinal microbiota, microbially derived secondary bile acids, and health markers in healthy adults: a randomized controlled trial. J Nutr 148, 861867.CrossRefGoogle ScholarPubMed
Aslam, H, Marx, W, Rocks, T, et al. (2020) The effects of dairy and dairy derivatives on the gut microbiota: a systematic literature review. Gut Microbe 12, 1799533.CrossRefGoogle ScholarPubMed
Moco, S, Martin, F-PJ & Rezzi, S (2012) Metabolomics view on gut microbiome modulation by polyphenol-rich foods. J Proteome Res 11, 47814790.CrossRefGoogle ScholarPubMed
Tuohy, KM, Conterno, L, Gasperotti, M, et al. (2012) Up-regulating the human intestinal microbiome using whole plant foods, polyphenols, and/or fiber. J Agr Food Chem 60, 87768782.CrossRefGoogle ScholarPubMed
Nash, V, Ranadheera, CS, Georgousopoulou, EN, et al. (2018) The effects of grape and red wine polyphenols on gut microbiota – a systematic review. Food Res Int 113, 277287.CrossRefGoogle ScholarPubMed
Mailing, LJ, Allen, JM, Buford, TW, et al. (2019) Exercise and the gut microbiome: a review of the evidence, potential mechanisms, and implications for human health. Exerc Sport Sci Rev 47, 7585.CrossRefGoogle ScholarPubMed
Chambers, ES, Preston, T, Frost, G, et al. (2018) Role of gut microbiota-generated short-chain fatty acids in metabolic and cardiovascular. Health Curr Nutr Rep 7, 198206.CrossRefGoogle ScholarPubMed
De Filippis, F, Pellegrini, N, Vannini, L, et al. (2016) High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut 65, 18121821.CrossRefGoogle ScholarPubMed
Gutierrez-Diaz, I, Fernandez-Navarro, T, Sanchez, B, et al. (2016) Mediterranean diet and faecal microbiota: a transversal study. Food Funct 7, 23472356.CrossRefGoogle ScholarPubMed
Mitsou, EK, Kakali, A, Antonopoulou, S, et al. (2017) Adherence to the Mediterranean diet is associated with the gut microbiota pattern and gastrointestinal characteristics in an adult population. Br J Nutr 117, 16451655.CrossRefGoogle Scholar
Garcia-Mantrana, I, Selma-Royo, M, Alcantara, C, et al. (2018) Shifts on gut microbiota associated to Mediterranean diet adherence and specific dietary intakes on general adult population. Front Microbiol 9, 890.CrossRefGoogle ScholarPubMed
Li, M, van Esch, BCAM, Henricks, PAJ, et al. (2018) The anti-inflammatory effects of short chain fatty acids on lipopolysaccharide- or tumor necrosis factor α-stimulated endothelial cells via activation of GPR41/43 and inhibition of HDACs. Front Pharmacol 9, 533.CrossRefGoogle ScholarPubMed
Kittana, H, Gomes-Neto, JC, Heck, K, et al. (2018) Commensal Escherichia coli strains can promote intestinal inflammation via differential interleukin-6. Production 9, 2318.Google ScholarPubMed
Galle, F, Valeriani, F, Cattaruzza, MS, et al. (2020) Mediterranean diet, physical activity and gut microbiome composition: a cross-sectional study among healthy young Italian adults. Nutrients 12, 2164.CrossRefGoogle ScholarPubMed
Pessione, E (2012) Lactic acid bacteria contribution to gut microbiota complexity: lights and shadows. Front Cell Infect Microbio 2, 86.Google ScholarPubMed
Cancello, R, Turroni, S, Rampelli, S, et al. (2019) Effect of short-term dietary intervention and probiotic mix supplementation on the gut microbiota of elderly obese women. Nutrients 11, 3011.CrossRefGoogle ScholarPubMed
Haro, C, Garcia-Carpintero, S, Alcala-Diaz, JF, et al. (2016) The gut microbial community in metabolic syndrome patients is modified by diet. J Nutr Biochem 27, 2731.CrossRefGoogle ScholarPubMed
Ghosh, TS, Rampelli, S, Jeffery, IB, et al. (2020) Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries. Gut 69, 12181228.CrossRefGoogle ScholarPubMed
Pagliai, G, Russo, E, Niccolai, E, et al. (2020) Influence of a 3-month low-calorie Mediterranean diet compared to the vegetarian diet on human gut microbiota and SCFA: the CARDIVEG Study. Eur J Nutr 59, 20112024.CrossRefGoogle Scholar
Meslier, V, Laiola, M, Roager, HM, et al. (2020) Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake. Gut 69, 12581268.CrossRefGoogle ScholarPubMed
Zhu, C, Sawrey-Kubicek, L, Beals, E, et al. (2020) Human gut microbiome composition and tryptophan metabolites were changed differently by fast food and Mediterranean diet in 4 d: a pilot study. Nutr Res 77, 6272.CrossRefGoogle Scholar
Burton, KJ, Rosikiewicz, M, Pimentel, G, et al. (2017) Probiotic yogurt and acidified milk similarly reduce postprandial inflammation and both alter the gut microbiota of healthy, young men. Br J Nutr 117, 13121322.CrossRefGoogle ScholarPubMed
Kellingray, L, Tapp, HS, Saha, S, et al. (2017) Consumption of a diet rich in Brassica vegetables is associated with a reduced abundance of sulphate-reducing bacteria: a randomised crossover study. Mol Nutr Food Res 61, 1600992.CrossRefGoogle Scholar
Shin, J-H, Jung, S, Kim, S-A, et al. (2019) Differential effects of typical Korean v. American-style diets on gut microbial composition and metabolic profile in healthy overweight Koreans: a randomized crossover trial. Nutrients 11, 2450.CrossRefGoogle Scholar
Clarke, SF, Murphy, EF, O’Sullivan, O, et al. (2014) Exercise and associated dietary extremes impact on gut microbial diversity. Gut 63, 19131920.CrossRefGoogle ScholarPubMed
Derrien, M, Belzer, C & de Vos, WM (2017) Akkermansia muciniphila and its role in regulating host functions. Microb Pathogenesis 106, 171181.CrossRefGoogle ScholarPubMed
Bressa, C, Bailén-Andrino, M, Pérez-Santiago, J, et al. (2017) Differences in gut microbiota profile between women with active lifestyle and sedentary women. PLoS One 12, e0171352.CrossRefGoogle ScholarPubMed
Estaki, M, Pither, J, Baumeister, P, et al. (2016) Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions. Microbiome 4, 42.CrossRefGoogle ScholarPubMed
Durk, RP, Castillo, E, Márquez-Magaña, L, et al. (2019) Gut microbiota composition is related to cardiorespiratory fitness in healthy young adults. Int J Sport Nutr Exerc Metab 29, 249253.CrossRefGoogle ScholarPubMed
Munukka, E, Ahtiainen, JP, Puigbó, P, et al. (2018) Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women. Front Microbiol 9, 2323.CrossRefGoogle Scholar
Allen, JM, Mailing, LJ, Niemiro, GM, et al. (2018) Exercise alters gut microbiota composition and function in lean and obese humans. Med Sci Sports Exerc 50, 747757.CrossRefGoogle ScholarPubMed
Cronin, O, Barton, W, Skuse, P, et al. (2018) A prospective metagenomic and metabolomic analysis of the impact of exercise and/or whey protein supplementation on the gut microbiome of sedentary adults. mSystems 3, e00044.CrossRefGoogle ScholarPubMed
Motiani, KK, Collado, MC, Eskelinen, J-J, et al. (2020) Exercise training modulates gut microbiota profile and improves endotoxemia. Med Sci Sport Exerc 52, 94104.CrossRefGoogle ScholarPubMed
Rettedal, EA, Cree, JME, Adams, SE, et al. (2020) Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men. Exp Physiol 105, 12681279.CrossRefGoogle ScholarPubMed
Kern, T, Blond, MB, Hansen, TH, et al. (2020) Structured exercise alters the gut microbiota in humans with overweight and obesity – a randomized controlled trial. Int J Obes 44, 125135.CrossRefGoogle ScholarPubMed
Zhu, Q, Jiang, S & Du, G (2020) Effects of exercise frequency on the gut microbiota in elderly individuals. MicrobiologyOpen 9, e1053.CrossRefGoogle ScholarPubMed
Langsetmo, L, Johnson, A, Demmer, RT, et al. (2019) The association between objectively measured physical activity and the gut microbiome among older community dwelling men. J Nutr Health Aging 23, 538546.CrossRefGoogle ScholarPubMed
Morita, E, Yokoyama, H, Imai, D, et al. (2019) Aerobic exercise training with brisk walking increases intestinal bacteroides in healthy elderly women. Nutrients 11, 868.CrossRefGoogle ScholarPubMed
Belkaid, Y & Hand Timothy, W (2014) Role of the microbiota in immunity and inflammation. Cell 157, 121141.CrossRefGoogle ScholarPubMed
Penders, J, Stobberingh, EE, Brandt, PV, et al. (2007) The role of the intestinal microbiota in the development of atopic disorders. Allergy 62, 12231236.CrossRefGoogle ScholarPubMed
Arrieta, M-C, Stiemsma, LT, Amenyogbe, N, et al. (2014) The intestinal microbiome in early life: health and disease. Front Immunol 5, 427.CrossRefGoogle ScholarPubMed
Spychala, MS, Venna, VR, Jandzinski, M, et al. (2018) Age-related changes in the gut microbiota influence systemic inflammation and stroke outcome. Ann Neurol 84, 2336.CrossRefGoogle ScholarPubMed
Fransen, F, van Beek, AA, Borghuis, T, et al. (2017) Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol 8, 1385.CrossRefGoogle ScholarPubMed
Thevaranjan, N, Puchta, A, Schulz, C, et al. (2017) Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21, 45566.e4.CrossRefGoogle ScholarPubMed
Rizzatti, G, Lopetuso, LR, Gibiino, G, et al. (2017) Proteobacteria: a common factor in human diseases. Biomed Res Int 2017, 9351507.CrossRefGoogle ScholarPubMed
Peng, L, Li, Z-R, Green, RS, et al. (2009) Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr 139, 16191625.CrossRefGoogle ScholarPubMed
Vinolo, MAR, Rodrigues, HG, Nachbar, RT, et al. (2011) Regulation of inflammation by short chain fatty acids. Nutrients 3, 858876.CrossRefGoogle Scholar
Man, AWC, Zhou, Y, Xia, N, et al. (2020) Involvement of gut microbiota, microbial metabolites and interaction with polyphenol in host immunometabolism. Nutrients 12, 3054.CrossRefGoogle ScholarPubMed
Pandey, KB & Rizvi, SI (2009) Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev 2, 270278.CrossRefGoogle ScholarPubMed
González-Sarrías, A, Larrosa, M, Tomás-Barberán, FA, et al. (2010) NF-κB-dependent anti-inflammatory activity of urolithins, gut microbiota ellagic acid-derived metabolites, in human colonic fibroblasts. Br J Nutr 104, 503512.CrossRefGoogle ScholarPubMed
Zheng, J, Li, Q, He, L, et al. (2020) Protocatechuic acid inhibits vulnerable atherosclerotic lesion progression in older apoe-/- mice. J Nutr 150, 11671177.CrossRefGoogle ScholarPubMed
Bosi, A, Banfi, D, Bistoletti, M, et al. (2020) Tryptophan metabolites along the microbiota-gut-brain axis: an interkingdom communication system influencing the gut in health and disease. Int J Tryptophan Research 13, 1178646920928984.CrossRefGoogle ScholarPubMed
Agus, A, Planchais, J & Sokol, H (2018) Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23, 716724.CrossRefGoogle ScholarPubMed
Mezrich, JD, Fechner, JH, Zhang, X, et al. (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185, 31903198.CrossRefGoogle ScholarPubMed
Kennedy, PJ, Cryan, JF, Dinan, TG, et al. (2017) Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology 112, 399412.CrossRefGoogle ScholarPubMed
Dehhaghi, M, Kazemi Shariat Panahi, H & Guillemin, GJ (2019) Microorganisms, tryptophan metabolism, and kynurenine pathway: a complex interconnected loop influencing human health status. Int J Tryptophan Res 12, 1178646919852996.CrossRefGoogle ScholarPubMed
Dinan, TG & Cryan, JF (2017) The microbiome-gut-brain axis in health and disease. Gastroenterol Clin North Am 46, 7789.CrossRefGoogle ScholarPubMed
Mayer, EA (2011) Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 12, 453466.CrossRefGoogle ScholarPubMed
Meguid, MM, Yang, Z-J & Gleason, JR (1996) The gut-brain brain-gut axis in anorexia: toward an understanding of food intake regulation. Nutrition 12, S57S62.CrossRefGoogle ScholarPubMed
Pavlov, VA & Tracey, KJ (2005) The cholinergic anti-inflammatory pathway. Brain Behav Immun 19, 493499.CrossRefGoogle ScholarPubMed
Bonaz, B, Bazin, T & Pellissier, S (2018) The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci 12, 49.CrossRefGoogle ScholarPubMed
Breit, S, Kupferberg, A, Rogler, G, et al. (2018) Vagus nerve as modulator of the brain–gut axis in psychiatric and inflammatory disorders. Front Psychiatr 9, 44.CrossRefGoogle ScholarPubMed
Balfegó, M, Canivell, S, Hanzu, FA, et al. (2016) Effects of sardine-enriched diet on metabolic control, inflammation and gut microbiota in drug-naïve patients with type 2 diabetes: a pilot randomized trial. Lipids Health Dis 15, 78.CrossRefGoogle ScholarPubMed
Menni, C, Zierer, J, Pallister, T, et al. (2017) n-3 fatty acids correlate with gut microbiome diversity and production of N-carbamylglutamate in middle aged and elderly women. Sci Rep 7, 11079.CrossRefGoogle ScholarPubMed
Noriega, BS, Sanchez-Gonzalez, MA, Salyakina, D, et al. (2016) Understanding the impact of n-3 rich diet on the gut microbiota. Case Rep Med 2016, 3089303.CrossRefGoogle Scholar
Dhillon, J, Li, Z & Ortiz, RM (2019) Almond snacking for 8 weeks increases alpha-diversity of the gastrointestinal microbiome and decreases bacteroides fragilis abundance compared with an isocaloric snack in college freshmen. Curr Dev Nutr 3, nzz079.CrossRefGoogle Scholar
Burns, AM, Zitt, MA, Rowe, CC, et al. (2016) Diet quality improves for parents and children when almonds are incorporated into their daily diet: a randomized, crossover study. Nutr Res 36, 8089.CrossRefGoogle Scholar
Ukhanova, M, Wang, X, Baer, D, et al. (2014) Effects of almond and pistachio consumption on gut microbiota composition in a randomised cross-over human feeding study. Br J Nutr 111, 17.CrossRefGoogle Scholar
Roager, HM, Vogt, JK, Kristensen, M, et al. (2019) Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial. Gut 68, 8393.CrossRefGoogle ScholarPubMed
Ampatzoglou, A, Atwal, KK, Maidens, CM, et al. (2015) Increased whole grain consumption does not affect blood biochemistry, body composition, or gut microbiology in healthy, low-habitual whole grain consumers. J Nutr 145, 215221.CrossRefGoogle ScholarPubMed
Christensen, EG, Licht, TR, Kristensen, M, et al. (2013) Bifidogenic effect of whole-grain wheat during a 12-week energy-restricted dietary intervention in postmenopausal women. Eur J Clin Nutr 67, 13161321.CrossRefGoogle ScholarPubMed
Costabile, A, Klinder, A, Fava, F, et al. (2008) Whole-grain wheat breakfast cereal has a prebiotic effect on the human gut microbiota: a double-blind, placebo-controlled, crossover study. Br J Nutr 99, 110120.CrossRefGoogle Scholar
Martínez, I, Lattimer, JM, Hubach, KL, et al. (2013) Gut microbiome composition is linked to whole grain-induced immunological improvements. ISME J 7, 269280.CrossRefGoogle ScholarPubMed
Shinohara, K, Ohashi, Y, Kawasumi, K, et al. (2010) Effect of apple intake on fecal microbiota and metabolites in humans. Anaerobe 16, 510515.CrossRefGoogle ScholarPubMed
Hiel, S, Bindels, LB, Pachikian, BD, et al. (2019) Effects of a diet based on inulin-rich vegetables on gut health and nutritional behavior in healthy humans. Am J Clin Nutr 109, 16831695.CrossRefGoogle ScholarPubMed
Kopf, JC, Suhr, MJ, Clarke, J, et al. (2018) Role of whole grains v. fruits and vegetables in reducing subclinical inflammation and promoting gastrointestinal health in individuals affected by overweight and obesity: a randomized controlled trial. Nutr J 17, 72.CrossRefGoogle Scholar
Jiang, Z, Sun, T-Y, He, Y, et al. (2020) Dietary fruit and vegetable intake, gut microbiota, and type 2 diabetes: results from two large human cohort studies. BMC Med 18, 371.CrossRefGoogle ScholarPubMed
Partula, V, Mondot, S, Torres, MJ, et al. (2019) Associations between usual diet and gut microbiota composition: results from the Milieu Intérieur cross-sectional study. Am J Clin Nutr 109, 14721483.CrossRefGoogle ScholarPubMed
Moreno-Indias, I, Sánchez-Alcoholado, L, Pérez-Martínez, P, et al. (2016) Red wine polyphenols modulate fecal microbiota and reduce markers of the metabolic syndrome in obese patients. Food Funct 7, 17751787.CrossRefGoogle ScholarPubMed
Queipo-Ortuño, MI, Boto-Ordóñez, M, Murri, M, et al. (2012) Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers. Am J Clin Nutr 95, 13231334.CrossRefGoogle ScholarPubMed
Cuervo, A, Reyes-Gavilán, CG, Ruas-Madiedo, P, et al. (2015) Red wine consumption is associated with fecal microbiota and malondialdehyde in a human population. J Am Coll Nutr 34, 135141.CrossRefGoogle Scholar
Fernandez-Raudales, D, Hoeflinger, JL, Bringe, NA, et al. (2012) Consumption of different soymilk formulations differentially affects the gut microbiomes of overweight and obese men. Gut Microbe 3, 490500.CrossRefGoogle ScholarPubMed
Odamaki, T, Sugahara, H, Yonezawa, S, et al. (2012) Effect of the oral intake of yogurt containing Bifidobacterium longum BB536 on the cell numbers of enterotoxigenic Bacteroides fragilis in microbiota. Anaerobe 18, 1418.CrossRefGoogle ScholarPubMed
Odamaki, T, Kato, K, Sugahara, H, et al. (2016) Effect of probiotic yoghurt on animal-based diet-induced change in gut microbiota: an open, randomised, parallel-group study. Beneficial Microbes 7, 473484.CrossRefGoogle ScholarPubMed
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Table 1. Summary of studies assessing the impact of Mediterranean diet component and a whole Mediterranean diet intervention on the human gut microbiota

Figure 1

Table 2. Summary studies assessing the impact of physical activity status or an exercise intervention on the human gut microbiota