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Food for thought: The role of nutrition in the microbiota-gut–brain axis

  • Author Footnotes
    1 Authors contributed equally to the completion of the manuscript.
    Clara Seira Oriach
    Footnotes
    1 Authors contributed equally to the completion of the manuscript.
    Affiliations
    Department of Psychiatry and Neurobehavioural Science, University College Cork, Ireland

    APC Microbiome Institute, University College Cork, Cork, Ireland
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  • Author Footnotes
    1 Authors contributed equally to the completion of the manuscript.
    Ruairi C. Robertson
    Footnotes
    1 Authors contributed equally to the completion of the manuscript.
    Affiliations
    School of Microbiology, University College Cork, Cork, Ireland

    Teagasc Moorepark Food Research Centre, Fermoy, Co. Cork, Ireland

    APC Microbiome Institute, University College Cork, Cork, Ireland
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  • Catherine Stanton
    Affiliations
    Teagasc Moorepark Food Research Centre, Fermoy, Co. Cork, Ireland

    APC Microbiome Institute, University College Cork, Cork, Ireland
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  • John F. Cryan
    Affiliations
    APC Microbiome Institute, University College Cork, Cork, Ireland

    Department of Anatomy and Neuroscience, University College Cork, Ireland
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  • Timothy G. Dinan
    Correspondence
    Corresponding author. Department of Psychiatry, Cork University Hospital, Wilton, Cork, Ireland.
    Affiliations
    Department of Psychiatry and Neurobehavioural Science, University College Cork, Ireland

    APC Microbiome Institute, University College Cork, Cork, Ireland
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  • Author Footnotes
    1 Authors contributed equally to the completion of the manuscript.
Open AccessPublished:February 10, 2016DOI:https://doi.org/10.1016/j.yclnex.2016.01.003

      Summary

      Recent research has provided strong evidence for the role of the commensal gut microbiota in brain function and behaviour. Many potential pathways are involved in this bidirectional communication between the gut microbiota and the brain such as immune mechanisms, the vagus nerve and microbial neurometabolite production. Dysbiosis of gut microbial function has been associated with behavioural and neurophysical deficits, therefore research focused on developing novel therapeutic strategies to treat psychiatric disorders by targeting the gut microbiota is rapidly growing. Numerous factors can influence the gut microbiota composition such as health status, mode of birth delivery and genetics, but diet is considered among the most crucial factors impacting on the human gut microbiota from infancy to old age. Thus, dietary interventions may have the potential to modulate psychiatric symptoms associated with gut–brain axis dysfunction. Further clinical and in vivo studies are needed to better understand the mechanisms underlying the link between nutrition, gut microbiota and control of behaviour and mental health.

      Keywords

      1. Introduction

      The microbial population residing in the small and large intestine represents the largest microbial population of the human microbiota. Estimates suggest that bacterial cells within the gut microbiota outnumber human eukaryotic cells by ten to one [
      • Hamady M.
      • Knight R.
      Microbial community profiling for human microbiome projects: tools, techniques, and challenges.
      ]. Moreover, the genes encoded by the gut microbiota, the gut microbiome, outnumber the human genome by one hundred to one [
      • Qin J.
      • Li R.
      • Raes J.
      • Arumugam M.
      • Burgdorf K.S.
      • Manichanh C.
      • et al.
      A human gut microbial gene catalogue established by metagenomic sequencing.
      ]. This complex ecosystem is formed mainly by bacteria, but also viruses, archae, protozoa and fungi. Due to the advances in genomic technologies it has been possible to unravel around 75% of the adult gut microbiota bacterial composition, which is predominantly composed of the Firmicutes and Bacteroidetes phyla [
      • Collado M.C.
      • Cernada M.
      • Baüerl C.
      • Vento M.
      • Pérez-Martínez G.
      Microbial ecology and host-microbiota interactions during early life stages.
      ].
      Furthermore, the gut microbiota plays a major role in host health by shaping the development of the immune system, metabolizing dietary nutrients (such as fatty acids, glucose and bile acids) and drugs, digesting complex indigestible polysaccharides and synthesizing vitamins and bioactive molecules [
      • Lankelma J.
      • Nieuwdorp M.
      • de Vos W.
      • Wiersinga W.
      The gut microbiota in internal medicine: implications for health and disease.
      ].
      Throughout different life stages, various changes occur in the microbial diversity of humans. Early studies suggested that the foetus first came in contact with microbes during birth. However, it has been posited that as early as the prenatal period, an initial inoculum of microbes may be translocated via the bloodstream and placenta from the mother to the foetus, thus contradicting the “sterile womb” hypothesis [
      • Borre Y.E.
      • O'Keeffe G.W.
      • Clarke G.
      • Stanton C.
      • Dinan T.G.
      • Cryan J.F.
      Microbiota and neurodevelopmental windows: implications for brain disorders.
      ].
      After birth, the first colonizers of the gut are facultative anaerobes such as Streptococcus, Enterobacteriaceae and Staphylococcus. These colonizers consume oxygen, creating an anaerobic environment leading to an increase of Clostridium, Bacteroides and Bifidobacteria, which are strict anaerobes. During this early post-natal period, diet (breast milk/formula feeding) plays a key role in shaping the gut microbiota composition [
      • Thum C.
      • Cookson A.L.
      • Otter D.E.
      • McNabb W.C.
      • Hodgkinson A.J.
      • Dyer J.
      • et al.
      Can nutritional modulation of maternal intestinal microbiota influence the development of the infant gastrointestinal tract?.
      ]. This unstable infant gut microbiota with low diversity goes through a number of compositional changes during the first two years of life. From the second year of life onward, the microbial composition undergoes an important shift toward the stable gut microbiota profile of the adult, which is composed mainly of Bacteroidetes and Firmicutes. During healthy adulthood the gut microbiota remains relatively stable until ageing, when considerable changes occur [
      • Claesson M.J.
      • Jeffery I.B.
      • Conde S.
      • Power S.E.
      • O'Connor E.M.
      • Cusack S.
      • et al.
      Gut microbiota composition correlates with diet and health in the elderly.
      ].
      The intestinal microbes are markedly affected by numerous factors such as host genetics, mode of delivery, lifestyle (urbanization and global mobility), medical interventions (use of antibiotics, vaccinations and hygiene) and health status [
      • Burokas A.
      • Moloney R.D.
      • Dinan T.G.
      • Cryan J.F.
      Chapter one-microbiota regulation of the mammalian gut–brain axis.
      ]. Furthermore, diet has repeatedly shown to be one of the most important factors affecting gut microbiota establishment and composition throughout the lifespan [
      • Lankelma J.
      • Nieuwdorp M.
      • de Vos W.
      • Wiersinga W.
      The gut microbiota in internal medicine: implications for health and disease.
      ]. Indeed, more than 50% of the variation of gut microbiota has been related to dietary changes [
      • Zhang C.
      • Zhang M.
      • Wang S.
      • Han R.
      • Cao Y.
      • Hua W.
      • et al.
      Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice.
      ] and major changes in diet during adulthood can modify the microbiota in a matter of days [
      • David L.A.
      • Maurice C.F.
      • Carmody R.N.
      • Gootenberg D.B.
      • Button J.E.
      • Wolfe B.E.
      • et al.
      Diet rapidly and reproducibly alters the human gut microbiome.
      ].
      Furthermore, an alteration of gut microbiota and metabolism, through dietary or other environmental influences, can cause a state of dysbiosis, which is characterized by an overgrowth of potentially pathogenic organisms (pathobionts) [
      • Kamada N.
      • Chen G.Y.
      • Inohara N.
      • Nunez G.
      Control of pathogens and pathobionts by the gut microbiota.
      ]. This change in the balance of symbionts/pathobionts can induce reduced intestinal barrier function (leaky gut) and subsequent chronic inflammation. Such dysbiosis may be associated to some metabolic and inflammatory disorders, visceral pain and even alterations to central nervous system (CNS) functioning [
      • DuPont A.W.
      • DuPont H.L.
      The intestinal microbiota and chronic disorders of the gut.
      ,
      • Sekirov I.
      • Russell S.L.
      • Antunes L.C.M.
      • Finlay B.B.
      Gut microbiota in health and disease.
      ]. Hence the relationship between the gut microbiota, chronic inflammation and the CNS suggest that microbial dysbiosis could alter brain function and hence contribute to behavioural and cognitive abnormalities [
      • Cryan J.F.
      • Dinan T.G.
      Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour.
      ]. A wealth of preclinical research is now showing potential for the treatment of dysbiosis, through dietary measures, to improve cognitive and behavioural outcomes.
      Given such evidence, there is a growing appreciation for the importance of the gut microbiota in health and disease, including mental health. Bearing in mind that diet is one of the most crucial factors in the development of the human gut microbiota from infancy to old age, this review focuses on the role of the gut–brain axis in brain function and behaviour and the potential nutritional interventions to target this axis as psychiatric disease therapies.

      2. How does diet influence human microbiota?

      The human gut harbours over ten thousand species of microorganisms [
      • Eckburg P.B.
      • Bik E.M.
      • Bernstein C.N.
      • Purdom E.
      • Dethlefsen L.
      • Sargent M.
      • et al.
      Diversity of the human intestinal microbial flora.
      ], hence such taxonomic diversity requires a wide array of nutrients and energy sources for normal microbial growth and function. Narrowing of host dietary diversity and reduced intake of essential nutrients can therefore reduce availability of substrates for specific microbial growth and contribute to intestinal dysbiosis.
      Over recent decades, modern dietary patterns have undergone major compositional changes, with increased intakes of red meat, high fat foods, and refined sugars. This ‘Westernization’ of diets together with sedentary lifestyles results in modifications to the gut microbiota, which may partially contribute to the higher incidences of chronic inflammatory disorders, such as cardiovascular disease, obesity, depression, allergies, diabetes and autoimmune disorders [
      • Maslowski K.M.
      • Mackay C.R.
      Diet, gut microbiota and immune responses.
      ]. It is therefore clear that in order to improve the nutritional value of food and thus, human health, it is essential to understand the biological interactions between the diet and microbiota.
      Many human studies have assessed dietary impact on the gut microbiota. However, as is the case with many human studies, they are limited by the difficulties to control potential confounding variables such as habitual diets and lifestyle behaviours. Moreover, it is worth noting that, typically, sequencing of the human gut microbiota is carried out on faecal samples, which may not accurately reflect the microbiota composition of the different intestinal segments. Despite these limitations, much of this human data is useful to assess the role of varying dietary patterns on microbiota composition and function.

      2.1 Rural vs western diet

      Many studies comparing rural and western communities have revealed specific gut microbiota adaptations to their respective environments. The adaptations to westernization have resulted in an important loss of several bacterial species, and hence subsequent reduction in microbial diversity and stability. Recent studies have clearly showed this reduction in microbiota diversity such as the one comparing an Italian urban control group compared to a hunter–gatherer community [
      • Schnorr S.L.
      • Candela M.
      • Rampelli S.
      • Centanni M.
      • Consolandi C.
      • Basaglia G.
      • et al.
      Gut microbiome of the Hadza hunter-gatherers.
      ]. Moreover, recent investigations have reported the impact of diet on the microbial biodiversity within different human populations [
      • De Filippo C.
      • Cavalieri D.
      • Di Paola M.
      • Ramazzotti M.
      • Poullet J.B.
      • Massart S.
      • et al.
      Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.
      ]. African children, who consume a low-fat and high-fibre diet, presented less potentially pathogenic bacteria and greater degree of diversity and microbial richness than European children consuming a high-fat diet (Western diet). African children had a depletion in Firmicutes and a greater abundance of the phylum Bacteroidetes (Xylanibacter and Prevotella), while European children showed a significant increase of Firmicutes (Faecalibacterium and Acetitomaculum) and Enterobacteriaceae (Shigella and Escherichia) [
      • De Filippo C.
      • Cavalieri D.
      • Di Paola M.
      • Ramazzotti M.
      • Poullet J.B.
      • Massart S.
      • et al.
      Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.
      ]. Similar findings were observed in terms of an increase of Prevotella genus in rural African populations compared to US Americans [
      • Ou J.
      • Carbonero F.
      • Zoetendal E.G.
      • DeLany J.P.
      • Wang M.
      • Newton K.
      • et al.
      Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans.
      ].

      2.2 Mediterranean diet

      The Mediterranean diet is characterised by an abundance of fruits, vegetable, grains and monounsaturated or n-3 polyunsaturated fats. Hence it is regarded as the gold-standard for optimum health. A recent study showed the ability of a Mediterranean-inspired anti-inflammatory diet to reduce inflammation in Crohn's disease. The results demonstrated a small reduction of the acute phase protein C-reactive protein (CRP), an increase in Bacteroidetes and Clostridium clusters and a decrease in Proteobacteria and Bacillaceae population [
      • Marlow G.
      • Ellett S.
      • Ferguson I.R.
      • Zhu S.
      • Karunasinghe N.
      • Jesuthasan A.C.
      • et al.
      Transcriptomics to study the effect of a Mediterranean-inspired diet on inflammation in Crohn's disease patients.
      ]. Similarly De Filippis et al. recently observed that Italian subjects with a high adherence to a Mediterranean diet had greater abundance of Prevotella and short chain fatty acids. Conversely, those with low adherence had higher urinary trimethylamine oxide (TMAO), which has associations with gut dysfunction, cardiovascular disease and colorectal cancer [
      • De Filippis F.
      • Pellegrini N.
      • Vannini L.
      • Jeffery I.B.
      • La Storia A.
      • Laghi L.
      • et al.
      High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome.
      ].

      2.3 Vegetarian/vegan diets

      Vegetarian diets have also gained recognition as a healthy and therapeutic dietary pattern for a number of chronic diseases, while vegan diets may confer protective benefits beyond that of vegetarian diets [
      • Glick-Bauer M.
      • Yeh M.-C.
      The health advantage of a vegan diet: exploring the gut microbiota connection.
      ]. Vegan diets may have protective effects against metabolic and inflammatory diseases. Moreover, they appear to lead to a unique gut microbiota profile characterized by a reduction of pathobionts [
      • Glick-Bauer M.
      • Yeh M.-C.
      The health advantage of a vegan diet: exploring the gut microbiota connection.
      ]. Some studies have shown that vegetarian and vegan diets significantly decrease microbial counts of Bacteroides fragilis compared to an omnivore diet [
      • Ferrocino I.
      • Di Cagno R.
      • De Angelis M.
      • Turroni S.
      • Vannini L.
      • Bancalari E.
      • et al.
      Fecal microbiota in healthy subjects following omnivore, vegetarian and vegan diets: culturable populations and rRNA DGGE profiling.
      ]. Another study comparing vegetarian to omnivore diet observed a higher ratio (%) of Bacteroides–Prevotella, Bacteroides thetaiotaomicron, Clostridium clostridioforme and Faecalibacterium prausnitzii but a lower ratio (%) of the Clostridium cluster XIVa in vegetarian diet [
      • Matijašić B.B.
      • Obermajer T.
      • Lipoglavšek L.
      • Grabnar I.
      • Avguštin G.
      • Rogelj I.
      Association of dietary type with fecal microbiota in vegetarians and omnivores in Slovenia.
      ].

      2.4 High-fibre diets

      Numerous studies support the idea that diets rich in plant fibres may promote the diversification of the microbiota by promoting hydrolytic bacteria and stimulating the production of short chain fatty acids [
      • De Filippo C.
      • Cavalieri D.
      • Di Paola M.
      • Ramazzotti M.
      • Poullet J.B.
      • Massart S.
      • et al.
      Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.
      ]. High-fibre diets have been positively associated with Actinobacteria and Bacteroidetes presence [
      • Wu G.D.
      • Chen J.
      • Hoffmann C.
      • Bittinger K.
      • Chen Y.-Y.
      • Keilbaugh S.A.
      • et al.
      Linking long-term dietary patterns with gut microbial enterotypes.
      ]. One study showed that three diets with different fibre-rich whole grains (barley, brown rice or combination of both) increased microbial diversity, the Firmicutes/Bacteroidetes ratio, and the abundance of the genus Blautia in fecal samples [
      • Martínez I.
      • Lattimer J.M.
      • Hubach K.L.
      • Case J.A.
      • Yang J.
      • Weber C.G.
      • et al.
      Gut microbiome composition is linked to whole grain-induced immunological improvements.
      ]. Furthermore, the administration of whole grain barley induced an increase in Bifidobacteria which is considered a positive indicator of prebiotic activity [
      • Carvalho-Wells A.L.
      • Helmolz K.
      • Nodet C.
      • Molzer C.
      • Leonard C.
      • McKevith B.
      • et al.
      Determination of the in vivo prebiotic potential of a maize-based whole grain breakfast cereal: a human feeding study.
      ]. A recent study found an elevation of Bifidobacteria and a reduction of Bacteroides spp. and Clostridium histolitycum group in a cohort of overweight adults after administration of prebiotics (GOS) [
      • Vulevic J.
      • Juric A.
      • Tzortzis G.
      • Gibson G.R.
      A mixture of trans-galactooligosaccharides reduces markers of metabolic syndrome and modulates the fecal microbiota and immune function of overweight adults.
      ]. Davis et al. showed as well that an administration of GOS increased abundance of Bifidobacteriaceae and decreased Bacteroidaceae family [
      • Davis L.
      • Martínez I.
      • Walter J.
      • Goin C.
      • Hutkins R.W.
      Barcoded pyrosequencing reveals that consumption of galactooligosaccharides results in a highly specific bifidogenic response in humans.
      ].

      2.5 High-fat diets

      Over the last few decades, the increase in the consumption of high-fat diets has been associated with the obesity epidemic [
      • Torres-Fuentes C.
      • Schellekens H.
      • Dinan T.G.
      • Cryan J.F.
      A natural solution for obesity: bioactives for the prevention and treatment of weight gain. A review.
      ]. Many studies have shown that high-fat diets lead to a decrease in Bacteroidetes and an increase in Firmicutes [
      • Murphy E.A.
      • Velazquez K.T.
      • Herbert K.M.
      Influence of high-fat diet on gut microbiota: a driving force for chronic disease risk.
      ]. These effects may be associated with increased gut permeability, a higher capacity for energy harvest and storage, and inflammation [
      • Murphy E.A.
      • Velazquez K.T.
      • Herbert K.M.
      Influence of high-fat diet on gut microbiota: a driving force for chronic disease risk.
      ].
      Several studies have focused on dietary supplementation as a possible way to attenuate the gut microbiota dysbiosis and metabolic impairments produced by high-fat diets. For example, polyphenols, conjugated linoleic acid and short chain fatty acids supplementation during high-fat diet consumption, have displayed an improvement of gut microbiota dysbiosis [
      • Chaplin A.
      • Parra P.
      • Serra F.
      • Palou A.
      Conjugated linoleic acid supplementation under a high-fat diet modulates stomach protein expression and intestinal microbiota in adult mice.
      ,
      • den Besten G.
      • Bleeker A.
      • Gerding A.
      • van Eunen K.
      • Havinga R.
      • van Dijk T.H.
      • et al.
      Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation.
      ,
      • Roopchand D.E.
      • Carmody R.N.
      • Kuhn P.
      • Moskal K.
      • Rojas-Silva P.
      • Turnbaugh P.J.
      • et al.
      Dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and attenuate high fat diet-induced metabolic syndrome.
      ].

      2.6 High-protein diets

      The western diet has experienced a considerable increase in protein content in recent times. This has led to much research examining variations in macronutrients intake in order to manage body weight [
      • Johnstone A.M.
      Safety and efficacy of high-protein diets for weight loss.
      ]. Dietary proteins undergo luminal proteolysis and subsequent metabolism by the large intestine microbiota triggering the production of numerous amino acid-derived metabolites such as phenols, indoles, amines, sulphide, ammonia and monocarboxylic acids [
      • Nyangale E.P.
      • Mottram D.S.
      • Gibson G.R.
      Gut microbial activity, implications for health and disease: the potential role of metabolite analysis.
      ].
      Dietary protein intake in humans has been associated with the Bacteroides enterotype [
      • Wu G.D.
      • Chen J.
      • Hoffmann C.
      • Bittinger K.
      • Chen Y.-Y.
      • Keilbaugh S.A.
      • et al.
      Linking long-term dietary patterns with gut microbial enterotypes.
      ]. An animal-based diet in humans showed an increase in the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and a decrease in the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii) [
      • David L.A.
      • Maurice C.F.
      • Carmody R.N.
      • Gootenberg D.B.
      • Button J.E.
      • Wolfe B.E.
      • et al.
      Diet rapidly and reproducibly alters the human gut microbiome.
      ]. Interestingly, Clarke et al. showed the importance of exercise in the relationship between the microbiota, host immunity and host metabolism, and the important role played by the diet. They compared male elite professional rugby players to healthy male controls, finding a positive correlation between protein consumption with microbial diversity [
      • Clarke S.F.
      • Murphy E.F.
      • O'Sullivan O.
      • Lucey A.J.
      • Humphreys M.
      • Hogan A.
      • et al.
      Exercise and associated dietary extremes impact on gut microbial diversity.
      ].

      3. Gut-microbiota–brain communication

      As previously discussed, diet significantly modifies host gut microbiota composition and function. Simultaneously, however, gut microbiota determine what the host is capable of extracting from its diet, from nutrients to bioactive signalling molecules such as neurometabolites, vitamins and short-chain fatty acids (SCFA) [
      • Tan H.
      • O'Toole P.W.
      Impact of diet on the human intestinal microbiota.
      ]. Many of these molecules such as serotonin and gamma-aminobutyric acid (GABA), have neuro-active functions due to their capacity to modulate neural signalling within the enteric nervous system and consequently influence brain function and host behaviour [
      • Wall R.
      • Cryan J.F.
      • Ross R.P.
      • Fitzgerald G.F.
      • Dinan T.G.
      • Stanton C.
      Bacterial neuroactive compounds produced by psychobiotics. Microbial endocrinology: the microbiota-gut-brain axis in health and disease.
      ].
      This gut–brain axis, the bidirectional communication system between the gastrointestinal system and the CNS, plays an important role in homeostasis between neural (both enteric and central nervous systems), hormonal and immunological signalling [
      • Cryan J.F.
      • Dinan T.G.
      Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour.
      ]. Through this complex network the gut can influence the brain via visceral messages, and conversely, the brain is able to influence gastrointestinal functions (like motility, secretion and mucin production) and immune functions, such as the modulation of cytokine production by cells of the mucosal immune system [
      • Tracey K.J.
      Reflex control of immunity.
      ].
      Both luminal nutrients and gut microbiota metabolites stimulate enteroendrocrine cells (EECs) located throughout the gastrointestinal (GI) tract, which represents the largest endocrine organ in the human body [
      • Rehfeld J.
      A centenary of gastrointestinal endocrinology.
      ]. These EECs contain most of the nutrient receptors such as those for aminoacids, peptones, SCFAs, long-chain fatty acids (LCFAs) and oleoylethanolamide (OEA) (Fig. 1). Molecular sensing by these EEC's are crucial in the control of multiple functions during digestion, the initiation of neural and hormonal responses or changes in mucosal ion transport which controls appetite, insulin secretion and motility [
      • Furness J.B.
      • Rivera L.R.
      • Cho H.-J.
      • Bravo D.M.
      • Callaghan B.
      The gut as a sensory organ.
      ]. Moreover, as the nervous and endocrine signalling between the gut and the brain is essential for the modulation of many GI functions, the sensing receptors of the gut that control the release of many hormones play a key role (Fig. 1). Several interacting factors such as diet and microbiota composition modulate the activation of different sensory receptors in the gut, and consequently stimulate up or down-regulation of hormonal release which can induce a number of functional GI changes. Interestingly, increasing evidence indicates that animals fed on a high-fat diet present numerous changes in gastrointestinal function, particularly in the secretion and signalling of gastrointestinal hormones, which may predispose to an increase in energy intake, and consequently, to weight gain and obesity [
      • Little T.J.
      • Horowitz M.
      • Feinle-Bisset C.
      Modulation by high-fat diets of gastrointestinal function and hormones associated with the regulation of energy intake: implications for the pathophysiology of obesity.
      ].
      Figure thumbnail gr1
      Fig. 1Interactions between luminal nutrients and gut microbiota metabolites with the gut sensory receptors, and the key communications between endocrine, neuronal and immune systems. Dietary composition determines the type of nutrients that reach the luminal gastrointestinal tract. Different dietary patterns can alter the composition of the gut microbiota and consequently the production of their metabolites, which can influence: epithelial permeability by acting on the cells from the immune system
      (
      • Hamady M.
      • Knight R.
      Microbial community profiling for human microbiome projects: tools, techniques, and challenges.
      )
      , activity of enteroendocrine cells
      (
      • Qin J.
      • Li R.
      • Raes J.
      • Arumugam M.
      • Burgdorf K.S.
      • Manichanh C.
      • et al.
      A human gut microbial gene catalogue established by metagenomic sequencing.
      )
      or tight junction protein function
      (
      • Collado M.C.
      • Cernada M.
      • Baüerl C.
      • Vento M.
      • Pérez-Martínez G.
      Microbial ecology and host-microbiota interactions during early life stages.
      )
      . The gut luminal content is continuously monitored by the intestine to optimize nutrient assimilation and protect against hazards which can affect its integrity. Therefore, the intestine is conferred with a range of sensory receptors which interact with major effector systems such as the endocrine system, the nervous system, the gut immune system, and the nonimmune defence systems of the gut. Hormone release triggered by the activation of nutrient-specific receptors found on the enteroendrocrine cells, occurs along the entire gastrointestinal tract from the stomach to the large intestine. There are several types of enteroendocrine cells such as L cells or I cells with sensory receptors that stimulate the release of different types of hormones
      (
      • Lankelma J.
      • Nieuwdorp M.
      • de Vos W.
      • Wiersinga W.
      The gut microbiota in internal medicine: implications for health and disease.
      )
      , which have a wide range of effects such as satiety through the hypothalamus, gastrointestinal motility and acid secretion. Abbreviations: Aas, aminoacids; Ach, acetylcholine; APCs, antigen-presenting cells; CCK, cholecystokinin; DA, dopamine; GABA, gamma-aminobutyric acid; GIP, gastric inhibitory peptide; GLP, glucagon-like peptide; IPANs, intrinsic primary afferent neuron; LCFAs, long-chain fatty acids; NE, norepinephrine; OEA, oleoylethanolamide; PYY, peptide YY; SCFAs, short-chain fatty acids.
      In addition to its role as a sensory organ, the gut forms part of the enteric nervous system, which makes up a comprehensive division of the autonomic nervous system, containing between 200 and 600 million neurons [
      • Furness J.B.
      • Rivera L.R.
      • Cho H.-J.
      • Bravo D.M.
      • Callaghan B.
      The gut as a sensory organ.
      ]. The vagus nerve (the major nerve of the parasympathetic division of the autonomic nervous system) is crucially involved in bidirectional signalling between the gastrointestinal and nervous systems (Fig. 2). A landmark study by Bravo et al. [
      • Bravo J.A.
      • Forsythe P.
      • Chew M.V.
      • Escaravage E.
      • Savignac H.M.
      • Dinan T.G.
      • et al.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      ] found that probiotic modulation of the gut microbiota induced behavioural and neurochemical changes in mice. However, this was not apparent in mice that had undergone vagotomy suggesting a crucial role for the vagus nerve in the gut–brain axis.
      Figure thumbnail gr2
      Fig. 2Impact of diet on the gut microbiota and routes of communication involved in the gut–brain axis. Diet is one of the most crucial factors in the development of the human gut microbiota. Different dietary patterns can change the gut microbiota composition by keeping a balanced diversity of the gut microbiota (symbiosis) or causing a state of dysbiosis which is characterized by an overgrowth of potentially pathological organisms (pathobionts). A state of dysbiosis leads to an increased inflammation and leaky gut. Many mechanisms have shown to be involved in this bidirectional pathway between the gut microbiota and brain including vagus nerve signalling, immune activation, tryptophan metabolism and production of microbial metabolites and neurometabolites. Many of these bacterial metabolites significantly impact neurological function, therefore there is potential for dietary interventions that increase bacterial metabolism and promote growth of beneficial bacteria, to beneficially modulate the gut–brain axis and modulate CNS function. Abbreviations: GABA, gamma-aminobutyric acid; DA, dopamine; NE, norepinephrine; Ach, acetylcholine; SCFAs, short-chain fatty acids; 5-HT,serotonine; CNS, central nervous system.
      The human intestine also acts as an endocrine organ through direct and indirect production of microbial metabolites and neurometabolites such as short chain fatty acids (SCFAs), vitamins and neurotransmitters, which have also been shown to influence gut–brain interactions [
      • Burokas A.
      • Moloney R.D.
      • Dinan T.G.
      • Cryan J.F.
      Chapter one-microbiota regulation of the mammalian gut–brain axis.
      ]. GABA and serotonin are neurotransmitters that can influence host behaviour and are produced directly or indirectly by certain commensal microbes [
      • Barrett E.
      • Ross R.
      • O'Toole P.
      • Fitzgerald G.
      • Stanton C.
      γ-Aminobutyric acid production by culturable bacteria from the human intestine.
      ,
      • Reigstad C.S.
      • Salmonson C.E.
      • Rainey J.F.
      • Szurszewski J.H.
      • Linden D.R.
      • Sonnenburg J.L.
      • et al.
      Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells.
      ]. SCFAs including butyrate, propionate and acetate can be produced by species such as Roseburia spp and Faecalibacterium following fermentation of indigestible polysaccharides [
      • Brestoff J.R.
      • Artis D.
      Commensal bacteria at the interface of host metabolism and the immune system.
      ]. Butyrate and propionate can modulate brain functioning, in particular appetite regulation and energy homeostasis [
      • Byrne C.
      • Chambers E.
      • Morrison D.
      • Frost G.
      The role of short chain fatty acids in appetite regulation and energy homeostasis.
      ] through regulation of neuropeptide production.
      The role of the gut microbiota in immune activation also has strong associations with neurological functioning. The gut microbiota regulate intestinal epithelial barrier integrity and hence control the translocation of viable bacteria or bacterial endotoxins into the bloodstream [
      • Bischoff S.C.
      • Barbara G.
      • Buurman W.
      • Ockhuizen T.
      • Schulzke J.-D.
      • Serino M.
      • et al.
      Intestinal permeability–a new target for disease prevention and therapy.
      ]. Increased intestinal permeability can lead to increased lipopolysaccharide (LPS) in the bloodstream, which increases inflammatory status. Diet and obesity significantly alter gut microbiota composition and hence have been shown to affect inflammatory status. Cani et al. showed that prebiotic supplementation dampened inflammatory status and improved gut barrier function in genetically obese mice [
      • Cani P.D.
      • Possemiers S.
      • Van de Wiele T.
      • Guiot Y.
      • Everard A.
      • Rottier O.
      • et al.
      Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability.
      ]. Many supporting studies have demonstrated the potential for high fat and other obesogenic diets to promote inflammation and microbiota-targeted interventions, such as prebiotics and probiotics to reverse inflammatory status [
      • Everard A.
      • Lazarevic V.
      • Gaïa N.
      • Johansson M.
      • Ståhlman M.
      • Backhed F.
      • et al.
      Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity.
      ]. Chronic inflammation has been linked to a number of neurological disorders including depression and dementia [
      • Yong V.W.
      Inflammation in neurological disorders: a help or a hindrance?.
      ] and hence microbiota-associated chronic inflammation may influence risk of such disorders.
      Due to the fact that many of these gastrointestinal pathways significantly influence neurological function, there is potential for dietary interventions that increase bacterial metabolism and promote growth of beneficial bacteria, to positively modulate the gut–brain axis and improve symptoms of psychiatric illness. Moreover, bearing in mind the potential link between the gut microbiota and anxiety-related behaviour [
      • Burokas A.
      • Moloney R.D.
      • Dinan T.G.
      • Cryan J.F.
      Chapter one-microbiota regulation of the mammalian gut–brain axis.
      ], research has recently focused on the health benefits of probiotic administration on psychiatric illnesses [
      • Dinan T.G.
      • Stanton C.
      • Cryan J.F.
      Psychobiotics: a novel class of psychotropic.
      ].

      4. Microbiota-targeted dietary interventions and behavioural outcomes

      The gut microbiota have been implicated in a number of clinical neuropsychiatric disorders [
      • Cryan J.F.
      • Dinan T.G.
      Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour.
      ]. Also, the role of nutrition in the aetiology and treatment of psychiatric disorders has come to light in recent times [
      • Sarris J.
      • Logan A.C.
      • Akbaraly T.N.
      • Amminger G.P.
      • Balanzá-Martínez V.
      • Freeman M.P.
      • et al.
      Nutritional medicine as mainstream in psychiatry.
      ]. The development of next generation sequencing technologies has also allowed for increased understanding of human gut microbial composition in healthy and disease states and how environmental factors such as diet influence this composition.

      4.1 Probiotic interventions

      A number of studies have reported certain probiotic strains, primarily Lactobacillus and Bifidobacteria, to enhance brain function in both rodents and humans. Hence there is potential for ‘psychobiotics’ (live organisms that, when ingested, confer a benefit to host psychiatric health) to modulate the gut microbiota and act as therapies for psychiatric disorders [
      • Dinan T.G.
      • Stanton C.
      • Cryan J.F.
      Psychobiotics: a novel class of psychotropic.
      ]. Table 1 summarizes a non-comprehensive list of human and preclinical studies investigating the role of probiotics in behaviours associated with psychiatric illness. Despite the promising evidence in animals, these results have yet to be fully translated into humans. However with larger randomised controlled trials, there is potential for psychobiotics to be effective psychiatric therapeutics.
      Table 1Probiotic interventions and behavioural outcomes.
      InterventionSpeciesHealth statusMicrobiota changesBehavioural/neurochemical outcomesReferences
      Lactobacillus caseiHumansHealthy↑ mood (self reported)

      ↓ memory
      • Benton D.
      • Williams C.
      • Brown A.
      Impact of consuming a milk drink containing a probiotic on mood and cognition.
      Bifidobacteria longumMiceHealthy anxious strain (BALB/c)↑ memory and cognitive performance (novel object recognition, barnes maze, fear conditioning)
      • Savignac H.
      • Tramullas M.
      • Kiely B.
      • Dinan T.
      • Cryan J.
      Bifidobacteria modulate cognitive processes in an anxious mouse strain.
      VSL#3RatsAgedBacteroidetes↓ deficit in age-related LTP

      ↓ microglial activation

      ↑ BDNF and synapsin
      • Distrutti E.
      • O'Reilly J.-A.
      • McDonald C.
      • Cipriani S.
      • Renga B.
      • Lynch M.A.
      • et al.
      Modulation of intestinal microbiota by the probiotic VSL# 3 resets brain gene expression and ameliorates the age-related deficit in LTP.
      Lactobacillus helveticusMiceHealthy or fed western-dietNormalized the increase in Proteobacteria following “western diet” feeding↑ memory (Barnes maze)

      ↓ anxiety-like behaviour (Barnes maze)
      • Ohland C.L.
      • Kish L.
      • Bell H.
      • Thiesen A.
      • Hotte N.
      • Pankiv E.
      • et al.
      Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.
      Bacteroides fragilisMiceMIA treatedRestored relative abundance of lachnospiraceae following MIA treatment↓ anxiety-like behaviour (Open field)

      ↑ communication (ultrasonic vocalization)

      ↓ stereotyped behaviour (marble burying)
      • Hsiao E.Y.
      • McBride S.W.
      • Hsien S.
      • Sharon G.
      • Hyde E.R.
      • McCue T.
      • et al.
      Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.
      Lactobacillus caseiHumansChronic fatigue syndromeBifidobacteria

      Lactobacillus
      ↓ anxiety
      • Rao A.V.
      • Bested A.C.
      • Beaulne T.M.
      • Katzman M.A.
      • Iorio C.
      • Berardi J.M.
      • et al.
      A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome.
      Lactobacillus helveticus and Bifidobacterium longumRatsHealthy↓ anxiety (conditioned defensive burying)
      • Messaoudi M.
      • Violle N.
      • Bisson J.-F.
      • Desor D.
      • Javelot H.
      • Rougeot C.
      Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers.
      HumansHealthy↓ anxiety
      Bifidobacteria infantisRatsHealthy↓ proinflammatory immune response

      ↑ tryptophan
      • Desbonnet L.
      • Garrett L.
      • Clarke G.
      • Bienenstock J.
      • Dinan T.G.
      The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat.
      Lactobacillus rhamnosus and Bifidobacterium animalisHumansSchizophrenicMicrobiota data not reported however probiotic group significantly less likely to experience severe bowel difficultyNo observed differences
      • Dickerson F.B.
      • Stallings C.
      • Origoni A.
      • Katsafanas E.
      • Savage C.L.
      • Schweinfurth L.A.
      • et al.
      Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. The primary care companion for CNS disorders.
      Bifidobacterium infantisRatsHealthy normosensitive (Sprague–Dawley) and healthy hypersensitive (Wistar–Kyoto)↓ visceral pain (colorectal distension)
      • McKernan D.
      • Fitzgerald P.
      • Dinan T.
      • Cryan J.
      The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat.
      Lactobacillus rhamnosusMiceHealthy anxious strain (BALB/C)↓ corticosterone, anxiety behaviour, depressive behaviour. Altered GABA receptor expression
      • Bravo J.A.
      • Forsythe P.
      • Chew M.V.
      • Escaravage E.
      • Savignac H.M.
      • Dinan T.G.
      • et al.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      Abbreviations: MIA, maternal immune activation; LTP, long-term potentiation; GABA, gamma-aminobutyric acid.

      4.2 Dietary interventions

      Many studies have shown a clear association between the gut microbiota and behavioural alterations, and given that gut microbiota is affected by diet, the composition of the diet may be a crucial factor contributing to these behavioural changes, as summarized in Table 2.
      Table 2Microbiota-targeted dietary interventions and behavioural outcomes.
      DietSpeciesIntervention lengthMicrobiota changesBehavioural outcomesBiochemical outcomes (possible mechanisms)References
      High-fat dietMice13 weeksFirmicutes (mainly Ruminococcaceae and Lachnospiraceae)

      Bacteroidetes (S24-7)
      ↓ Burrowing (Burrowing Test)

      ↓ Memory (Morris water maze test)
      No difference between diet groups was observed for sucrose preferences, LPS, cholesterol, HbA1c, BDNF and the cytokines IL-1α, IL-1β, IL-6, IL-10, IL-12(p70), IL-17 and TNF-α. Low-grade levels of the systemic inflammatory mediators IL-6, IL-12p70 and IL-17A correlated to memory, anxiety, anhedonia and species-typical behaviour
      • Jørgensen B.P.
      • Hansen J.T.
      • Krych L.
      • Larsen C.
      • Klein A.B.
      • Nielsen D.S.
      • et al.
      A possible link between food and mood: dietary impact on gut microbiota and behavior in BALB/c mice.
      High-fat dietMice2–5 weeksClostridiales and Erysipelotrichales

      Bacteroides
      No significant differences from the control mice, except for remaining focused on the old platform position during the reversal probe trial
      • Magnusson K.
      • Hauck L.
      • Jeffrey B.
      • Elias V.
      • Humphrey A.
      • Nath R.
      • et al.
      Relationships between diet-related changes in the gut microbiome and cognitive flexibility.
      High-sucrose dietMice2–5 weeksClostridiales, Lactobacillus (Enterococcus, Lactococcus and Lactobacillus) and Lactococcus

      Bacteroides
      ↓ Learning (Morris water maze test) Cognitive deficits (in spatial short-term memory) Impairments in early development of a spatial bias for long-term memory, short-term memory and reversal training, compared to mice on normal diet
      • Magnusson K.
      • Hauck L.
      • Jeffrey B.
      • Elias V.
      • Humphrey A.
      • Nath R.
      • et al.
      Relationships between diet-related changes in the gut microbiome and cognitive flexibility.
      MgD dietMice6 weeksPrincipal Component Analysis plots illustrating differences in GM composition. The GM profile of MgD mice differed significantly from mice fed a standard control diet↑ FST – Increased immobility (depressive-like phenotype)Strong tendency towards decreased mRNA IL-6 levels in the MgD mice. The GM of MgD mice correlated significantly to hippocampal IL-6 levels
      • Winther G.
      • Pyndt Jørgensen B.M.
      • Elfving B.
      • Nielsen D.S.
      • Kihl P.
      • Lund S.
      • et al.
      Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour.
      MgD dietMice6 weeks↓ Bacterial diversity of the gut Principal component analysis plots illustrating differences in GM composition between mice fed a control diet or an MgD dietAltered anxiety-like behaviour

      (↓ Latency to enter the light compartment in the Light Dark Box test)
      • Pyndt Jørgensen B.
      • Winther G.
      • Kihl P.
      • Nielsen D.S.
      • Wegener G.
      • Hansen A.K.
      • et al.
      Dietary magnesium deficiency affects gut microbiota and anxiety-like behaviour in C57BL/6N mice.
      Meat-containing dietsMice3 months↑ Bacterial diversity↑ Working and reference (temporary and long-term) memory.

      ↓ Anxiety-like behaviour
      • Li W.
      • Dowd S.E.
      • Scurlock B.
      • Acosta-Martinez V.
      • Lyte M.
      Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria.
      Western-style diet high in fatMice21 daysFirmicutes/Bacteroidetes ratio

      ↑ Abundance of Proteobacteria and Spirochaetes
      Altered anxiety-like behaviour↓ total levels of SCFAs in cecal contents

      ↓ levels of acetic, propionic and butyric acids

      ↑ levels of caproic acid
      • Ohland C.L.
      • Kish L.
      • Bell H.
      • Thiesen A.
      • Hotte N.
      • Pankiv E.
      • et al.
      Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.
      High-fat diet (fecal transplantation from donors on high-fat diet)Mice10 weeksSequencing-based phylogenetic analysis confirmed the presence of distinct core microbiota between groups, with alterations in α- and β-diversity, modulation in taxonomic distribution, and statistically significant alterations to metabolically active taxaDisrupted exploratory, cognitive, and stereotypical behaviourDisrupted markers of intestinal barrier function

      ↑ circulating endotoxin

      ↑ lymphocyte expression of ionized calcium-binding adapter molecule 1

      ↑ toll-like receptor 2

      ↑ toll-like receptor 4
      • Bruce-Keller A.J.
      • Salbaum J.M.
      • Luo M.
      • Blanchard E.
      • Taylor C.M.
      • Welsh D.A.
      • et al.
      Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity.
      High-fat dietMice8 weeksFirmicutes

      Bacteroidetes and Tenericutes
      Robust anxiety phenotype
      • Kang S.S.
      • Jeraldo P.R.
      • Kurti A.
      • Miller M.
      • Cook M.D.
      • Whitlock K.
      • et al.
      Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition.
      Diet supplemented with prebiotics (trans-GOS)Human8 weeksEnhanced BifidobacteriaImproved anxiety (HAD scale)
      • Silk D.
      • Davis A.
      • Vulevic J.
      • Tzortzis G.
      • Gibson G.
      Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome.
      Abbreviations: HAD, Hospital Anxiety and Depression scale; SCFAs, short-chain fatty acids; GM, gut microbiota; LPS, Lipopolysaccharide; HbA1c, hemoglobin A1c; BDNF, brain-derived neurotrophic factor; trans-GOS, trans-galactooligosaccharides; MgD diet, diet deficient in Magnesium.
      Large macronutrient alterations as reflected in western style diets have been shown to induce microbial dysbiosis, which has been linked to impaired cognition. Magnusson et al. examined microbiota compositional changes following high fat, high sucrose or standard chow diets and assessed associations with cognitive capabilities in mice [
      • Magnusson K.
      • Hauck L.
      • Jeffrey B.
      • Elias V.
      • Humphrey A.
      • Nath R.
      • et al.
      Relationships between diet-related changes in the gut microbiome and cognitive flexibility.
      ]. Lactobacillus was significantly increased in the high sucrose group whereas Erysipelotrichales was significantly increased in the high fat group. High fat and high sucrose both had increased Coriobacteriales and reduced Bacteroides. Both high-energy treatments induced impaired cognition in the Morris water-maze and step-down latency tasks. In addition these behavioural changes displayed significant correlations with the alterations in Lactobacillus, Erysipelotrichales, Coriobacteriales and Bacteroides. These results suggest that the cognitive changes induced by the western-style diets are mediated through alterations to the gut microbiota. Jørgensen et al. performed a similar study with the same treatment groups and found similar correlations between microbiota alteration and memory which was also associated with inflammatory status [
      • Jørgensen B.P.
      • Hansen J.T.
      • Krych L.
      • Larsen C.
      • Klein A.B.
      • Nielsen D.S.
      • et al.
      A possible link between food and mood: dietary impact on gut microbiota and behavior in BALB/c mice.
      ].
      Li et al. also reported diet-induced changes to microbial diversity to improve cognition and working memory in mice. In this study, a meat-containing diet led to greater gut microbiota diversity than found in the control diet group. Moreover, the meat-containing diet group had improved working and reference memory on the hole-board open field test and less anxiety-like behaviour, assessed during the novel encounter in the hole-board open field [
      • Li W.
      • Dowd S.E.
      • Scurlock B.
      • Acosta-Martinez V.
      • Lyte M.
      Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria.
      ].
      Mental decline is increased by obesity, which may be in part regulated by gut microbiota dysbiosis. A recent study showed that an obese-type microbiota, induced by high-fat feeding, induced cognitive disruptions when transplanted into healthy rodents [
      • Bruce-Keller A.J.
      • Salbaum J.M.
      • Luo M.
      • Blanchard E.
      • Taylor C.M.
      • Welsh D.A.
      • et al.
      Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity.
      ]. The high-fat diet microbiota led to a significant increase of anxiety-like behaviour in the elevated plus maze, open field, and marble burying test. Moreover, this transfer of the high-fat diet microbiota decreased the cued fear memory in comparison to mice that received microbiota from chow-fed mice. Furthermore, inflammatory markers in the medial prefrontal cortex and intestinal permeability were increased in the mice who received the high-fat diet microbiota, suggesting that immune signalling pathways may be key mediators of microbiota–brain communication. These interesting results revealed that even in the absence of obesity, an obese-type microbiota profile could induce behaviour deficits similar to those seen in obesity and hence suggesting the potential for microbiota-based dietary interventions to treat obese-associated psychiatric disorders.
      In addition, Ohland et al. reported a western-style diet to induce anxiety-like behaviour in mice, as assessed in the Barnes maze [
      • Ohland C.L.
      • Kish L.
      • Bell H.
      • Thiesen A.
      • Hotte N.
      • Pankiv E.
      • et al.
      Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.
      ]. Moreover, western-style diet feeding increased the Firmicutes/Bacteroidetes ratio, and the abundance of Proteobacteria and Spirochaetes as well as reducing total SCFA contents. This increased anxiety-like behaviour was not apparent in mice who had been fed a western-style diet supplemented with the probiotic Lactobacillus helveticus.
      Another study found that mice on a high-fat diet presented major shifts in the gut microbiota (increase of Firmicutes and decrease of Bacteroidetes and Tenericutes) and a robust anxiety phenotype [
      • Kang S.S.
      • Jeraldo P.R.
      • Kurti A.
      • Miller M.
      • Cook M.D.
      • Whitlock K.
      • et al.
      Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition.
      ].
      A diet deficient in Mg, increased depressive-like behaviour and altered the gut microbiota, which suggested that magnesium deficiency could be a mediator of the behavioural effects through an altered gut microbiota [
      • Winther G.
      • Pyndt Jørgensen B.M.
      • Elfving B.
      • Nielsen D.S.
      • Kihl P.
      • Lund S.
      • et al.
      Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour.
      ]. Interestingly, a significant correlation was found between the gut microbiota of the diet deficient in Mg and a decrease in hippocampal IL-6 levels, suggesting that this immune-modulation could be the mechanism by which diet induced changes in the gut microbiota composition alter behaviour [
      • Winther G.
      • Pyndt Jørgensen B.M.
      • Elfving B.
      • Nielsen D.S.
      • Kihl P.
      • Lund S.
      • et al.
      Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour.
      ]. A similar study found that a diet deficient in Mg decreased bacterial diversity and altered anxiety-like behaviour [
      • Pyndt Jørgensen B.
      • Winther G.
      • Kihl P.
      • Nielsen D.S.
      • Wegener G.
      • Hansen A.K.
      • et al.
      Dietary magnesium deficiency affects gut microbiota and anxiety-like behaviour in C57BL/6N mice.
      ].
      Certain prebiotics have the potential to influence central nervous system functioning through stimulation of specific microbial growth and production of SCFAs. Tarr et al. reported that a social disruption stressor significantly altered gut microbiota composition in mice, which resulted in anxiety-like behaviour and a reduction in the growth of neurons in the denate gyrus region of the hippocampus [
      • Tarr A.J.
      • Galley J.D.
      • Fisher S.E.
      • Chichlowski M.
      • Berg B.M.
      • Bailey M.T.
      The prebiotics 3′ Sialyllactose and 6′ Sialyllactose diminish stressor-induced anxiety-like behavior and colonic microbiota alterations: evidence for effects on the gut–brain axis.
      ]. Interestingly, supplementation of the human milk oligosaccharides 3′ Sialyllactose or 6′ Sialyllactose, which have anti-inflammatory properties and stimulate bifidobacterial growth, prevented the stressor-induced alterations to the gut microbiota, in addition to preventing the behavioural, microbial and neurophysical defects [
      • Tarr A.J.
      • Galley J.D.
      • Fisher S.E.
      • Chichlowski M.
      • Berg B.M.
      • Bailey M.T.
      The prebiotics 3′ Sialyllactose and 6′ Sialyllactose diminish stressor-induced anxiety-like behavior and colonic microbiota alterations: evidence for effects on the gut–brain axis.
      ].
      A number of small clinical controlled trials have assessed the efficacy of certain prebiotics on psychological outcomes with promising results. Schmidt et al. demonstrated that 3-week supplementation with a GOS prebiotic, which has been shown to stimulate bifidobacterial growth, in healthy volunteers significantly reduced waking cortisol response, a stress hormone strongly linked to anxiety and depression [
      • Schmidt K.
      • Cowen P.J.
      • Harmer C.J.
      • Tzortzis G.
      • Errington S.
      • Burnet P.W.
      Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers.
      ]. Moreover, a Bimuno®-galactooligosaccharides (B-GOS) cohort demonstrated altered behavioural outcomes through a decrease in attentional vigilance to negative versus positive information in a dot-probe task compared to placebo. It is interesting to note, however, that fructooligosaccharide (FOS) supplementation had no effect. These results suggest that shaping of microbiota composition through prebiotic intake could influence behavioural outcomes [
      • Schmidt K.
      • Cowen P.J.
      • Harmer C.J.
      • Tzortzis G.
      • Errington S.
      • Burnet P.W.
      Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers.
      ]. In humans, prebiotic supplementation with trans-galactooligosaccharides (trans-GOS) not only enhanced bifidobacterial growth and improved bloating symptoms, but in addition significantly reduced anxiety scores in IBS sufferers [
      • Silk D.
      • Davis A.
      • Vulevic J.
      • Tzortzis G.
      • Gibson G.
      Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome.
      ].

      5. Conclusions and future implications

      It is evident that there are a number of major metabolic, endocrine and neural pathways connecting the gut and the brain. Indeed, the trillions of microbes and microbial by-products within the gut contribute to the plasticity of these pathways. Despite the rapid growth of this area of research, it is still in its infancy. Relatively little is known about the extent to which bacterial metabolites can influence brain function, something which could be addressed with further advances in metabolomic technologies. In addition, the complexity of the pathways involved in the gut–brain axis contributes to the difficulty of identifying true mechanisms of action. Moreover, the role of individual nutrients to affect signalling within these pathways requires further examination.
      Sequencing technologies have grown extensively in recent times allowing deeper insight into gut microbial composition and associations between altered microbiota and psychiatric illnesses. Further research in this field should address mechanistic evidence for gut microbiota to alter brain and behaviour. The majority of the data available, is preclinical and few of these promising studies have been translated into humans, which warrants the need for more clinical trials in the area. There are very little data reporting clinical interventions targeting the microbiota in psychiatric illness.
      Indeed, diet has a significant impact on the microbiota and hence dietary interventions can beneficially modulate microbial diversity and function. Caution must be taken on assigning the term ‘probiotic’ to a specific strain of bacteria until its health effects can be replicated in both humans and animals. Indeed, commercial availability of true ‘psychobiotics’ (a live bacteria that may benefit mental health) will only become apparent after rigorous human trials. Prebiotics and other larger dietary interventions, including dietary fats and polyphenols also pose potential to alter the gut–brain axis and hence neuropsychiatric disorders, and may be feasible as long-term interventions for mental health.
      In conclusion, diet-induced gut microbiota modifications may be associated with brain dysfunction, behavioural and metabolic deficiencies. The emerging evidence of a microbiota-gut–brain axis dysregulation in certain neuropsychiatric disorders warrants further clinical and in vivo studies to investigate gut microbiota-targeted interventions as novel therapeutic strategies. Indeed, dietary interventions to treat dysfunction of the gut–brain axis may pose potential as therapeutic strategies for psychiatric disorders.

      Conflict of interest

      None.

      Acknowledgements

      The authors are supported in part by Science Foundation Ireland in the form of a centre grant (APC Microbiome Institute grant number SFI/12/RC/2273); the Health Research Board of Ireland (Grant Numbers HRA_POR/2011/23 and HRA_POR/2012/32); the Sea Change Strategy, NutraMara programme (Grant-Aid Agreement No. MFFRI/07/01); and the SMART FOOD project: ‘Science Based ‘Intelligent’/Functional and Medical Foods for Optimum Brain Health, Targeting Depression and Cognition’ project (Ref No. 13/F/411) with the support of the Marine Institute and the Department of Agriculture, Food and the Marine (DAFM) in Ireland.

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