Microbiota-gut-brain axis: the mediator of exercise and brain health

Abstract

The brain controls the nerve system, allowing complex emotional and cognitive activities. The microbiota-gut-brain axis is a bidirectional neural, hormonal, and immune signaling pathway that could link the gastrointestinal tract to the brain. Over the past few decades, gut microbiota has been demonstrated to be an essential component of the gastrointestinal tract that plays a crucial role in regulating most functions of various body organs. The effects of the microbiota on the brain occur through the production of neurotransmitters, hormones, and metabolites, regulation of host-produced metabolites, or through the synthesis of metabolites by the microbiota themselves. This affects the host's behavior, mood, attention state, and the brain's food reward system. Meanwhile, there is an intimate association between the gut microbiota and exercise. Exercise can change gut microbiota numerically and qualitatively, which may be partially responsible for the widespread benefits of regular physical activity on human health. Functional magnetic resonance imaging (fMRI) is a non-invasive method to show areas of brain activity enabling the delineation of specific brain regions involved in neurocognitive disorders. Through combining exercise tasks and fMRI techniques, researchers can observe the effects of exercise on higher brain functions. However, exercise's effects on brain health via gut microbiota have been little studied. This article reviews and highlights the connections between these three interactions, which will help us to further understand the positive effects of exercise on brain health and provide new strategies and approaches for the prevention and treatment of brain diseases.

Keywords

brain health / microbiota / exercise / fMRI / anxiety disorders / depression / cognition / food reward

Author contributions

Piao Kang (Writing - original draft, Writing - review & editing), and Alan Zi-Xuan Wang (Writing - review & editing)

Conflict of interest

The authors declare no conflict of interest..

References

[1] Abraham D, Feher J, Scuderi GL, et al. (2019) Exercise and probiotics attenuate the development of Alzheimer's disease in transgenic mice: role of microbiome. Exp Gerontol 115:122-31.

[2] Agus A, Planchais J, Sokol H (2018) Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23:716-24.

[3] Akbari E, Asemi Z, Daneshvar Kakhaki R, et al. (2016) Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: a randomized, double-blind and controlled trial. Front Aging Neurosci 8:256.

[4] Alderman BL, Olson RL, Brush CJ, et al. (2016) MAP training: combining meditation and aerobic exercise reduces depression and rumination while enhancing synchronized brain activity. Transl Psychiatry 6:e726.

[5] 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 50:747-57.

[6] Amin N, Liu J, Bonnechere B, et al. (2023) Interplay of metabolome and gut microbiome in individuals with major depressive disorder vs control individuals. JAMA Psychiatry 80:597-609.

[7] Andersson E, Hovland A, Taube J, et al. (2022) Physical activity has an acute effect on depression and anxiety syndromes. Lakartidningen 119:22035.

[8] Angrist M, Yang A, Kantor B, et al. (2020) Good problems to have? Policy and societal implications of a disease-modifying therapy for presymptomatic late-onset Alzheimer's disease. Life Sci Soc Policy 16:11.

[9] Barbosa DAN, Gattas S, Salgado JS, et al. (2023) An orexigenic subnetwork within the human hippocampus. Nature 621:381-88.

[10] Barton W, Penney NC, Cronin O, et al. (2018) The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. Gut 67:625-33.

[11] Beaulieu K, Hopkins M, Gibbons C, et al. (2020) Exercise training reduces reward for high-fat food in adults with overweight/obesity. Med Sci Sports Exerc 52:900-08.

[12] Beaulieu K, Oustric P, Finlayson G (2020) The impact of physical activity on food reward: review and conceptual synthesis of evi dence from observational, acute, and chronic exercise training studies. Curr Obes Rep 9:63-80.

[13] Benakis C, Martin-Gallausiaux C, Trezzi JP, et al. (2020) The microbiome-gut-brain axis in acute and chronic brain diseases. Curr Opin Neurobiol 61:1-9.

[14] Bercik P, Denou E, Collins J, et al. (2011) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141:599-609, 09.e1-3.

[15] Berridge KC (1996) Food reward: brain substrates of wanting and liking. Neurosci Biobehav Rev 20:1-25.

[16] Berthoud HR, Münzberg H, Morrison CD (2017) Blaming the brain for obesity: integration of hedonic and homeostatic mechanisms. Gastroenterology 152:1728-38.

[17] Bieszczad KM, Bechay K, Rusche JR, et al. (2015) Histone deacetylase inhibition via RGFP966 releases the brakes on sensory cortical plasticity and the specificity of memory formation. J Neurosci 35:13124-32.

[18] Born JM, Lemmens SG, Martens MJ, et al. (2011) Differences between liking and wanting signals in the human brain and relations with cognitive dietary restraint and body mass index. Am J Clin Nutr 94:392-403.

[19] 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.

[20] Broman-Fulks JJ, Kelso K, Zawilinski L (2015) Effects of a single bout of aerobic exercise versus resistance training on cognitive vulnerabilities for anxiety disorders. Cogn Behav Ther 44: 240-51.

[21] Brondel L, Quilliot D, Mouillot T, et al. (2022) Taste of fat and obesity: different hypotheses and our point of view. Nutrients 14:555.

[22] Byrne CS, Chambers ES, Alhabeeb H, et al. (2016) Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods. Am J Clin Nutr 104:5-14.

[23] Campaniello D, Corbo MR, Sinigaglia M, et al. (2022) How diet and physical activity modulate gut microbiota: evidence, and perspectives. Nutrients 14:2456.

[24] Campbell S, Macqueen G (2004) The role of the hippocampus in the pathophysiology of major depression. J Psychiatry Neurosci 29:41726.

[25] Camuso S, Canterini S (2023) Brain-derived neurotrophic factor in main neurodegenerative diseases. Neural Regen Res 18:554-55.

[26] Castellanos N, Diez GG, Antúnez-Almagro C, et al. (2019) A critical mutualism-competition inter play underlies the loss of microbial diversity in sedentary lifestyle. Front Microbiol 10:3142.

[27] Castrén E, Monteggia LM (2021) Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biol Psychiatry 90:128-36.

[28] Cervenka I, Agudelo LZ, Ruas JL (2017) Kynurenines: tryptophan's metabolites in exercise, inflammation, and mental health. Science 357:eaaf9794.

[29] Clark A, Mach N (2016) Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes. J Int Soc Sports Nutr 13:43.

[30] Clarke G, Grenham S, Scully P, et al. (2013) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18:666-73.

[31] Clarke SF, Murphy EF, O'Sullivan O, et al. (2014) Exercise and associated dietary extremes impact on gut microbial diversity. Gut 63:1913-20.

[32] Connor M, Hargreaves EA, Scanlon OK, et al. (2023) The effect of acute exercise on state anxiety: a systematic review. Sports 11:145.

[33] Cornier MA, Melanson EL, Salzberg AK, et al. (2012) The effects of exercise on the neuronal response to food cues. Physiol Behav 105:1028-34.

[34] Cotman CW, Berchtold NC, Christie LA (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30:464-72.

[35] Crabtree DR, Chambers ES, Hardwick RM, et al. (2014) The effects of high-intensity exercise on neural responses to images of food. Am J Clin Nutr 99:258-67.

[36] Cryan JF, O'Riordan KJ, Cowan CSM, et al. (2019) The microbiota-gutbrain axis. Physiol Rev 99:1877-2013.

[37] Dalile B, Van Oudenhove L, Vervliet B, et al. (2019) The role of shortchain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol 16:461-78.

[38] Dalton A, Mermier C, Zuhl M (2019) Exercise influence on the microbiome-gut-brain axis. Gut Microbes 10:555-68.

[39] Dao MC, Everard A, Aron-Wisnewsky J, et al. (2016) Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65:426-36.

[40] Davranche K, Tempest GD, Gajdos T, et al. (2018) Impact of physical and cognitive exertion on cognitive control. Front Psychol 9:2369.

[41] De Caro C, Iannone LF, Citraro R, et al. (2019) Can we 'seize' the gut microbiota to treat epilepsy? Neurosci Biobehav Rev 107:750-64.

[42] de la Cuesta-Zuluaga J, Kelley ST, Chen Y, et al. (2019) Age- and sexdependent patterns of gut microbial diversity in human adults. Msystems 4:10-1128.

[43] de Meirelles LR, Matsuura C, Resende Ade C, et al. (2014) Chronic exercise leads to antiaggregant, antioxidant and anti-inflammatory effects in heart failure patients. Eur J Prev Cardiol 21:1225-32.

[44] de Souza Moura AM, Lamego MK, Paes F, et al. (2015) Effects of aerobic exercise on anxiety disorders: a systematic review. CNS Neurol Disord Drug Targets 14:1184-93.

[45] De Vadder F, Kovatcheva-Datchary P, Goncalves D, et al. (2014) Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156:84-96.

[46] Dinan TG, Stilling RM, Stanton C, et al. (2015) Collective unconscious: how gut microbes shape human behavior. J Psychiatr Res 63: 1-9.

[47] Ding Z, Du L (2022) Swimming exercise ameliorates depressivelike behavior by anti-inflammation activity, rebalancing gut Escherichia coli and Lactobacilli. Brain Res 1797, 148113.

[48] Ding Z, Du L (2022) Swimming exercise ameliorates depressivelike behavior by anti-inflammation activity, rebalancing gut Escherichia coli and Lactobacilli. Brain Res 1797:148113.

[49] Donoso F, Cryan JF, Olavarría-Ramírez L, et al. (2023) Inflammation, lifestyle factors, and the microbiome-gut-brain axis: relevance to depression and antidepressant action. Clin Pharmacol Ther 113:246-59.

[50] Duncan SH, Belenguer A, Holtrop G, et al. (2007) Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Appl Environ Microb 73:1073-8.

[51] 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 29:249-53.

[52] Dziewiecka H, Buttar HS, Kasperska A, et al. (2022) Physical activity induced alterations of gut microbiota in humans: a systematic review. BMC Sports Sci Med Rehabil 14:122.

[53] Elli M, Colombo O, Tagliabue A (2010) A common core microbiota between obese individuals and their lean relatives? Evaluation of the predisposition to obesity on the basis of the fecal microflora profile. Med Hypotheses 75:350-2.

[54] Erny D, Hrabě de Angelis AL, Jaitin D, et al. (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18:965-77.

[55] Estaki M, Morck DW, Ghosh S, et al. (2020) Physical activity shapes the intestinal microbiome and immunity of healthy mice but has no protective effects against colitis in MUC2(-/-) mice. Msystems 5:10-1128.

[56] Evans CC, LePard KJ, Kwak JW, et al. (2014) Exercise prevents weight gain and alters the gut microbiota in a mouse model of high fat diet-induced obesity. PLoS ONE 9:e92193.

[57] Evero N, Hackett LC, Clark RD, et al. (2012) Aerobic exercise reduces neuronal responses in food reward brain regions. J Appl Physiol 112:1612-9.

[58] Evrensel A, Ünsalver B, Ceylan ME (2020) Immune-kynurenine pathways and the gut microbiota-brain axis in anxiety disorders. Adv Exp Med Biol 1191:155-67.

[59] Fart F, Rajan SK, Wall R, et al. (2020) Differences in gut microbiome composition between senior orienteering athletes and community-dwelling older adults. Nutrients 12:2610.

[60] Feng X, Uchida Y, Koch L, et al. (2017) Exercise Prevents Enhanced Postoperative Neuroinflammation and Cognitive Decline and Rectifies the Gut Microbiome in a Rat Model of Metabolic Syndrome. Front Immunol 8, 1768.

[61] Feng X, Uchida Y, Koch L, et al. (2017) Exercise prevents enhanced postoperative neuroinflammation and cognitive decline and rectifies the gut microbiome in a rat model of metabolic syndrome.. Front Immunol 8:1768.

[62] Fjell AM, Walhovd KB (2010) Structural brain changes in aging: courses, causes and cognitive consequences. Rev Neurosci 21:187221.

[63] Flint HJ, Scott KP, Louis P, et al. (2012) The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol 9:577-89.

[64] Fonzo GA, Etkin A (2017) Affective neuroimaging in generalized anxiety disorder: an integrated review. Dialogues Clin Neurosci 19:16979.

[65] Fülling C, Dinan TG, Cryan JF (2019) Gut microbe to brain signaling: what happens in vagus.... Neuron 101:998-1002.

[66] Gabanyi I, Lepousez G, Wheeler R, et al. (2022) Bacterial sensing via neuronal Nod 2 regulates appetite and body temperature. Science 376:eabj3986.

[67] Ge X, Zheng M, Hu M, et al. (2023) Butyrate ameliorates quinolinic acid-induced cognitive decline in obesity models. J Clin Invest 133:e154612.

[68] Geerlings MI, Gerritsen L (2017) Late-life depression, hippocampal volumes, and hypothalamic-pituitary-adrenal axis regulation: a systematic review and meta-analysis. Biol Psychiatry 82:339-50.

[69] Generoso JS, Giridharan VV, Lee J, et al. (2021) The role of the microbiota-gut-brain axis in neuropsychiatric disorders. Braz J Psychiatry 43:293-305.

[70] Gérard P (2016) Gut microbiota and obesity. Cell Mol Life Sci 73:147-62.

[71] Golomb SM, Guldner IH, Zhao A, et al. (2020) Multi-modal single-cell analysis reveals brain immune landscape plasticity during aging and gut microbiota dysbiosis. Cell Rep 33:108438.

[72] Gomez-Cabrera MC, Domenech E, Viña J (2008) Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic Biol Med 44:126-31.

[73] Goodwin RD (2003) Association between physical activity and mental disorders among adults in the United States. Prev Med 36:698-703.

[74] Gourgouvelis J, Yielder P, Murphy B (2017) Exercise promotes neuroplasticity in both healthy and depressed brains: an fMRI pilot study. Neural Plast 2017:8305287.

[75] Govindarajan N, Agis-Balboa RC, Walter J, et al. (2011) Sodium butyrate improves memory function in an Alzheimer's disease mouse model when administered at an advanced stage of disease progression. J Alzheimers Dis 26:187-97.

[76] Guan JS, Haggarty SJ, Giacometti E, et al. (2009) HDAC 2 negatively regulates memory formation and synaptic plasticity. Nature 459:5560.

[77] Guilloteau P, Martin L, Eeckhaut V, et al. (2010) From the gut to the peripheral tissues: the multiple effects of butyrate. Nutr Res Rev 23:366-84.

[78] Haeger A, Costa AS, Schulz JB, et al. (2019) Cerebral changes improved by physical activity during cognitive decline: a systematic review on MRI studies. Neuroimage Clin 23:101933.

[79] Han S, Li XX, Wei S, et al. (2023) Orbitofrontal cortex-hippocampus potentiation mediates relief for depression: a randomized double-blind trial and TMS-EEG study. Cell Rep Med 4:101060.

[80] Harvey SB, ∅verland S, Hatch SL, et al. (2018) Exercise and the prevention of depression: results of the HUNT Cohort Study. Am J Psychiatry 175:28-36.

[81] Huang X, Li B, Yu F, et al. (2020) Path analysis from physical activity to quality of life among dementia patients: a dual-path mediating model. J Adu Nurs 76:546-54.

[82] Jiang HY, Zhang X, Yu ZH, et al. (2018) Altered gut microbiota profile in patients with generalized anxiety disorder. J Psychiatr Res 104:130-36.

[83] Joisten N, Kummerhoff F, Koliamitra C, et al. (2020) Exercise and the kynurenine pathway: current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training. Exerc Immunol Rev 26:24-42.

[84] Kang SS, Jeraldo PR, Kurti A, et al. (2014) Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition. Mol Neurodegener 9, 36.

[85] Kang SS, Jeraldo PR, Kurti A, et al. (2014) Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition. Mol Neurodegener 9: 36.

[86] Karamacoska D, Butt A, Leung IHK, et al. (2023) Brain function effects of exercise interventions for cognitive decline: a systematic review and meta-analysis. Front Neurosci 17: 1127065.

[87] Kasarello K, Cudnoch-Jedrzejewska A, Czarzasta K (2023) Communication of gut microbiota and brain via immune and neuroendocrine signaling. Front Microbiol 14:1118529.

[88] Kelly JR, Borre Y, OB C, et al. (2016) Transferring the blues: depressionassociated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res 82:109-18.

[89] Kenwood MM, Kalin NH, Barbas H (2022) The prefrontal cortex, pathological anxiety, and anxiety disorders. Neuropsychopharmacology 47:260-75.

[90] Killgore WD, Kipman M, Schwab ZJ, et al. (2013) Physical exercise and brain responses to images of high-calorie food. Neuroreport 24:962-7.

[91] Kim N, Jeon SH, Ju IG, et al. (2021) Transplantation of gut microbiota derived from Alzheimer's disease mouse model impairs memory function and neurogenesis in C57BL/ 6 mice. Brain Behav Immun 98:357-65.

[92] Koppel I, Timmusk T (2013) Differential regulation of BDNF expression in cortical neurons by class-selective histone deacetylase inhibitors. Neuropharmacology 75:106-15.

[93] Lai Z, Shan W, Li J, et al. (2021) Appropriate exercise level attenuates gut dysbiosis and valeric acid increase to improve neuroplasticity and cognitive function after surgery in mice. Mol Psychiatry 26, 7167-87.

[94] Lai Z, Shan W, Li J, et al. (2021) Appropriate exercise level attenuates gut dysbiosis and valeric acid increase to improve neuroplasticity and cognitive function after surgery in mice. Mol Psychiatry 26:7167-87.

[95] Lambert JE, Myslicki JP, Bomhof MR, et al. (2015) Exercise training modifies gut microbiota in normal and diabetic mice. Appl Physiol Nutr Metab 40:749-52.

[96] Langoni CDS, Resende TL, Barcellos AB, et al. (2019) The effect of group exercises on balance, mobility, and depressive symptoms in older adults with mild cognitive impairment: a randomized controlled trial. Clin Rehabil 33:439-49.

[97] LeBouthillier DM, Asmundson GJG (2017) The efficacy of aerobic exercise and resistance training as transdiagnostic interventions for anxiety-related disorders and constructs: a randomized controlled trial. J Anxiety Disord 52:43-52.

[98] Lee HJ, Lim SM, Kim DH (2018) Lactobacillus johnsonii CJLJ103 attenuates scopolamine-induced memory impairment in mice by increasing BDNF expression and inhibiting NF-κb activation.. J Microbiol Biotechnol 28:1443-46.

[99] Leichsenring F, Heim N, Steinert C (2023) A review of anxiety disorders. JAMA 329:1315-16.

[100] Leigh SJ, Morris MJ (2020) Diet, inflammation and the gut microbiome: mechanisms for obesity-associated cognitive impairment. Biochim Biophys Acta Mol Basis Dis 1866:165767.

[101] Lensu S, Pekkala S (2021) Gut microbiota, microbial metabolites and human physical performance. Metabolites 11:716.

[102] Li R, Liu R, Chen L, et al. (2023) Microbiota from exercise mice counteracts high-fat high-cholesterol diet-induced cognitive impairment in C57BL/ 6 mice. Oxid Med Cell Longev 2023:2766250.

[103] Li Y, Luo Y, Tang J, et al. (2021) The positive effects of running exercise on hippocampal astrocytes in a rat model of depression. Transl Psychiatry 11:83.

[104] Li Y, Ning L, Yin Y, et al. (2020) Age-related shifts in gut microbiota contribute to cognitive decline in aged rats. Aging 12:7801-17.

[105] Li Z, Yi CX, Katiraei S, et al. (2018) Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit. Gut 67:1269-79.

[106] Long X, Liu D, Gao Q, et al. (2021) Bifidobacterium adolescentis alleviates liver steatosis and steatohepatitis by increasing fibroblast growth factor 21 sensitivity. Front Endocrinol 12:773340.

[107] Loprinzi PD, Day S, Hendry R, et al. (2021) The effects of acute exercise on short- and long-term memory: considerations for the timing of exercise and phases of memory. Eur J Psychol 17: 85-103.

[108] Louis P, Flint HJ (2009) Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol Lett 294:1-8.

[109] Luo S, O'Connor SG, Belcher BR, et al. (2018) Effects of physical activity and sedentary behavior on brain response to high-calorie food cues in young adults. Obesity (Silver Spring) 26:540-46.

[110] Lyte M (2014) Microbial endocrinology and the microbiota-gut-brain axis. Adv Exp Med Biol 817:3-24.

[111] MacKay M, Yang BH, Dursun SM, et al. (2024) The gut-brain axis and the microbiome in anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder. Curr Neuropharmacol 22:866-83.

[112] Madiha S, Batool Z, Tabassum S, et al. (2021) Quercetin exhibits potent antioxidant activity, restores motor and non-motor deficits induced by rotenone toxicity. PLoS ONE 16:e0258928.

[113] 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 47:75-85.

[114] Maitra M, Mitsuhashi H, Rahimian R, et al. (2023) Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes. Nat Commun 14:2912.

[115] Manaf FA, Lawler NG, Peiffer JJ, et al. (2018) Characterizing the plasma metabolome during and following a maximal exercise cycling test. J Appl Physiol 125:1193-203.

[116] Mayer EA (2011) Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 12:453-66.

[117] Mayer EA, Nance K, Chen S (2022) The gut-brain axis. Annu Rev Med 73:439-53.

[118] McGillivray JE, Debruin H, Kumbhare D, et al. (2021) The effect of exercise on neural activation and cognition: a review of task-based fMRI studies. Crit Rev Biomed Eng 49:21-52.

[119] Modi HN, Singh H, Yang GZ, et al. (2017) A decade of imaging surgeons' brain function (part I): terminology, techniques, and clinical translation. Surgery 162:1121-30.

[120] Mollinedo Cardalda I, López A, Cancela Carral JM (2019) The effects of different types of physical exercise on physical and cognitive function in frail institutionalized older adults with mild to moderate cognitive impairment. A randomized controlled trial. Arch Gerontol Geriatr 83:223-30.

[121] Morais LH, Schreiber HL, Mazmanian SK (2021) The gut microbiotabrain axis in behaviour and brain disorders. Nat Rev Micro 19:24155.

[122] Moreau D, Chou E (2019) The acute effect of high-intensity exercise on executive function: a meta-analysis. Perspect Psychol Sci 14:73464.

[123] Motger-Albertí A, Fernández-Real JM. (2023) Gut microbiome and cognitive functions in metabolic diseases. In M. Federici, R Menghini (eds), Gut Microbiome, Microbial Metabolites and Cardiometabolic Risk(pp.1-27). Chamonix: Springer International Publishing.

[124] Motiani KK, Collado MC, Eskelinen JJ, et al. (2020) Exercise training modulates gut microbiota profile and improves endotoxemia. Med Sci Sports Exerc 52:94-104.

[125] Mrdjen D, Pavlovic A, Hartmann FJ, et al. (2018) High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48:380-95. e6.

[126] 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.

[127] Mutrie N, Richards K, Lawrie S, et al. (2018) Can physical activity prevent or treat clinical depression? The Exercise Effect on Mental Health:Neurobiological Mechanisms. Boca Raton, Florida: Chemical Rubber Company Press.

[128] Nagamatsu LS, Handy TC, Hsu CL, et al. (2012) Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Arch Intern Med 172: 666-8.

[129] Nobari H, Nejad HA, Kargarfard M, et al. (2021) The effect of acute intense exercise on activity of antioxidant enzymes in smokers and non-smokers. Biomolecules 11:171.

[130] Numakawa T, Odaka H, Adachi N (2018) Actions of brain-derived neurotrophin factor in the neurogenesis and neuronal function, and its involvement in the pathophysiology of brain diseases. Int J Mol Sci 19:3650.

[131] Ogbonnaya ES, Clarke G, Shanahan F, et al. (2015) Adult hippocampal neurogenesis is regulated by the microbiome. Biol Psychiatry 78:e7-9.

[132] Oldendorf WH (1973) Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids. Am J Physiol 224:1450-3.

[133] Olson RL, Brush CJ, Ehmann PJ, et al. (2017) A randomized trial of aerobic exercise on cognitive control in major depression. Clin Neurophysiol 128:903-13.

[134] Osadchiy V, Martin CR, Mayer EA (2019) The gut-brain axis and the microbiome: mechanisms and clinical implications. Clin Gastroenterol Hepatol 17:322-32.

[135] Parker A, Fonseca S, Carding SR (2020) Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health. Gut Microbes 11:135-57.

[136] Pascale A, Marchesi N, Govoni S, et al. (2020) Targeting the microbiota in pharmacology of psychiatric disorders. Pharmacol Res 157:104856.

[137] Pearce M, Garcia L, Abbas A, et al. (2022) Association between physical activity and risk of depression: a systematic review and metaanalysis. JAMA Psychiatry 79:550-59.

[138] Petriz BA, Castro AP, Almeida JA, et al. (2014) Exercise induction of gut microbiota modifications in obese, non-obese and hypertensive rats. BMC Genomics [Electronic Resource] 15:511.

[139] Podyma B, Johnson DA, Sipe L, et al. (2020) The p75 neurotrophin receptor in AgRP neurons is necessary for homeostatic feeding and food anticipation. eLife 9:e52623.

[140] Podyma B, Parekh K, Güler AD, et al. (2021) Metabolic homeostasis via BDNF and its receptors. Trends Endocrinol Metab 32:488-99.

[141] Polityńska B, Pokorska O, Wojtukiewicz AM, et al. (2022) Is depression the missing link between inflammatory mediators and cancer? Pharmacol Ther 240:108293.

[142] Pourhamzeh M, Moravej FG, Arabi M, et al. (2022) The roles of serotonin in neuropsychiatric disorders. Cell Mol Neurobiol 42:1671-92.

[143] Rajendram R, Patel VB, Preedy VR (2021) Recommended resources on the neuroscience of depression:genetics, cell biology, neurology, behavior, and diet. In The Neuroscience of Depression(pp.53137): New York: Academic Press.

[144] Ramos-Sanchez CP, Schuch FB, Seedat S, et al. (2021) The anxiolytic effects of exercise for people with anxiety and related disorders: an update of the available meta-analytic evidence. Psychiatry Res 302:114046.

[145] Ranuh R, Athiyyah AF, Darma A, et al. (2019) Effect of the probiotic Lactobacillus plantarum IS-10506 on BDNF and 5HT stimulation: role of intestinal microbiota on the gut-brain axis. Iran J Microbiol 11:145-50.

[146] Ray MT, Shannon Weickert C, Webster MJ (2014) Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders. Transl Psychiatry 4:e389.

[147] Rezaei S, Gharepapagh E, Rashidi F, et al. (2023) Machine learning applied to functional magnetic resonance imaging in anxiety disorders. J Affect Disord 342:54-62.

[148] Richard DM, Dawes MA, Mathias CW, et al. (2009) L-tryptophan: basic metabolic functions, behavioral research and therapeutic indications. Int J Tryptophan Res 2:45-60.

[149] Roth W, Zadeh K, Vekariya R, et al. (2021) Tryptophan metabolism and gut-brain homeostasis. Int J Mol Sci 22:2973.

[150] Rupnik M, Wilcox MH, Gerding DN (2009) Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Micro 7:526-36.

[151] Saanijoki T, Nummenmaa L, Tuulari JJ, et al. (2018) Aerobic exercise modulates anticipatory reward processing via the μ-opioid receptor system. Hum Brain Mapp 39:3972-83.

[152] Schultz W, Tremblay L, Hollerman JR (2000) Reward processing in primate orbitofrontal cortex and basal ganglia. Cereb Cortex 10:27284.

[153] Shang A, Bieszczad KM (2022) Epigenetic mechanisms regulate cue memory underlying discriminative behavior. Neurosci Biobehav Rev 141:104811.

[154] Sharon G, Cruz NJ, Kang DW, et al. (2019) Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell 177:1600-18. e17.

[155] Singh B, Olds T, Curtis R, et al. (2023) Effectiveness of physical activity interventions for improving depression, anxiety and distress: an overview of systematic reviews. BrJ Sports Med 57:1203-09.

[156] Sleiman SF, Henry J, Al-Haddad R, et al. (2016) Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife 5:e15092.

[157] Smith JC, Nielson KA, Antuono P, et al. (2013) Semantic memory functional MRI and cognitive function after exercise intervention in mild cognitive impairment. J Alzheimers Dis 37:197-215.

[158] Soares NL, Dorand VAM, Cavalcante HC, et al. (2021) Does intermittent fasting associated with aerobic training influence parameters related to the gut-brain axis of Wistar rats? J Affect Disord 293, 176-85.

[159] Soares NL, Dorand VAM, Cavalcante HC, et al. (2021) Does intermittent fasting associated with aerobic training influence parameters related to the gut-brain axis of Wistar rats? J Affect Disord 293:176-85.

[160] Socała K, Doboszewska U, Szopa A, et al. (2021) The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacol Res 172:105840.

[161] Stallone D, Nicolaidis S (1989) Increased food intake and carbohydrate preference in the rat following treatment with the serotonin antagonist metergoline. Neurosci Lett 102:319-24.

[162] Steinhäuser JL, Teed AR, Al-Zoubi O, et al. (2023) Reduced vmPFCinsula functional connectivity in generalized anxiety disorder: a Bayesian confirmation study. Sci Rep 13:9626.

[163] Stilling RM, van de Wouw M, Clarke G, et al. (2016) The neuropharmacology of butyrate: the bread and butter of the microbiota-gut-brain axis? Neurochem Int 99:110-32.

[164] Ströhle A (2009) Physical activity, exercise, depression and anxiety disorders. J Neural Transm 116:777-84.

[165] Sudo M, Costello JT, McMorris T, et al. (2022) The effects of acute highintensity aerobic exercise on cognitive performance: a structured narrative review. Front Behav Neurosci 16:957677.

[166] Suo C, Singh MF, Gates N, et al. (2016) Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise. Mol Psychiatry 21:1633-42.

[167] Suryani D, Subhan Alfaqih M, Gunadi JW, et al. (2022) Type, intensity, and duration of exercise as regulator of gut microbiome profile. Curr Sports Med Rep 21:84-91.

[168] Tabone M, Bressa C, García-Merino JA, et al. (2021) The effect of acute moderate-intensity exercise on the serum and fecal metabolomes and the gut microbiota of cross-country endurance athletes. Sci Rep 11:3558.

[169] Taniguchi H, Tanisawa K, Sun X, et al. (2018) Effects of short-term endurance exercise on gut microbiota in elderly men. Physiol Rep 6:e13935.

[170] Tarumi T, Rossetti H, Thomas BP, et al. (2019) Exercise training in amnestic mild cognitive impairment: a one-year randomized controlled trial. J Alzheimers Dis 71:421-33.

[171] Taubert M, Lohmann G, Margulies DS, et al. (2011) Long-term effects of motor training on resting-state networks and underlying brain structure. Neuroimage 57:1492-8.

[172] Taylor S, Workman L (2021) Cognitive Psychology: The Basics. London: Routledge.

[173] Thackray AE, Hinton EC, Alanazi TM, et al. (2023) Exploring the acute effects of running on cerebral blood flow and food cue reactivity in healthy young men using functional magnetic resonance imaging. Hum Brain Mapp 44:3815-32.

[174] Thivel D, Julian V, Miguet M, et al. (2020) Introducing eccentric cycling during a multidisciplinary weight loss intervention might prevent adolescents with obesity from increasing their food intake: the TEXTOO study. Physiol Behav 214:112744.

[175] Trevelline BK, Kohl KD (2022) The gut microbiome influences host diet selection behavior. Proc Natl Acad Sci USA 119:e2117537119.

[176] Voss MW, Erickson KI, Prakash RS, et al. (2010) Functional connectivity: a source of variance in the association between cardiorespiratory fitness and cognition? Neuropsychologia 48: 1394-406.

[177] Voss MW, Prakash RS, Erickson KI, et al. (2010) Plasticity of brain networks in a randomized intervention trial of exercise training in older adults. Front Aging Neurosci 2:1803.

[178] Wang G, Zhou HH, Luo L, et al. (2021) Voluntary wheel running is capable of improving cognitive function only in the young but not the middle-aged male APPSwe/PS1De9 mice. Neurochem Int 145, 105010.

[179] Wang G, Zhou HH, Luo L, et al. (2021) Voluntary wheel running is capable of improving cognitive function only in the young but not the middle-aged male APPSwe/PS1De9 mice. Neurochem Int 145:105010.

[180] Wang R, Cai Y, Lu W, et al. (2023) Exercise effect on the gut microbiota in young adolescents with subthreshold depression: a randomized psychoeducation-controlled Trial. Psychiatry Res 319: 115005.

[181] Wang Y, Pan Y, Li H (2020) What is brain health and why is it important? BMJ 371:m3683.

[182] Watanabe C, Oyanagi E, Aoki T, et al. (2023) Antidepressant properties of voluntary exercise mediated by gut microbiota. Biosci Biotechnol Biochem 87, 1407-19.

[183] Watanabe C, Oyanagi E, Aoki T, et al. (2023) Antidepressant properties of voluntary exercise mediated by gut microbiota. Biosci Biotechnol Biochem 87:1407-19.

[184] Wei GX, Dong HM, Yang Z, et al. (2014) Tai Chi Chuan optimizes the functional organization of the intrinsic human brain architecture in older adults. Front Aging Neurosci 6:74.

[185] Wei GX, Xu T, Fan FM, et al. (2013) Can Taichi reshape the brain? A brain morphometry study. PLoS ONE 8:e61038.

[186] Wilke J, Giesche F, Klier K, et al. (2019) Acute effects of resistance exercise on cognitive function in healthy adults: a systematic review with multilevel meta-analysis. Sports Med 49:905-16.

[187] Won J, Callow DD, Pena GS, et al. (2021) Evidence for exercise-related plasticity in functional and structural neural network connectivity. Neurosci Biobehav Rev 131:923-40.

[188] Xie Y, Wu Z, Sun L, et al. (2021) The effects and mechanisms of exercise on the treatment of depression.. Front Psychiatry 12:705559.

[189] Xie Y, Wu Z, Zhou L, et al. (2022) Swimming exercise modulates gut microbiota in CUMS-induced depressed mice. Neuropsychiatr Dis Treat 18:749-60.

[190] Xie Y, Wu Z, Zhou L, et al. (2022) Swimming Exercise Modulates Gut Microbiota in CUMS-Induced Depressed Mice. Neuropsychiatr Dis Treat 18:749-60.

[191] Xiong J, Ye M, Wang L, et al. (2021) Effects of physical exercise on executive function in cognitively healthy older adults: a systematic review and meta-analysis of randomized controlled trials: physical exercise for executive function. Int J Nurs Stud 114:103810.

[192] Yao Y, Wang K, Xiang H (2022) Association between cognitive function and ambient particulate matters in middle-aged and elderly Chinese adults: evidence from the China Health and Retirement Longitudinal Study (CHARLS). Sci Total Environ 828: 154297.

[193] Yogev-Seligmann G, Eisenstein T, Ash E, et al. (2021) Neurocognitive plasticity is associated with cardio respiratory fitness following physical exercise in older adults with amnestic mild cognitive impairment. J Alzheimers Dis 81:91-112.

[194] Zhao J, Bi W, Zhang J, et al. (2020) USP 8 protects against lipopolysaccharide-induced cognitive and motor deficits by modulating microglia phenotypes through TLR4/MyD88/NF-κB signaling pathway in mice. Brain Behav Immun 88:582-96.

[195] Zhao JL, Jiang WT, Wang X, et al. (2020) Exercise, brain plasticity, and depression. CNS Neurosci Ther 26:885-95.

[196] Zhao X, Zhang Z, Hu B, et al. (2018) Response of gut microbiota to metabolite changes induced by endurance exercise. Front Microbiol 9:765.

[197] Zhu Q, Jiang S, Du G (2020) Effects of exercise frequency on the gut microbiota in elderly individuals. Microbiol Open 9:e1053.

[198] Zlatar ZZ, Towler S, McGregor KM, et al. (2013) Functional language networks in sedentary and physically active older adults. J Int Neuropsychol Soc 19:625-34.