Cognitive dysfunction, one of the major concerns of increased life expectancy, is prevalent in patients with metabolic disorders. Added to the inflammation in the context of aging (inflammaging), low-grade chronic inflammation (metaflammation) accompanies metabolic diseases. Peripheral and central inflammation underlie metabolic syndrome - related cognitive dysfunction. The gut microbiota is increasingly recognized to be linked to both inflammaging and metaflammation in parallel to the pathophysiology of obesity, type 2 diabetes and the metabolic syndrome. Microbiota composition, diversity and diverse metabolites have been related to different metabolic features and cognitive traits. The study of different mouse models has contributed to identify characteristic microbiota profiles and shifts in the microbial gene richness in association with cognitive function. Diet, exercise and prebiotics, probiotics or symbiotics significantly influence cognition and changes in the microbiota. Few studies have analyzed the gut microbiota composition in association with cognitive function in humans. Impaired attention, mental flexibility and executive function have been observed in association with a microbiota ecosystem in cross-sectional and longitudinal studies. Nevertheless, the evidence in humans is still scarce and not causal relationships may be inferred, so larger and long-term studies are required to gain insight into the possible role of microbiota in human cognition.
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Institute for Health Metrics and Evaluation [IHME]. Findings from the global burden of disease study 2017. Seattle, WA: IHME; 2018.
GBD 2017 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years [DALYs] for 359 diseases and injuries and healthy life expectancy [HALE] for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Diseases Study 2017. Lancet. 2018;392:1859–1922.
Sachdev PS, Lipnicki DM, Kochan NA, Crawford JD, Thalamuthu A, Andrews G, et al. The prevalence of mild cognitive impairment in diverse geographical and ethnocultural regions: the COSMIC collaboration. PLoS One. 2015;10:e0142388.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington DC; 2013.
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Kokmen E, Tangelos EG. Aging, memory and mild cognitive impairment. Int Psychogeriatr. 1997;9:65–9.
Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J, Relkin N, et al. Practice parameter: diagnosis of dementia [an evidence-based review]. Report of the quality standards Subcommittee of the American Academy of neurology. Neurology. 2001;56:1143–53.
Roberts R, Knopman DS. Classification and epidemiology of MCI. Clin Geriatr Med. 2013;29:753–72.
Ismail Z, Elbayoumi H, Fischer CE, Hogan DB, Millikin CP, Schweizer T, et al. Prevalence of depression in patients with mild cognitive impairment: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74:58–67.
Mirza SS, Ikram MA, Bos D, Mihaescu R, Hofman A, Tiemeir H. Mild cognitive impairment and risk of depression and anxiety: a population-based study. Alzheimers Dement. 2017;13:130–9.
Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention and care. Lancet. 2017;390:2673–734.
Falony G, Joosens M, Viera-Silva S, Wang J, Darzi Y, Faust K, et al. Population-level analysis of gut microbiome variation. Science. 2016;352:560–4.
Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, et al. Host-gut microbiota metabolic interactions. Science. 2012;336:1262–7.
Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 2011;12:453–66.
Bäckhed F, Fraser CM, Ringel Y, Sanders ME, Sartor RB, Sherman PM, et al. Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications. Cell Host Microbe. 2012;12:611–22.
Aziz Q, Doré J, Emmanuel A, Guarner F, Quigley EM. Gut microbiota and gastrointestinal health: current concepts and future directions. Neurogastroenterol Motil. 2013;25:4–15.
Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol. 2018;14:591–604.
O’Brien PD, Hinder LM, Callaghan BC, Fedman EL. Neurological consequences of obesity. Lancet Neurol. 2017;16:465–77.
Farruggia MC, Small DM. Effects of adiposity and metabolic dysfunction on cognition: a review. Physiol Behav. 2019;208:112578.
Tilg H, Zmora N, Adolph TE, Elinav E. The intestinal microbiota fuelling metabolic inflammation. Nat Rev Immunol. 2019; 10.1038/s41577-019-0198-4,
Pistollato F, Sumalla Cano S, Elio I, Masias Vergara M, Giampieri F, Battino M. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease. Nutr Rev. 2016;74:624–34.
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Circulation. 2009;120:1640–5.
O’Neill S, O’Driscoll L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev. 2015;16:1–12.
Beydoun MA, Beydoun H, Wang Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and metaanalysis. Obes Rev. 2008;9:204–18.
Pugazhenthi S, Qin L, Reddy PH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim Biophys Acta Mol basis Dis. 1863;2017:1037–45.
Polanco JC, Li C, Bodea LG, Martinez-Marmol R, Meunier FA, Götz J. Amyloid-β and tau complexity-towards improved biomarkers and targeted therapies. Nat Rev Neurol. 2018;14:22–39.
Bharadwaj P, Wijesekara N, Liyanapathirana M, Newsholme P, Ittner L, Fraser P, et al. The link between type 2 diabetes and neurodegeneration: roles for amyloid-β, amylin, and tau proteins. J Alzheimers Dis. 2017;59:421–32.
Willette AA, Johnson SC, Birdsill AC, Sager MA, Christian B, Baker LD, et al. Insulin resistance predicts brain amyloid deposition in late middle-aged adults. Alzheimers Dement. 2015;11:504–510.e1.
Walker JM, Dixit S, Saulsberry AC, May JM, Harrison FE. Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, β-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer’s disease. Neurobiol Dis. 2017;100:87–98.
Veronese N, Facchini S, Stubbs B, Luchini C, Solmi M, Manzato E, et al. Weight loss is associated with improvements in cognitive function among overweight and obese people: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2017;72:87–94.
Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, et al. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;41:615–31.
Consolim-Colombo FM, Sangaleti CT, Costa FO, Morais TL, Lopes HF, Motta JM, et al. Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial. JCI Insight. 2017;2. pii: 93340.
Wu Y, Ma Y, Liu Z, Geng Q, Chen Z, Zhang Y. Alterations of myelin morphology and oligodendrocyte development in early stage of Alzheimer’s disease mouse model. Neurosci Lett. 2017;642:102–6.
Dean DC 3rd, Hurley SA, Kecskemeti SR, O’Grady JP, Canda C, Davenport-Sis NJ, et al. Association of amyloid pathology with myelin alteration in preclinical Alzheimer disease. JAMA Neurol. 2017;74:41–9.
O’Grady JP, Dean DC 3rd, Yang KL, Canda CM, Hoscheidt SM, Starks EJ, et al. Elevated insulin and insulin resistance are associated with altered myelin in cognitively unimpaired middle-aged adults. Obesity [SilverSpring]. 2019;27:1464–1471.
Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7.
King E, O’Brien JT, Donaghy P, Morris C, Barnett N, Olsen K, et al. Peripheral inflammation in prodromal Alzheimer’s and Lewy body dementias. J Neurol Neurosurg Psychiatry. 2018;89:339–45.
Wood H. Dementia: peripheral inflammation could be a prodromal indicator of dementia. Nat Rev Neurol. 2018;14:127.
Cai D. Neuroinflammation and Neurodegeneration in overnutrition-induced diseases. Trend Endocrinol Metab. 2013;24:40–7.
Schain M, Kreisl WC. Neuroinflammation in neurodegenerative disorders - a review. Curr Neurol Neurosci Rep. 2017;17:25.
Jais A, Brüning JC. Hypothalamic inflammation in obesity and metabolic disease. J Clin Invest. 2017;127:24–32.
Guillemot-Legris O, Mucciolo GC. Obesity-induced Neuroinflammation: beyond the hypothalamus. Trends Neurosci. 2017;40:237–53.
Biessels GJ, Reagan LP. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci. 2015;16:660–71.
Tracey KJ. The inflammatory reflex. Nature. 2002;420:853–9.
Chang EH, Chanvan SS, Pavlov VA. Cholinergic control of inflammation, metabolic dysfunction and cognitive impairment in obesity-associated disorders: mechanism and novel therapeutic opportunities. Front Neurosci. 2019;13:263.
Franceschi C, Garagnani P, Parnin P, Giuliani C, Santoto A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14:576–90.
Deleidi M, Jäggle M, Rubino G. Immune aging, dysmetabolism, and inflammation in neurological diseases. Front Neurosci. 2015;9:172.
Burcelin R. Gut microbiota and immune crosstalk in metabolic disease. Mol Metab. 2016;5:771–81.
Gérard P. Gut microbiota and obesity. Cell Mol Life Sci. 2016;73:147–62.
Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490:55–60.
Festi D, Schiumerini R, Henry Eusebi L, Marasco G, Taddia M, Colecchia A. Gut microbiota and metabolic syndrome. World J Gastroenterol. 2014;20:16079–94.
Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541–6.
Jiang W, Wu N, Wang X, Chi Y, Zhang Y, Qiu X, et al. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep. 2015;5:8096.
Zweigner J, Schumann RR, Weber JR. The role of lipopolysaccharide-binding protein in modulating the innate immune response. Microbes Infect. 2006;8:946–52.
Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–72.
Moreno-Navarrete JM, Escoté X, Ortega F, Serino M, Campbell M, Michalski MC, et al. A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction. Diabetologia. 2013;56:2524–37.
Hoyles L, Fernández-Real JM, Federici M, Serino M, Abbott J, Charpentier J, et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med. 2018;24:1070–80.
Gribble FM, Reimann F. Function and mechanism of enteroendocrine cells and gut hormones in metabolism. Nat Rev Endocrinol. 2019;15:226–37.
Sanna S, van Zuydam NR, Mahajan A, Kurilshikov A, Vich Vila A, Võsa U, et al. Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat Genet. 2019;51:600–5.
Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022–3.
Gao R, Zhu C, Li H, Yin M, Pan C, Huang L, et al. Dysbiosis signatures of gut microbiota along the sequence from healthy, young patients to those with overweight and obesity. Obesity (Silver Spring). 2018;26:351–61.
Debédat J, Clément K, Aron-Wisnewsky J. Gut microbiota dysbiosis in human obesity: impact of bariatric surgery. Curr Obes Rep. 2019;8:229–42.
He Y, Wu W, Wu S, Zheng HM, Li P, Sheng HF, et al. Linking gut microbiota, metabolic syndrome and economic status based on a population-level analysis. Microbiome. 2018;6:172.
Tilg H, Moschen AR. Microbiota and diabetes: an evolving relationship. Gut. 2014;63:1513–21.
Cani PD, de Vos WM. Next-generation beneficial microbes: the case of Akkermansia muciniphila. Front Microbiol. 2017;8:1765.
Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry. 2016;21:738–48.
Quigley EMM. Microbiota-brain-gut Axis and neurodegenerative diseases. Curr Neurol Neurosci Rep. 2017;17:94.
Liu P, Wu L, Peng G, Han Y, Tang R, Ge J, et al. Altered microbiomes distinguish Alzheimer’s disease from amnestic mild cognitive impairment and health in a Chinese cohort. Brain Behav Immun. 2019;80:633–43.
Gao X, Liu X, Xu J, Xue C, Xue Y, Wang Y. Dietary trimethylamine N-oxide exacerbactes impaired glucosa tolerance in mice fed a high fat diet. J Biosci Bioeng. 2014;118:476–81.
Dambrova M, Latkovskis G, Kuka J, Strele I, Konrade I, Grinberga S, et al. Diabetes is associated with higher trimethylamine N-oxide plasma levels. Exp Clin Endocrinol Diabetes. 2016;124:251–6.
Sanguinetti E, Collado MC, Marrachelli VG, Monleon D, Selma-Royo M, Pardo-Tendero MM, et al. Microbiome-metabolome signatures in mice genetically prone to develop dementia, fed a normal or fatty diet. Sci Rep. 2018;8:4907.
Li D, Ke Y, Zhan R, Liu C, Zhao M, Zeng A, et al. Trimethylamine-N-oxide promotes brain aging and cognitive impairment in mice. Aging Cell. 2018;49:e12768.
Vogt NM, Romano KA, Darst BF, Engelman CD, Johnson SC, Carlsson CM, et al. The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimers Res Ther. 2018;10:124.
Sarkar A, Harty S, Lehto SM, Moeller AH, Dinan TG, Dunbar RIM, et al. The microbiome in psychology and cognitive neuroscience. Trends Cogn Sci. 2018;22:611–36.
Yang Y, Zhong Z, Wang B, Xia X, Yao W, Huang L, et al. Early-life high-fat diet-induced obesity programs hippocampal development and cognitive functions via regulation of gut commensal Akkermansia muciniphila. Neuropsychopharmacology. 2019;44:2054–64.
Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110:9066–71.
Kang SS, Jeraldo PR, Kurti A, Miller ME, Cook MD, Whitlock K, et al. Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition. Mol Neurodegener. 2014;9:36.
Zhang P, Yu Y, Qin Y, Zhou Y, Tang R, Wang Q, et al. Alterations to the microbiota-colon-brain axis in high-fat-diet-induced obese mice compared to diet-resistant mice. J Nutr Biochem. 2019;65:54–65.
Jena PK, Sheng L, Di Lucente J, Jin LW, Maezawa I, Wan YY. Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet-induced systemic inflammation, microglial activation, and reduced neuroplasticity. FASEB J. 2018;32:2866–77.
Magnusson KR, Hauck L, Jeffrey BM, Elias V, Humphrey A, Nath R, et al. Relationships between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience. 2015;300:128–40.
Liu Z, Yuan T, Dai X, Shi L, Liu X. Intermittent fasting alleviates diabetes-induced cognitive decline via gut microbiota-metabolites-brain axis [OR32–04-19]. Curr Dev Nutr. 2019;3:nzz052. https://doi.org/10.1093/cdn/nzz052.OR32-04-19.
Marungruang N, Kovalenko T, Osadchenko I, Voss U, Huang F, Burleigh S, et al. Lingonberries and their two separated fractions differently alter the gut microbiota, improve metabolic functions, reduce gut inflammatory properties, and improve brain function in ApoE−/− mice fed high-fat diet. Nutr Neurosci. 2018:1–13.
López P, Sánchez M, Pérez-Cruz C, Velázquez-Villegas LA, Syeda T, Aguilar-López M, et al. Long-term genistein consumption modifies gut microbiota, improving glucose metabolism, metabolic endotoxemia, and cognitive function in mica fed a high-fat diet. Mol Nutr Food Res. 2018;62:e1800313.
Lv M, Yang S, Cai L, Qin LQ, Li BY, Wan Z. Effects of quercetin intervention on cognition function in APP/PS1 mice was affected by vitamin D status. Mol Nutr Food Res. 2018;62:e1800621.
Chunchai T, Thunapong W, Yasom S, Wanchai K, Eaimworawuthikul S, Metzler G, et al. Decreased microglial activation through gut-brain axis by prebiotics, probiotics, or symbiotics effectively restored cognitive function in obese-insulin resistant rats. J Neuroinflammation. 2018;15:11.
Fernández-Real JM, Serino M, Blasco G, Puig J, Daunis-i-Estadella J, Ricart W, et al. Gut microbiota interacts with brain microstructure and function. J Clin Endocrinol Metab. 2015;100:4505–13.
Meadowcroft MD, Peters DG, Dewal RP, Connor JR, Yang QX. The effect of iron in MRI and transverse relaxation of amyloid-beta plaques in Alzheimer’s disease. NMR Biomed. 2015;28:297–305.
Palomo-Buitrago ME, Sabater-Masdeu M, Moreno-Navarrete JM, Caballano-Infantes E, Arnoriaga-Rodríguez M, Coll C, et al. Glutamate interactions with obesity, insulin resistance, cognition and gut microbiota composition. Acta Diabetol. 2019;56:569–79.
Anderson JR, Carroll I, Azcarate-Peril MA, Rochette AD, Heinberg LJ, Peat C, et al. A preliminary examination of gut microbiota, sleep, and cognitive flexibility in healthy older adults. Sleep Med. 2017;38:104–7.
Blasco G, Moreno-Navarrete JM, Rivero M, Pérez-Brocal V, Garre-Olmo J, Puig J, et al. The gut metagenome changes in parallel to waist circumference, brain iron deposition, and cognitive function. J Clin Endocrinol Metab. 2017;102:2962–73.
Janelidze S, Stomrud E, Palmqvist S, Zetterberg H, van Western D, Jeromin A, et al. Plasma β-amyloid in Alzheimer’s disease and vascular disease. Sci Rep. 2016;6:26801.
María Arnoriaga-Rodríguez is funded by a predoctoral “FIS” contract (PI16/02173) from the Instituto de Salud Carlos III, Spain.
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Arnoriaga-Rodríguez, M., Fernández-Real, J.M. Microbiota impacts on chronic inflammation and metabolic syndrome - related cognitive dysfunction. Rev Endocr Metab Disord 20, 473–480 (2019). https://doi.org/10.1007/s11154-019-09537-5
- Cognitive dysfunction
- Low-grade inflammation
- Metabolic disorders