Abstract
Obesity is one of the most serious public health challenges in the world. Obesity during early life has been associated with an increased risk of neurodevelopmental disorders, including deficits in learning and memory, yet the underlying mechanisms remain unclear. Here, we show that early life high-fat diet (HFD) feeding impairs hippocampus–dependent contextual/spatial learning and memory, and alters the gut microbiota, particularly by depleting Akkermansia muciniphila (A. muciniphila), in mice. Transplantation of the HFD microbiota confers hippocampus-dependent learning and memory deficits to mice fed a chow diet. Oral treatment of HFD-fed mice with the gut commensal A. muciniphila corrects gut permeability, reduces hippocampal microgliosis and proinflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6) expression, and restores neuronal development and synapse plasticity, thus ameliorates defects in learning and memory. Interestingly, treatment of mice with lipopolysaccharide (LPS) mimics HFD-induced hippocampus-dependent cognitive impairment in chow-fed mice. In line with these findings, pharmacologic blockade of Toll-like receptor 4 (TLR4) signalling or antibiotics treatment both effectively prevent hippocampus-dependent learning and memory deficits in HFD-fed mice. Collectively, our findings demonstrate an unexpected pivotal role of gut microbiota in HFD-induced cognitive deficits and identify a potential probiotic therapy for obesity associated with cognitive dysfunction during early life.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Vainik U, Baker TE, Dadar M, Zeighami Y, Michaud A, Zhang Y, et al. Neurobehavioral correlates of obesity are largely heritable. Proc Natl Acad Sci USA. 2018;115:9312–7.
Bocarsly ME, Fasolino M, Kane GA, LaMarca EA, Kirschen GW, Karatsoreos IN, et al. Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function. Proc Natl Acad Sci USA. 2015;112:15731–6.
Sellbom KS, Gunstad J. Cognitive function and decline in obesity. J Alzheimers Dis. 2012;30(Suppl 2):S89–95.
Agusti A, Garcia-Pardo MP, Lopez-Almela I, Campillo I, Maes M, Romani-Perez M, et al. Interplay between the gut—brain axis, obesity, and cognitive function. Front Neurosci. 2018;12:155.
Boitard C, Cavaroc A, Sauvant J, Aubert A, Castanon N, Laye S, et al. Impairment of hippocampal-dependent memory induced by juvenile high-fat diet intake is associated with enhanced hippocampal inflammation in rats. Brain Behav Immun. 2014;40:9–17.
Valcarcel-Ares MN, Tucsek Z, Kiss T, Giles CB, Tarantini S, Yabluchanskiy A, et al. Obesity in aging exacerbates neuroinflammation, dysregulating synaptic function-related genes, and altering eicosanoid synthesis in the mouse hippocampus: potential role in impaired synaptic plasticity and cognitive decline. J Gerontol A Biol Sci Med Sci. 2019;74:290–8.
Wu TR, Lin CS, Chang CJ, Lin TL, Martel J, Ko YF, et al. Gut commensal Parabacteroides goldsteinii plays a predominant role in the anti-obesity effects of polysaccharides isolated from Hirsutella sinensis. Gut. 2019;68:248–62.
Skelly DT, Griffin EW, Murray CL, Harney S, O’Boyle C, Hennessy E, et al. Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms. Mol Psychiatr. 2018. https://doi.org/10.1038/s41380-018-0075-8.
Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else? Science. 2013;339:156–61.
Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–89.
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.
Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I, et al. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell. 2018;173:1073–81.
Song WM, Colonna M. The identity and function of microglia in neurodegeneration. Nat Immunol. 2018;19:1048–58.
Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nat Neurosci. 2018;21:1359–69.
De Luca SN, Ziko I, Sominsky L, Nguyen JC, Dinan T, Miller AA, et al. Early life overfeeding impairs spatial memory performance by reducing microglial sensitivity to learning. J Neuroinflammation. 2016;13:112.
Wadhwa M, Prabhakar A, Ray K, Roy K, Kumari P, Jha PK, et al. Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation. J Neuroinflamm. 2017;14:222.
Sato K. Effects of microglia on neurogenesis. Glia. 2015;63:1394–405.
Bruce-Keller AJ, Salbaum JM, Luo M, Blanchard Et, Taylor CM, Welsh DA, et al. Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biol Psychiatry. 2015;77:607–15.
Guillemot-Legris O, Muccioli GG. Obesity-induced neuroinflammation: beyond the hypothalamus. Trends Neurosci. 2017;40:237–53.
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 USA. 2013;110:9066–71.
Collado MC, Derrien M, Isolauri E, de Vos WM, Salminen S. Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl Environ Microbiol. 2007;73:7767–70.
Derrien M, Collado MC, Ben-Amor K, Salminen S, de Vos WM. The Mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Appl Environ Microbiol. 2008;74:1646–8.
Reunanen J, Kainulainen V, Huuskonen L, Ottman N, Belzer C, Huhtinen H, et al. Akkermansia muciniphila Adheres to enterocytes and strengthens the integrity of the epithelial cell layer. Appl Environ Microbiol. 2015;81:3655–62.
Derrien M, Vaughan EE, Plugge CM, de Vos WM. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol. 2004;54:1469–76.
Belzer C, de Vos WM. Microbes inside—from diversity to function: the case of Akkermansia. Isme j. 2012;6:1449–58.
Plovier H, Everard A, Druart C, Depommier C, Van Hul M, Geurts L, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med. 2017;23:107–13.
Grander C, Adolph TE, Wieser V, Lowe P, Wrzosek L, Gyongyosi B, et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut. 2018;67:891–901.
Hanninen A, Toivonen R, Poysti S, Belzer C, Plovier H, Ouwerkerk JP, et al. Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice. Gut. 2018;67:1445–53.
Olson CA, Vuong HE, Yano JM, Liang QY, Nusbaum DJ, Hsiao EY. The Gut microbiota mediates the anti-seizure effects of the ketogenic Diet. Cell. 2018;173:1728–41.
Chevalier C, Stojanovic O, Colin DJ, Suarez-Zamorano N, Tarallo V, Veyrat-Durebex C, et al. ut microbiota orchestrates energy homeostasis during cold. Cell. 2015;163:1360–74.
Liu B, Zupan B, Laird E, Klein S, Gleason G, Bozinoski M, et al. Maternal hematopoietic TNF, via milk chemokines, programs hippocampal development and memory. Nat Neurosci. 2014;17:97–105.
Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter GB, et al. Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nature. 2012;489:385–90.
Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell. 2016;165:1762–75.
Boitard C, Etchamendy N, Sauvant J, Aubert A, Tronel S, Marighetto A, et al. Juvenile, but not adult exposure to high-fat diet impairs relational memory and hippocampal neurogenesis in mice. Hippocampus. 2012;22:2095–100.
Matsunaga N, Tsuchimori N, Matsumoto T, Ii M. TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol. 2011;79:34–41.
Coats SR, Pham TT, Bainbridge BW, Reife RA, Darveau RP. MD-2 mediates the ability of tetra-acylated and penta-acylated lipopolysaccharides to antagonize Escherichia coli lipopolysaccharide at the TLR4 signaling complex. J Immunol. 2005;175:4490–8.
Turnbaugh PJ, Backhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3:213–23.
Bliss ES, Whiteside E. The gut–brain axis, the human gut microbiota and their integration in the development of obesity. Front Physiol. 2018;9:900.
Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 2000;24:417–63.
Monda V, La Marra M, Perrella R, Caviglia G, Iavarone A, Chieffi S, et al. Obesity and brain illness: from cognitive and psychological evidences to obesity paradox. Diabetes Metab Syndr Obes. 2017;10:473–9.
Kundakovic M, Champagne FA. Early-life experience, epigenetics, and the developing brain. Neuropsychopharmacol. 2015;40:141–53.
Wang S, Huang XF, Zhang P, Newell KA, Wang H, Zheng K, et al. Dietary teasaponin ameliorates alteration of gut microbiota and cognitive decline in diet-induced obese mice. Sci Rep. 2017;7:12203.
Wang S, Huang XF, Zhang P, Wang H, Zhang Q, Yu S, et al. Chronic rhein treatment improves recognition memory in high-fat diet-induced obese male mice. J Nutr Biochem. 2016;36:42–50.
Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57:1470–81.
Cani PD, 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. Gut. 2009;58:1091–103.
Trotta T, Porro C, Calvello R, Panaro MA. Biological role of Toll-like receptor-4 in the brain. J Neuroimmunal. 2014;268:1–12.
Funding and Disclosure
This study was supported by grants from the National Natural Science Foundation of China (81703841 to Y.J.Y.), China Postdoctoral Science Foundation (2018T110955 to Y.J.Y., 2017M612929 to Y.J.Y.), Sichuan Province Postdoctoral Science Foundation (008072001 to Y.J.Y.), and Chengdu University of TCM Science Foundation (ZRQN1718 to Y.J.Y., BSH2018003 to Y.J.Y.). The authors declare no competing interests.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yang, Y., Zhong, Z., Wang, B. et al. Early-life high-fat diet-induced obesity programs hippocampal development and cognitive functions via regulation of gut commensal Akkermansia muciniphila. Neuropsychopharmacol. 44, 2054–2064 (2019). https://doi.org/10.1038/s41386-019-0437-1
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41386-019-0437-1
This article is cited by
-
The endocannabinoidome–gut microbiome–brain axis as a novel therapeutic target for autism spectrum disorder
Journal of Biomedical Science (2025)
-
The association between Weight-adjusted-Waist Index (WWI) and cognitive function in older adults: a cross-sectional NHANES 2011–2014 study
BMC Public Health (2024)
-
Lacidophilin tablets alleviate constipation through regulation of intestinal microflora by promoting the colonization of Akkermansia sps
Scientific Reports (2024)
-
Intestinal Akkermansia muciniphila is Beneficial to Functional Recovery Following Ischemic Stroke
Journal of Neuroimmune Pharmacology (2024)
-
Memory defects in post-dauer Caenorhabditis elegans are a result of altered insulin signalling
Journal of Biosciences (2024)
