Maternal obese-Type gut microbiota differentially impact cognition, anxiety and compulsive behavior in male and female offspring in mice

PLoS ONE

Volumn 12, Issue 4, 2017, Pages

  Bruce Keller, Annadora J ^a   Fernandez Kim, Sun Ok ^a   Townsend, R Leigh ^a   Kruger, Claudia ^a   Carmouche, Richard ^a   Newman, Susan ^a   Salbaum, J Michael ^a   Berthoud, Hans Rudolf ^a  

^a PENNINGTON BIOMEDICAL RESEARCH CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMAL BEHAVIOR; ANIMAL EXPERIMENT; ANXIETY; ARTICLE; BODY WEIGHT; BREEDING; COGNITION; COMPULSION; CONTROLLED STUDY; DYSBIOSIS; FEMALE; FIRMICUTES; INTESTINE FLORA; LIPID DIET; LOW FAT DIET; MALE; MATERNAL BEHAVIOR; MATERNAL DEPRIVATION; MATERNAL NUTRITION; MATERNAL OBESITY; METAGENOMICS; MICROBIAL DIVERSITY; MOUSE; NEWBORN; NONHUMAN; PHENOTYPE; PROGENY; TAXONOMY; ANIMAL; ANIMAL COMMUNICATION; C57BL MOUSE; COMPULSIVE BEHAVIOR; MICROBIOLOGY; OBESITY; PREGNANCY; PRENATAL EXPOSURE;

ADIPOSITY; ANIMAL COMMUNICATION; ANIMALS; ANIMALS, NEWBORN; ANXIETY; COGNITION; COMPULSIVE BEHAVIOR; FEMALE; GASTROINTESTINAL MICROBIOME; MALE; MATERNAL NUTRITIONAL PHYSIOLOGICAL PHENOMENA; MICE, INBRED C57BL; OBESITY; PREGNANCY; PRENATAL EXPOSURE DELAYED EFFECTS;

EID: 85018842511     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0175577     Document Type: Article

References (90)

1. Pinto RQ, Soares I, Carvalho-Correia E, Mesquita AR. Gene-environment interactions in psychopathology throughout early childhood: A systematic review. Psychiatr Genet 2015; 25:223-33. https://doi.org/10.1097/YPG.0000000000000106 PMID: 26313931.
2. Delorme R, Ey E, Toro R, Leboyer M, Gillberg C, Bourgeron T. Progress toward treatments for synaptic defects in autism. Nat Med. 2013; 19:685-94. https://doi.org/10.1038/nm.3193 PMID: 23744158.
3. SuÈdhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008; 455:903-11. https://doi.org/10.1038/nature07456 PMID: 18923512.
4. Shih RA, Belmonte PL, Zandi PP. A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev Psychiatry. 2004; 16:260-83. https://doi.org/10.1080/09540260400014401 PMID: 16194760.
5. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. 2012; 82:1-8.
6. Friedman JE. Obesity and Gestational Diabetes Mellitus Pathways for Programming in Mouse, Monkey, and Man-Where Do We Go Next? The 2014 Norbert Freinkel Award Lecture. Diabetes Care. 2015; 38:1402-11. https://doi.org/10.2337/dc15-0628 PMID: 26207051.
7. Maftei O, Whitrow M J., Davies M J., Giles L C., Owens J A., Moore V M. Maternal body size prior to pregnancy, gestational diabetes and weight gain: Associations with insulin resistance in children at 9-10 years. Diabet Med 2015; 32:174-80. https://doi.org/10.1111/dme.12637 PMID: 25407383.
8. Avila C, Holloway AC, Hahn MK, Morrison KM, Restivo M, Anglin R, et al. An Overview of Links Between Obesity and Mental Health. Curr Obes Rep. 2015; 4:303-10. https://doi.org/10.1007/s13679-015-0164-9 PMID: 26627487.
9. Kim KA, Gu W, Lee IA, Joh EH, Kim DH. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One. 2012; 7(10)::e47713. https://doi.org/10.1371/journal.pone.0047713 PMID: 23091640.
10. Robles Alonso V, Guarner F. Linking the gut microbiota to human health. Br J Nutr. 2013; 109 Suppl 2: S21-6.
11. Collins SM, Kassam Z, Bercik P. The adoptive transfer of behavioral phenotype via the intestinal microbiota: Experimental evidence and clinical implications. Curr Opin Microbiol. 2013; 16:240-5. https://doi.org/10.1016/j.mib.2013.06.004 PMID: 23845749.
12. Jarchum I, Pamer EG. Regulation of innate and adaptive immunity by the commensal microbiota. Curr Opin Immunol. 2011; 23:353-60. https://doi.org/10.1016/j.coi.2011.03.001 PMID: 21466955.
13. Aziz Q, Dore J, Emmanuel A, Guarner F, Quigley EM. Gut microbiota and gastrointestinal health: current concepts and future directions. Neurogastroenterol Motil. 2013; 25:4-15. https://doi.org/10.1111/nmo.12046 PMID: 23279728.
14. Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013; 13:800-12. https://doi.org/10.1038/nrc3610 PMID: 24132111.
15. Douglas-Escobar M, Elliott E, Neu J. Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr. 2013; 167:374-9. https://doi.org/10.1001/jamapediatrics.2013.497 PMID: 23400224.
16. Dinan TG, Quigley EM. Probiotics in the treatment of depression: science or science fiction? Psychiatry. 2011; 45:1023-5.
17. Gonzalez A, Stombaugh J, Lozupone C, Turnbaugh PJ, Gordon JI, Knight R. The mind-body-microbial continuum. Dialogues Clin Neurosci 2011; 13:55-62. PMID: 21485746.
18. Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2012; 302:G168-75. https://doi.org/10.1152/ajpgi.00190.2011 PMID: 21940902.
19. Lyte M. Microbial endocrinology in the microbiome-gut-brain axis: how bacterial production and utilization of neurochemicals influence behavior. PLoS Pathog. 2013; 9:e1003726. https://doi.org/10.1371/journal.ppat.1003726 PMID: 24244158.
20. Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances. Part IIIconvergence toward clinical trials. Gut Pathog. 2013; 5:4. https://doi.org/10.1186/1757-4749-5-4 PMID: 23497650.
21. 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. https://doi.org/10.1016/j.biopsych.2014.07.012 PMID: 25173628.
22. Diaz Heijtz R, Wang S, Anuar F, Qian Y, BjoÈrkholm B, Samuelsson A, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011; 108:3047-52. https://doi.org/10.1073/pnas.1010529108 PMID: 21282636.
23. O' Mahony SM, Stilling RM, Dinan TG, Cryan JF. The microbiome and childhood diseases: Focus on brain-gut axis. Birth Defects Res C Embryo Today 2015;Epub ahead of prin.
24. Selkrig J, Wong P, Zhang X, Pettersson S. Metabolic tinkering by the gut microbiome: Implications for brain development and function. Gut Microbes. 5:369-80. https://doi.org/10.4161/gmic.28681 PMID: 24685620.
25. Buie T, Fuchs GJI, Furuta GT, Kooros K, Levy J, Lewis JD, et al. Recommendations for evaluation and treatment of common gastrointestinal problems in children with ASDs. Pediatrics. 2010; 125(Suppl 1): S19-S29.
26. Finegold SM. Desulfovibrio species are potentially important in regressive autism. Med Hypotheses. 2011; 77:270-4. https://doi.org/10.1016/j.mehy.2011.04.032 PMID: 21592674.
27. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism. 2013; 4:42. https://doi.org/10.1186/2040-2392-4-42 PMID: 24188502.
28. Rosenfeld CS. Microbiome disturbances and autism spectrum disorders. Drug Metab Dispos. 2015; 43:1557-71. https://doi.org/10.1124/dmd.115.063826 PMID: 25852213.
29. Chu DM, Meyer KM, Prince AL, Aagaard KM. Impact of maternal nutrition in pregnancy and lactation on offspring gut microbial composition and function. Gut Microbes. 2016; 7:459-70. https://doi.org/10.1080/19490976.2016.1241357 PMID: 27686144.
30. Lyall K, Munger KL, O'ReillyEÂ J, Santangelo SL, Ascherio A. Maternal dietary fat intake in association with autism spectrum disorders. Am J Epidemiol. 2013; 178:209-20. https://doi.org/10.1093/aje/kws433 PMID: 23813699.
31. Li YM, Ou JJ, Liu L, Zhang D, Zhao JP, Tang SY. Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-Analysis. J Autism Dev Disord. 2015;Epub ahead of print.
32. Sullivan EL, Nousen EK, Chamlou KA. Maternal high fat diet consumption during the perinatal period programs offspring behavior. Physiol Behav. 2014; 123:236-42. https://doi.org/10.1016/j.physbeh.2012.07.014 PMID: 23085399.
33. Myles IA, Fontecilla NM, Janelsins BM, Vithayathil PJ, Segre JA, Datta SK. Parental dietary fat intake alters offspring microbiome and immunity. J Immunol. 2013; 191:3200-9. https://doi.org/10.4049/jimmunol.1301057 PMID: 23935191.
34. Galley JD, Bailey M, Kamp Dush C, Schoppe-Sullivan S, Christian LM. Maternal obesity is associated with alterations in the gut microbiome in toddlers. PLoS One. 2014; 9:e113026. https://doi.org/10.1371/journal.pone.0113026 PMID: 25409177.
35. 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 Host Microbe. 2016; 165:1762-75.
36. Reikvam DH, Erofeev A, Sandvik A, Grcic V, Jahnsen FL, Gaustad P, et al. Depletion of murine intestinal microbiota: Effects on gut mucosa and epithelial gene expression. PLoS One. 2011; 6:e17996. https://doi.org/10.1371/journal.pone.0017996 PMID: 21445311.
37. Scattoni ML, Crawley J, Ricceri L. Ultrasonic vocalizations: A tool for behavioural phenotyping of mouse models of neurodevelopmental disorders. Neurosci Biobehav Rev. 2009; 33:508-15. https://doi.org/10.1016/j.neubiorev.2008.08.003 PMID: 18771687.
38. Silverman JL, Yang M, Lord C, Crawley JN. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 2010; 11:490-502. https://doi.org/10.1038/nrn2851 PMID: 20559336.
39. Choleris E, Thomas AW, Kavaliers M, Prato FS. A detailed ethological analysis of the mouse open field test: Effects of diazepam, chlordiazepoxide and an extremely low frequency pulsed magnetic field. Neurosci Biobehav Rev. 2001; 25:235-60. PMID: 11378179.
40. Angoa-Perez M, Kane M, Briggs DI, Francescutti DM, Kuhn DM. Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice. J Vis Exp. 2013; 82:50978.
41. Freeman LR, Zhang L, Nair A, Dasuri K, Francis J, Fernandez-Kim SO, et al. Obesity increases cerebrocortical reactive oxygen species and impairs brain function. Free Radic Biol Med. 2013; 56:226-33. https://doi.org/10.1016/j.freeradbiomed.2012.08.577 PMID: 23116605.
42. Yuan S, Cohen DB, Ravel J, Abdo Z, Forney LJ. Evaluation of methods for the extraction and purification of DNA from the human microbiome. PLoS One. 2012; 7:e33865. https://doi.org/10.1371/journal.pone.0033865 PMID: 22457796.
43. Kozich JJ, Westcott SL, Baxter NT, Highlander SK, Schloss PD. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol. 2013; 79:5112-20. https://doi.org/10.1128/AEM.01043-13 PMID: 23793624.
44. Edgar RC. UPARSE: highly accurate OTU sequences from microbial amplicon reads. Nat Methods. 2013; 10:996-8. https://doi.org/10.1038/nmeth.2604 PMID: 23955772.
45. Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 2013; 41:D590- 6. https://doi.org/10.1093/nar/gks1219 PMID: 23193283.
46. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15:550. https://doi.org/10.1186/s13059-014-0550-8 PMID: 25516281.
47. Lozupone C, Hamady M, Knight R. UniFracan online tool for comparing microbial community diversity in a phylogenetic context. BMC Bioinformatics. 2006; 7:371. https://doi.org/10.1186/1471-2105-7-371 PMID: 16893466.
48. Njung'e K, Handley SL. Evaluation of marble-burying behavior as a model of anxiety. Pharmacol Biochem Behav. 1991; 38:63-7. PMID: 2017455.
49. Veena SR, Gale CR, Krishnaveni GV, Kehoe SH, Srinivasan K, Fall CH. Association between maternal nutritional status in pregnancy and offspring cognitive function during childhood and adolescence; a systematic review. BMC Pregnancy Childbirth. 2016; 16:220. https://doi.org/10.1186/s12884-016-1011-z PMID: 27520466.
50. Yu Z, Han S, Zhu J, Sun X, Ji C, Guo X. Pre-pregnancy body mass index in relation to infant birth weight and offspring overweight/obesity: A systematic review and meta-Analysis. PLoS One. 2013; 8:e61627. https://doi.org/10.1371/journal.pone.0061627 PMID: 23613888.
51. Nahum Sacks K, Friger M, Shoham-Vardi I, Abokaf H, Spiegel E, Sergienko R, et al. Prenatal exposure to gestational diabetes mellitus as an independent risk factor for long-Term neuropsychiatric morbidity of the offspring. Am J Obstet Gynecol. 2016; 215:380.e1-.e7.
52. White CL, Pistell PJ, Purpera MN, Gupta S, Fernandez-Kim SO, Hise TL, et al. Effects of high fat diet on Morris maze performance, oxidative stress, and inflammation in rats: contributions of maternal diet. Neurobiol Dis. 2009; 35:3-13. https://doi.org/10.1016/j.nbd.2009.04.002 PMID: 19374947.
53. White CL, Purpera MN, Morrison CD. Maternal obesity is necessary for the programming effect of a high-fat diet on offspring. Am J Physiol Regul Integr Comp Physiol. 2009; 35:3-13.
54. Kang SS, Kurti A, Fair DA, Fryer JD. Dietary intervention rescues maternal obesity induced behavior deficits and neuroinflammation in offspring. J Neuroinflammation. 2014; 11:156. https://doi.org/10.1186/s12974-014-0156-9 PMID: 25212412.
55. Bilbo SD, Tsang V. Enduring consequences of maternal obesity for brain inflammation and behavior of offspring. FASEB J 2010; 24:2104-15. https://doi.org/10.1096/fj.09-144014 PMID: 20124437.
56. Rodriguez JS, RodrõÂguez-GonzaÂlez GL, Reyes-Castro LA, Iba ñez C, RamõÂrez A, Chavira R, et al. Maternal obesity in the rat programs male offspring exploratory, learning and motivation behavior: prevention by dietary intervention pre-gestation or in gestation. Int J Dev Neurosci. 2012; 30:75-81. https://doi.org/10.1016/j.ijdevneu.2011.12.012 PMID: 22239918.
57. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity among adults: United States, 2011- 2012. NCHS Data Brief. 2013; 131:1-8.
58. Boyle CA, Boulet S, Schieve LA, Cohen RA, Blumberg SJ, Yeargin-Allsopp M, et al. Trends in the prevalence of developmental disabilities in US children, 1997-2008. Pediatrics. 2011; 127:1034-42. https://doi.org/10.1542/peds.2010-2989 PMID: 21606152.
59. Olfson M, Blanco C, Wang S, Laje G, Correll CU. National trends in the mental health care of children, adolescents, and adults by office-based physicians. JAMA Psychiatry. 2014; 71:81-90. https://doi.org/10.1001/jamapsychiatry.2013.3074 PMID: 24285382.
60. Ohland CL, 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. Psychoneuroendocrinology 2013; 38:1738-47. https://doi.org/10.1016/j.psyneuen.2013.02.008 PMID: 23566632.
61. Christian LM, Galley JD, Hade EM, Schoppe-Sullivan S, Kamp Dush C, Bailey MT. Gut microbiome composition is associated with temperament during early childhood. Brain Behav Immun. 2015; 45:118-27. https://doi.org/10.1016/j.bbi.2014.10.018 PMID: 25449582.
62. El Aidy S, Stilling R, Dinan TG, Cryan JF. Microbiome to Brain: Unravelling the Multidirectional Axes of Communication. Adv Exp Med Biol. 2106; 874:301-36. https://doi.org/10.1007/978-3-319-20215-0-15 PMID: 26589226.
63. Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, et al. The microbiome-gutbrain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 2013; 18:666-73. https://doi.org/10.1038/mp.2012.77 PMID: 22688187.
64. Aiken CE, Ozanne SE. Sex differences in developmental programming models. Reproduction. 2013; 145:R1-13. https://doi.org/10.1530/REP-11-0489 PMID: 23081892.
65. Maloney CA, Hay SM, Young LE, Sinclair KD, Rees WD. A methyl-deficient diet fed to rat dams during the peri-conception period programs glucose homeostasis in adult male but not female offspring. Journal of Nutrition. 2011; 141:95-100. https://doi.org/10.3945/jn.109.119453 PMID: 21106931.
66. Mueller BR, Bale TL. Early prenatal stress impact on coping strategies and learning performance is sex dependent. Physiology & Behavior. 2007; 91:55-65.
67. Lerch S, Dormann C, Brandwein C, Gass P, Chourbaji S. The scent of stress: Environmental challenge in the peripartum environment of mice affects emotional behaviours of the adult offspring in a sex-specific manner. Lab Anim. 2016; 50:167-78. https://doi.org/10.1177/0023677215603260 PMID: 26408077.
68. Majidi-Zolbanin J, Doosti MH, Kosari-Nasab M, Salari AA. Prenatal maternal immune activation increases anxiety-And depressive-like behaviors in offspring with experimental autoimmune encephalomyelitis. Neuroscience. 2015; 294:69-81. https://doi.org/10.1016/j.neuroscience.2015.03.016 PMID: 25779966.
69. Xuan IC, Hampson DR. Gender-dependent effects of maternal immune activation on the behavior of mouse offspring. PLoS One. 2014; 9:e104433. https://doi.org/10.1371/journal.pone.0104433 PMID: 25111339.
70. Wilcoxon JS, Schwartz J, Aird F, Redei EE. Sexually dimorphic effects of maternal alcohol intake and adrenalectomy on left ventricular hypertrophy in rat offspring. American Journal of Physiology Endocrinology and Metabolism 2003; 285:E31-E9. https://doi.org/10.1152/ajpendo.00552.2002 PMID: 12618362.
71. Gallou-Kabani C, Gabory A, Tost J, Karimi M, Mayeur S, Lesage J, et al. Sex-And diet-specific changes of imprinted gene expression and DNA methylation in mouse placenta under a high-fat diet. PLoS One. 2010; 5:e14398. https://doi.org/10.1371/journal.pone.0014398 PMID: 21200436.
72. Mao J, Zhang X, Sieli P, Falduto MT, Torres KE, Rosenfeld CS. Contrasting effects of different maternal diets on sexually dimorphic gene expression in the murine placenta. Proc Natl Acad Sci U S A. 2010 107:5557-62. https://doi.org/10.1073/pnas.1000440107 PMID: 20212133.
73. Sood R, Zehnder JL, Druzin ML, Brown PO. Gene expression patterns in human placenta. Proc Natl Acad Sci USA 2006; 103:5478-83. https://doi.org/10.1073/pnas.0508035103 PMID: 16567644.
74. Gabory A, Ferry L, Fajardy I, Jouneau L, Gothie J, Vige A, et al. Maternal diets trigger sex-specific divergent trajectories of gene expression and epigenetic systems in mouse placenta. PLoS One. 2012; 7: E47986. https://doi.org/10.1371/journal.pone.0047986 PMID: 23144842.
75. Kim DW, Young SL, Grattan DR, Jasoni CL. Obesity during pregnancy disrupts placental morphology, cell proliferation, and inflammation in a sex-specific manner across gestation in the mouse. Biol Reprod. 2014; 90:130. https://doi.org/10.1095/biolreprod.113.117259 PMID: 24829026.
76. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-Associated gut microbiome with increased capacity for energy harvest. Nature. 2006; 444:1027-31. https://doi.org/10.1038/nature05414 PMID: 17183312.
77. Turnbaugh PJ, BaÈckhed 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. https://doi.org/10.1016/j.chom.2008.02.015 PMID: 18407065.
78. Zhang H, DiBaise JK, Zuccolo A, Kudrna D, Braidotti M, Yu Y, et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci U S A. 2009; 106:2365-70. https://doi.org/10.1073/pnas.0812600106 PMID: 19164560.
79. Sweeney TE, Morton JM. The human gut microbiome: A review of the effect of obesity and surgically induced weight loss. JAMA Surg. 2013; 148:563-9. https://doi.org/10.1001/jamasurg.2013.5 PMID: 23571517.
80. Murphy EF, Cotter PD, Hogan A, O'Sullivan O, Joyce A, Fouhy F, et al. Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut Pathog. 2013; 62:220-6.
81. Johnson EL, Heaver SL, Walters WA, Ley RE. Microbiome and metabolic disease: revisiting the bacterial phylum Bacteroidetes. J Mol Med (Berl). 2016;[Epub ahead of print].
82. Macfarlane S, Macfarlane GT. Regulation of short-chain fatty acid production. Proc Nutr Soc. 2003; 62:67-7. https://doi.org/10.1079/PNS2002207 PMID: 12740060.
83. Shoaie S, Karlsson F, Mardinoglu A, Nookaew I, Bordel S, Nielsen J. Understanding the interactions between bacteria in the human gut through metabolic modeling. Sci Rep. 2013; 3:2532. https://doi.org/10.1038/srep02532 PMID: 23982459.
84. Canani R. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol. 2011; 17:1519. https://doi.org/10.3748/wjg.v17.i12 PMID: 21472114.
85. Peng L, Li Z, Green R, Holzman I, Lin J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-Activated protein kinase in Caco-2 cell monolayers. J Nutr Biochem. 2009; 139:1619-25.
86. Stilling RM, van de Wouw M, Clarke G, Stanton C, Dinan TG, Cryan JF. The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? Neurochem Int. 2016; 99:110-32. https://doi.org/10.1016/j.neuint.2016.06.011 PMID: 27346602.
87. 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. https://doi.org/10.1073/pnas.1219451110 PMID: 23671105.
88. Yi P, Li L. The germfree murine animal: An important animal model for research on the relationship between gut microbiota and the host. Vet Microbiol. 2012; 157:1-7. https://doi.org/10.1016/j.vetmic.2011.10.024 PMID: 22079217.
89. Luckey TD. Effects of microbes on germfree animals. Adv Appl Microbiol. 1965; 7:169-223. PMID: 5321875.
90. Berg RD. The indigenous gastrointestinal microflora. Trends Microbiol. 1996; 4:430-5. PMID: 8950812.