Abstract
Oligosaccharides are potential prebiotic which maintains gut microbiota and improves gut health. The association of gut and brain is named as gut-brain-axis. Gut dysbiosis disrupts gut-brain-axis and effectively contributes to psychiatric disorders. In the present study, Xylo-oligosaccharide (XOS) and Quercetin were used as therapeutic interventions against gut dysbiosis mediated cognitive decline. Gut dysbiosis was established in mice through administration of Ampicillin Sodium, orally for 14 days. XOS and quercetin were administered separately or in combination along with antibiotic. Gene expression studies using mice faecal samples showed both XOS and quercetin could revive Lactobacillus, Bifidobacterium, Firmicutes and Clostridium which were reduced due to antibiotic treatment. FITC-dextran concentration in serum revealed XOS and quercetin protected intestinal barrier integrity against antibiotic associated damage. This was verified by histopathological studies showing restored intestinal architecture. Moreover, intestinal inflammation which increased after antibiotic treated animals was reduced upon XOS and quercetin treatment. Behavioural studies demonstrated that gut dysbiosis reduced fear conditioning, spatial and recognition memory which were reversed upon XOS and quercetin treatment. XOS and quercetin also reduced inflammation and acetylcholine esterase which were heightened in antibiotic treated animal brain. They also reduced oxidative stress, pro-inflammatory cytokines and chemokines and protected hippocampal neurons. In conclusion, XOS and quercetin effectively reduced antibiotic associated gut dysbiosis and prevented gut dysbiosis associated cognitive decline in mice.
Graphic Abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aachary AA, Prapulla SG (2011) Xylooligosaccharides (XOS) as an emerging prebiotic: microbial synthesis, utilization, structural characterization, bioactive properties, and applications. Compr Rev Food Sci F 10(1):2–16. https://doi.org/10.1111/j.1541-4337.2010.00135.x
Ameen N, Shafi S (2016) Biochemical and in-vivo antioxidant parameters for evaluation of memory enhancing activity. Int j Pharm Chem Biol Sci 6(3):265–270
Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13(2):93–110. https://doi.org/10.1007/s10339-011-0430-z
Boughton-Smith NK, Wallace JL, Whitle BJR (1988) Relationship between arachidonic acid metabolism, myeloperoxidase activity and leukocyte infiltration in a rat model of inflammatory bowel disease. Agents Actions 25(1–2):115–123. https://doi.org/10.1007/BF01969102
Cardona F, Andrés-Lacueva C, Tulipani S, Tinahones FJ, Queipo-Ortuño MI (2013) Benefits of polyphenols on gut microbiota and implications in human health. J Nutr Biochem 24(8):1415–1422. https://doi.org/10.1016/j.jnutbio.2013.05.001
Coburn-Litvak PS, Pothakos K, Tata DA, McCloskey DP, Anderson BJ (2003) Chronic administration of corticosterone impairs spatial reference memory before spatial working memory in rats. Neurobiol Learn Mem 80(1):11–23. https://doi.org/10.1016/S1074-7427(03)00019-4
Collins SM, Bercik P (2009) The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 136(6):2003–2014. https://doi.org/10.1053/j.gastro.2009.01.075
Conductier G, Blondeau N, Guyon A, Nahon JL, Rovère C (2010) The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol 224(1–2):93–100. https://doi.org/10.1016/j.jneuroim.2010.05.010
Costa LG, Garrick JM, Roquè PJ, Pellacani C (2016) Mechanisms of neuroprotection by quercetin: counteracting oxidative stress and more. Oxid Med Cell Longev. https://doi.org/10.1155/2016/2986796
Didari T, Solki S, Mozaffari S, Nikfar S, Abdollahi M (2014) A systematic review of the safety of probiotics. Expert Opin Drug Saf 13(2):227–239. https://doi.org/10.1517/14740338.2014.872627
Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial flora. Science 308:1635–1638. https://doi.org/10.1126/science.1110591
Ellman GL, Courtney KD, Andres V Jr, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2):88–95. https://doi.org/10.1016/0006-2952(61)90145-9
Forsythe P, Sudo N, Dinan T, Taylor VH, Bienenstock J (2009) Mood and gut feelings. Brain Behav Immun 24(1):9–16. https://doi.org/10.1016/j.bbi.2009.05.058
Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes JD, Dodiya HB, Keshavarzian A (2011) Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One 6(12):e28032. https://doi.org/10.1371/journal.pone.0028032
Frohlich EE, Farzi A, Mayerhofer R, Reichmann F, Jacan A, Wagner B, Zinser E, Bordag N, Magnes C, Fröhlich E, Kashofer K, Gorkiewicz G, Holzer P (2016) Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication. Brain Behav Immun 56:140–155. https://doi.org/10.1016/j.bbi.2016.02.020
Fu CJ, Carter JN, Li Y, Porter JH, Kerley MS (2006) Comparison of agar plate and real-time PCR on enumeration of Lactobacillus, Clostridium perfringens and total anaerobic bacteria in dog faeces. Lett Appl Microbiol 42(5):490–494. https://doi.org/10.1111/j.1472-765X.2006.01893.x
Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ, MacQueen G, Sherman PM (2011) Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60(3):307–317. https://doi.org/10.1136/gut.2009.202515
Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2:108–115. https://doi.org/10.1038/84209
Gibson GR, Roberfroid MB (1995) Dietary modulation of the human colonic microbiota: Introducing the concept of prebiotics. J Nutr 125:1401–1412. https://doi.org/10.1093/jn/125.6.1401
Gibson GR, Probert HM, Van Loo JAE, Rastall R, Roberfroid MB (2004) Dietary modulation of the human colonic microbiota: Updating the concept of prebiotics. Nutr Res Rev 17(2):259–275. https://doi.org/10.1079/NRR200479
Guinane CM, Cotter PD (2013) Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Ther Adv Gastroenterol 6(4):295–308. https://doi.org/10.1177/1756283X13482996
Guo X, Xia X, Tang R, Zhou J, Zhao H, Wang K (2008) Development of a real-time PCR method for Firmicutes and Bacteroidetes in faeces and its application to quantify intestinal population of obese and lean pigs. Lett Appl Microbiol 47(5):367–373. https://doi.org/10.1111/j.1472-765X.2008.02408.x
Hammond RS, Tull LE, Stackman RW (2004) On the delay-dependent involvement of the hippocampus in object recognition memory. Neurobiol Learn Mem 82(1):26–34. https://doi.org/10.1016/j.nlm.2004.03.005
Howarth GS, Francis GL, Cool JC, Xu X, Byard RW, Read LC (1996) Milk growth factors enriched from cheese whey ameliorate intestinal damage by methotrexate when administered orally to rats. J Nutr 126(10):2519–2530. https://doi.org/10.1093/jn/126.10.2519
Itoh J, Nabeshima T, Kameyama T (1990) Utility of an elevated plus-maze for the evaluation of memory in mice: effects of nootropics, scopolamine and electroconvulsive shock. Psychopharmacology 101(1):27–33. https://doi.org/10.1007/BF02253713
Jang HM, Lee HJ, Jang SE, Han MJ, Kim DH (2018) Evidence for interplay among antibacterial-induced gut microbiota disturbance, neuro-inflammation, and anxiety in mice. Mucosal Immunol 11:1386–1397
Joshi D, Roy S, Banerjee S (2018) Prebiotics: A functional food in health and disease. In: Mandal, S.C., Mandal, V., Konishi, T. (ed) Natural Products & Drug Discovery Elsevier, Amsterdam, pp 507–523
Jung TH, Park JH, Jeon WM, Han KS (2015) Butyrate modulates bacterial adherence on LS174T human colorectal cells by stimulating mucin secretion and MAPK signalling pathway. Nutr Res Pract 9:343–349. https://doi.org/10.4162/nrp.2015.9.4.343
Katouli M (2010) Population structure of gut Escherichia coli and its role in development of extra-intestinal infections. Iran J Microbiol 2(2):59
Katyare SS, Pandya JD (2005) A simplified fluorimetric method for corticosterone estimation in rat serum, tissues and mitochondria. http://hdl.handle.net/123456789/3503
Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, Wilson KE, Glover LE, Kominsky DJ, Magnuson A, Weir TL (2015) Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17(5):662–671
Khan H, Ullah H, Aschner M, Cheang WS, Akkol EK (2020) Neuroprotective effects of quercetin in Alzheimer’s disease. Biomolecules 10(1):59. https://doi.org/10.3390/biom10010059
Khan J, Islam MN (2012) Morphology of the intestinal barrier in different physiological and pathological conditions. Histopathology-Reviews and Recent Advances. Intech Publishers, Rijeka, Croatia, pp 133–152
Lavefve L, Howard LR, Carbonero F (2020) Berry polyphenols metabolism and impact on human gut microbiota and health. Food Funct 11:45–65. https://doi.org/10.1039/C9FO01634A
Leo EM, Campos MS (2019) Systemic oxidative stress: a key point in neurodegeneration—a review. J Nutr Health Aging 23(8):694–699. https://doi.org/10.1007/s12603-019-1240-8
Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Human gut microbes associated with obesity. Nature 444(7122):1022–1023. https://doi.org/10.1038/4441022a
Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, Liu H, Yin Y (2016) Quercetin, inflammation and immunity. Nutrients 8(3):167. https://doi.org/10.3390/nu8030167
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262
Mehta BK, Banerjee S (2019) Minocycline reverses diabetes-associated cognitive impairment in rats. Pharmacol Rep 71(4):713–720. https://doi.org/10.1016/j.pharep.2019.03.012
Messaoudi M, Rozan P, Nejdi A, Hidalgo S, Desor D (2005) Behavioural and cognitive effects of oligofructose-enriched inulin in rats. Br J Nutr 93(S1):S27–S30. https://doi.org/10.1079/BJN20041348
Mocsai A (2013) Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Exp Med 210:1283–1299. https://doi.org/10.1084/jem.20122220
Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. BBA-Gen Subjects 582(1):67–78. https://doi.org/10.1016/0304-4165(79)90289-7
Ogren SO (1985) Evidence for a role of brain serotonergic neurotransmission in avoidance learning. Acta Physiol Scand Suppl 544:1–71
Ouwehand AC, Bergsma N, Parhiala R, Lahtinen S, Gueimonde M, Finne-Soveri H, Strandberg T, Pitkälä K, Salminen S (2008) Bifidobacterium microbiota and parameters of immune function in elderly subjects. FEMS Immunol Med Microbiol 53(1):18–25. https://doi.org/10.1111/j.1574-695X.2008.00392.x
Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, Harmsen HJ, Faber KN, Hermoso MA (2019) Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol 10:277
Penders J, Vink C, Driessen C, London N, Thijs C, Stobberingh EE (2005) Quantification of Bifidobacterium spp., Escherichia coli and Clostridium difficile in faecal samples of breast-fed and formula-fed infants by real-time PCR. FEMS Microbiol Lett 243(1):141–147. https://doi.org/10.1016/j.femsle.2004.11.052
Peng L, Li ZR, Green RS, Holzman IR, Lin J (2009) Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr 139:1619–1625. https://doi.org/10.3945/jn.109.104638
Pocernich CB, Butterfield DA (2012) Elevation of glutathione as a therapeutic strategy in Alzheimer disease. Biochim. Biophys. Acta (BBA)-Molecular Basis of Disease. 1822(5):625–630. https://doi.org/10.1016/j.bbadis.2011.10.003
Prisciandaro LD, Geier MS, Butler RN, Cummins AG, Howarth GS (2011) Probiotic factors partially improve parameters of 5-fluorouracil-induced intestinal mucositis in rats. Cancer Biol Ther 11(7):671–677. https://doi.org/10.4161/cbt.11.7.14896
Pulli B, Ali M, Forghani R, Schob S, Hsieh KL, Wojtkiewicz G, Linnoila JJ, Chen JW (2013) Measuring myeloperoxidase activity in biological samples. PLoS One 8(7). https://doi.org/10.1371/journal.pone.0067976
Quigley EM (2013) Gut bacteria in health and disease. Gastroenterol Hepatol 9(9):560
Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, de los Reyes-Gavilán CG, Salazar N, (2016) Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol 7:185. https://doi.org/10.3389/fmicb.2016.00185
Roy Sarkar S, Banerjee S (2019) Gut microbiota in neurodegenerative disorders. J Neuroimmunol 328:98–104. https://doi.org/10.1016/j.jneuroim.2019.01.004
Roy Sarkar S, Mitra Mazumder P, Banerjee S (2020) Probiotics protect against gut dysbiosis associated decline in learning and memory. J Neuroimmunol 348:577390. https://doi.org/10.1016/j.jneuroim.2020.577390
Roy Sarkar S, Mitra Mazumder P, Chatterjee K, Sarkar A, Adhikary M, Mukhopadhyay K, Banerjee S (2021) Saccharomyces boulardii ameliorates gut dysbiosis associated cognitive decline. Physiol & Behav 236:113411. https://doi.org/10.1016/j.physbeh.2021.113411
Savignac HM, Corona G, Mills H, Chen L, Spencer JP, Tzortzis G, Burnet PW (2013) Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-d-aspartate receptor subunits and d-serine. Neurochem Int 63:756–764. https://doi.org/10.1016/j.neuint.2013.10.006
Savignac HM, Tramullas M, Kiely B, Dinan TG, Cryan JF (2015) Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav Brain Res 287:59–72. https://doi.org/10.1016/j.bbr.2015.02.044
Servin AL (2004) Antagonistic activities of Lactobacilli and Bifidobacteria against microbial pathogens. FEMS Microbiol Rev 28:405–440. https://doi.org/10.1016/j.femsre.2004.01.003
Sharma AC, Kulkarni SK (1992) Evaluation of learning and memory mechanisms employing elevated plus-maze in rats and mice. Prog Neuropsychopharmacol Biol Psychiatry 16(1):117–125. https://doi.org/10.1016/0278-5846(92)90014-6
Shi T, Bian X, Yao Z, Wang Y, Gao W, Guo C (2020) Quercetin improves gut dysbiosis in antibiotic-treated mice. Food Funct 11(9):8003–8013. https://doi.org/10.1039/D0FO01439G
Shi Y, Kellingray L, Zhai Q, Gall GL, Narbad A, Zhao J, Zhang H, Chen W (2018) Structural and functional alterations in the microbial community and immunological consequences in a mouse model of antibiotic-induced dysbiosis. Front Microbiol 9:1948. https://doi.org/10.3389/fmicb.2018.01948
Silber RH, Busch RD, Oslapas R (1958) Practical procedure for estimation of corticosterone or hydrocortisone. Clin Chem 4(4):278–285. https://doi.org/10.1093/clinchem/4.4.278
Silvers JM, Harrod SB, Mactutus CF, Booze RM (2007) Automation of the novel object recognition task for use in adolescent rats. J Neurosci Met 166:99–103. https://doi.org/10.1016/j.jneumeth.2007.06.032
Song ZH, Xiao K, Ke YL, Jiao LF, Hu CH (2015) Zinc oxide influences mitogen-activated protein kinase and TGF-β1 signaling pathways, and enhances intestinal barrier integrity in weaned pigs. Innate Immun 21(4):341–348. https://doi.org/10.1177/1753425914536450
Stilling RM, Dinan TG, Cryan JF (2014) Microbial genes, brain & behaviour–epigenetic regulation of the gut–brain axis. Genes Brain Behav 13(1):69–86. https://doi.org/10.1111/gbb.12109
Stock AJ, Kasus-Jacobi A, Pereira HA (2018) The role of neutrophil granule proteins in neuroinflammation and Alzheimer’s disease. J Neuroinflammation 15(1):1–15. https://doi.org/10.1186/s12974-018-1284-4
Sudo N (2014) Microbiome, HPA axis and production of endocrine hormones in the gut. Adv Exp Med Biol 817:177–194. https://doi.org/10.1007/978-1-4939-0897-4_8
Tanaka S, Kondo H, Kanda K, Ashino T, Nakamachi T, Sekikawa K, Iwakura Y, Shioda S, Numazawa S, Yoshida T (2011) Involvement of interleukin-1 in lipopolysaccaride-induced microglial activation and learning and memory deficits. J Neurosci Res 89(4):506–514. https://doi.org/10.1002/jnr.22582
Wang B, Yu B, Karim M, Hu H, Sun Y, McGreevy P, Petocz P, Held S, Brand-Miller J (2007) Dietary sialic acid supplementation improves learning and memory in piglets. Am J Clin Nutr 85:561–569. https://doi.org/10.1093/ajcn/85.2.561
Wang L, Llorente C, Hartmann P, Yang AM, Chen P, Schnabl B (2015a) Methods to determine intestinal permeability and bacterial translocation during liver disease. J Immunol Methods 421:44–53. https://doi.org/10.1016/j.jim.2014.12.015
Wang T, Hu X, Liang S, Li W, Wu X, Wang L, Jin F (2015b) Lactobacillus fermentum NS9 restores the antibiotic induced physiological and psychological abnormalities in rats. Benef Microbes 6(5):707–717. https://doi.org/10.3920/BM2014.0177
Acknowledgements
The authors sincerely acknowledge the Institute Research Fellowship Program, Department of Pharmaceutical Sciences and Technology and Department of Bioengineering of Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of Interest/Competing Interests
The authors declared no competing financial interests.
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
Sarkar, S.R., Mazumder, P.M. & Banerjee, S. Oligosaccharide and Flavanoid Mediated Prebiotic Interventions to Treat Gut Dysbiosis Associated Cognitive Decline. J Neuroimmune Pharmacol 17, 94–110 (2022). https://doi.org/10.1007/s11481-021-10041-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-021-10041-4