Targeting Gut Dysbiosis and Microbiome Metabolites for the Development
of Therapeutic Modalities for Neurological Disorders

Matthew   D.   Wiefels; Emily      Furar; Rebecca   S.   Eshraghi; Jeenu      Mittal; Idil      Memis; Moeed      Moosa; Rahul      Mittal; Adrien   A.   Eshraghi
Abstract

The gut microbiota, composed of numerous species of microbes, works in synergy with the various organ systems in the body to bolster our overall health and well-being. The most well-known function of the gut microbiome is to facilitate the metabolism and absorption of crucial nutrients, such as complex carbohydrates, while also generating vitamins. In addition, the gut microbiome plays a crucial role in regulating the functioning of the central nervous system (CNS). Host genetics, including specific genes and single nucleotide polymorphisms (SNPs), have been implicated in the pathophysiology of neurological disorders, including Parkinson’s disease (PD), Alzheimer’s disease (AD), and autism spectrum disorder (ASD). The gut microbiome dysbiosis also plays a role in the pathogenesis of these neurodegenerative disorders, thus perturbing the gut-brain axis. Overproduction of certain metabolites synthesized by the gut microbiome, such as short-chain fatty acids (SCFAs) and p-cresyl sulfate, are known to interfere with microglial function and trigger misfolding of alpha-synuclein protein, which can build up inside neurons and cause damage. By determining the association of the gut microbiome and its metabolites with various diseases, such as neurological disorders, future research will pave the way for the development of effective preventive and treatment modalities.
Keywords: gut microbiome, gut metabolite, gut dysbiosis, therapeutic modalities, neurological disorders, Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder
Graphical Abstract

[1]
Verhaar, B.J.H.; Hendriksen, H.M.A.; de Leeuw, F.A.; Doorduijn, A.S.; van Leeuwenstijn, M.; Teunissen, C.E.; Barkhof, F.; Scheltens, P.; Kraaij, R.; van Duijn, C.M.; Nieuwdorp, M.; Muller, M.; van der Flier, W.M. Gut microbiota composition is related to AD pathology. Front. Immunol.,  2022, 12, 794519.
 [http://dx.doi.org/10.3389/fimmu.2021.794519] [PMID: 35173707]

[2]
Konopelski, P.; Mogilnicka, I. Biological effects of indole-3-propionic acid, a gut microbiota-derived metabolite, and its precursor tryptophan in mammals’ health and disease. Int. J. Mol. Sci.,  2022, 23(3), 1222.
 [http://dx.doi.org/10.3390/ijms23031222] [PMID: 35163143]

[3]
Eshraghi, R.S.; Davies, C.; Iyengar, R.; Perez, L.; Mittal, R.; Eshraghi, A.A. Gut-induced inflammation during development may compromise the blood-brain barrier and predispose to autism spectrum disorder. J. Clin. Med.,  2020, 10(1), 27.
 [http://dx.doi.org/10.3390/jcm10010027] [PMID: 33374296]

[4]
Eshraghi, R.S.; Deth, R.C.; Mittal, R.; Aranke, M.; Kay, S.I.S.; Moshiree, B.; Eshraghi, A.A. Early disruption of the microbiome leading to decreased antioxidant capacity and epigenetic changes: Implications for the rise in autism. Front. Cell. Neurosci.,  2018, 12, 256.
 [http://dx.doi.org/10.3389/fncel.2018.00256] [PMID: 30158857]

[5]
Kim, C.H.; Jung, J.; Lee, Y.; Kim, K.; Kang, S.; Kang, G.; Chu, H.; Kim, S.Y.; Lee, S. Comparison of metabolites and gut microbes between patients with Parkinson’s disease and healthy individuals – a pilot clinical observational study (STROBE compliant). Healthcare (Basel),  2022, 10(2), 302.
 [http://dx.doi.org/10.3390/healthcare10020302] [PMID: 35206916]

[6]
Chen, S.J.; Chen, C.C.; Liao, H.Y.; Lin, Y.T.; Wu, Y.W.; Liou, J.M.; Wu, M.S.; Kuo, C.H.; Lin, C.H. Association of fecal and plasma levels of short-chain fatty acids with gut microbiota and clinical severity in patients with Parkinson disease. Neurology,  2022, 98(8), e848-e858.
 [http://dx.doi.org/10.1212/WNL.0000000000013225] [PMID: 34996879]

[7]
Sampson, T.R.; Debelius, J.W.; Thron, T.; Janssen, S.; Shastri, G.G.; Ilhan, Z.E.; Challis, C.; Schretter, C.E.; Rocha, S.; Gradinaru, V.; Chesselet, M.F.; Keshavarzian, A.; Shannon, K.M.; Krajmalnik-Brown, R.; Wittung-Stafshede, P.; Knight, R.; Mazmanian, S.K. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell,  2016, 167(6), 1469-1480.e12.
 [http://dx.doi.org/10.1016/j.cell.2016.11.018] [PMID: 27912057]

[8]
Brody, H. The gut microbiome. Nature,  2020, 577(7792), S5.
 [http://dx.doi.org/10.1038/d41586-020-00194-2] [PMID: 31996824]

[9]
Cresci, G.A.; Bawden, E. Gut microbiome. Nutr. Clin. Pract.,  2015, 30(6), 734-746.
 [http://dx.doi.org/10.1177/0884533615609899] [PMID: 26449893]

[10]
Lozupone, C.A.; Stombaugh, J.I.; Gordon, J.I.; Jansson, J.K.; Knight, R. Diversity, stability and resilience of the human gut microbiota. Nature,  2012, 489(7415), 220-230.
 [http://dx.doi.org/10.1038/nature11550] [PMID: 22972295]

[11]
Shreiner, A.B.; Kao, J.Y.; Young, V.B. The gut microbiome in health and in disease. Curr. Opin. Gastroenterol.,  2015, 31(1), 69-75.
 [http://dx.doi.org/10.1097/MOG.0000000000000139] [PMID: 25394236]

[12]
Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature,  2012, 486(7402), 207-214.
 [http://dx.doi.org/10.1038/nature11234] [PMID: 22699609]

[13]
Manor, O.; Dai, C.L.; Kornilov, S.A.; Smith, B.; Price, N.D.; Lovejoy, J.C.; Gibbons, S.M.; Magis, A.T. Health and disease markers correlate with gut microbiome composition across thousands of people. Nat. Commun.,  2020, 11(1), 5206.
 [http://dx.doi.org/10.1038/s41467-020-18871-1] [PMID: 33060586]

[14]
Wu, Y.T.; Shen, S.J.; Liao, K.F.; Huang, C.Y. Dietary plant and animal protein sources oppositely modulate fecal Bilophila and Lachnoclostridium in vegetarians and omnivores. Microbiol. Spectr.,  2022, 10(2), e02047-e21.
 [http://dx.doi.org/10.1128/spectrum.02047-21] [PMID: 35285706]

[15]
Tanes, C.; Bittinger, K.; Gao, Y.; Friedman, E.S.; Nessel, L.; Paladhi, U.R.; Chau, L.; Panfen, E.; Fischbach, M.A.; Braun, J.; Xavier, R.J.; Clish, C.B.; Li, H.; Bushman, F.D.; Lewis, J.D.; Wu, G.D. Role of dietary fiber in the recovery of the human gut microbiome and its metabolome. Cell Host Microbe,  2021, 29(3), 394-407.e5.
 [http://dx.doi.org/10.1016/j.chom.2020.12.012] [PMID: 33440171]

[16]
Cahana, I.; Iraqi, F.A. Impact of host genetics on gut microbiome: Take‐home lessons from human and mouse studies. Animal Model. Exp. Med.,  2020, 3(3), 229-236.
 [http://dx.doi.org/10.1002/ame2.12134] [PMID: 33024944]

[17]
Kurilshikov, A.; Medina-Gomez, C.; Bacigalupe, R.; Radjabzadeh, D.; Wang, J.; Demirkan, A.; Le Roy, C.I.; Raygoza Garay, J.A.; Finnicum, C.T.; Liu, X.; Zhernakova, D.V.; Bonder, M.J.; Hansen, T.H.; Frost, F.; Rühlemann, M.C.; Turpin, W.; Moon, J.Y.; Kim, H.N.; Lüll, K.; Barkan, E.; Shah, S.A.; Fornage, M.; Szopinska-Tokov, J.; Wallen, Z.D.; Borisevich, D.; Agreus, L.; Andreasson, A.; Bang, C.; Bedrani, L.; Bell, J.T.; Bisgaard, H.; Boehnke, M.; Boomsma, D.I.; Burk, R.D.; Claringbould, A.; Croitoru, K.; Davies, G.E.; van Duijn, C.M.; Duijts, L.; Falony, G.; Fu, J.; van der Graaf, A.; Hansen, T.; Homuth, G.; Hughes, D.A.; Ijzerman, R.G.; Jackson, M.A.; Jaddoe, V.W.V.; Joossens, M.; Jørgensen, T.; Keszthelyi, D.; Knight, R.; Laakso, M.; Laudes, M.; Launer, L.J.; Lieb, W.; Lusis, A.J.; Masclee, A.A.M.; Moll, H.A.; Mujagic, Z.; Qibin, Q.; Rothschild, D.; Shin, H.; Sørensen, S.J.; Steves, C.J.; Thorsen, J.; Timpson, N.J.; Tito, R.Y.; Vieira-Silva, S.; Völker, U.; Völzke, H.; Võsa, U.; Wade, K.H.; Walter, S.; Watanabe, K.; Weiss, S.; Weiss, F.U.; Weissbrod, O.; Westra, H.J.; Willemsen, G.; Payami, H.; Jonkers, D.M.A.E.; Arias Vasquez, A.; de Geus, E.J.C.; Meyer, K.A.; Stokholm, J.; Segal, E.; Org, E.; Wijmenga, C.; Kim, H.L.; Kaplan, R.C.; Spector, T.D.; Uitterlinden, A.G.; Rivadeneira, F.; Franke, A.; Lerch, M.M.; Franke, L.; Sanna, S.; D’Amato, M.; Pedersen, O.; Paterson, A.D.; Kraaij, R.; Raes, J.; Zhernakova, A. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat. Genet.,  2021, 53(2), 156-165.
 [http://dx.doi.org/10.1038/s41588-020-00763-1] [PMID: 33462485]

[18]
Schmidt, V.; Enav, H.; Spector, T.D.; Youngblut, N.D.; Ley, R.E. Strain-level analysis of Bifidobacterium spp. from gut microbiomes of adults with differing lactase persistence genotypes. mSystems,  2020, 5(5), e00911-e00920.
 [http://dx.doi.org/10.1128/mSystems.00911-20] [PMID: 32994293]

[19]
Kolde, R.; Franzosa, E.A.; Rahnavard, G.; Hall, A.B.; Vlamakis, H.; Stevens, C.; Daly, M.J.; Xavier, R.J.; Huttenhower, C. Host genetic variation and its microbiome interactions within the Human Microbiome Project. Genome Med.,  2018, 10(1), 6.
 [http://dx.doi.org/10.1186/s13073-018-0515-8] [PMID: 29378630]

[20]
Lim, M.Y.; You, H.J.; Yoon, H.S.; Kwon, B.; Lee, J.Y.; Lee, S.; Song, Y.M.; Lee, K.; Sung, J.; Ko, G. The effect of heritability and host genetics on the gut microbiota and metabolic syndrome. Gut,  2017, 66(6), 1031-1038.
 [http://dx.doi.org/10.1136/gutjnl-2015-311326] [PMID: 27053630]

[21]
Montgomery, T.L.; Künstner, A.; Kennedy, J.J.; Fang, Q.; Asarian, L.; Culp-Hill, R.; D’Alessandro, A.; Teuscher, C.; Busch, H.; Krementsov, D.N. Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity. Proc. Natl. Acad. Sci. USA,  2020, 117(44), 27516-27527.
 [http://dx.doi.org/10.1073/pnas.2002817117] [PMID: 33077601]

[22]
Turpin, W.; Espin-Garcia, O.; Xu, W.; Silverberg, M.S.; Kevans, D.; Smith, M.I.; Guttman, D.S.; Griffiths, A.; Panaccione, R.; Otley, A.; Xu, L.; Shestopaloff, K.; Moreno-Hagelsieb, G.; Paterson, A.D.; Croitoru, K. Association of host genome with intestinal microbial composition in a large healthy cohort. Nat. Genet.,  2016, 48(11), 1413-1417.
 [http://dx.doi.org/10.1038/ng.3693] [PMID: 27694960]

[23]
Bubier, J.A.; Chesler, E.J.; Weinstock, G.M. Host genetic control of gut microbiome composition. Mamm. Genome,  2021, 32(4), 263-281.
 [http://dx.doi.org/10.1007/s00335-021-09884-2] [PMID: 34159422]

[24]
Tang, J.; Wu, X.; Mou, M.; Wang, C.; Wang, L.; Li, F.; Guo, M.; Yin, J.; Xie, W.; Wang, X.; Wang, Y.; Ding, Y.; Xue, W.; Zhu, F. GIMICA: Host genetic and immune factors shaping human microbiota. Nucleic Acids Res.,  2021, 49(D1), D715-D722.
 [http://dx.doi.org/10.1093/nar/gkaa851] [PMID: 33045729]

[25]
Silva, Y.P.; Bernardi, A.; Frozza, R.L. The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front. Endocrinol. (Lausanne),  2020, 11, 25.
 [http://dx.doi.org/10.3389/fendo.2020.00025] [PMID: 32082260]

[26]
Mitchell, R.W.; On, N.H.; Del Bigio, M.R.; Miller, D.W.; Hatch, G.M. Fatty acid transport protein expression in human brain and potential role in fatty acid transport across human brain microvessel endothelial cells. J. Neurochem.,  2011, 117(4), no.
 [http://dx.doi.org/10.1111/j.1471-4159.2011.07245.x] [PMID: 21395585]

[27]
Lee, J.; Venna, V.R.; Durgan, D.J.; Shi, H.; Hudobenko, J.; Putluri, N.; Petrosino, J.; McCullough, L.D.; Bryan, R.M. Young versus aged microbiota transplants to germ-free mice: Increased short-chain fatty acids and improved cognitive performance. Gut Microbes,  2020, 12(1), 1814107.
 [http://dx.doi.org/10.1080/19490976.2020.1814107] [PMID: 32897773]

[28]
Unger, M.M.; Spiegel, J.; Dillmann, K.U.; Grundmann, D.; Philippeit, H.; Bürmann, J.; Faßbender, K.; Schwiertz, A.; Schäfer, K.H. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat. Disord.,  2016, 32, 66-72.
 [http://dx.doi.org/10.1016/j.parkreldis.2016.08.019] [PMID: 27591074]

[29]
Thomas, R.H.; Meeking, M.M.; Mepham, J.R.; Tichenoff, L.; Possmayer, F.; Liu, S.; MacFabe, D.F. The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: Further development of a rodent model of autism spectrum disorders. J. Neuroinflammation,  2012, 9(1), 695.
 [http://dx.doi.org/10.1186/1742-2094-9-153] [PMID: 22747852]

[30]
Thomas, R.H.; Foley, K.A.; Mepham, J.R.; Tichenoff, L.J.; Possmayer, F.; MacFabe, D.F. Altered brain phospholipid and acylcarnitine profiles in propionic acid infused rodents: Further development of a potential model of autism spectrum disorders. J. Neurochem.,  2010, 113(2), 515-529.
 [http://dx.doi.org/10.1111/j.1471-4159.2010.06614.x] [PMID: 20405543]

[31]
MacFabe, D.F.; Cain, N.E.; Boon, F.; Ossenkopp, K.P.; Cain, D.P. Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder. Behav. Brain Res.,  2011, 217(1), 47-54.
 [http://dx.doi.org/10.1016/j.bbr.2010.10.005] [PMID: 20937326]

[32]
Shultz, S.R.; MacFabe, D.F.; Martin, S.; Jackson, J.; Taylor, R.; Boon, F.; Ossenkopp, K.P.; Cain, D.P. Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long–Evans rat: Further development of a rodent model of autism. Behav. Brain Res.,  2009, 200(1), 33-41.
 [http://dx.doi.org/10.1016/j.bbr.2008.12.023] [PMID: 19154758]

[33]
Shultz, S.R.; MacFabe, D.F.; Ossenkopp, K.P.; Scratch, S.; Whelan, J.; Taylor, R.; Cain, D.P. Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: Implications for an animal model of autism. Neuropharmacology,  2008, 54(6), 901-911.
 [http://dx.doi.org/10.1016/j.neuropharm.2008.01.013] [PMID: 18395759]

[34]
Zheng, W.; He, R.; Yan, Z.; Huang, Y.; Huang, W.; Cai, Z.; Su, Y.; Liu, S.; Deng, Y.; Wang, Q.; Xie, H. Regulation of immune-driven pathogenesis in Parkinson’s disease by gut microbiota. Brain Behav. Immun.,  2020, 87, 890-897.
 [http://dx.doi.org/10.1016/j.bbi.2020.01.009] [PMID: 31931152]

[35]
Sharon, G.; Cruz, N.J.; Kang, D.W.; Gandal, M.J.; Wang, B.; Kim, Y.M.; Zink, E.M.; Casey, C.P.; Taylor, B.C.; Lane, C.J.; Bramer, L.M.; Isern, N.G.; Hoyt, D.W.; Noecker, C.; Sweredoski, M.J.; Moradian, A.; Borenstein, E.; Jansson, J.K.; Knight, R.; Metz, T.O.; Lois, C.; Geschwind, D.H.; Krajmalnik-Brown, R.; Mazmanian, S.K.; Mazmanian, S.K. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell,  2019, 177(6), 1600-1618.e17.
 [http://dx.doi.org/10.1016/j.cell.2019.05.004] [PMID: 31150625]

[36]
Mersman, B.; Zaidi, W.; Syed, N.I.; Xu, F. Taurine promotes neurite outgrowth and synapse development of both vertebrate and invertebrate central neurons. Front. Synaptic Neurosci.,  2020, 12, 29.
 [http://dx.doi.org/10.3389/fnsyn.2020.00029] [PMID: 32792935]

[37]
Kaelberer, M.M.; Buchanan, K.L.; Klein, M.E.; Barth, B.B.; Montoya, M.M.; Shen, X.; Bohórquez, D.V. A gut-brain neural circuit for nutrient sensory transduction. Science,  2018, 361(6408), eaat5236.
 [http://dx.doi.org/10.1126/science.aat5236] [PMID: 30237325]

[38]
Needham, B.D.; Kaddurah-Daouk, R.; Mazmanian, S.K. Gut microbial molecules in behavioural and neurodegenerative conditions. Nat. Rev. Neurosci.,  2020, 21(12), 717-731.
 [http://dx.doi.org/10.1038/s41583-020-00381-0] [PMID: 33067567]

[39]
Bermudez-Martin, P.; Becker, J.A.J.; Caramello, N.; Fernandez, S.P.; Costa-Campos, R.; Canaguier, J.; Barbosa, S.; Martinez-Gili, L.; Myridakis, A.; Dumas, M.E.; Bruneau, A.; Cherbuy, C.; Langella, P.; Callebert, J.; Launay, J.M.; Chabry, J.; Barik, J.; Le Merrer, J.; Glaichenhaus, N.; Davidovic, L. The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota. Microbiome,  2021, 9(1), 157.
 [http://dx.doi.org/10.1186/s40168-021-01103-z] [PMID: 34238386]

[40]
Needham, B.D.; Adame, M.D.; Serena, G.; Rose, D.R.; Preston, G.M.; Conrad, M.C.; Campbell, A.S.; Donabedian, D.H.; Fasano, A.; Ashwood, P.; Mazmanian, S.K. Plasma and fecal metabolite profiles in autism spectrum disorder. Biol. Psychiatry,  2021, 89(5), 451-462.
 [http://dx.doi.org/10.1016/j.biopsych.2020.09.025] [PMID: 33342544]

[41]
Hsiao, E.Y.; McBride, S.W.; Hsien, S.; Sharon, G.; Hyde, E.R.; McCue, T.; Codelli, J.A.; Chow, J.; Reisman, S.E.; Petrosino, J.F.; Patterson, P.H.; Mazmanian, S.K. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell,  2013, 155(7), 1451-1463.
 [http://dx.doi.org/10.1016/j.cell.2013.11.024] [PMID: 24315484]

[42]
Gabriele, S.; Sacco, R.; Cerullo, S.; Neri, C.; Urbani, A.; Tripi, G.; Malvy, J.; Barthelemy, C.; Bonnet-Brihault, F.; Persico, A.M. Urinary p -cresol is elevated in young French children with autism spectrum disorder: A replication study. Biomarkers,  2014, 19(6), 463-470.
 [http://dx.doi.org/10.3109/1354750X.2014.936911] [PMID: 25010144]

[43]
Gacias, M.; Gaspari, S.; Santos, P.M.G.; Tamburini, S.; Andrade, M.; Zhang, F.; Shen, N.; Tolstikov, V.; Kiebish, M.A.; Dupree, J.L.; Zachariou, V.; Clemente, J.C.; Casaccia, P. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. eLife,  2016, 5, e13442.
 [http://dx.doi.org/10.7554/eLife.13442] [PMID: 27097105]

[44]
Guzmán-Salas, S.; Weber, A.; Malci, A.; Lin, X.; Herrera-Molina, R.; Cerpa, W.; Dorador, C.; Signorelli, J.; Zamorano, P. The metaboliteP ‐cresol impairs dendritic development, synaptogenesis, and synapse function in hippocampal neurons: Implications for autism spectrum disorder. J. Neurochem.,  2022, 161(4), 335-349.
 [http://dx.doi.org/10.1111/jnc.15604] [PMID: 35257373]

[45]
Daneberga, Z.; Nakazawa-Miklasevica, M.; Berga-Svitina, E.; Murmane, D.; Isarova, D.; Cupane, L.; Masinska, M.; Nartisa, I.; Lazdane, A.; Miklasevics, E. Urinary organic acids spectra in children with altered gut microbiota composition and autistic spectrum disorder. Nord. J. Psychiatry,  2021, 1-7.
 [http://dx.doi.org/10.1080/08039488.2021.2014954] [PMID: 34935590]

[46]
Kang, D.W.; Adams, J.B.; Vargason, T.; Santiago, M.; Hahn, J.; Krajmalnik-Brown, R. Distinct fecal and plasma metabolites in children with autism spectrum disorders and their modulation after microbiota transfer therapy. MSphere,  2020, 5(5), e00314-e00320.
 [http://dx.doi.org/10.1128/mSphere.00314-20] [PMID: 33087514]

[47]
Gevi, F.; Belardo, A.; Zolla, L. A metabolomics approach to investigate urine levels of neurotransmitters and related metabolites in autistic children. Biochim. Biophys. Acta Mol. Basis Dis.,  2020, 1866(10), 165859.
 [http://dx.doi.org/10.1016/j.bbadis.2020.165859] [PMID: 32512190]

[48]
Kang, D.W.; Ilhan, Z.E.; Isern, N.G.; Hoyt, D.W.; Howsmon, D.P.; Shaffer, M.; Lozupone, C.A.; Hahn, J.; Adams, J.B.; Krajmalnik-Brown, R. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe,  2018, 49, 121-131.
 [http://dx.doi.org/10.1016/j.anaerobe.2017.12.007] [PMID: 29274915]

[49]
Altieri, L.; Neri, C.; Sacco, R.; Curatolo, P.; Benvenuto, A.; Muratori, F.; Santocchi, E.; Bravaccio, C.; Lenti, C.; Saccani, M.; Rigardetto, R.; Gandione, M.; Urbani, A.; Persico, A.M. Urinary p -cresol is elevated in small children with severe autism spectrum disorder. Biomarkers,  2011, 16(3), 252-260.
 [http://dx.doi.org/10.3109/1354750X.2010.548010] [PMID: 21329489]

[50]
Velasquez, M.; Ramezani, A.; Manal, A.; Raj, D. Trimethylamine N-oxide: The good, the bad and the unknown. Toxins (Basel),  2016, 8(11), 326.
 [http://dx.doi.org/10.3390/toxins8110326] [PMID: 27834801]

[51]
Hoyles, L.; Pontifex, M.G.; Rodriguez-Ramiro, I.; Anis-Alavi, M.A.; Jelane, K.S.; Snelling, T.; Solito, E.; Fonseca, S.; Carvalho, A.L.; Carding, S.R.; Müller, M.; Glen, R.C.; Vauzour, D.; McArthur, S. Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide. Microbiome,  2021, 9(1), 235.
 [http://dx.doi.org/10.1186/s40168-021-01181-z] [PMID: 34836554]

[52]
Gobbetti, T.; Cooray, S.N. Annexin A1 and resolution of inflammation: Tissue repairing properties and signalling signature. Biol. Chem.,  2016, 397(10), 981-993.
 [http://dx.doi.org/10.1515/hsz-2016-0200] [PMID: 27447237]

[53]
Cristante, E.; McArthur, S.; Mauro, C.; Maggioli, E.; Romero, I.A.; Wylezinska-Arridge, M.; Couraud, P.O.; Lopez-Tremoleda, J.; Christian, H.C.; Weksler, B.B.; Malaspina, A.; Solito, E. Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications. Proc. Natl. Acad. Sci. USA,  2013, 110(3), 832-841.
 [http://dx.doi.org/10.1073/pnas.1209362110] [PMID: 23277546]

[54]
Matheoud, D.; Cannon, T.; Voisin, A.; Penttinen, A.M.; Ramet, L.; Fahmy, A.M.; Ducrot, C.; Laplante, A.; Bourque, M.J.; Zhu, L.; Cayrol, R.; Le Campion, A.; McBride, H.M.; Gruenheid, S.; Trudeau, L.E.; Desjardins, M. Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice. Nature,  2019, 571(7766), 565-569.
 [http://dx.doi.org/10.1038/s41586-019-1405-y] [PMID: 31316206]

[55]
Wei, G.Z.; Martin, K.A.; Xing, P.Y.; Agrawal, R.; Whiley, L.; Wood, T.K.; Hejndorf, S.; Ng, Y.Z.; Low, J.Z.Y.; Rossant, J.; Nechanitzky, R.; Holmes, E.; Nicholson, J.K.; Tan, E.K.; Matthews, P.M.; Pettersson, S. Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA,  2021, 118(27), e2021091118.
 [http://dx.doi.org/10.1073/pnas.2021091118] [PMID: 34210797]

[56]
Agirman, G.; Yu, K.B.; Hsiao, E.Y. Signaling inflammation across the gut-brain axis. Science,  2021, 374(6571), 1087-1092.
 [http://dx.doi.org/10.1126/science.abi6087] [PMID: 34822299]

[57]
Campos-Acuña, J.; Elgueta, D.; Pacheco, R. T-cell-driven inflammation as a mediator of the gut-brain axis involved in Parkinson’s disease. Front. Immunol.,  2019, 10, 239.
 [http://dx.doi.org/10.3389/fimmu.2019.00239] [PMID: 30828335]

[58]
Singh, V.; Roth, S.; Llovera, G.; Sadler, R.; Garzetti, D.; Stecher, B.; Dichgans, M.; Liesz, A. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J. Neurosci.,  2016, 36(28), 7428-7440.
 [http://dx.doi.org/10.1523/JNEUROSCI.1114-16.2016] [PMID: 27413153]

[59]
Rothhammer, V.; Mascanfroni, I.D.; Bunse, L.; Takenaka, M.C.; Kenison, J.E.; Mayo, L.; Chao, C.C.; Patel, B.; Yan, R.; Blain, M.; Alvarez, J.I.; Kébir, H.; Anandasabapathy, N.; Izquierdo, G.; Jung, S.; Obholzer, N.; Pochet, N.; Clish, C.B.; Prinz, M.; Prat, A.; Antel, J.; Quintana, F.J. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med.,  2016, 22(6), 586-597.
 [http://dx.doi.org/10.1038/nm.4106] [PMID: 27158906]

[60]
Wolf, S.A.; Boddeke, H.W.G.M.; Kettenmann, H. Microglia in physiology and disease. Annu. Rev. Physiol.,  2017, 79(1), 619-643.
 [http://dx.doi.org/10.1146/annurev-physiol-022516-034406] [PMID: 27959620]

[61]
Erny, D.; Hrabě de Angelis, A.L.; Jaitin, D.; Wieghofer, P.; Staszewski, O.; David, E.; Keren-Shaul, H.; Mahlakoiv, T.; Jakobshagen, K.; Buch, T.; Schwierzeck, V.; Utermöhlen, O.; Chun, E.; Garrett, W.S.; McCoy, K.D.; Diefenbach, A.; Staeheli, P.; Stecher, B.; Amit, I.; Prinz, M. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci.,  2015, 18(7), 965-977.
 [http://dx.doi.org/10.1038/nn.4030] [PMID: 26030851]

[62]
Martins-Silva, T.; Salatino-Oliveira, A.; Genro, J.P.; Meyer, F.D.T.; Li, Y.; Rohde, L.A.; Hutz, M.H.; Tovo-Rodrigues, L. Host genetics influences the relationship between the gut microbiome and psychiatric disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2021, 106, 110153.
 [http://dx.doi.org/10.1016/j.pnpbp.2020.110153] [PMID: 33130294]

[63]
Santos, S.F.; de Oliveira, H.L.; Yamada, E.S.; Neves, B.C.; Pereira, A., Jr The gut and Parkinson’s disease—a bidirectional pathway. Front. Neurol.,  2019, 10, 574.
 [http://dx.doi.org/10.3389/fneur.2019.00574] [PMID: 31214110]

[64]
Perez Visñuk, D.; Savoy de Giori, G.; LeBlanc, J.G.; de Moreno de LeBlanc, A. Neuroprotective effects associated with immune modulation by selected lactic acid bacteria in a Parkinson’s disease model. Nutrition,  2020, 79-80, 110995.
 [http://dx.doi.org/10.1016/j.nut.2020.110995] [PMID: 32977125]

[65]
Cheng, L.H.; Liu, Y.W.; Wu, C.C.; Wang, S.; Tsai, Y.C. Psychobiotics in mental health, neurodegenerative and neurodevelopmental disorders. Yao Wu Shi Pin Fen Xi,  2019, 27(3), 632-648.
 [PMID: 31324280]

[66]
Cerdó, T.; Ruíz, A.; Suárez, A.; Campoy, C. Probiotic, prebiotic, and brain development. Nutrients,  2017, 9(11), 1247.
 [http://dx.doi.org/10.3390/nu9111247] [PMID: 29135961]

[67]
Tahami Monfared, A.A.; Byrnes, M.J.; White, L.A.; Zhang, Q. Alzheimer’s disease: Epidemiology and clinical progression. Neurol. Ther.,  2022, 11(2), 553-569.
 [http://dx.doi.org/10.1007/s40120-022-00338-8] [PMID: 35286590]

[68]
Fisher, R.A.; Miners, J.S.; Love, S. Pathological changes within the cerebral vasculature in Alzheimer’s disease: New perspectives. Brain Pathol.,  2022, e13061.
 [http://dx.doi.org/10.1111/bpa.13061] [PMID: 35289012]

[69]
Scheltens, P.; De Strooper, B.; Kivipelto, M.; Holstege, H.; Chételat, G.; Teunissen, C.E.; Cummings, J.; van der Flier, W.M. Alzheimer’s disease. Lancet,  2021, 397(10284), 1577-1590.
 [http://dx.doi.org/10.1016/S0140-6736(20)32205-4] [PMID: 33667416]

[70]
Rezaei, A.Z.; Sepehri, G.; Salami, M. Probiotic treatment improves the impaired spatial cognitive performance and restores synaptic plasticity in an animal model of Alzheimer’s disease. Behav. Brain Res.,  2019, 376, 112183.
 [http://dx.doi.org/10.1016/j.bbr.2019.112183] [PMID: 31472194]

[71]
Babür, E.; Tan, B.; Delibaş, S.; Yousef, M.; Dursun, N.; Süer, C. Depotentiation of long-term potentiation is associated with epitope-specific tau hyper-/hypophosphorylation in the hippocampus of adult rats. J. Mol. Neurosci.,  2019, 67(2), 193-203.
 [http://dx.doi.org/10.1007/s12031-018-1224-x] [PMID: 30498986]

[72]
Athari, N.A.S.; Djazayeri, A.; Safa, M.; Azami, K.; Djalali, M.; Sharifzadeh, M.; Vafa, M. Probiotics improve insulin resistance status in an experimental model of Alzheimer’s disease. Med. J. Islam. Repub. Iran,  2017, 31(1), 699-704.
 [http://dx.doi.org/10.14196/mjiri.31.103] [PMID: 29951404]

[73]
Yamin, G. NMDA receptor-dependent signaling pathways that underlie amyloid β-protein disruption of LTP in the hippocampus. J. Neurosci. Res.,  2009, 87(8), 1729-1736.
 [http://dx.doi.org/10.1002/jnr.21998] [PMID: 19170166]

[74]
Wiatrak, B.; Jawień, P.; Matuszewska, A.; Szeląg, A.; Kubis-Kubiak, A. Effect of amyloid-β on the redox system activity in SH-SY5Y cells preincubated with lipopolysaccharide or co-cultured with microglia cells. Biomed. Pharmacother.,  2022, 149, 112880.
 [http://dx.doi.org/10.1016/j.biopha.2022.112880] [PMID: 35367762]

[75]
Hemert, S.V.; Ormel, G. Influence of the multispecies probiotic Ecologic® BARRIER on parameters of intestinal barrier function. Food Nutr. Sci.,  2014, 5(18), 1739-1745.
 [http://dx.doi.org/10.4236/fns.2014.518187]

[76]
Romo-Araiza, A.; Gutiérrez-Salmeán, G.; Galván, E.J.; Hernández-Frausto, M.; Herrera-López, G.; Romo-Parra, H.; García-Contreras, V.; Fernández-Presas, A.M.; Jasso-Chávez, R.; Borlongan, C.V.; Ibarra, A. Probiotics and prebiotics as a therapeutic strategy to improve memory in a model of middle-aged rats. Front. Aging Neurosci.,  2018, 10, 416.
 [http://dx.doi.org/10.3389/fnagi.2018.00416] [PMID: 30618722]

[77]
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed; ATA: Washington, USA, 2013. 

[78]
Gao, J.; Wang, X.; Sun, H.; Cao, Y.; Liang, S.; Wang, H.; Wang, Y.; Yang, F.; Zhang, F.; Wu, L. Neuroprotective effects of docosahexaenoic acid on hippocampal cell death and learning and memory impairments in a valproic acid‐induced rat autism model. Int. J. Dev. Neurosci.,  2016, 49(1), 67-78.
 [http://dx.doi.org/10.1016/j.ijdevneu.2015.11.006] [PMID: 26639559]

[79]
Dan, Z.; Mao, X.; Liu, Q.; Guo, M.; Zhuang, Y.; Liu, Z.; Chen, K.; Chen, J.; Xu, R.; Tang, J.; Qin, L.; Gu, B.; Liu, K.; Su, C.; Zhang, F.; Xia, Y.; Hu, Z.; Liu, X. Altered gut microbial profile is associated with abnormal metabolism activity of Autism Spectrum Disorder. Gut Microbes,  2020, 11(5), 1246-1267.
 [http://dx.doi.org/10.1080/19490976.2020.1747329] [PMID: 32312186]

[80]
Golubeva, A.V.; Joyce, S.A.; Moloney, G.; Burokas, A.; Sherwin, E.; Arboleya, S.; Flynn, I.; Khochanskiy, D.; Moya-Pérez, A.; Peterson, V.; Rea, K.; Murphy, K.; Makarova, O.; Buravkov, S.; Hyland, N.P.; Stanton, C.; Clarke, G.; Gahan, C.G.M.; Dinan, T.G.; Cryan, J.F. Microbiota-related changes in bile acid & tryptophan metabolism are associated with gastrointestinal dysfunction in a mouse model of autism. EBioMedicine,  2017, 24, 166-178.
 [http://dx.doi.org/10.1016/j.ebiom.2017.09.020] [PMID: 28965876]

[81]
Liu, Z.; Mao, X.; Dan, Z.; Pei, Y.; Xu, R.; Guo, M.; Liu, K.; Zhang, F.; Chen, J.; Su, C.; Zhuang, Y.; Tang, J.; Xia, Y.; Qin, L.; Hu, Z.; Liu, X. Gene variations in Autism Spectrum Disorder are associated with alternation of gut microbiota, metabolites and cytokines. Gut Microbes,  2021, 13(1), 1854967.
 [http://dx.doi.org/10.1080/19490976.2020.1854967] [PMID: 33412999]

[82]
Sabit, H.; Tombuloglu, H.; Rehman, S.; Almandil, N.B.; Cevik, E.; Abdel-Ghany, S.; Rashwan, S.; Abasiyanik, M.F.; Yee Waye, M.M. Gut microbiota metabolites in autistic children: An epigenetic perspective. Heliyon,  2021, 7(1), e06105.
 [http://dx.doi.org/10.1016/j.heliyon.2021.e06105] [PMID: 33553761]

[83]
Jyonouchi, H.; Sun, S.; Itokazu, N. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology,  2002, 46(2), 76-84.
 [http://dx.doi.org/10.1159/000065416] [PMID: 12378124]

[84]
MacFabe, D.; Cain, D.; Rodriguezcapote, K.; Franklin, A.; Hoffman, J.; Boon, F.; Taylor, A.; Kavaliers, M.; Ossenkopp, K. Neurobiological effects of intraventricular propionic acid in rats: Possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav. Brain Res.,  2007, 176(1), 149-169.
 [http://dx.doi.org/10.1016/j.bbr.2006.07.025] [PMID: 16950524]

[85]
De Angelis, M.; Piccolo, M.; Vannini, L.; Siragusa, S.; De Giacomo, A.; Serrazzanetti, D.I.; Cristofori, F.; Guerzoni, M.E.; Gobbetti, M.; Francavilla, R. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One,  2013, 8(10), e76993.
 [http://dx.doi.org/10.1371/journal.pone.0076993] [PMID: 24130822]

[86]
D’Eufemia, P.; Celli, M.; Finocchiaro, R.; Pacifico, L.; Viozzi, L.; Zaccagnini, M.; Cardi, E.; Giardini, O. Abnormal intestinal permeability in children with autism. Acta Paediatr.,  1996, 85(9), 1076-1079.
 [http://dx.doi.org/10.1111/j.1651-2227.1996.tb14220.x] [PMID: 8888921]

[87]
Kang, D.W.; Park, J.G.; Ilhan, Z.E.; Wallstrom, G.; LaBaer, J.; Adams, J.B.; Krajmalnik-Brown, R. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One,  2013, 8(7), e68322.
 [http://dx.doi.org/10.1371/journal.pone.0068322] [PMID: 23844187]

[88]
Luna, R.A.; Oezguen, N.; Balderas, M.; Venkatachalam, A.; Runge, J.K.; Versalovic, J.; Veenstra-VanderWeele, J.; Anderson, G.M.; Savidge, T.; Williams, K.C. Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder. Cell. Mol. Gastroenterol. Hepatol.,  2017, 3(2), 218-230.
 [http://dx.doi.org/10.1016/j.jcmgh.2016.11.008] [PMID: 28275689]

[89]
McElhanon, B.O.; McCracken, C.; Karpen, S.; Sharp, W.G. Gastrointestinal symptoms in autism spectrum disorder: A meta-analysis. Pediatrics,  2014, 133(5), 872-883.
 [http://dx.doi.org/10.1542/peds.2013-3995] [PMID: 24777214]

[90]
Tomova, A.; Husarova, V.; Lakatosova, S.; Bakos, J.; Vlkova, B.; Babinska, K.; Ostatnikova, D. Gastrointestinal microbiota in children with autism in Slovakia. Physiol. Behav.,  2015, 138, 179-187.
 [http://dx.doi.org/10.1016/j.physbeh.2014.10.033] [PMID: 25446201]

[91]
Peralta-Marzal, L.N.; Prince, N.; Bajic, D.; Roussin, L.; Naudon, L.; Rabot, S.; Garssen, J.; Kraneveld, A.D.; Perez-Pardo, P. The impact of gut microbiota-derived metabolites in autism spectrum disorders. Int. J. Mol. Sci.,  2021, 22(18), 10052.
 [http://dx.doi.org/10.3390/ijms221810052] [PMID: 34576216]

[92]
Kociszewska, D.; Vlajkovic, S.M. The association of inflammatory gut diseases with neuroinflammatory and auditory disorders. Front. Biosci. (Elite Ed.),  2022, 14(2), 8.
 [http://dx.doi.org/10.31083/j.fbe1402008] [PMID: 35730449]

[93]
Frost, G.; Sleeth, M.L.; Sahuri-Arisoylu, M.; Lizarbe, B.; Cerdan, S.; Brody, L.; Anastasovska, J.; Ghourab, S.; Hankir, M.; Zhang, S.; Carling, D.; Swann, J.R.; Gibson, G.; Viardot, A.; Morrison, D.; Louise, T.E.; Bell, J.D. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun.,  2014, 5(1), 3611.
 [http://dx.doi.org/10.1038/ncomms4611] [PMID: 24781306]

[94]
Morimoto, M.; Hashimoto, T.; Tsuda, Y.; Nakatsu, T.; Kitaoka, T.; Kyotani, S. Assessment of oxidative stress in autism spectrum disorder using reactive oxygen metabolites and biological antioxidant potential. PLoS One,  2020, 15(5), e0233550.
 [http://dx.doi.org/10.1371/journal.pone.0233550] [PMID: 32442231]

[95]
Greene, W.C.; Chen, L.F. Regulation of NF-kappaB action by reversible acetylation. Novartis Found. Symp.,  2004, 259, 208-217.
 [PMID: 15171256]

[96]
Nankova, B.B.; Agarwal, R.; MacFabe, D.F.; La Gamma, E.F. Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells-possible relevance to autism spectrum disorders. PLoS One,  2014, 9(8), e103740.
 [http://dx.doi.org/10.1371/journal.pone.0103740] [PMID: 25170769]

[97]
Al-Lahham, S.H.; Peppelenbosch, M.P.; Roelofsen, H.; Vonk, R.J.; Venema, K. Biological effects of propionic acid in humans; metabolism, potential applications and underlying mechanisms. Biochim. Biophys. Acta Mol. Cell Biol. Lipids,  2010, 1801(11), 1175-1183.
 [http://dx.doi.org/10.1016/j.bbalip.2010.07.007] [PMID: 20691280]

[98]
Chelakkot, C.; Ghim, J.; Ryu, S.H. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp. Mol. Med.,  2018, 50(8), 1-9.
 [http://dx.doi.org/10.1038/s12276-018-0126-x] [PMID: 30115904]

[99]
Günzel, D.; Yu, A.S.L. Claudins and the modulation of tight junction permeability. Physiol. Rev.,  2013, 93(2), 525-569.
 [http://dx.doi.org/10.1152/physrev.00019.2012] [PMID: 23589827]

[100]
Beatch, M.; Jesaitis, L.A.; Gallin, W.J.; Goodenough, D.A.; Stevenson, B.R. The tight junction protein ZO-2 contains three PDZ (PSD-95/Discs-Large/ZO-1) domains and an alternatively spliced region. J. Biol. Chem.,  1996, 271(42), 25723-25726.
 [http://dx.doi.org/10.1074/jbc.271.42.25723] [PMID: 8824195]

[101]
Itoh, M.; Furuse, M.; Morita, K.; Kubota, K.; Saitou, M.; Tsukita, S. Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J. Cell Biol.,  1999, 147(6), 1351-1363.
 [http://dx.doi.org/10.1083/jcb.147.6.1351] [PMID: 10601346]

[102]
Feldman, G.; Mullin, J.; Ryan, M. Occludin: Structure, function and regulation. Adv. Drug Deliv. Rev.,  2005, 57(6), 883-917.
 [http://dx.doi.org/10.1016/j.addr.2005.01.009] [PMID: 15820558]

[103]
Allam-Ndoul, B.; Castonguay-Paradis, S.; Veilleux, A. Gut microbiota and intestinal trans-epithelial permeability. Int. J. Mol. Sci.,  2020, 21(17), 6402.
 [http://dx.doi.org/10.3390/ijms21176402] [PMID: 32899147]

[104]
Han, X.; Lee, A.; Huang, S.; Gao, J.; Spence, J.R.; Owyang, C. Lactobacillus rhamnosus GG prevents epithelial barrier dysfunction induced by interferon-gamma and fecal supernatants from irritable bowel syndrome patients in human intestinal enteroids and colonoids. Gut Microbes,  2019, 10(1), 59-76.
 [http://dx.doi.org/10.1080/19490976.2018.1479625] [PMID: 30040527]

[105]
Yoshida, N.; Emoto, T.; Yamashita, T.; Watanabe, H.; Hayashi, T.; Tabata, T.; Hoshi, N.; Hatano, N.; Ozawa, G.; Sasaki, N.; Mizoguchi, T.; Amin, H.Z.; Hirota, Y.; Ogawa, W.; Yamada, T.; Hirata, K. Bacteroides vulgatus and Bacteroides dorei reduce gut microbial lipopolysaccharide production and inhibit atherosclerosis. Circulation,  2018, 138(22), 2486-2498.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033714] [PMID: 30571343]

[106]
Chelakkot, C.; Choi, Y.; Kim, D.K.; Park, H.T.; Ghim, J.; Kwon, Y.; Jeon, J.; Kim, M.S.; Jee, Y.K.; Gho, Y.S.; Park, H.S.; Kim, Y.K.; Ryu, S.H. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp. Mol. Med.,  2018, 50(2), e450.
 [http://dx.doi.org/10.1038/emm.2017.282] [PMID: 29472701]

[107]
Anderson, R.C.; Cookson, A.L.; McNabb, W.C.; Park, Z.; McCann, M.J.; Kelly, W.J.; Roy, N.C. Lactobacillus plantarum MB452 enhances the function of the intestinal barrier by increasing the expression levels of genes involved in tight junction formation. BMC Microbiol.,  2010, 10(1), 316.
 [http://dx.doi.org/10.1186/1471-2180-10-316] [PMID: 21143932]

[108]
Bhattarai, Y. Microbiota-gut-brain axis: Interaction of gut microbes and their metabolites with host epithelial barriers. Neurogastroenterol. Motil.,  2018, 30(6), e13366.
 [http://dx.doi.org/10.1111/nmo.13366] [PMID: 29878576]

[109]
Ma, X.; Fan, P.X.; Li, L.S.; Qiao, S.Y.; Zhang, G.L.; Li, D.F. Butyrate promotes the recovering of intestinal wound healing through its positive effect on the tight junctions. J. Anim. Sci.,  2012, 90(Suppl. 4), 266-268.
 [http://dx.doi.org/10.2527/jas.50965] [PMID: 23365351]

[110]
Pradhan, S.; Karve, S.S.; Weiss, A.A.; Hawkins, J.; Poling, H.M.; Helmrath, M.A.; Wells, J.M.; McCauley, H.A. Tissue responses to Shiga toxin in human intestinal organoids. Cell. Mol. Gastroenterol. Hepatol.,  2020, 10(1), 171-190.
 [http://dx.doi.org/10.1016/j.jcmgh.2020.02.006] [PMID: 32145469]

[111]
Shi, H.; Yu, Y.; Lin, D.; Zheng, P.; Zhang, P.; Hu, M.; Wang, Q.; Pan, W.; Yang, X.; Hu, T.; Li, Q.; Tang, R.; Zhou, F.; Zheng, K.; Huang, X.F. β-glucan attenuates cognitive impairment via the gut-brain axis in diet-induced obese mice. Microbiome,  2020, 8(1), 143.
 [http://dx.doi.org/10.1186/s40168-020-00920-y] [PMID: 33008466]

[112]
Tulyeu, J.; Kumagai, H.; Jimbo, E.; Watanabe, S.; Yokoyama, K.; Cui, L.; Osaka, H.; Mieno, M.; Yamagata, T. Probiotics prevents sensitization to oral antigen and subsequent increases in intestinal tight junction permeability in juvenile-young adult rats. Microorganisms,  2019, 7(10), 463.
 [http://dx.doi.org/10.3390/microorganisms7100463] [PMID: 31623229]

[113]
Davenport, E.R.; Sanders, J.G.; Song, S.J.; Amato, K.R.; Clark, A.G.; Knight, R. The human microbiome in evolution. BMC Biol.,  2017, 15(1), 127.
 [http://dx.doi.org/10.1186/s12915-017-0454-7] [PMID: 29282061]

[114]
Wang, X.; Zhang, A.; Miao, J.; Sun, H.; Yan, G.; Wu, F.; Wang, X. Gut microbiota as important modulator of metabolism in health and disease. RSC Advances,  2018, 8(74), 42380-42389.
 [http://dx.doi.org/10.1039/C8RA08094A] [PMID: 35558413]

[115]
Gagliardi, A.; Totino, V.; Cacciotti, F.; Iebba, V.; Neroni, B.; Bonfiglio, G.; Trancassini, M.; Passariello, C.; Pantanella, F.; Schippa, S. Rebuilding the gut microbiota ecosystem. Int. J. Environ. Res. Public Health,  2018, 15(8), 1679.
 [http://dx.doi.org/10.3390/ijerph15081679] [PMID: 30087270]

[116]
Manzoor, S.; Wani, S.M.; Ahmad Mir, S.; Rizwan, D. Role of probiotics and prebiotics in mitigation of different diseases. Nutrition,  2022, 96, 111602.
 [http://dx.doi.org/10.1016/j.nut.2022.111602] [PMID: 35182833]

[117]
Chen, M.; Liu, C.; Dai, M.; Wang, Q.; Li, C.; Hung, W. Bifidobacterium lactis BL-99 modulates intestinal inflammation and functions in zebrafish models. PLoS One,  2022, 17(2), e0262942.
 [http://dx.doi.org/10.1371/journal.pone.0262942] [PMID: 35171916]

[118]
Lu, J.; Lu, L.; Yu, Y.; Baranowski, J.; Claud, E.C. Maternal administration of probiotics promotes brain development and protects offspring’s brain from postnatal inflammatory insults in C57/BL6J mice. Sci. Rep.,  2020, 10(1), 8178.
 [http://dx.doi.org/10.1038/s41598-020-65180-0] [PMID: 32424168]

[119]
Tamtaji, O.R.; Taghizadeh, M.; Daneshvar Kakhaki, R.; Kouchaki, E.; Bahmani, F.; Borzabadi, S.; Oryan, S.; Mafi, A.; Asemi, Z. Clinical and metabolic response to probiotic administration in people with Parkinson’s disease: A randomized, double-blind, placebo-controlled trial. Clin. Nutr.,  2019, 38(3), 1031-1035.
 [http://dx.doi.org/10.1016/j.clnu.2018.05.018] [PMID: 29891223]

[120]
Chudzik, A.; Orzyłowska, A.; Rola, R.; Stanisz, G.J. Probiotics, prebiotics and postbiotics on mitigation of depression symptoms: Modulation of the brain-gut-microbiome axis. Biomolecules,  2021, 11(7), 1000.
 [http://dx.doi.org/10.3390/biom11071000] [PMID: 34356624]

[121]
Żółkiewicz, J.; Marzec, A.; Ruszczyński, M.; Feleszko, W. Postbiotics— a step beyond pre- and probiotics. Nutrients,  2020, 12(8), 2189.
 [http://dx.doi.org/10.3390/nu12082189] [PMID: 32717965]

[122]
Gu, Z.; Meng, S.; Wang, Y.; Lyu, B.; Li, P.; Shang, N. A novel bioactive postbiotics: From microbiota-derived extracellular nanoparticles to health promoting. Crit. Rev. Food Sci. Nutr.,  2022, 1-15. Advance online publication
 [http://dx.doi.org/10.1080/10408398.2022.2039897] [PMID: 35179102]

[123]
Hill, C.; Guarner, F.; Reid, G.; Gibson, G.R.; Merenstein, D.J.; Pot, B.; Morelli, L.; Canani, R.B.; Flint, H.J.; Salminen, S.; Calder, P.C.; Sanders, M.E. The international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol.,  2014, 11(8), 506-514.
 [http://dx.doi.org/10.1038/nrgastro.2014.66] [PMID: 24912386]

[124]
Vallianou, N.; Stratigou, T.; Christodoulatos, G.S.; Tsigalou, C.; Dalamaga, M. Probiotics, prebiotics, synbiotics, postbiotics, and obesity: Current evidence, controversies, and perspectives. Curr. Obes. Rep.,  2020, 9(3), 179-192.
 [http://dx.doi.org/10.1007/s13679-020-00379-w] [PMID: 32472285]

[125]
Li, H.Y.; Zhou, D.D.; Gan, R.Y.; Huang, S.Y.; Zhao, C.N.; Shang, A.; Xu, X.Y.; Li, H.B. Effects and mechanisms of probiotics, prebiotics, synbiotics, and postbiotics on metabolic diseases targeting gut microbiota: A narrative review. Nutrients,  2021, 13(9), 3211.
 [http://dx.doi.org/10.3390/nu13093211] [PMID: 34579087]

[126]
Garrett, W.S.; Lord, G.M.; Punit, S.; Lugo-Villarino, G.; Mazmanian, S.K.; Ito, S.; Glickman, J.N.; Glimcher, L.H. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell,  2007, 131(1), 33-45.
 [http://dx.doi.org/10.1016/j.cell.2007.08.017] [PMID: 17923086]

[127]
Richards, J.L.; Yap, Y.A.; McLeod, K.H.; Mackay, C.R.; Mariño, E. Dietary metabolites and the gut microbiota: An alternative approach to control inflammatory and autoimmune diseases. Clin. Transl. Immunology,  2016, 5(5), e82.
 [http://dx.doi.org/10.1038/cti.2016.29] [PMID: 27350881]

[128]
Sonnenburg, E.D.; Smits, S.A.; Tikhonov, M.; Higginbottom, S.K.; Wingreen, N.S.; Sonnenburg, J.L. Diet-induced extinctions in the gut microbiota compound over generations. Nature,  2016, 529(7585), 212-215.
 [http://dx.doi.org/10.1038/nature16504] [PMID: 26762459]

[129]
Hua, X.; Zhu, J.; Yang, T.; Guo, M.; Li, Q.; Chen, J.; Li, T. The gut microbiota and associated metabolites are altered in sleep disorder of children with autism spectrum disorders. Front. Psychiatry,  2020, 11, 855.
 [http://dx.doi.org/10.3389/fpsyt.2020.00855] [PMID: 32982808]

[130]
Agus, A.; Planchais, J.; Sokol, H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe,  2018, 23(6), 716-724.
 [http://dx.doi.org/10.1016/j.chom.2018.05.003] [PMID: 29902437]

[131]
Ossenkopp, K.P.; Foley, K.A.; Gibson, J.; Fudge, M.A.; Kavaliers, M.; Cain, D.P.; MacFabe, D.F. Systemic treatment with the enteric bacterial fermentation product, propionic acid, produces both conditioned taste avoidance and conditioned place avoidance in rats. Behav. Brain Res.,  2012, 227(1), 134-141.
 [http://dx.doi.org/10.1016/j.bbr.2011.10.045] [PMID: 22085877]

[132]
Hou, Y.; Li, X.; Liu, C.; Zhang, M.; Zhang, X.; Ge, S.; Zhao, L. Neuroprotective effects of short-chain fatty acids in MPTP induced mice model of Parkinson’s disease. Exp. Gerontol.,  2021, 150, 111376.
 [http://dx.doi.org/10.1016/j.exger.2021.111376] [PMID: 33905875]

[133]
Page, M.J.; Pretorius, E. Platelet behavior contributes to neuropathologies: A focus on Alzheimer’s and Parkinson’s disease. Semin. Thromb. Hemost.,  2022, 48(3), 382-404.
 [http://dx.doi.org/10.1055/s-0041-1733960] [PMID: 34624913]

[134]
Abdel-Rahman, E.A.; Zaky, E.A.; Aboulsaoud, M.; Elhossiny, R.M.; Youssef, W.Y.; Mahmoud, A.M.; Ali, S.S. Autism spectrum disorder (ASD)-associated mitochondrial deficits are revealed in children’s platelets but unimproved by hyperbaric oxygen therapy. Free Radic. Res.,  2021, 55(1), 26-40.
 [http://dx.doi.org/10.1080/10715762.2020.1856376] [PMID: 33402007]

[135]
Xie, Z.; Liu, X.; Huang, X.; Liu, Q.; Yang, M.; Huang, D.; Zhao, P.; Tian, J.; Wang, X.; Hou, J. Remodelling of gut microbiota by Berberine attenuates trimethylamine N-oxide-induced platelet hyperreaction and thrombus formation. Eur. J. Pharmacol.,  2021, 911, 174526.
 [http://dx.doi.org/10.1016/j.ejphar.2021.174526] [PMID: 34599914]

[136]
Anderson, G.; Rodriguez, M.; Reiter, R.J. Multiple sclerosis: Melatonin, orexin, and ceramide interact with platelet activation coagulation factors and gut-microbiome-derived butyrate in the circadian dysregulation of mitochondria in glia and immune cells. Int. J. Mol. Sci.,  2019, 20(21), 5500.
 [http://dx.doi.org/10.3390/ijms20215500] [PMID: 31694154]

[137]
Chen, Z.; Liu, C.; Jiang, Y.; Liu, H.; Shao, L.; Zhang, K.; Cheng, D.; Zhou, Y.; Chong, W. HDAC inhibitor attenuated NETs formation induced by activated platelets in vitro, partially through downregulating platelet secretion. Shock,  2020, 54(3), 321-329.
 [http://dx.doi.org/10.1097/SHK.0000000000001518] [PMID: 32044829]

[138]
Anderson, G.; Maes, M. Gut dysbiosis dysregulates central and systemic homeostasis via suboptimal mitochondrial function: Assessment, treatment and classification implications. Curr. Top. Med. Chem.,  2020, 20(7), 524-539.
 [http://dx.doi.org/10.2174/1568026620666200131094445] [PMID: 32003689]

[139]
Ghafouri-Fard, S.; Namvar, A.; Arsang-Jang, S.; Komaki, A.; Taheri, M. Expression analysis of BDNF, BACE1, and their natural occurring antisenses in autistic patients. J. Mol. Neurosci.,  2020, 70(2), 194-200.
 [http://dx.doi.org/10.1007/s12031-019-01432-7] [PMID: 31760580]
Cite As
Current Neuropharmacology

Targeting Gut Dysbiosis and Microbiome Metabolites for the Development of Therapeutic Modalities for Neurological Disorders

Abstract

Graphical Abstract
