Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Gut Microbiota Metabolite Messengers in Brain Function and Pathology at a View of Cell Type-Based Receptor and Enzyme Reaction

  • Bada Lee (Department of Biomedicinal and Pharmaceutical Sciences, Graduate School, Kyung Hee University) ;
  • Soo Min Lee (Department of Biomedicinal and Pharmaceutical Sciences, Graduate School, Kyung Hee University) ;
  • Jae Won Song (Department of Regulatory Science, Graduate School, Kyung Hee University) ;
  • Jin Woo Choi (Department of Biomedicinal and Pharmaceutical Sciences, Graduate School, Kyung Hee University)
  • Received : 2024.01.10
  • Accepted : 2024.05.25
  • Published : 2024.07.01
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Abstract

The human gastrointestinal (GI) tract houses a diverse microbial community, known as the gut microbiome comprising bacteria, viruses, fungi, and protozoa. The gut microbiome plays a crucial role in maintaining the body's equilibrium and has recently been discovered to influence the functioning of the central nervous system (CNS). The communication between the nervous system and the GI tract occurs through a two-way network called the gut-brain axis. The nervous system and the GI tract can modulate each other through activated neuronal cells, the immune system, and metabolites produced by the gut microbiome. Extensive research both in preclinical and clinical realms, has highlighted the complex relationship between the gut and diseases associated with the CNS, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review aims to delineate receptor and target enzymes linked with gut microbiota metabolites and explore their specific roles within the brain, particularly their impact on CNS-related diseases.

Keywords

Acknowledgement

This research was supported by Medical Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF2017R1A5A2014768), grant (21153MFDS601) from Ministry of Food and Drug Safety in 2024, and National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) NRF-2022R1A2C2009281.

References

  1. Abdelkader, N. F., Safar, M. M. and Salem, H. A. (2016) Ursodeoxycholic acid ameliorates apoptotic cascade in the rotenone model of Parkinson's disease: modulation of mitochondrial perturbations. Mol. Neurobiol. 53, 810-817. https://doi.org/10.1007/s12035-014-9043-8
  2. Aguilera, P., Chanez-Cardenas, M. E., Floriano-Sanchez, E., Barrera, D., Santamaria, A., Sanchez-Gonzalez, D. J., Perez-Severiano, F., Pedraza-Chaverri, J. and Jimenez, P. D. (2007) Time-related changes in constitutive and inducible nitric oxide synthases in the rat striatum in a model of Huntington's disease. Neurotoxicology 28, 1200-1207. https://doi.org/10.1016/j.neuro.2007.07.010
  3. Ahmed, H., Leyrolle, Q., Koistinen, V., Karkkainen, O., Laye, S., Delzenne, N. and Hanhineva, K. (2022) Microbiota-derived metabolites as drivers of gut-brain communication. Gut Microbes 14, 2102878.
  4. Aho, V. T. E., Houser, M. C., Pereira, P. A. B., Chang, J., Rudi, K., Paulin, L., Hertzberg, V., Auvinen, P., Tansey, M. G. and Scheperjans, F. (2021) Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson's disease. Mol. Neurodegener. 16, 6.
  5. Akhtar, M., Chen, Y., Ma, Z., Zhang, X., Shi, D., Khan, J. A. and Liu, H. (2022) Gut microbiota-derived short chain fatty acids are potential mediators in gut inflammation. Anim. Nutr. 8, 350-360. https://doi.org/10.1016/j.aninu.2021.11.005
  6. Amori, L., Wu, H. Q., Marinozzi, M., Pellicciari, R., Guidetti, P. and Schwarcz, R. (2009) Specific inhibition of kynurenate synthesis enhances extracellular dopamine levels in the rodent striatum. Neuroscience 159, 196-203. https://doi.org/10.1016/j.neuroscience.2008.11.055
  7. Anderson, M. A., Burda, J. E., Ren, Y., Ao, Y., O'Shea, T. M., Kawaguchi, R., Coppola, G., Khakh, B. S., Deming, T. J. and Sofroniew, M. V. (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195-200. https://doi.org/10.1038/nature17623
  8. Andoh, A. and Nishida, A. (2022) Alteration of the gut microbiome in inflammatory bowel disease. Digestion 104, 16-23. https://doi.org/10.1159/000525925
  9. Ang, Z., Er, J. Z. and Ding, J. L. (2015) The short-chain fatty acid receptor GPR43 is transcriptionally regulated by XBP1 in human monocytes. Sci. Rep. 5, 8134.
  10. Bachmann, C., Colombo, J.-P. and Beruter, J. (1979) Short chain fatty acids in plasma and brain: Quantitative determination by gas chromatography. Clin. Chim. Acta 92, 153-159. https://doi.org/10.1016/0009-8981(79)90109-8
  11. Belanger, M., Allaman, I. and Magistretti, P. J. (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 14, 724-738. https://doi.org/10.1016/j.cmet.2011.08.016
  12. Benevides, L., Burman, S., Martin, R., Robert, V., Thomas, M., Miquel, S., Chain, F., Sokol, H., Bermudez-Humaran, L. G., Morrison, M., Langella, P., Azevedo, V. A., Chatel, J. M. and Soares, S. (2017) New insights into the diversity of the genus faecalibacterium. Front. Microbiol. 8, 1790.
  13. Bergman, E. N. (1990) Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol. Rev. 70, 567-590. https://doi.org/10.1152/physrev.1990.70.2.567
  14. Blad, C. C., Tang, C. and Offermanns, S. (2012) G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat. Rev. Drug Discov. 11, 603-619. https://doi.org/10.1038/nrd3777
  15. Bloemen, J. G., Venema, K., van de Poll, M. C., Olde Damink, S. W., Buurman, W. A. and Dejong, C. H. (2009) Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clin. Nutr. 28, 657-661. https://doi.org/10.1016/j.clnu.2009.05.011
  16. Boddy, S. L., Giovannelli, I., Sassani, M., Cooper-Knock, J., Snyder, M. P., Segal, E., Elinav, E., Barker, L. A., Shaw, P. J. and McDermott, C. J. (2021) The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS). BMC Med. 19, 13.
  17. Bonaz, B., Bazin, T. and Pellissier, S. (2018) The vagus nerve at the interface of the microbiota-gut-brain axis. Front. Neurosci. 12, 49.
  18. Bottner, M., Zorenkov, D., Hellwig, I., Barrenschee, M., Harde, J., Fricke, T., Deuschl, G., Egberts, J. H., Becker, T., Fritscher-Ravens, A., Arlt, A. and Wedel, T. (2012) Expression pattern and localization of alpha-synuclein in the human enteric nervous system. Neurobiol. Dis. 48, 474-480. https://doi.org/10.1016/j.nbd.2012.07.018
  19. Braidy, N., Grant, R., Adams, S., Brew, B. J. and Guillemin, G. J. (2009) Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox. Res. 16, 77-86. https://doi.org/10.1007/s12640-009-9051-z
  20. Braniste, V., Al-Asmakh, M., Kowal, C., Anuar, F., Abbaspour, A., Toth, M., Korecka, A., Bakocevic, N., Ng, L. G., Kundu, P., Gulyas, B., Halldin, C., Hultenby, K., Nilsson, H., Hebert, H., Volpe, B. T., Diamond, B. and Pettersson, S. (2014) The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med. 6, 263ra158.
  21. Bravo, J. A., Forsythe, P., Chew, M. V., Escaravage, E., Savignac, H. M., Dinan, T. G., Bienenstock, J. and Cryan, J. F. (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl. Acad. Sci. U. S. A. 108, 16050-16055. https://doi.org/10.1073/pnas.1102999108
  22. Brown, A. J., Goldsworthy, S. M., Barnes, A. A., Eilert, M. M., Tcheang, L., Daniels, D., Muir, A. I., Wigglesworth, M. J., Kinghorn, I., Fraser, N. J., Pike, N. B., Strum, J. C., Steplewski, K. M., Murdock, P. R., Holder, J. C., Marshall, F. H., Szekeres, P. G., Wilson, S., Ignar, D. M., Foord, S. M., Wise, A. and Dowell, S. J. (2003) The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids*. J. Biol. Chem. 278, 11312-11319. https://doi.org/10.1074/jbc.M211609200
  23. Browning, K. N. and Travagli, R. A. (2014) Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr. Physiol. 4, 1339-1368. https://doi.org/10.1002/cphy.c130055
  24. Browning, K. N., Verheijden, S. and Boeckxstaens, G. E. (2017) The vagus nerve in appetite regulation, mood, and intestinal inflammation. Gastroenterology 152, 730-744. https://doi.org/10.1053/j.gastro.2016.10.046
  25. Byrne, C. S., Chambers, E. S., Alhabeeb, H., Chhina, N., Morrison, D. J., Preston, T., Tedford, C., Fitzpatrick, J., Irani, C., Busza, A., Garcia-Perez, I., Fountana, S., Holmes, E., Goldstone, A. P. and Frost, G. S. (2016) Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods. Am. J. Clin. Nutr. 104, 5-14. https://doi.org/10.3945/ajcn.115.126706
  26. Caetano-Silva, M. E., Rund, L., Hutchinson, N. T., Woods, J. A., Steelman, A. J. and Johnson, R. W. (2023) Inhibition of inflammatory microglia by dietary fiber and short-chain fatty acids. Sci. Rep. 13, 2819.
  27. Calabresi, P., Mechelli, A., Natale, G., Volpicelli-Daley, L., Di Lazzaro, G. and Ghiglieri, V. (2023) Alpha-synuclein in Parkinson's disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 14, 176.
  28. Cantu-Jungles, T. M., Rasmussen, H. E. and Hamaker, B. R. (2019) Potential of prebiotic butyrogenic fibers in Parkinson's disease. Front. Neurol. 10, 663.
  29. Castellanos-Jankiewicz, A., Guzman-Quevedo, O., Fenelon, V. S., Zizzari, P., Quarta, C., Bellocchio, L., Tailleux, A., Charton, J., Fernandois, D., Henricsson, M., Piveteau, C., Simon, V., Allard, C., Quemener, S., Guinot, V., Hennuyer, N., Perino, A., Duveau, A., Maitre, M., Leste-Lasserre, T., Clark, S., Dupuy, N., Cannich, A., Gonzales, D., Deprez, B., Mithieux, G., Dombrowicz, D., Backhed, F., Prevot, V., Marsicano, G., Staels, B., Schoonjans, K. and Cota, D. (2021) Hypothalamic bile acid-TGR5 signaling protects from obesity. Cell Metab. 33, 1483-1492.e10. https://doi.org/10.1016/j.cmet.2021.04.009
  30. Cattaneo, A., Cattane, N., Galluzzi, S., Provasi, S., Lopizzo, N., Festari, C., Ferrari, C., Guerra, U. P., Paghera, B., Muscio, C., Bianchetti, A., Volta, G. D., Turla, M., Cotelli, M. S., Gennuso, M., Prelle, A., Zanetti, O., Lussignoli, G., Mirabile, D., Bellandi, D., Gentile, S., Belotti, G., Villani, D., Harach, T., Bolmont, T., Padovani, A., Boccardi, M. and Frisoni, G. B. (2017) Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol. Aging 49, 60-68. https://doi.org/10.1016/j.neurobiolaging.2016.08.019
  31. Cerovic, M., Forloni, G. and Balducci, C. (2019) Neuroinflammation and the gut microbiota: possible alternative therapeutic targets to counteract Alzheimer's disease? Front. Aging Neurosci. 11, 284.
  32. Chen, S. J., Chen, C. C., Liao, H. Y., Lin, Y. T., Wu, Y. W., Liou, J. M., Wu, M. S., Kuo, C. H. and Lin, C. H. (2022) Association of fecal and plasma levels of short-chain fatty acids with gut microbiota and clinical severity in patients with Parkinson disease. Neurology 98, e848-e858. https://doi.org/10.1212/WNL.0000000000013225
  33. Chen, Y.-G. (2018) Research progress in the pathogenesis of Alzheimer's disease. Chin. Med. J. 131, 1618-1624. https://doi.org/10.4103/0366-6999.235112
  34. Chen, Y., Stankovic, R., Cullen, K. M., Meininger, V., Garner, B., Coggan, S., Grant, R., Brew, B. J. and Guillemin, G. J. (2010) The kynurenine pathway and inflammation in amyotrophic lateral sclerosis. Neurotox. Res. 18, 132-142. https://doi.org/10.1007/s12640-009-9129-7
  35. Chess, A. C., Simoni, M. K., Alling, T. E. and Bucci, D. J. (2007) Elevations of endogenous kynurenic acid produce spatial working memory deficits. Schizophr. Bull. 33, 797-804. https://doi.org/10.1093/schbul/sbl033
  36. Chiang, J. Y. (2013) Bile acid metabolism and signaling. Compr. Physiol. 3, 1191-1212. https://doi.org/10.1002/cphy.c120023
  37. Choi, Y., Huh, E., Lee, S., Kim, J. H., Park, M. G., Seo, S. Y., Kim, S. Y. and Oh, M. S. (2023) 5-Hydroxytryptophan reduces levodopainduced dyskinesia via regulating AKT/mTOR/S6K and CREB/DeltaFosB signals in a mouse model of Parkinson's disease. Biomol. Ther. (Seoul) 31, 402-410. https://doi.org/10.4062/biomolther.2022.141
  38. Clairembault, T., Leclair-Visonneau, L., Neunlist, M. and Derkinderen, P. (2015) Enteric glial cells: new players in Parkinson's disease? Mov. Disord. 30, 494-498. https://doi.org/10.1002/mds.25979
  39. Clarke, G., Grenham, S., Scully, P., Fitzgerald, P., Moloney, R. D., Shanahan, F., Dinan, T. G. and Cryan, J. F. (2013) The microbiome-gutbrain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 18, 666-673. https://doi.org/10.1038/mp.2012.77
  40. Clausen, M. R. and Mortensen, P. B. (1994) Kinetic studies on the metabolism of short-chain fatty acids and glucose by isolated rat colonocytes. Gastroenterology 106, 423-432. https://doi.org/10.1016/0016-5085(94)90601-7
  41. Colombo, A. V., Sadler, R. K., Llovera, G., Singh, V., Roth, S., Heindl, S., Sebastian Monasor, L., Verhoeven, A., Peters, F., Parhizkar, S., Kamp, F., Gomez de Aguero, M., MacPherson, A. J., Winkler, E., Herms, J., Benakis, C., Dichgans, M., Steiner, H., Giera, M., Haass, C., Tahirovic, S. and Liesz, A. (2021) Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition. eLife 10, e59826.
  42. Connick, J. H. and Stone, T. W. (1986) The effect of kainic, quinolinic and beta-kainic acids on the release of endogenous amino acids from rat brain slices. Biochem. Pharmacol. 35, 3631-3635. https://doi.org/10.1016/0006-2952(86)90636-2
  43. Cook, S. I. and Sellin, J. H. (1998) Review article: short chain fatty acids in health and disease. Aliment. Pharmacol. Ther. 12, 499-507. https://doi.org/10.1046/j.1365-2036.1998.00337.x
  44. Covasa, M. and Ritter, R. C. (2005) Reduced CCK-induced Fos expression in the hindbrain, nodose ganglia, and enteric neurons of rats lacking CCK-1 receptors. Brain Res. 1051, 155-163. https://doi.org/10.1016/j.brainres.2005.06.003
  45. Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., Guzzetta, K. E., Jaggar, M., Long-Smith, C. M., Lyte, J. M., Martin, J. A., Molinero-Perez, A., Moloney, G., Morelli, E., Morillas, E., O'Connor, R., Cruz-Pereira, J. S., Peterson, V. L., Rea, K., Ritz, N. L., Sherwin, E., Spichak, S., Teichman, E. M., van de Wouw, M., Ventura-Silva, A. P., Wallace-Fitzsimons, S. E., Hyland, N., Clarke, G. and Dinan, T. G. (2019) The microbiota-gut-brain axis. Physiol. Rev. 99, 1877-2013. https://doi.org/10.1152/physrev.00018.2018
  46. Cummings, J. H. and Macfarlane, G. T. (1991) The control and consequences of bacterial fermentation in the human colon. J. Appl. Bacteriol. 70, 443-459. https://doi.org/10.1111/j.1365-2672.1991.tb02739.x
  47. Cummings, J. H., Pomare, E. W., Branch, W. J., Naylor, C. P. and Macfarlane, G. T. (1987) Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28, 1221.
  48. de Ruijter, A. J., van Gennip, A. H., Caron, H. N., Kemp, S. and van Kuilenburg, A. B. (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J. 370, 737-749. https://doi.org/10.1042/bj20021321
  49. De Silva, A. and Bloom, S. R. (2012) Gut hormones and appetite control: a focus on PYY and GLP-1 as therapeutic targets in obesity. Gut Liver 6, 10-20. https://doi.org/10.5009/gnl.2012.6.1.10
  50. De Vadder, F., Kovatcheva-Datchary, P., Goncalves, D., Vinera, J., Zitoun, C., Duchampt, A., Backhed, F. and Mithieux, G. (2014) Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84-96. https://doi.org/10.1016/j.cell.2013.12.016
  51. Dempsey, J. L., Little, M. and Cui, J. Y. (2019) Gut microbiome: an intermediary to neurotoxicity. Neurotoxicology 75, 41-69. https://doi.org/10.1016/j.neuro.2019.08.005
  52. Ding, R. X., Goh, W. R., Wu, R. N., Yue, X. Q., Luo, X., Khine, W. W. T., Wu, J. R. and Lee, Y. K. (2019) Revisit gut microbiota and its impact on human health and disease. J. Food Drug Anal. 27, 623-631. https://doi.org/10.1016/j.jfda.2018.12.012
  53. Dionisio, P. A., Amaral, J. D., Ribeiro, M. F., Lo, A. C., D'Hooge, R. and Rodrigues, C. M. (2015) Amyloid-beta pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset. Neurobiol. Aging 36, 228-240. https://doi.org/10.1016/j.neurobiolaging.2014.08.034
  54. Dodge, J. C., Yu, J., Sardi, S. P. and Shihabuddin, L. S. (2021) Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis. Sci. Rep. 11, 803.
  55. Donohoe, D. R., Collins, L. B., Wali, A., Bigler, R., Sun, W. and Bultman, S. J. (2012) The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol. Cell 48, 612-626. https://doi.org/10.1016/j.molcel.2012.08.033
  56. Duan, W.-X., Wang, F., Liu, J.-Y. and Liu, C.-F. (2023) Relationship between Short-chain fatty acids and Parkinson's disease: a review from pathology to clinic. Neurosci. Bull. 40, 500-516.
  57. Duncan, S. H., Barcenilla, A., Stewart, C. S., Pryde, S. E. and Flint, H. J. (2002) Acetate utilization and butyryl coenzyme A (CoA): acetate-CoA transferase in butyrate-producing bacteria from the human large intestine. Appl. Environ. Microbiol. 68, 5186-5190. https://doi.org/10.1128/AEM.68.10.5186-5190.2002
  58. Durk, M. R., Han, K., Chow, E. C., Ahrens, R., Henderson, J. T., Fraser, P. E. and Pang, K. S. (2014) 1alpha,25-Dihydroxyvitamin D3 reduces cerebral amyloid-beta accumulation and improves cognition in mouse models of Alzheimer's disease. J. Neurosci. 34, 7091-7101. https://doi.org/10.1523/JNEUROSCI.2711-13.2014
  59. Edwards, B. S., Bologa, C., Young, S. M., Balakin, K. V., Prossnitz, E. R., Savchuck, N. P., Sklar, L. A. and Oprea, T. I. (2005) Integration of virtual screening with high-throughput flow cytometry to identify novel small molecule formylpeptide receptor antagonists. Mol. Pharmacol. 68, 1301-1310. https://doi.org/10.1124/mol.105.014068
  60. Eicher, T. P. and Mohajeri, M. H. (2022) Overlapping mechanisms of action of brain-active bacteria and bacterial metabolites in the pathogenesis of common brain diseases. Nutrients 14, 2661.
  61. El Hage, R., Hernandez-Sanabria, E., Calatayud Arroyo, M., Props, R. and Van de Wiele, T. (2019) Propionate-producing consortium restores antibiotic-induced dysbiosis in a dynamic in vitro model of the human intestinal microbial ecosystem. Front. Microbiol. 10, 1206.
  62. Erber, A. C., Cetin, H., Berry, D. and Schernhammer, E. S. (2020) The role of gut microbiota, butyrate and proton pump inhibitors in amyotrophic lateral sclerosis: a systematic review. Int. J. Neurosci. 130, 727-735. https://doi.org/10.1080/00207454.2019.1702549
  63. Erny, D., Hrabe de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., Schwierzeck, V., Utermohlen, O., Chun, E., Garrett, W. S., McCoy, K. D., Diefenbach, A., Staeheli, P., Stecher, B., Amit, I. and Prinz, M. (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965-977. https://doi.org/10.1038/nn.4030
  64. Fan, Y. and Pedersen, O. (2021) Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol. 19, 55-71. https://doi.org/10.1038/s41579-020-0433-9
  65. Fang, X., Wang, X., Yang, S., Meng, F., Wang, X., Wei, H. and Chen, T. (2016) Evaluation of the microbial diversity in amyotrophic lateral sclerosis using high-throughput sequencing. Front. Microbiol. 7, 1479.
  66. Fanning, A. S., Mitic, L. L. and Anderson, J. M. (1999) Transmembrane proteins in the tight junction barrier. J. Am. Soc. Nephrol. 10, 1337-1345. https://doi.org/10.1681/ASN.V1061337
  67. Ferrari, C., Macchiarulo, A., Costantino, G. and Pellicciari, R. (2006) Pharmacophore model for bile acids recognition by the FPR receptor. J. Comput. Aided Mol. Des. 20, 295-303. https://doi.org/10.1007/s10822-006-9055-1
  68. Ferrell, J. M. and Chiang, J. Y. L. (2021) Bile acid receptors and signaling crosstalk in the liver, gut and brain. Liver Res. 5, 105-118.  https://doi.org/10.1016/j.livres.2021.07.002
  69. Fock, E. and Parnova, R. (2023) Mechanisms of blood-brain barrier protection by microbiota-derived short-chain fatty acids. Cells 12, 657.
  70. Forsyth, C. B., Shannon, K. M., Kordower, J. H., Voigt, R. M., Shaikh, M., Jaglin, J. A., Estes, J. D., Dodiya, H. B. and 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, e28032.
  71. Foster, J. A., Rinaman, L. and Cryan, J. F. (2017) Stress & the gut-brain axis: regulation by the microbiome. Neurobiol. Stress 7, 124-136. https://doi.org/10.1016/j.ynstr.2017.03.001
  72. Freeland, K. R., Wilson, C. and Wolever, T. M. (2010) Adaptation of colonic fermentation and glucagon-like peptide-1 secretion with increased wheat fibre intake for 1 year in hyperinsulinaemic human subjects. Br. J. Nutr. 103, 82-90. https://doi.org/10.1017/S0007114509991462
  73. 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 Thomas, E. and Bell, J. D. (2014) The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 5, 3611.
  74. Fu, X., Liu, Z., Zhu, C., Mou, H. and Kong, Q. (2019) Nondigestible carbohydrates, butyrate, and butyrate-producing bacteria. Crit. Rev. Food Sci. Nutr. 59, S130-S152. https://doi.org/10.1080/10408398.2018.1542587
  75. Fulling, C., Dinan, T. G. and Cryan, J. F. (2019) Gut microbe to brain signaling: what happens in vagus. Neuron 101, 998-1002. https://doi.org/10.1016/j.neuron.2019.02.008
  76. Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., Nakanishi, Y., Uetake, C., Kato, K., Kato, T., Takahashi, M., Fukuda, N. N., Murakami, S., Miyauchi, E., Hino, S., Atarashi, K., Onawa, S., Fujimura, Y., Lockett, T., Clarke, J. M., Topping, D. L., Tomita, M., Hori, S., Ohara, O., Morita, T., Koseki, H., Kikuchi, J., Honda, K., Hase, K. and Ohno, H. (2013) Commensal microbederived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446-450. https://doi.org/10.1038/nature12721
  77. Ganapathy, V., Thangaraju, M., Prasad, P. D., Martin, P. M. and Singh, N. (2013) Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host. Curr. Opin. Pharmacol. 13, 869-874. https://doi.org/10.1016/j.coph.2013.08.006
  78. Gao, C., Li, B., He, Y., Huang, P., Du, J., He, G., Zhang, P., Tang, H. and Chen, S. (2023) Early changes of fecal short-chain fatty acid levels in patients with mild cognitive impairments. CNS Neurosci. Ther. 29, 3657-3666. https://doi.org/10.1111/cns.14252
  79. Garrison, A. M., Parrott, J. M., Tunon, A., Delgado, J., Redus, L. and O'Connor, J. C. (2018) Kynurenine pathway metabolic balance influences microglia activity: targeting kynurenine monooxygenase to dampen neuroinflammation. Psychoneuroendocrinology 94, 1-10. https://doi.org/10.1016/j.psyneuen.2018.04.019
  80. Gerhart, D. Z., Enerson, B. E., Zhdankina, O. Y., Leino, R. L. and Drewes, L. R. (1997) Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am. J. Physiol. 273, E207-E213. https://doi.org/10.1152/ajpendo.1997.273.1.E207
  81. Gershon, M. D. and Margolis, K. G. (2021) The gut, its microbiome, and the brain: connections and communications. J. Clin. Invest. 131, e143768.
  82. Ghit, A., Assal, D., Al-Shami, A. S. and Hussein, D. E. E. (2021) GABA(A) receptors: structure, function, pharmacology, and related disorders. J. Genet. Eng. Biotechnol. 19, 123.
  83. Gong, C. X. and Iqbal, K. (2008) Hyperphosphorylation of microtubuleassociated protein tau: a promising therapeutic target for Alzheimer disease. Curr. Med. Chem. 15, 2321-2328. https://doi.org/10.2174/092986708785909111
  84. Graff, J. and Tsai, L.-H. (2013) Histone acetylation: molecular mnemonics on the chromatin. Nat. Rev. Neurosci. 14, 97-111. https://doi.org/10.1038/nrn3427
  85. Graham, S. F., Rey, N. L., Ugur, Z., Yilmaz, A., Sherman, E., Maddens, M., Bahado-Singh, R. O., Becker, K., Schulz, E., Meyerdirk, L. K., Steiner, J. A., Ma, J. and Brundin, P. (2018) Metabolomic profiling of bile acids in an experimental model of prodromal Parkinson's disease. Metabolites 8, 71.
  86. Grant, S. M. and DeMorrow, S. (2020) Bile acid signaling in neurodegenerative and neurological disorders. Int. J. Mol. Sci. 21, 5982.
  87. Gurling, H. M., Kalsi, G., Brynjolfson, J., Sigmundsson, T., Sherrington, R., Mankoo, B. S., Read, T., Murphy, P., Blaveri, E., McQuillin, A., Petursson, H. and Curtis, D. (2001) Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23. Am. J. Hum. Genet. 68, 661-673. https://doi.org/10.1086/318788
  88. Hamel, D., Sanchez, M., Duhamel, F., Roy, O., Honore, J.-C., Noueihed, B., Zhou, T., Nadeau-Vallee, M., Hou, X., Lavoie, J.-C., Mitchell, G., Mamer, O. A. and Chemtob, S. (2014) G-protein-coupled receptor 91 and succinate are key contributors in neonatal postcerebral hypoxia-ischemia recovery. Arterioscler. Thromb. Vasc. Biol. 34, 285-293. https://doi.org/10.1161/ATVBAHA.113.302131
  89. Hamer, H. M., Jonkers, D., Venema, K., Vanhoutvin, S., Troost, F. J. and Brummer, R. J. (2008) Review article: the role of butyrate on colonic function. Aliment. Pharmacol. Ther. 27, 104-119. https://doi.org/10.1111/j.1365-2036.2007.03562.x
  90. Han, G. H., Kim, S. J., Ko, W. K., Lee, D., Lee, J. S., Nah, H., Han, I. B. and Sohn, S. (2020) Injectable hydrogel containing tauroursodeoxycholic acid for anti-neuroinflammatory therapy after spinal cord injury in rats. Mol. Neurobiol. 57, 4007-4017. https://doi.org/10.1007/s12035-020-02010-4
  91. Haussler, M. R., Whitfield, G. K., Kaneko, I., Haussler, C. A., Hsieh, D., Hsieh, J. C. and Jurutka, P. W. (2013) Molecular mechanisms of vitamin D action. Calcif. Tissue Int. 92, 77-98. https://doi.org/10.1007/s00223-012-9619-0
  92. Heston, M. B., Hanslik, K. L., Zarbock, K. R., Harding, S. J., Davenport-Sis, N. J., Kerby, R. L., Chin, N., Sun, Y., Hoeft, A., Deming, Y., Vogt, N. M., Betthauser, T. J., Johnson, S. C., Asthana, S., Kollmorgen, G., Suridjan, I., Wild, N., Zetterberg, H., Blennow, K., Rey, F. E., Bendlin, B. B. and Ulland, T. K. (2023) Gut inflammation associated with age and Alzheimer's disease pathology: a human cohort study. Sci. Rep. 13, 18924.
  93. Hoglund, E., Overli, O. and Winberg, S. (2019) Tryptophan metabolic pathways and brain serotonergic activity: a comparative review. Front. Endocrinol. 10, 158.
  94. Honarpisheh, P., Reynolds, C. R., Blasco Conesa, M. P., Moruno Manchon, J. F., Putluri, N., Bhattacharjee, M. B., Urayama, A., McCullough, L. D. and Ganesh, B. P. (2020) Dysregulated gut homeostasis observed prior to the accumulation of the brain amyloid-β in Tg2576 mice. Int. J. Mol. Sci. 21, 1711.
  95. Howell, E. H. and Cameron, S. J. (2016) Neprilysin inhibition: a brief review of past pharmacological strategies for heart failure treatment and future directions. Cardiol. J. 23, 591-598. https://doi.org/10.5603/CJ.a2016.0063
  96. Hoyles, L., Snelling, T., Umlai, U.-K., Nicholson, J. K., Carding, S. R., Glen, R. C. and McArthur, S. (2018) Microbiome-host systems interactions: protective effects of propionate upon the blood-brain barrier. Microbiome 6, 55.
  97. Hu, J., Kyrou, I., Tan, B. K., Dimitriadis, G. K., Ramanjaneya, M., Tripathi, G., Patel, V., James, S., Kawan, M., Chen, J. and Randeva, H. S. (2016) Short-chain fatty acid acetate stimulates adipogenesis and mitochondrial biogenesis via GPR43 in brown adipocytes. Endocrinology 157, 1881-1894. https://doi.org/10.1210/en.2015-1944
  98. Huang, C., Wang, J., Hu, W., Wang, C., Lu, X., Tong, L., Wu, F. and Zhang, W. (2016) Identification of functional farnesoid X receptors in brain neurons. FEBS Lett. 590, 3233-3242. https://doi.org/10.1002/1873-3468.12373
  99. Huang, F., Wang, T., Lan, Y., Yang, L., Pan, W., Zhu, Y., Lv, B., Wei, Y., Shi, H., Wu, H., Zhang, B., Wang, J., Duan, X., Hu, Z. and Wu, X. (2015) Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior. Front. Behav. Neurosci. 9, 70.
  100. Hurley, M. J., Bates, R., Macnaughtan, J. and Schapira, A. H. V. (2022) Bile acids and neurological disease. Pharmacol. Ther. 240, 108311.
  101. Ibrahim, W. W., Sayed, R. H., Kandil, E. A. and Wadie, W. (2022) Niacin mitigates blood-brain barrier tight junctional proteins dysregulation and cerebral inflammation in ketamine rat model of psychosis: role of GPR109A receptor. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 119, 110583.
  102. Inan, M. S., Rasoulpour, R. J., Yin, L., Hubbard, A. K., Rosenberg, D. W. and Giardina, C. (2000) The luminal short-chain fatty acid butyrate modulates NF-kappaB activity in a human colonic epithelial cell line. Gastroenterology 118, 724-734. https://doi.org/10.1016/S0016-5085(00)70142-9
  103. Jaglin, M., Rhimi, M., Philippe, C., Pons, N., Bruneau, A., Goustard, B., Dauge, V., Maguin, E., Naudon, L. and Rabot, S. (2018) Indole, a signaling molecule produced by the gut microbiota, negatively impacts emotional behaviors in rats. Front. Neurosci. 12, 216.
  104. Jain, S., Rathod, V., Prajapati, R., Nandekar, P. P. and Sangamwar, A. T. (2014) Pregnane X receptor and P-glycoprotein: a connexion for Alzheimer's disease management. Mol. Divers. 18, 895-909. https://doi.org/10.1007/s11030-014-9550-6
  105. Jaronen, M. and Quintana, F. J. (2014) Immunological relevance of the coevolution of IDO1 and AHR. Front. Immunol. 5, 521.
  106. Jiang, L., Zhang, H., Xiao, D., Wei, H. and Chen, Y. (2021a) Farnesoid X receptor (FXR): structures and ligands. Comput. Struct. Biotechnol. J. 19, 2148-2159. https://doi.org/10.1016/j.csbj.2021.04.029
  107. Jiang, Y., Li, K., Li, X., Xu, L. and Yang, Z. (2021b) Sodium butyrate ameliorates the impairment of synaptic plasticity by inhibiting the neuroinflammation in 5XFAD mice. Chem. Biol. Interact. 341, 109452.
  108. Juricek, L., Carcaud, J., Pelhaitre, A., Riday, T. T., Chevallier, A., Lanzini, J., Auzeil, N., Laprevote, O., Dumont, F., Jacques, S., Letourneur, F., Massaad, C., Agulhon, C., Barouki, R., Beraneck, M. and Coumoul, X. (2017) AhR-deficiency as a cause of demyelinating disease and inflammation. Sci Rep 7, 9794.
  109. Kaluzna-Czaplinska, J., Gatarek, P., Chirumbolo, S., Chartrand, M. S. and Bjorklund, G. (2019) How important is tryptophan in human health? Crit. Rev. Food Sci. Nutr. 59, 72-88. https://doi.org/10.1080/10408398.2017.1357534
  110. Keshavarzian, A., Green, S. J., Engen, P. A., Voigt, R. M., Naqib, A., Forsyth, C. B., Mutlu, E. and Shannon, K. M. (2015) Colonic bacterial composition in Parkinson's disease. Mov. Disord. 30, 1351-1360. https://doi.org/10.1002/mds.26307
  111. Kim, G.-H. and Shim, J.-O. (2023) Gut microbiota affects brain development and behavior. Clin. Exp. Pediatr. 66, 274-280. https://doi.org/10.3345/cep.2021.01550
  112. Kim, M. H., Kang, S. G., Park, J. H., Yanagisawa, M. and Kim, C. H. (2013) Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145, 396-406.e1-e10. https://doi.org/10.1053/j.gastro.2013.04.056
  113. Kimura, I., Inoue, D., Maeda, T., Hara, T., Ichimura, A., Miyauchi, S., Kobayashi, M., Hirasawa, A. and Tsujimoto, G. (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. U. S. A. 108, 8030-8035. https://doi.org/10.1073/pnas.1016088108
  114. Kimura, A., Naka, T., Nakahama, T., Chinen, I., Masuda, K., Nohara, K., Fujii-Kuriyama, Y. and Kishimoto, T. (2009) Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J Exp Med 206, 2027-2035. https://doi.org/10.1084/jem.20090560
  115. Kipnis, J. (2016) Multifaceted interactions between adaptive immunity and the central nervous system. Science 353, 766-771. https://doi.org/10.1126/science.aag2638
  116. Klampfer, L., Huang, J., Sasazuki, T., Shirasawa, S. and Augenlicht, L. (2003) Inhibition of interferon gamma signaling by the short chain fatty acid butyrate. Mol. Cancer Res. 1, 855-862.
  117. Kobayashi, Y., Sugahara, H., Shimada, K., Mitsuyama, E., Kuhara, T., Yasuoka, A., Kondo, T., Abe, K. and Xiao, J. Z. (2017) Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer's disease. Sci. Rep. 7, 13510.
  118. Konradsson-Geuken, A., Wu, H. Q., Gash, C. R., Alexander, K. S., Campbell, A., Sozeri, Y., Pellicciari, R., Schwarcz, R. and Bruno, J. P. (2010) Cortical kynurenic acid bi-directionally modulates prefrontal glutamate levels as assessed by microdialysis and rapid electrochemistry. Neuroscience 169, 1848-1859. https://doi.org/10.1016/j.neuroscience.2010.05.052
  119. Kubicova, L., Hadacek, F., Bachmann, G., Weckwerth, W. and Chobot, V. (2019) Coordination complex formation and redox properties of kynurenic and xanthurenic acid can affect brain tissue homeodynamics. Antioxidants (Basel) 8, 476.
  120. Kuhn, T., Stepien, M., Lopez-Nogueroles, M., Damms-Machado, A., Sookthai, D., Johnson, T., Roca, M., Husing, A., Maldonado, S. G., Cross, A. J., Murphy, N., Freisling, H., Rinaldi, S., Scalbert, A., Fedirko, V., Severi, G., Boutron-Ruault, M. C., Mancini, F. R., Sowah, S. A., Boeing, H., Jakszyn, P., Sanchez, M. J., Merino, S., Colorado-Yohar, S., Barricarte, A., Khaw, K. T., Schmidt, J. A., Perez-Cornago, A., Trichopoulou, A., Karakatsani, A., Thriskos, P., Palli, D., Agnoli, C., Tumino, R., Sacerdote, C., Panico, S., Buenode-Mesquita, B., van Gils, C. H., Heath, A. K., Gunter, M. J., Riboli, E., Lahoz, A., Jenab, M. and Kaaks, R. (2020) Prediagnostic plasma bile acid levels and colon cancer risk: a prospective study. J. Natl. Cancer Inst. 112, 516-524. https://doi.org/10.1093/jnci/djz166
  121. Kuo, M.-H. and Allis, C. D. (1998) Roles of histone acetyltransferases and deacetylases in gene regulation. BioEssays 20, 615-626. https://doi.org/10.1002/(SICI)1521-1878(199808)20:8<615::AID-BIES4>3.0.CO;2-H
  122. Laffin, M., Fedorak, R., Zalasky, A., Park, H., Gill, A., Agrawal, A., Keshteli, A., Hotte, N. and Madsen, K. L. (2019) A high-sugar diet rapidly enhances susceptibility to colitis via depletion of luminal shortchain fatty acids in mice. Sci. Rep. 9, 12294.
  123. Lay, C., Sutren, M., Rochet, V., Saunier, K., Dore, J. and RigottierGois, L. (2005) Design and validation of 16S rRNA probes to enumerate members of the Clostridium leptum subgroup in human faecal microbiota. Environ. Microbiol. 7, 933-946. https://doi.org/10.1111/j.1462-2920.2005.00763.x
  124. Le Poul, E., Loison, C., Struyf, S., Springael, J. Y., Lannoy, V., Decobecq, M. E., Brezillon, S., Dupriez, V., Vassart, G., Van Damme, J., Parmentier, M. and Detheux, M. (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J. Biol. Chem. 278, 25481-25489. https://doi.org/10.1074/jbc.M301403200
  125. Lee, H., Lee, Y., Kim, J., An, J., Lee, S., Kong, H., Song, Y., Lee, C. K. and Kim, K. (2018) Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. Gut Microbes 9, 155-165. https://doi.org/10.1080/19490976.2017.1405209
  126. Lee, Y. H., Lin, C. H., Hsu, P. C., Sun, Y. Y., Huang, Y. J., Zhuo, J. H., Wang, C. Y., Gan, Y. L., Hung, C. C., Kuan, C. Y. and Shie, F. S. (2015) Aryl hydrocarbon receptor mediates both proinflammatory and anti-inflammatory effects in lipopolysaccharide-activated microglia. Glia 63, 1138-1154. https://doi.org/10.1002/glia.22805
  127. Leino, R. L., Gerhart, D. Z. and Drewes, L. R. (1999) Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study. Dev. Brain Res. 113, 47-54.
  128. Li, C., Liang, Y. and Qiao, Y. (2022) Messengers from the gut: gut microbiota-derived metabolites on host regulation. Front. Microbiol. 13, 863407.
  129. Li, F. and Tsien, J. Z. (2009) Memory and the NMDA receptors. N. Engl. J. Med. 361, 302-303. https://doi.org/10.1056/NEJMcibr0902052
  130. Li, H., Gao, Z., Zhang, J., Ye, X., Xu, A., Ye, J. and Jia, W. (2012) Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3. Diabetes 61, 797-806. https://doi.org/10.2337/db11-0846
  131. Li, H., Sun, J., Du, J., Wang, F., Fang, R., Yu, C., Xiong, J., Chen, W., Lu, Z. and Liu, J. (2018) Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injury via the gut-brain axis. Neurogastroenterol. Motil. 30, e13260.
  132. Li, P., Killinger, B. A., Ensink, E., Beddows, I., Yilmaz, A., Lubben, N., Lamp, J., Schilthuis, M., Vega, I. E., Woltjer, R., Pospisilik, J. A., Brundin, P., Brundin, L., Graham, S. F. and Labrie, V. (2021) Gut microbiota dysbiosis is associated with elevated bile acids in Parkinson's disease. Metabolites 11, 29.
  133. Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Munch, A. E., Chung, W. S., Peterson, T. C., Wilton, D. K., Frouin, A., Napier, B. A., Panicker, N., Kumar, M., Buckwalter, M. S., Rowitch, D. H., Dawson, V. L., Dawson, T. M., Stevens, B. and Barres, B. A. (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481-487. https://doi.org/10.1038/nature21029
  134. Liu, J., Sun, J., Wang, F., Yu, X., Ling, Z., Li, H., Zhang, H., Jin, J., Chen, W. and Pang, M. (2015) Neuroprotective effects of Clostridium butyricum against vascular dementia in mice via metabolic butyrate. BioMed Res. Int. 2015, 412946.
  135. Liu, J., Wang, F., Liu, S., Du, J., Hu, X., Xiong, J., Fang, R., Chen, W. and Sun, J. (2017) Sodium butyrate exerts protective effect against Parkinson's disease in mice via stimulation of glucagon like peptide-1. J. Neurol. Sci. 381, 176-181.
  136. Liu, X.-F., Shao, J.-H., Liao, Y.-T., Wang, L.-N., Jia, Y., Dong, P.-J., Liu, Z.-Z., He, D.-D., Li, C. and Zhang, X. (2023) Regulation of short-chain fatty acids in the immune system. Front. Immunol. 14, 1186892.
  137. Lonsdale, J., Thomas, J., Salvatore, M., Phillips, R., Lo, E., Shad, S., Hasz, R., Walters, G., Garcia, F., Young, N., Foster, B., Moser, M., Karasik, E., Gillard, B., Ramsey, K., Sullivan, S., Bridge, J., Magazine, H., Syron, J., Fleming, J., Siminoff, L., Traino, H., Mosavel, M., Barker, L., Jewell, S., Rohrer, D., Maxim, D., Filkins, D., Harbach, P., Cortadillo, E., Berghuis, B., Turner, L., Hudson, E., Feenstra, K., Sobin, L., Robb, J., Branton, P., Korzeniewski, G., Shive, C., Tabor, D., Qi, L., Groch, K., Nampally, S., Buia, S., Zimmerman, A., Smith, A., Burges, R., Robinson, K., Valentino, K., Bradbury, D., Cosentino, M., Diaz-Mayoral, N., Kennedy, M., Engel, T., Williams, P., Erickson, K., Ardlie, K., Winckler, W., Getz, G., DeLuca, D., MacArthur, D., Kellis, M., Thomson, A., Young, T., Gelfand, E., Donovan, M., Meng, Y., Grant, G., Mash, D., Marcus, Y., Basile, M., Liu, J., Zhu, J., Tu, Z., Cox, N. J., Nicolae, D. L., Gamazon, E. R., Im, H. K., Konkashbaev, A., Pritchard, J., Stevens, M., Flutre, T., Wen, X., Dermitzakis, E. T., Lappalainen, T., Guigo, R., Monlong, J., Sammeth, M., Koller, D., Battle, A., Mostafavi, S., McCarthy, M., Rivas, M., Maller, J., Rusyn, I., Nobel, A., Wright, F., Shabalin, A., Feolo, M., Sharopova, N., Sturcke, A., Paschal, J., Anderson, J. M., Wilder, E. L., Derr, L. K., Green, E. D., Struewing, J. P., Temple, G., Volpi, S., Boyer, J. T., Thomson, E. J., Guyer, M. S., Ng, C., Abdallah, A., Colantuoni, D., Insel, T. R., Koester, S. E., Little, A. R., Bender, P. K., Lehner, T., Yao, Y., Compton, C. C., Vaught, J. B., Sawyer, S., Lockhart, N. C., Demchok, J. and Moore, H. F. (2013) The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580-585. https://doi.org/10.1038/ng.2653
  138. Lugo-Huitron, R., Ugalde Muniz, P., Pineda, B., Pedraza-Chaverri, J., Rios, C. and Perez-de la Cruz, V. (2013) Quinolinic acid: an endogenous neurotoxin with multiple targets. Oxid. Med. Cell. Longev. 2013, 104024.
  139. Ma, N., He, T., Johnston, L. J. and Ma, X. (2020) Host-microbiome interactions: the aryl hydrocarbon receptor as a critical node in tryptophan metabolites to brain signaling. Gut Microbes 11, 1203-1219. https://doi.org/10.1080/19490976.2020.1758008
  140. Ma, X., Fan, P. X., Li, L. S., Qiao, S. Y., Zhang, G. L. and Li, D. F. (2012) Butyrate promotes the recovering of intestinal wound healing through its positive effect on the tight junctions. J. Anim. Sci. 90 Suppl 4, 266-268. https://doi.org/10.2527/jas.50965
  141. Madhogaria, B., Bhowmik, P. and Kundu, A. (2022) Correlation between human gut microbiome and diseases. Infect. Med. (Beijing) 1, 180-191. https://doi.org/10.1016/j.imj.2022.08.004
  142. MahmoudianDehkordi, S., Arnold, M., Nho, K., Ahmad, S., Jia, W., Xie, G., Louie, G., Kueider-Paisley, A., Moseley, M. A., Thompson, J. W., St John Williams, L., Tenenbaum, J. D., Blach, C., Baillie, R., Han, X., Bhattacharyya, S., Toledo, J. B., Schafferer, S., Klein, S., Koal, T., Risacher, S. L., Kling, M. A., Motsinger-Reif, A., Rotroff, D. M., Jack, J., Hankemeier, T., Bennett, D. A., De Jager, P. L., Trojanowski, J. Q., Shaw, L. M., Weiner, M. W., Doraiswamy, P. M., van Duijn, C. M., Saykin, A. J., Kastenmuller, G. and Kaddurah-Daouk, R.; Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium (2019) Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-an emerging role for gut microbiome. Alzheimers Dement. 15, 76-92. https://doi.org/10.1016/j.jalz.2018.07.217
  143. Makishima, M., Lu, T. T., Xie, W., Whitfield, G. K., Domoto, H., Evans, R. M., Haussler, M. R. and Mangelsdorf, D. J. (2002) Vitamin D receptor as an intestinal bile acid sensor. Science 296, 1313-1316. https://doi.org/10.1126/science.1070477
  144. Marsland, B. J. (2016) Regulating inflammation with microbial metabolites. Nat. Med. 22, 581-583. https://doi.org/10.1038/nm.4117
  145. Marti-Masso, J. F., Bergareche, A., Makarov, V., Ruiz-Martinez, J., Gorostidi, A., Lopez de Munain, A., Poza, J. J., Striano, P., Buxbaum, J. D. and Paisan-Ruiz, C. (2013) The ACMSD gene, involved in tryptophan metabolism, is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism. J. Mol. Med. (Berl.) 91, 1399-1406. https://doi.org/10.1007/s00109-013-1075-4
  146. Maruta, H. and Yamashita, H. (2020) Acetic acid stimulates G-proteincoupled receptor GPR43 and induces intracellular calcium influx in L6 myotube cells. PLoS One 15, e0239428.
  147. Mayer, E. A. (2011) Gut feelings: the emerging biology of gut-brain communication. Nat. Rev. Neurosci. 12, 453-466. https://doi.org/10.1038/nrn3071
  148. Mayo-Martinez, L., Paz Lorenzo, M., Martos-Moreno, G. A., Graell, M., Barbas, C., Ruperez, F. J., Argente, J. and Garcia, A. (2024) Short-chain fatty acids in plasma and feces: an optimized and validated LC-QqQ-MS method applied to study anorexia nervosa. Microchem. J. 200, 110255.
  149. McMillin, M., Frampton, G., Grant, S., Khan, S., Diocares, J., Petrescu, A., Wyatt, A., Kain, J., Jefferson, B. and DeMorrow, S. (2017) Bile acid-mediated sphingosine-1-phosphate receptor 2 signaling promotes neuroinflammation during hepatic encephalopathy in mice. Front. Cell. Neurosci. 11, 191.
  150. McMillin, M., Frampton, G., Quinn, M., Ashfaq, S., de los Santos, M., 3rd, Grant, S. and DeMorrow, S. (2016) Bile acid signaling is involved in the neurological decline in a murine model of acute liver failure. Am. J. Pathol. 186, 312-323. https://doi.org/10.1016/j.ajpath.2015.10.005
  151. Meek, A. R., Simms, G. A. and Weaver, D. F. (2013) Searching for an endogenous anti-Alzheimer molecule: identifying small molecules in the brain that slow Alzheimer disease progression by inhibition of ss-amyloid aggregation. J. Psychiatry Neurosci. 38, 269-275. https://doi.org/10.1503/jpn.120166
  152. Miller, T. L. and Wolin, M. J. (1996) Pathways of acetate, propionate, and butyrate formation by the human fecal microbial flora. Appl. Environ. Microbiol. 62, 1589-1592. https://doi.org/10.1128/aem.62.5.1589-1592.1996
  153. Mittal, R., Debs, L. H., Patel, A. P., Nguyen, D., Patel, K., O'Connor, G., Grati, M., Mittal, J., Yan, D., Eshraghi, A. A., Deo, S. K., Daunert, S. and Liu, X. Z. (2017) Neurotransmitters: the critical modulators regulating gut-brain axis. J. Cell. Physiol. 232, 2359-2372. https://doi.org/10.1002/jcp.25518
  154. Mollica, A., Stefanucci, A., Costante, R. and Pinnen, F. (2012) Role of formyl peptide receptors (FPR) in abnormal inflammation responses involved in neurodegenerative diseases. Antiinflamm. Antiallergy Agents Med. Chem. 11, 20-36. https://doi.org/10.2174/187152312803476246
  155. Mollica, M. P., Mattace Raso, G., Cavaliere, G., Trinchese, G., De Filippo, C., Aceto, S., Prisco, M., Pirozzi, C., Di Guida, F., Lama, A., Crispino, M., Tronino, D., Di Vaio, P., Berni Canani, R., Calignano, A. and Meli, R. (2017) Butyrate regulates liver mitochondrial function, efficiency, and dynamics in insulin-resistant obese mice. Diabetes 66, 1405-1418. https://doi.org/10.2337/db16-0924
  156. Morais, L. H., Schreiber, H. L. and Mazmanian, S. K. (2021) The gut microbiota-brain axis in behaviour and brain disorders. Nat. Rev. Microbiol. 19, 241-255. https://doi.org/10.1038/s41579-020-00460-0
  157. Morland, C., Froland, A.-S., Pettersen, M. N., Storm-Mathisen, J., Gundersen, V., Rise, F. and Hassel, B. (2018) Propionate enters GABAergic neurons, inhibits GABA transaminase, causes GABA accumulation and lethargy in a model of propionic acidemia. Biochem. J. 475, 749-758. https://doi.org/10.1042/BCJ20170814
  158. Motataianu, A., serban, G. and Andone, S. (2023) The role of short-chain fatty acids in microbiota-gut-brain cross-talk with a focus on amyotrophic lateral sclerosis: a systematic review. Int. J. Mol. Sci. 24, 15094.
  159. Nagpal, R., Neth, B. J., Wang, S., Craft, S. and Yadav, H. (2019) Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer's disease markers in subjects with mild cognitive impairment. EBioMedicine 47, 529-542. https://doi.org/10.1016/j.ebiom.2019.08.032
  160. Natividad, J. M., Agus, A., Planchais, J., Lamas, B., Jarry, A. C., Martin, R., Michel, M. L., Chong-Nguyen, C., Roussel, R., Straube, M., Jegou, S., McQuitty, C., Le Gall, M., da Costa, G., Lecornet, E., Michaudel, C., Modoux, M., Glodt, J., Bridonneau, C., Sovran, B., Dupraz, L., Bado, A., Richard, M. L., Langella, P., Hansel, B., Launay, J. M., Xavier, R. J., Duboc, H. and Sokol, H. (2018) Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab. 28, 737-749.e4. https://doi.org/10.1016/j.cmet.2018.07.001
  161. Nguyen, N. M., Duong, M. T. H., Nguyen, P. L., Bui, B. P., Ahn, H. C. and Cho, J. (2022) Efonidipine inhibits JNK and NF-kappaB pathway to attenuate inflammation and cell migration induced by lipopolysaccharide in microglial cells. Biomol. Ther. (Seoul) 30, 455-464. https://doi.org/10.4062/biomolther.2022.076
  162. Nho, K., Kueider-Paisley, A., Mahmoudian-Dehkordi, S., Arnold, M., Risacher, S. L., Louie, G., Blach, C., Baillie, R., Han, X., Kastenmuller, G., Jia, W., Xie, G., Ahmad, S., Hankemeier, T., van Duijn, C. M., Trojanowski, J. Q., Shaw, L. M., Weiner, M. W., Doraiswamy, P. M., Saykin, A. J. and Kaddurah-Daouk, R.; Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium (2019) Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: relationship to neuroimaging and CSF biomarkers. Alzheimers Dement. 15, 232-244. https://doi.org/10.1016/j.jalz.2018.08.012
  163. Nicolas, G. R. and Chang, P. V. (2019) Deciphering the chemical lexicon of host-gut microbiota interactions. Trends Pharmacol. Sci. 40, 430-445. https://doi.org/10.1016/j.tips.2019.04.006
  164. Nilsson, N. E., Kotarsky, K., Owman, C. and Olde, B. (2003) Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem. Biophys. Res. Commun. 303, 1047-1052. https://doi.org/10.1016/S0006-291X(03)00488-1
  165. Nohr, M. K., Egerod, K. L., Christiansen, S. H., Gille, A., Offermanns, S., Schwartz, T. W. and Moller, M. (2015) Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience 290, 126-137. https://doi.org/10.1016/j.neuroscience.2015.01.040
  166. Nunes, A. F., Amaral, J. D., Lo, A. C., Fonseca, M. B., Viana, R. J., Callaerts-Vegh, Z., D'Hooge, R. and Rodrigues, C. M. (2012) TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-beta deposition in APP/PS1 mice. Mol. Neurobiol. 45, 440-454. https://doi.org/10.1007/s12035-012-8256-y
  167. Oldendorf, W. (1973) Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids. Am. J. Physiol. 224, 1450-1453. https://doi.org/10.1152/ajplegacy.1973.224.6.1450
  168. Opeyemi, O. M., Rogers, M. B., Firek, B. A., Janesko-Feldman, K., Vagni, V., Mullett, S. J., Wendell, S. G., Nelson, B. P., New, L. A. and Marino, E. (2021) Sustained dysbiosis and decreased fecal short-chain fatty acids after traumatic brain injury and impact on neurologic outcome. J. Neurotrauma 38, 2610-2621. https://doi.org/10.1089/neu.2020.7506
  169. Osadchiy, V., Labus, J. S., Gupta, A., Jacobs, J., Ashe-McNalley, C., Hsiao, E. Y. and Mayer, E. A. (2018) Correlation of tryptophan metabolites with connectivity of extended central reward network in healthy subjects. PLoS One 13, e0201772.
  170. Ose, A., Kusuhara, H., Endo, C., Tohyama, K., Miyajima, M., Kitamura, S. and Sugiyama, Y. (2010) Functional characterization of mouse organic anion transporting peptide 1a4 in the uptake and efflux of drugs across the blood-brain barrier. Drug Metab. Dispos. 38, 168-176. https://doi.org/10.1124/dmd.109.029454
  171. Pantouris, G., Serys, M., Yuasa, H. J., Ball, H. J. and Mowat, C. G. (2014) Human indoleamine 2,3-dioxygenase-2 has substrate specificity and inhibition characteristics distinct from those of indoleamine 2,3-dioxygenase-1. Amino Acids 46, 2155-2163. https://doi.org/10.1007/s00726-014-1766-3
  172. Pardridge, W. M. (1979) The role of blood-brain barrier transport of tryptophan and other neutral amino acids in the regulation of substrate-limited pathways of brain amino acid metabolism. J. Neural Transm. Suppl. (15), 43-54.
  173. Park, B. O., Kang, J. S., Paudel, S., Park, S. G., Park, B. C., Han, S. B., Kwak, Y. S., Kim, J. H. and Kim, S. (2022) Novel GPR43 agonists exert an anti-inflammatory effect in a colitis model. Biomol. Ther. (Seoul) 30, 48-54. https://doi.org/10.4062/biomolther.2021.078
  174. Park, J. and Kim, C. H. (2021) Regulation of common neurological disorders by gut microbial metabolites. Exp. Mol. Med. 53, 1821-1833. https://doi.org/10.1038/s12276-021-00703-x
  175. Park, M. J. and Sohrabji, F. (2016) The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats. J. Neuroinflammation 13, 300.
  176. Parker, A., Fonseca, S. and Carding, S. R. (2020) Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health. Gut Microbes 11, 135-157. https://doi.org/10.1080/19490976.2019.1638722
  177. Peng, L., Li, Z. R., Green, R. S., Holzman, I. R. and 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
  178. Piccioni, A., Cicchinelli, S., Valletta, F., De Luca, G., Longhitano, Y., Candelli, M., Ojetti, V., Sardeo, F., Navarra, S., Covino, M. and Franceschi, F. (2022) Gut microbiota and autoimmune diseases: a charming real world together with probiotics. Curr. Med. Chem. 29, 3147-3159. https://doi.org/10.2174/0929867328666210922161913
  179. Pierozan, P., Zamoner, A., Soska, A. K., Silvestrin, R. B., Loureiro, S. O., Heimfarth, L., Mello e Souza, T., Wajner, M. and Pessoa-Pureur, R. (2010) Acute intrastriatal administration of quinolinic acid provokes hyperphosphorylation of cytoskeletal intermediate filament proteins in astrocytes and neurons of rats. Exp. Neurol. 224, 188-196. https://doi.org/10.1016/j.expneurol.2010.03.009
  180. Pocivavsek, A., Wu, H. Q., Potter, M. C., Elmer, G. I., Pellicciari, R. and Schwarcz, R. (2011) Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology 36, 2357-2367. https://doi.org/10.1038/npp.2011.127
  181. Potter, M. C., Elmer, G. I., Bergeron, R., Albuquerque, E. X., Guidetti, P., Wu, H. Q. and Schwarcz, R. (2010) Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior. Neuropsychopharmacology 35, 1734-1742. https://doi.org/10.1038/npp.2010.39
  182. Psichas, A., Sleeth, M., Murphy, K., Brooks, L., Bewick, G., Hanyaloglu, A., Ghatei, M., Bloom, S. and Frost, G. (2015) The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. 39, 424-429. https://doi.org/10.1038/ijo.2014.153
  183. Qiao, C. M., Sun, M. F., Jia, X. B., Shi, Y., Zhang, B. P., Zhou, Z. L., Zhao, L. P., Cui, C. and Shen, Y. Q. (2020) Sodium butyrate causes α-synuclein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway. Exp. Cell Res. 387, 111772.
  184. Qiu, Y., Shen, J., Jiang, W., Yang, Y., Liu, X. and Zeng, Y. (2022) Sphingosine 1-phosphate and its regulatory role in vascular endothelial cells. Histol. Histopathol. 37, 213-225.
  185. Ragsdale, S. W. and Pierce, E. (2008) Acetogenesis and the Wood-Ljungdahl pathway of CO(2) fixation. Biochim. Biophys. Acta 1784, 1873-1898. https://doi.org/10.1016/j.bbapap.2008.08.012
  186. Rahman, S., O'Connor, A. L., Becker, S. L., Patel, R. K., Martindale, R. G. and Tsikitis, V. L. (2023) Gut microbial metabolites and its impact on human health. Ann. Gastroenterol. 36, 360-368.
  187. Ramirez-Perez, O., Cruz-Ramon, V., Chinchilla-Lopez, P. and Mendez-Sanchez, N. (2017) The role of the gut microbiota in bile acid metabolism. Ann. Hepatol. 16 Suppl 1, S21-S26. https://doi.org/10.5604/01.3001.0010.5672
  188. Rassoulpour, A., Wu, H. Q., Ferre, S. and Schwarcz, R. (2005) Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J. Neurochem. 93, 762-765. https://doi.org/10.1111/j.1471-4159.2005.03134.x
  189. Razazan, A., Karunakar, P., Mishra, S. P., Sharma, S., Miller, B., Jain, S. and Yadav, H. (2021) Activation of microbiota sensing - free fatty acid receptor 2 signaling ameliorates amyloid-β induced neurotoxicity by modulating proteolysis-senescence axis. Front. Aging Neurosci. 13, 735933.
  190. Ren, Z., Pan, X., Li, J., Dong, X., Tu, X., Pan, L. L. and Sun, J. (2023) G protein coupled receptor 41 regulates fibroblast activation in pulmonary fibrosis via Gα(i/o) and downstream Smad2/3 and ERK1/2 phosphorylation. Pharmacol. Res. 191, 106754.
  191. Rey, F. E., Faith, J. J., Bain, J., Muehlbauer, M. J., Stevens, R. D., Newgard, C. B. and Gordon, J. I. (2010) Dissecting the in vivo metabolic potential of two human gut acetogens. J. Biol. Chem. 285, 22082-22090. https://doi.org/10.1074/jbc.M110.117713
  192. Ridlon, J. M., Harris, S. C., Bhowmik, S., Kang, D. J. and Hylemon, P. B. (2016) Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes 7, 22-39. https://doi.org/10.1080/19490976.2015.1127483
  193. Roediger, W. E. (1980) Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut 21, 793-798. https://doi.org/10.1136/gut.21.9.793
  194. Rothhammer, V., Borucki, D. M., Tjon, E. C., Takenaka, M. C., Chao, C. C., Ardura-Fabregat, A., de Lima, K. A., Gutierrez-Vazquez, C., Hewson, P., Staszewski, O., Blain, M., Healy, L., Neziraj, T., Borio, M., Wheeler, M., Dragin, L. L., Laplaud, D. A., Antel, J., Alvarez, J. I., Prinz, M. and Quintana, F. J. (2018) Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724-728. https://doi.org/10.1038/s41586-018-0119-x
  195. 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., Kebir, H., Anandasabapathy, N., Izquierdo, G., Jung, S., Obholzer, N., Pochet, N., Clish, C. B., Prinz, M., Prat, A., Antel, J. and Quintana, F. J. (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 22, 586-597. https://doi.org/10.1038/nm.4106
  196. Rothhammer, V. and Quintana, F. J. (2019) The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19, 184-197. https://doi.org/10.1038/s41577-019-0125-8
  197. Ryu, J. C., Zimmer, E. R., Rosa-Neto, P. and Yoon, S. O. (2019) Consequences of metabolic disruption in Alzheimer's disease pathology. Neurotherapeutics 16, 600-610. https://doi.org/10.1007/s13311-019-00755-y
  198. Saikachain, N., Sungkaworn, T., Muanprasat, C. and Asavapanumas, N. (2023) Neuroprotective effect of short-chain fatty acids against oxidative stress-induced SH-SY5Y injury via GPR43-dependent pathway. J. Neurochem. 166, 201-214. https://doi.org/10.1111/jnc.15827
  199. Salter, M. W. and Stevens, B. (2017) Microglia emerge as central players in brain disease. Nat. Med. 23, 1018-1027. https://doi.org/10.1038/nm.4397
  200. 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., KrajmalnikBrown, R., Wittung-Stafshede, P., Knight, R. and Mazmanian, S. K. (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell 167, 1469-1480.e12. https://doi.org/10.1016/j.cell.2016.11.018
  201. Sapieha, P., Sirinyan, M., Hamel, D., Zaniolo, K., Joyal, J. S., Cho, J. H., Honore, J. C., Kermorvant-Duchemin, E., Varma, D. R., Tremblay, S., Leduc, M., Rihakova, L., Hardy, P., Klein, W. H., Mu, X., Mamer, O., Lachapelle, P., Di Polo, A., Beausejour, C., Andelfinger, G., Mitchell, G., Sennlaub, F. and Chemtob, S. (2008) The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat. Med. 14, 1067-1076. https://doi.org/10.1038/nm.1873
  202. Sapkota, A., Gaire, B. P., Kang, M. G. and Choi, J. W. (2019) S1P(2) contributes to microglial activation and M1 polarization following cerebral ischemia through ERK1/2 and JNK. Sci. Rep. 9, 12106.
  203. Saresella, M., Marventano, I., Barone, M., La Rosa, F., Piancone, F., Mendozzi, L., d'Arma, A., Rossi, V., Roda, G. and Cas, M. D. (2020) Alterations in circulating fatty acid are associated with gut microbiota dysbiosis and inflammation in multiple sclerosis. Front. Immunol. 11, 543824.
  204. Schepetkin, I. A., Khlebnikov, A. I., Kirpotina, L. N. and Quinn, M. T. (2016) Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives. Int. Immunopharmacol. 37, 43-58. https://doi.org/10.1016/j.intimp.2015.08.036
  205. Schiering, C., Vonk, A., Das, S., Stockinger, B. and Wincent, E. (2018) Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells. Biochem. Pharmacol. 151, 47-58. https://doi.org/10.1016/j.bcp.2018.02.031
  206. Schroder, N., Schaffrath, A., Welter, J. A., Putzka, T., Griep, A., Ziegler, P., Brandt, E., Samer, S., Heneka, M. T., Kaddatz, H., Zhan, J., Kipp, E., Pufe, T., Tauber, S. C., Kipp, M. and Brandenburg, L. O. (2020) Inhibition of formyl peptide receptors improves the outcome in a mouse model of Alzheimer disease. J. Neuroinflammation 17, 131.
  207. Schubring, S. R., Fleischer, W., Lin, J. S., Haas, H. L. and Sergeeva, O. A. (2012) The bile steroid chenodeoxycholate is a potent antagonist at NMDA and GABA(A) receptors. Neurosci. Lett. 506, 322-326. https://doi.org/10.1016/j.neulet.2011.11.036
  208. Schwab, M., Reynders, V., Loitsch, S., Steinhilber, D., Stein, J. and Schroder, O. (2007) Involvement of different nuclear hormone receptors in butyrate-mediated inhibition of inducible NF kappa B signalling. Mol. Immunol. 44, 3625-3632. https://doi.org/10.1016/j.molimm.2007.04.010
  209. Senga, T., Iwamoto, S., Yoshida, T., Yokota, T., Adachi, K., Azuma, E., Hamaguchi, M. and Iwamoto, T. (2003) LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood 101, 1185-1187. https://doi.org/10.1182/blood-2002-06-1881
  210. Shackleford, G., Sampathkumar, N. K., Hichor, M., Weill, L., Meffre, D., Juricek, L., Laurendeau, I., Chevallier, A., Ortonne, N., Larousserie, F., Herbin, M., Bieche, I., Coumoul, X., Beraneck, M., Baulieu, E. E., Charbonnier, F., Pasmant, E. and Massaad, C. (2018) Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis. Proc. Natl. Acad. Sci. U. S. A. 115, E1319-E1328. https://doi.org/10.1073/pnas.1715999115
  211. Shepard, P. D., Joy, B., Clerkin, L. and Schwarcz, R. (2003) Micromolar brain levels of kynurenic acid are associated with a disruption of auditory sensory gating in the rat. Neuropsychopharmacology 28, 1454-1462. https://doi.org/10.1038/sj.npp.1300188
  212. Shih, R. H., Wang, C. Y. and Yang, C. M. (2015) NF-kappaB signaling pathways in neurological inflammation: a mini review. Front. Mol. Neurosci. 8, 77.
  213. Shimizu, H., Masujima, Y., Ushiroda, C., Mizushima, R., Taira, S., Ohue-Kitano, R. and Kimura, I. (2019) Dietary short-chain fatty acid intake improves the hepatic metabolic condition via FFAR3. Sci. Rep. 9, 16574.
  214. Silva, Y. P., Bernardi, A. and Frozza, R. L. (2020) The role of shortchain fatty acids from gut microbiota in gut-brain communication. Front. Endocrinol. 11, 25.
  215. Singh, N., Gurav, A., Sivaprakasam, S., Brady, E., Padia, R., Shi, H., Thangaraju, M., Prasad, P. D., Manicassamy, S., Munn, D. H., Lee, J. R., Offermanns, S. and Ganapathy, V. (2014) Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128-139. https://doi.org/10.1016/j.immuni.2013.12.007
  216. Singhal, R., Donde, H., Ghare, S., Stocke, K., Zhang, J., Vadhanam, M., Reddy, S., Gobejishvili, L., Chilton, P., Joshi-Barve, S., Feng, W., McClain, C., Hoffman, K., Petrosino, J., Vital, M. and Barve, S. (2021) Decrease in acetyl-CoA pathway utilizing butyrate-producing bacteria is a key pathogenic feature of alcohol-induced functional gut microbial dysbiosis and development of liver disease in mice. Gut Microbes 13, 1946367.
  217. Smith, B. C. and Denu, J. M. (2009) Chemical mechanisms of histone lysine and arginine modifications. Biochim. Biophys. Acta Gene Regul. Mech. 1789, 45-57. https://doi.org/10.1016/j.bbagrm.2008.06.005
  218. Smith, E. A. and Macfarlane, G. T. (1997) Dissimilatory amino acid metabolism in human colonic bacteria. Anaerobe 3, 327-337. https://doi.org/10.1006/anae.1997.0121
  219. Sochocka, M., Donskow-Lysoniewska, K., Diniz, B. S., Kurpas, D., Brzozowska, E. and Leszek, J. (2019) The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer's disease-a critical review. Mol. Neurobiol. 56, 1841-1851. https://doi.org/10.1007/s12035-018-1188-4
  220. Soliman, M. L., Puig, K. L., Combs, C. K. and Rosenberger, T. A. (2012) Acetate reduces microglia inflammatory signaling in vitro. J. Neurochem. 123, 555-567. https://doi.org/10.1111/j.1471-4159.2012.07955.x
  221. Sood, A., Fernandes, V., Preeti, K., Rajan, S., Khatri, D. K. and Singh, S. B. (2024) S1PR2 inhibition mitigates cognitive deficit in diabetic mice by modulating microglial activation via Akt-p53-TIGAR pathway. Int. Immunopharmacol. 126, 111278.
  222. Soret, R., Chevalier, J., De Coppet, P., Poupeau, G., Derkinderen, P., Segain, J. P. and Neunlist, M. (2010) Short-chain fatty acids regulate the enteric neurons and control gastrointestinal motility in rats. Gastroenterology 138, 1772-1782. https://doi.org/10.1053/j.gastro.2010.01.053
  223. Stanley, D., Moore, R. J. and Wong, C. H. (2018) An insight into intestinal mucosal microbiota disruption after stroke. Sci. Rep. 8, 568.
  224. Sun, E., Motolani, A., Campos, L. and Lu, T. (2022) The pivotal role of NF-kB in the pathogenesis and therapeutics of Alzheimer's disease. Int. J. Mol. Sci. 23, 8972.
  225. Sun, J. (2017) Commentary: target intestinal microbiota to alleviate disease progression in amyotrophic lateral sclerosis. J. Neurol. Neuromedicine 2, 13-15. https://doi.org/10.29245/2572.942X/2017/6.1136
  226. Sun, J., Xu, J., Ling, Y., Wang, F., Gong, T., Yang, C., Ye, S., Ye, K., Wei, D., Song, Z., Chen, D. and Liu, J. (2019) Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice. Transl. Psychiatry 9, 189.
  227. Sun, J., Xu, J., Yang, B., Chen, K., Kong, Y., Fang, N., Gong, T., Wang, F., Ling, Z. and Liu, J. (2020a) Effect of Clostridium butyricum against microglia-mediated neuroinflammation in Alzheimer's disease via regulating gut microbiota and metabolites butyrate. Mol. Nutr. Food Res. 64, e1900636.
  228. Sun, M., Ma, N., He, T., Johnston, L. J. and Ma, X. (2020b) Tryptophan (Trp) modulates gut homeostasis via aryl hydrocarbon receptor (AhR). Crit. Rev. Food Sci. Nutr. 60, 1760-1768. https://doi.org/10.1080/10408398.2019.1598334
  229. Swer, N. M., Venkidesh, B. S., Murali, T. S. and Mumbrekar, K. D. (2023) Gut microbiota-derived metabolites and their importance in neurological disorders. Mol. Biol. Rep. 50, 1663-1675. https://doi.org/10.1007/s11033-022-08038-0
  230. Szentirmai, E., Millican, N. S., Massie, A. R. and Kapas, L. (2019) Butyrate, a metabolite of intestinal bacteria, enhances sleep. Sci. Rep. 9, 7035.
  231. Takabe, K. and Spiegel, S. (2014) Export of sphingosine-1-phosphate and cancer progression. J. Lipid Res. 55, 1839-1846. https://doi.org/10.1194/jlr.R046656
  232. Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J. and Schoonjans, K. (2008) Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discov. 7, 678-693. https://doi.org/10.1038/nrd2619
  233. Thompson, B., Lu, S., Revilla, J., Uddin, M. J., Oakland, D. N., Brovero, S., Keles, S., Bresnick, E. H., Petri, W. A. and Burgess, S. L. (2023) Secondary bile acids function through the vitamin D receptor in myeloid progenitors to promote myelopoiesis. Blood Adv. 7, 4970-4982. https://doi.org/10.1182/bloodadvances.2022009618
  234. Tian, S. Y., Chen, S. M., Pan, C. X. and Li, Y. (2022) FXR: structures, biology, and drug development for NASH and fibrosis diseases. Acta Pharmacol. Sin. 43, 1120-1132. https://doi.org/10.1038/s41401-021-00849-4
  235. Torok, N., Torok, R., Szolnoki, Z., Somogyvari, F., Klivenyi, P. and Vecsei, L. (2015) The genetic link between Parkinson's disease and the kynurenine pathway is still missing. Parkinsons Dis. 2015, 474135.
  236. Tremlett, H., Bauer, K. C., Appel-Cresswell, S., Finlay, B. B. and Waubant, E. (2017) The gut microbiome in human neurological disease: a review. Ann. Neurol. 81, 369-382. https://doi.org/10.1002/ana.24901
  237. Uchida, Y., Ohtsuki, S., Katsukura, Y., Ikeda, C., Suzuki, T., Kamiie, J. and Terasaki, T. (2011) Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J. Neurochem. 117, 333-345. https://doi.org/10.1111/j.1471-4159.2011.07208.x
  238. Umeda, K., Ikenouchi, J., Katahira-Tayama, S., Furuse, K., Sasaki, H., Nakayama, M., Matsui, T., Tsukita, S., Furuse, M. and Tsukita, S. (2006) ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation. Cell 126, 741-754. https://doi.org/10.1016/j.cell.2006.06.043
  239. Unger, M. M., Spiegel, J., Dillmann, K.-U., Grundmann, D., Philippeit, H., Burmann, J., Fassbender, K., Schwiertz, A. and Schafer, K.-H. (2016) Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat. Disord. 32, 66-72. https://doi.org/10.1016/j.parkreldis.2016.08.019
  240. Valvassori, S. S., Resende, W. R., Budni, J., Dal-Pont, G. C., Bavaresco, D. V., Reus, G. Z., Carvalho, A. F., Goncalves, C. L., Furlanetto, C. B., Streck, E. L. and Quevedo, J. (2015) Sodium butyrate, a histone deacetylase inhibitor, reverses behavioral and mitochondrial alterations in animal models of depression induced by early- or late-life stress. Curr. Neurovasc. Res. 12, 312-320. https://doi.org/10.2174/1567202612666150728121121
  241. Vecsei, L., Szalardy, L., Fulop, F. and Toldi, J. (2013) Kynurenines in the CNS: recent advances and new questions. Nat. Rev. Drug Discov. 12, 64-82. https://doi.org/10.1038/nrd3793
  242. Veprik, A., Laufer, D., Weiss, S., Rubins, N. and Walker, M. D. (2016) GPR41 modulates insulin secretion and gene expression in pancreatic β-cells and modifies metabolic homeostasis in fed and fasting states. FASEB J. 30, 3860-3869. https://doi.org/10.1096/fj.201500030R
  243. Vernocchi, P., Del Chierico, F. and Putignani, L. (2016) Gut microbiota profiling: metabolomics based approach to unravel compounds affecting human health. Front. Microbiol. 7, 1144.
  244. Vinolo, M. A., Rodrigues, H. G., Nachbar, R. T. and Curi, R. (2011) Regulation of inflammation by short chain fatty acids. Nutrients 3, 858-876. https://doi.org/10.3390/nu3100858
  245. Wahlstrom, A., Sayin, S. I., Marschall, H. U. and Backhed, F. (2016) Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41-50. https://doi.org/10.1016/j.cmet.2016.05.005
  246. Waldecker, M., Kautenburger, T., Daumann, H., Busch, C. and Schrenk, D. (2008) Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J. Nutr. Biochem. 19, 587-593. https://doi.org/10.1016/j.jnutbio.2007.08.002
  247. Wallen, Z. D., Appah, M., Dean, M. N., Sesler, C. L., Factor, S. A., Molho, E., Zabetian, C. P., Standaert, D. G. and Payami, H. (2020) Characterizing dysbiosis of gut microbiome in PD: evidence for overabundance of opportunistic pathogens. NPJ Parkinsons Dis. 6, 11.
  248. Wallen, Z. D., Demirkan, A., Twa, G., Cohen, G., Dean, M. N., Standaert, D. G., Sampson, T. R. and Payami, H. (2022) Metagenomics of Parkinson's disease implicates the gut microbiome in multiple disease mechanisms. Nat. Commun. 13, 6958.
  249. Wang, P., Zhang, Y., Gong, Y., Yang, R., Chen, Z., Hu, W., Wu, Y., Gao, M., Xu, X., Qin, Y. and Huang, C. (2018) Sodium butyrate triggers a functional elongation of microglial process via Akt-small RhoGTPase activation and HDACs inhibition. Neurobiol. Dis. 111, 12-25. https://doi.org/10.1016/j.nbd.2017.12.006
  250. Wang, Z., Chen, W.-D. and Wang, Y.-D. (2021) Nuclear receptors: a bridge linking the gut microbiome and the host. Mol. Med. 27, 144.
  251. Warner, B. B. (2019) The contribution of the gut microbiome to neurodevelopment and neuropsychiatric disorders. Pediatr. Res. 85, 216-224. https://doi.org/10.1038/s41390-018-0191-9
  252. Wei, M., Huang, F., Zhao, L., Zhang, Y., Yang, W., Wang, S., Li, M., Han, X., Ge, K., Qu, C., Rajani, C., Xie, G., Zheng, X., Zhao, A., Bian, Z. and Jia, W. (2020) A dysregulated bile acid-gut microbiota axis contributes to obesity susceptibility. EBioMedicine 55, 102766.
  253. Wikoff, W. R., Anfora, A. T., Liu, J., Schultz, P. G., Lesley, S. A., Peters, E. C. and Siuzdak, G. (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl. Acad. Sci. U. S. A. 106, 3698-3703. https://doi.org/10.1073/pnas.0812874106
  254. Williams, B. B., Van Benschoten, A. H., Cimermancic, P., Donia, M. S., Zimmermann, M., Taketani, M., Ishihara, A., Kashyap, P. C., Fraser, J. S. and Fischbach, M. A. (2014) Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 16, 495-503. https://doi.org/10.1016/j.chom.2014.09.001
  255. Wilton, D. K., Dissing-Olesen, L. and Stevens, B. (2019) Neuron-glia signaling in synapse elimination. Ann. Rev. Neurosci. 42, 107-127. https://doi.org/10.1146/annurev-neuro-070918-050306
  256. Winston, J. A. and Theriot, C. M. (2020) Diversification of host bile acids by members of the gut microbiota. Gut Microbes 11, 158-171. https://doi.org/10.1080/19490976.2019.1674124
  257. Wu, L., Han, Y., Zheng, Z., Peng, G., Liu, P., Yue, S., Zhu, S., Chen, J., Lv, H., Shao, L., Sheng, Y., Wang, Y., Li, L., Li, L. and Wang, B. (2021a) Altered gut microbial metabolites in amnestic mild cognitive impairment and Alzheimer's disease: signals in host-microbe interplay. Nutrients 13, 228.
  258. Wu, S., Yi, J., Zhang, Y. G., Zhou, J. and Sun, J. (2015) Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model. Physiol. Rep. 3, e12356.
  259. Wu, Y.-L., Xu, J., Rong, X.-Y., Wang, F., Wang, H.-J. and Zhao, C. (2021b) Gut microbiota alterations and health status in aging adults: from correlation to causation. Aging Med. 4, 206-213. https://doi.org/10.1002/agm2.12167
  260. Wu, Y., Qiu, Y., Su, M., Wang, L., Gong, Q. and Wei, X. (2023) Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain. CNS Neurosci. Ther. 29, 1981-1998. https://doi.org/10.1111/cns.14154
  261. Xu, N., Bai, Y., Han, X., Yuan, J., Wang, L., He, Y., Yang, L., Wu, H., Shi, H. and Wu, X. (2023) Taurochenodeoxycholic acid reduces astrocytic neuroinflammation and alleviates experimental autoimmune encephalomyelitis in mice. Immunobiology 228, 152388.
  262. Yang, L. L., Millischer, V., Rodin, S., MacFabe, D. F., Villaescusa, J. C. and Lavebratt, C. (2020) Enteric short-chain fatty acids promote proliferation of human neural progenitor cells. J. Neurochem. 154, e14928.
  263. Yang, R. and Qian, L. (2022) Research on gut microbiota-derived secondary bile acids in cancer progression. Integr. Cancer Ther. 21, 15347354221114100.
  264. Yang, X., Ai, P., He, X., Mo, C., Zhang, Y., Xu, S., Lai, Y., Qian, Y. and Xiao, Q. (2022) Parkinson's disease is associated with impaired gut-blood barrier for short-chain fatty acids. Mov. Disord. 37, 1634-1643. https://doi.org/10.1002/mds.29063
  265. Yano, J. M., Yu, K., Donaldson, G. P., Shastri, G. G., Ann, P., Ma, L., Nagler, C. R., Ismagilov, R. F., Mazmanian, S. K. and Hsiao, E. Y. (2015) Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264-276. https://doi.org/10.1016/j.cell.2015.02.047
  266. Yoon, S. S. and Jo, S. A. (2012) Mechanisms of amyloid-beta peptide clearance: potential therapeutic targets for Alzheimer's disease. Biomol. Ther. (Seoul) 20, 245-255. https://doi.org/10.4062/biomolther.2012.20.3.245
  267. Zhang, L., Wang, Y., Xiayu, X., Shi, C., Chen, W., Song, N., Fu, X., Zhou, R., Xu, Y. F., Huang, L., Zhu, H., Han, Y. and Qin, C. (2017a) Altered gut microbiota in a mouse model of Alzheimer's disease. J. Alzheimers Dis. 60, 1241-1257. https://doi.org/10.3233/JAD-170020
  268. Zhang, Y.-G., Wu, S., Yi, J., Xia, Y., Jin, D., Zhou, J. and Sun, J. (2017b) Target intestinal microbiota to alleviate disease progression in amyotrophic lateral sclerosis. Clin. Ther. 39, 322-336. https://doi.org/10.1016/j.clinthera.2016.12.014
  269. Zhang, Z., Zhang, H., Chen, T., Shi, L., Wang, D. and Tang, D. (2022) Regulatory role of short-chain fatty acids in inflammatory bowel disease. Cell Commun. Signal. 20, 64.
  270. Zhou, Z., Xu, N., Matei, N., McBride, D. W., Ding, Y., Liang, H., Tang, J. and Zhang, J. H. (2021) Sodium butyrate attenuated neuronal apoptosis via GPR41/Gβγ/PI3K/Akt pathway after MCAO in rats. J. Cereb. Blood Flow Metabol. 41, 267-281. https://doi.org/10.1177/0271678X20910533
  271. Zhuang, Z. Q., Shen, L. L., Li, W. W., Fu, X., Zeng, F., Gui, L., Lu, Y., Cai, M., Zhu, C., Tan, Y. L., Zheng, P., Li, H. Y., Zhu, J., Zhou, H. D., Bu, X. L. and Wang, Y. J. (2018) Gut microbiota is altered in patients with Alzheimer's disease. J. Alzheimers Dis. 63, 1337-1346. https://doi.org/10.3233/JAD-180176
  272. Zou, F., Qiu, Y., Huang, Y., Zou, H., Cheng, X., Niu, Q., Luo, A. and Sun, J. (2021) Effects of short-chain fatty acids in inhibiting HDAC and activating p38 MAPK are critical for promoting B10 cell generation and function. Cell Death Dis. 12, 582.
  273. Zou, Y., Mu, M., Zhang, S., Li, C., Tian, K., Li, Z., Li, B., Wang, W., Cao, H., Sun, Q., Chen, H., Ge, D., Tao, H. and Tao, X. (2022) Vitamin D3 suppresses astrocyte activation and ameliorates coal dust-induced mood disorders in mice. J. Affect. Disord. 303, 138-147. https://doi.org/10.1016/j.jad.2022.02.026