Synergistic effects of NOD1 or NOD2 and TLR4 activation on mouse sickness behavior in relation to immune and brain activity markers
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Toll-like receptors (TLRs) and nuclear-binding domain (NOD)-like receptors (NLRs) are sensors of bacterial cell wall components to trigger an immune response. The TLR4 agonist lipopolysaccharide (LPS) is a strong immune activator leading to sickness and depressed mood. NOD agonists are less active but can prime immune cells to augment LPS-induced cytokine production. Since the impact of NOD and TLR co-activation in vivo has been little studied, the effects of the NOD1 agonist FK565 and the NOD2 agonist muramyl dipeptide (MDP), alone and in combination with LPS, on immune activation, brain function and sickness behavior were investigated in male C57BL/6N mice. Intraperitoneal injection of FK565 (0.001 or 0.003mg/kg) or MDP (1 or 3mg/kg) 4h before LPS (0.1 or 0.83mg/kg) significantly aggravated and prolonged the LPS-evoked sickness behavior as deduced from a decrease in locomotion, exploration, food intake and temperature. When given alone, FK565 and MDP had only minor effects. The exacerbation of sickness behavior induced by FK565 or MDP in combination with LPS was paralleled by enhanced plasma protein and cerebral mRNA levels of proinflammatory cytokines (IFN-γ, IL-1β, IL-6, TNF-α) as well as enhanced plasma levels of kynurenine. Immunohistochemical visualization of c-Fos in the brain revealed that NOD2 synergism with TLR4 resulted in increased activation of cerebral nuclei relevant to sickness. These data show that NOD1 or NOD2 synergizes with TLR4 in exacerbating the immune, sickness and brain responses to peripheral immune stimulation. Our findings demonstrate that the known interactions of NLRs and TLRs at the immune cell level extend to interactions affecting brain function and behavior.
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Colonization by microbiota regulates expression of critical HPA axis genes in hippocampus and modulates hippocampal serotonin concentration, which affects HPA activation.
“Colonization by microbiota has been shown to regulate the expression of critical HPA axis genes in hippocampus and modulate hippocampal serotonin concentration, which also affects HPA activation (Luo et al., 2018; Farzi et al., 2015; Shanks et al., 1995; Clarke et al., 2013).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Farzi et al., 2015
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Analyzing real-time PCR data by the comparative CT method
Schmittgen, T. D., & Livak, K. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.73 · Cited by 26,190 · see citing works
Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in <i>Tlr4</i> Gene
Poltorak, A., He, X., Smirnova, I., Liu, M.-Y., Huffel, C. V., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998) · Science · doi:10.1126/science.282.5396.2085 · Cited by 7,631 · see citing works
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395 · see citing works
Toll-like receptors and their crosstalk with other innate receptors in infection and immunity
Kawai, T., & Akira, S. (2011) · Immunity · doi:10.1016/j.immuni.2011.05.006 · Cited by 3,658 · see citing works
Biological basis of the behavior of sick animals
Hart, B. L. (1988) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(88)80004-6 · Cited by 2,223 · see citing works
Cryan, J. F., Mombereau, C., & Vassout, A. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.03.009 · Cited by 1,674 · see citing works
Assessing antidepressant activity in rodents: recent developments and future needs
Cryan, J. F., Markou, A., & Lucki, I. (2002) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(02)02017-5 · Cited by 1,551 · cited 1× · see citing works
“Mice were considered immobile when floating passively in the water, performing only those movements required to keep their heads above the water level (Cryan et al., 2002).”
Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-κB
Ogura, Y., Inohara, N., Benito, A., Chen, F. F., Yamaoka, S., & Núñez, G. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008072200 · Cited by 1,357 · see citing works
Chamaillard, M., Hashimoto, M., Horie, Y., Masumoto, J., Qiu, S., Saab, L., Ogura, Y., Kawasaki, A., Fukase, K., Kusumoto, S., et al. (2003) · Nature Immunology · doi:10.1038/ni945 · Cited by 1,323 · see citing works
O'Connor, J. C., Lawson, M. A., André, C., Moreau, M., Lestage, J., Castanon, N., Kelley, K. W., & Dantzer, R. (2009) · Molecular Psychiatry · doi:10.1038/sj.mp.4002148 · Cited by 1,278 · see citing works
Haroon, E., Raison, C. L., & Miller, A. H. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.205 · Cited by 1,000 · see citing works
Function of Nod‐like receptors in microbial recognition and host defense
Franchi, L., Warner, N. E., Viani, K. L., & Núñez, G. (2008) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00734.x · Cited by 900 · see citing works
Activation of innate immune antiviral responses by Nod2
Sabbah, A., Chang, T. H., Harnack, R., Frohlich, V. C., Tominaga, K., Dube, P. H., Xiang, Y., & Bose, S. (2009) · Nature Immunology · doi:10.1038/ni.1782 · Cited by 754 · see citing works
Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity
Dantzer, R. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.07.040 · Cited by 743 · see citing works
Nod1, an Apaf-1-like Activator of Caspase-9 and Nuclear Factor-κB
Inohara, N., Koseki, T., del Peso, L., Hu, Y., Yee, C., Chen, S., Carrio, R., Merino, J., Liu, D., Ni, J., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.21.14560 · Cited by 742 · see citing works
Endotoxin produces a depressive-like episode in rats
Yirmiya, R. (1996) · Brain Research · doi:10.1016/0006-8993(95)01415-2 · Cited by 604 · see citing works
RICK/RIP2 Mediates Innate Immune Responses Induced through Nod1 and Nod2 but Not TLRs
Park, J., Kim, Y., McDonald, C., Kanneganti, T., Hasegawa, M., Body–Malapel, M., Inohara, N., & Núñez, G. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.4.2380 · Cited by 532 · see citing works
Frenois, F., Moreau, M., O’Connor, J., Lawson, M., Micon, C., Lestage, J., Kelley, K. W., Dantzer, R., & Castanon, N. (2007) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2007.03.005 · Cited by 438 · see citing works
Immune–neural connections: how the immune system’s response to infectious agents influences behavior
McCusker, R. H., & Kelley, K. W. (2013) · Journal of Experimental Biology · doi:10.1242/jeb.073411 · Cited by 429 · see citing works
Dantzer, R., Konsman, J.-P., Bluthé, R.-M., & Kelley, K. W. (2000) · Autonomic Neuroscience · doi:10.1016/s1566-0702(00)00220-4 · Cited by 400 · see citing works
Chakravarty, S., & Herkenham, M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4268-04.2005 · Cited by 396 · see citing works
Hsu, L.-C., Ali, S. R., McGillivray, S. M., Tseng, P., Mariathasan, S., Humke, E. W., Eckmann, L., Powell, J. J., Nizet, V., Dixit, V. M., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802726105 · Cited by 388 · see citing works
Systemic Immune Activation Leads to Neuroinflammation and Sickness Behavior in Mice
Biesmans, S., Meert, T. F., Bouwknecht, J. A., Acton, P. D., Davoodi, N., Haes, P. D., Kuijlaars, J., Langlois, X., Matthews, L. J. R., Donck, L. V., et al. (2013) · Mediators of Inflammation · doi:10.1155/2013/271359 · Cited by 382 · see citing works
Fritz, J. H., Girardin, S. E., Fitting, C., Werts, C., Mengin‐Lecreulx, D., Caroff, M., Cavaillon, J., Philpott, D. J., & Adib‐Conquy, M. (2005) · European Journal of Immunology · doi:10.1002/eji.200526286 · Cited by 355 · see citing works
Regulation of the Antimicrobial Response by NLR Proteins
Elinav, E., Strowig, T., Henao‐Mejia, J., & Flavell, R. A. (2011) · Immunity · doi:10.1016/j.immuni.2011.05.007 · Cited by 355 · see citing works
Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1
Kamei, D., Yamakawa, K., Takegoshi, Y., Mikami-Nakanishi, M., Nakatani, Y., Oh‐ishi, S., Yasui, H., Azuma, Y., Hirasawa, N., Ohuchi, K., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400199200 · Cited by 278 · see citing works
Netea, M. G., Ferwerda, G., de Jong, D. J., Jansen, T., Jacobs, L., Kramer, M., Naber, A. H. J., Drenth, J. P. H., Girardin, S. E., Kullberg, B. J., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.10.6518 · Cited by 274 · see citing works
Salazar, A., Gonzalez-Rivera, B. L., Redus, L., Parrott, J. M., & O’Connor, J. C. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.03.010 · Cited by 261 · see citing works
Rudaya, A. Y., Steiner, A. A., Robbins, J. R., Dragic, A. S., & Romanovsky, A. A. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00370.2005 · Cited by 248 · see citing works
Masumoto, J., Yang, K., Varambally, S., Hasegawa, M., Tomlins, S. A., Qiu, S., Fujimoto, Y., Kawasaki, A., Foster, S. J., Horie, Y., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20051229 · Cited by 211 · see citing works
Uehara, A., Yang, S., Fujimoto, Y., Fukase, K., Kusumoto, S., Shibata, K., Sugawara, S., & Takada, H. (2004) · Cellular Microbiology · doi:10.1111/j.1462-5822.2004.00433.x · Cited by 197 · see citing works
Neuronal Activity and Neuropeptide Gene Transcription in the Brains of Immune‐Challenged Rats
Rivest, S., & Laflamme, N. (1995) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.1995.tb00788.x · Cited by 196 · see citing works
The Innate Immune Protein Nod2 Binds Directly to MDP, a Bacterial Cell Wall Fragment
Grimes, C. L., Ariyananda, L. D. Z., Melnyk, J. E., & O’Shea, E. K. (2012) · Journal of the American Chemical Society · doi:10.1021/ja303883c · Cited by 194 · see citing works
Hervé, C., Beyne, P., Jamault, H., & Delacoux, E. (1996) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/0378-4347(95)00341-x · Cited by 186 · see citing works
Schwartz, E. S., La, J., Scheff, N. N., Davis, B. M., Albers, K. M., & Gebhart, G. F. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.1806-12.2013 · Cited by 175 · see citing works
Mo, J., Boyle, J. P., Howard, C. B., Monie, T. P., Davis, B. K., & Duncan, J. A. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.344283 · Cited by 168 · see citing works
The Origin of the Synergistic Effect of Muramyl Dipeptide with Endotoxin and Peptidoglycan
Wolfert, M. A., Murray, T. F., Boons, G., & Moore, J. N. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204885200 · Cited by 156 · see citing works
Anatomic patterns of FOS immunostaining in rat brain following systemic endotoxin administration
Sagar, S. M., Price, K., Kasting, N. W., & Sharp, F. R. (1995) · Brain Research Bulletin · doi:10.1016/0361-9230(94)00217-o · Cited by 142 · see citing works
Dunn, A. J. (1988) · Life Sciences · doi:10.1016/0024-3205(88)90023-9 · Cited by 142 · see citing works
Lenczowski, M. J. P., Van Dam, A.-M., Poole, S., Larrick, J. W., & Tilders, F. J. H. (1997) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1997.273.6.r1870 · Cited by 115 · see citing works
André, C., O’Connor, J. C., Kelley, K. W., Lestage, J., Dantzer, R., & Castanon, N. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.06.011 · Cited by 111 · see citing works
Behavioral effects of lipopolysaccharide in rats: involvement of endogenous opioids
Yirmiya, R., Rosen, H., Donchin, O., & Ovadia, H. (1994) · Brain Research · doi:10.1016/0006-8993(94)91908-9 · Cited by 104 · see citing works
Murray, C., Skelly, D., & Cunningham, C. M. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-50 · Cited by 98 · see citing works
Active behaviours produced by antidepressants and opioids in the mouse tail suspension test
Berrocoso, E., Ikeda, K., Sora, I., Uhl, G. R., Sánchez‐Blázquez, P., & Micó, J. A. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711001842 · Cited by 95 · see citing works
Changes in behaviour and cytokine expression upon a peripheral immune challenge
Bay-Richter, C., Janelidze, S., Hallberg, L., & Brundin, L. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.03.060 · Cited by 93 · see citing works
Comparison of the effects of bacterial lipopolysaccharide and muramyl dipeptide on food intake
Langhans, W., Harlacher, R., Balkowski, G., & Scharrer, E. (1990) · Physiology & Behavior · doi:10.1016/0031-9384(90)90001-k · Cited by 85 · see citing works
Anisman, H., Gibb, J., & Hayley, S. P. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1166-z · Cited by 83 · see citing works
Terrence Deak, B., Bellamy, C., D’Agostino, L. G., Rosanoff, M., McElderry, N. K., & Bordner, K. A. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.11.024 · Cited by 82 · see citing works
Interleukin-1 mediates behavioural but not metabolic effects of tumor necrosis factor α in mice
Bluthé, R.-M., Dantzer, R., & Kelley, K. W. (1991) · European Journal of Pharmacology · doi:10.1016/0014-2999(91)90184-r · Cited by 79 · see citing works
Painsipp, E., Köfer, M. J., Sinner, F. M., & Holzer, P. D. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020719 · Cited by 77 · see citing works
Takada, H., & Galanos, C. (1987) · Infection and Immunity · doi:10.1128/iai.55.2.409-413.1987 · Cited by 75 · see citing works
Engeland, C. G., Kavaliers, M., & Ossenkopp, K. (2002) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(02)01024-9 · Cited by 75 · see citing works
PEPTIDOGLYCAN PRIMES FOR LPS-INDUCED RELEASE OF PROINFLAMMATORY CYTOKINES IN WHOLE HUMAN BLOOD
Wang, J. E., Jørgensen, P. F., Ellingsen, E. A., Almlöf, M., Thiemermann, C., Foster, S. J., Aasen, A. O., & Solberg, R. (2001) · Shock · doi:10.1097/00024382-200116030-00002 · Cited by 66 · see citing works
Bugajski, J., Gądek-Michalska, A., & Bugajski, A. J. (2004) · PubMed · Cited by 64 · see citing works
Selective NOD1 Agonists Cause Shock and Organ Injury/Dysfunction in Vivo
Cartwright, N., Murch, O., McMaster, S. K., Paul‐Clark, M. J., van Heel, D. A., Ryffel, B., Quesniaux, V. F. J., Evans, T. W., Thiemermann, C., & Mitchell, J. A. (2007) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200608-1103oc · Cited by 63 · see citing works
Thkada, H., Hirai, H., Fujiwara, T., Koga, T., Ogawa, T., & Hamada, S. (1990) · The Journal of Infectious Diseases · doi:10.1093/infdis/162.2.428 · Cited by 59 · see citing works
Wuchert, F., Ott, D., Murgott, J., Rafalzik, S., Hitzel, N., Roth, J., & Gerstberger, R. (2008) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2008.07.017 · Cited by 56 · see citing works
Gaykema, R. P. A., & Goehler, L. E. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.11.005 · Cited by 49 · see citing works
Sundquist, S. J., & Nisenbaum, L. K. (2004) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2004.05.007 · Cited by 47 · see citing works
Role for CD14, TLR2, and TLR4 in bacterial product-induced anorexia
von Meyenburg, C., Hrupka, B. H., Arsenijevic, D., Schwartz, G. J., Landmann, R., & Langhans, W. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00659.2003 · Cited by 47 · see citing works
Reichmann, F., Painsipp, E., & Holzer, P. D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054811 · Cited by 45 · see citing works
Antitumor effects of novel immunoactive peptides, FK-156 and its synthetic derivatives.
Izumi, S., Nakahara, K., GOTOH, T., Hashimoto, S., KINO, T., OKUHARA, M., AOKI, H., & Imanaka, H. (1983) · The Journal of Antibiotics · doi:10.7164/antibiotics.36.566 · Cited by 45 · see citing works
Avoidance of physical activity is a sensitive indicator of illness
Skinner, G. W., Mitchell, D., & Harden, L. M. (2008) · Physiology & Behavior · doi:10.1016/j.physbeh.2008.11.004 · Cited by 41 · see citing works
Dharancy, S., Body–Malapel, M., Louvet, A., Berrebi, D. D., Gantier, E., Gosset, P., Viala, J., Hollebecque, A., Moreno, C., Philpott, D. J., et al. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.12.008 · Cited by 41 · see citing works
Proinflammatory Mediators of Toxic Shock and Their Correlation to Lethality
Krakauer, T., Buckley, M. J., & Fisher, D. (2010) · Mediators of Inflammation · doi:10.1155/2010/517594 · Cited by 39 · see citing works
Somnogenic, pyrogenic, and hematologic effects of bacterial peptidoglycan
Johannsen, L., Toth, L. A., Rosenthal, R. S., Opp, M. R., Obál, F., Cady, A. B., & Krueger, J. M. (1990) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1990.258.1.r182 · Cited by 37 · see citing works
Contel, C. L., Temime, N., Charron, D. J., & Parant, M. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.150.10.4541 · Cited by 34 · see citing works
Parant, M., Pouillart, P., Contel, C. L., Parant, F., CHEDID, L. A., & Bahr, G. M. (1995) · Infection and Immunity · doi:10.1128/iai.63.1.110-115.1995 · Cited by 34 · see citing works
Peptidoglycan fragments decrease food intake and body weight gain in rats
Biberstine, K. J., & Rosenthal, R. S. (1994) · Infection and Immunity · doi:10.1128/iai.62.8.3276-3281.1994 · Cited by 24 · see citing works
Shikama, Y., Kuroishi, T., Nagai, Y., Iwakura, Y., Shimauchi, H., Takada, H., Sugawara, S., & Endo, Y. (2009) · Innate Immunity · doi:10.1177/1753425909347508 · Cited by 24 · see citing works
Immunoactive peptides, FK 156 and FK 565. IV. Activation of mouse macrophages.
Watanabe, Y., Tawara, S., MINE, Y., Kikuchi, H., Gotô, S., & Kuwahara, S. (1985) · The Journal of Antibiotics · doi:10.7164/antibiotics.38.1781 · Cited by 24 · see citing works
Lack of Response of Murine Peritoneal Macrophages to in vitro Activation by Muramyl Dipeptide (MDP)
Nagao, S., Akagawa, K. S., Yamada, K., Yagawa, K., Tokunaga, T., & Kotani, S. (1990) · Microbiology and Immunology · doi:10.1111/j.1348-0421.1990.tb01013.x · Cited by 21 · see citing works
Pharmacokinetics and feeding responses to muramyl dipeptide in rats
Fosset, S., Fromentin, G., Rampin, O., Lang, V., Mathieu, F., & Tomé, D. (2003) · Physiology & Behavior · doi:10.1016/s0031-9384(03)00065-9 · Cited by 19 · see citing works
Amino acids, serotonin, and 5-hydroxyindoleacetic acid following foot shock in rats
Małyszko, J., Urano, T., Takada, Y., & Takada, A. (1995) · Brain Research Bulletin · doi:10.1016/0361-9230(94)00178-4 · Cited by 17 · see citing works
Neuropeptide Y and peptide YY protect from weight loss caused by B acille C almette– G uérin in mice
Painsipp, E., Köfer, M. J., Farzi, A., Dischinger, U., Sinner, F. M., Herzog, H., & Holzer, P. D. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12354 · Cited by 16 · see citing works
Cloutier, C. J., Rodowa, M.-S., Cross-Mellor, S. K., Chan, M. Y. T., Kavaliers, M., & Ossenkopp, K. (2012) · Physiology & Behavior · doi:10.1016/j.physbeh.2012.02.005 · Cited by 14 · see citing works
Analgesic effects of chemically synthesized NOD1 and NOD2 agonists in mice
Sato, T., Shikama, Y., Shimauchi, H., Endo, Y., & Takada, H. (2010) · Innate Immunity · doi:10.1177/1753425909351904 · Cited by 10 · see citing works
Flagged first, then by citations
2 of the 79 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity
Zhernakova, A., Kurilshikov, A., Bonder, M. J., Tigchelaar, E. F., Schirmer, M., Vatanen, T., Mujagic, Z., Vila, A. V., Falony, G., Vieira-Silva, S., et al. (2016) · Science · doi:10.1126/science.aad3369 · Cited by 1,914 · see citing works
Gut microbiota and the neuroendocrine system
Farzi, A., Fröhlich, E. E., & Holzer, P. (2018) · Neurotherapeutics · doi:10.1007/s13311-017-0600-5 · Cited by 478 · see citing works
Mikulska, J., Juszczyk, G., Gawrońska-Grzywacz, M., & Herbet, M. (2021) · Brain Sciences · doi:10.3390/brainsci11101298 · Cited by 450 · see citing works
Dietary spermidine improves cognitive function
Schroeder, S., Hofer, S. J., Zimmermann, A., Pechlaner, R., Dammbrueck, C., Pendl, T., Marcello, G. M., Pogatschnigg, V., Bergmann, M., Müller, M., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108985 · Cited by 225 · see citing works
Kurilshikov, A., van den Munckhof, I. C. L., Chen, L., Bonder, M. J., Schraa, K., Rutten, J. H. W., Riksen, N. P., de Graaf, J., Oosting, M., Sanna, S., et al. (2019) · Circulation Research · doi:10.1161/circresaha.118.314642 · Cited by 178 · see citing works
Mithaiwala, M. N., Santana-Coelho, D., Porter, G. A., & O’Connor, J. C. (2021) · Cells · doi:10.3390/cells10061548 · Cited by 190 · see citing works
Tohidpour, A., Morgun, A. V., Boitsova, E. B., Malinovskaya, N. A., Martynova, G. P., Хилажева, Е. Д., Kopylevich, N. V., Gertsog, G. E., & Salmina, A. B. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00276 · Cited by 179 · see citing works
Farzi, A., Reichmann, F., & Holzer, P. (2015) · Acta Physiologica · doi:10.1111/apha.12445 · Cited by 145 · see citing works
The GPR 55 antagonist CID 16020046 protects against intestinal inflammation
Stančić, A., Jandl, K., Hasenoehrl, C., Reichmann, F., Marsche, G., Schuligoi, R., Heinemann, Á., Storr, M., & Schicho, R. (2015) · Neurogastroenterology & Motility · doi:10.1111/nmo.12639 · Cited by 99 · see citing works
Mayerhofer, R., Fröhlich, E. E., Reichmann, F., Farzi, A., Kogelnik, N., Fröhlich, E., Sattler, W., & Holzer, P. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.10.011 · Cited by 89 · see citing works
Brain modulation by the gut microbiota: From disease to therapy
Mitra, S., Dash, R., Nishan, A. A., Habiba, S. U., & Moon, I. S. (2023) · Journal of Advanced Research · doi:10.1016/j.jare.2022.12.001 · Cited by 87 · see citing works
Chan, K. L., Tam, T. H., Boroumand, P., Prescott, D., Costford, S. R., Escalante, N. K., Fine, N., Tu, Y., Robertson, S. J., Prabaharan, D., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.027 · Cited by 88 · see citing works
Kynurenine Pathway Metabolites as Biomarkers in Alzheimer’s Disease
Liang, Y., Xie, S., He, Y., Xu, M., Qiao, X., Zhu, Y. H., & Wu, W. (2022) · Disease Markers · doi:10.1155/2022/9484217 · Cited by 86 · see citing works
Visceral Inflammation and Immune Activation Stress the Brain
Holzer, P., Farzi, A., Hassan, A. M., Zenz, G., Jačan, A., & Reichmann, F. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01613 · Cited by 84 · see citing works
Diabesity and mood disorders: Multiple links through the microbiota-gut-brain axis
Farzi, A., Hassan, A. M., Zenz, G., & Holzer, P. D. (2018) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2018.11.003 · Cited by 78 · see citing works
Grabner, G. F., Eichmann, T. O., Wagner, B., Gao, Y., Farzi, A., Taschler, U., Radner, F. P. W., Schweiger, M., Lass, A., Holzer, P. D., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.683615 · Cited by 73 · see citing works
Nod-like receptors are critical for gut-brain axis signalling in mice
Pusceddu, M. M., Barboza, M., Keogh, C. E., Schneider, M., Stokes, P., Sladek, J. A., Kim, H. J. D., Torres‐Fuentes, C., Goldfild, L. R., Gillis, S. E., et al. (2019) · The Journal of Physiology · doi:10.1113/jp278640 · Cited by 69 · see citing works
Neuroinflammation in neurodegeneration via microbial infections
Tran, V. T. A., Lee, L. P., & Cho, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.907804 · Cited by 68 · see citing works
Hilliard, A. L., Mendonca, P., & Soliman, K. F. A. (2020) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2020.577269 · Cited by 64 · see citing works
Zhang, F., Fu, Y., Zhou, X., Pan, W. X., Shi, Y., Wang, M., Zhang, X., Qi, D., Li, L., Ma, K., et al. (2016) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2016.06.001 · Cited by 48 · see citing works
Jain, P., Hassan, A. M., Koyani, C. N., Mayerhofer, R., Reichmann, F., Farzi, A., Schuligoi, R., Malle, E., & Holzer, P. D. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00177 · Cited by 47 · see citing works
A novel biomarker panel for irritable bowel syndrome and the application in the general population
Mujagic, Z., Tigchelaar, E. F., Zhernakova, A., Ludwig, T. G., Ramiro‐Garcia, J., Baranska, A., Swertz, M. A., Masclee, A., Wijmenga, C., van Schooten, F., et al. (2016) · Scientific Reports · doi:10.1038/srep26420 · Cited by 46 · see citing works
Antidepressant-like effect of pramipexole in an inflammatory model of depression
Lieberknecht, V., Cunha, M. P., Junqueira, S. C., Coelho, I. D. S., de Souza, L. F., Santos, A. R. S., Rodrigues, A. L. S., Dutra, R. C., & Dafré, A. L. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.11.007 · Cited by 45 · see citing works
Stress in the microbiome-immune crosstalk
Beurel, E. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2327409 · Cited by 46 · see citing works
Petrella, C., Strimpakos, G., Torcinaro, A., Middei, S., Ricci, V., Gargari, G., Mora, D., Santa, F. D., & Vecchioli, S. F. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105795 · Cited by 38 · see citing works
Grill, M., Hasenoehrl, C., Kienzl, M., Kargl, J., & Schicho, R. (2018) · Histochemistry and Cell Biology · doi:10.1007/s00418-018-1719-0 · Cited by 28 · see citing works
Neuroimmune pharmacological approaches
Holzer, P. D., Hassan, A. M., Jain, P., Reichmann, F., & Farzi, A. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.09.003 · Cited by 27 · see citing works
Zenz, G., Jačan, A., Reichmann, F., Farzi, A., & Holzer, P. D. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00359 · Cited by 23 · see citing works
Considering the Microbiome in Stress-Related and Neurodevelopmental Trajectories to Schizophrenia
Hoffman, K. W., Lee, J. J., Corcoran, C. M., Kimhy, D., Kranz, T. M., & Malaspina, D. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00629 · Cited by 23 · see citing works
Root-Bernstein, R. S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134645 · Cited by 24 · see citing works
Chaskiel, L., Paul, F., Gerstberger, R., Hübschle, T., & Konsman, J. P. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.03.030 · Cited by 22 · see citing works
Gut-Brain Axis and its Neuro-Psychiatric Effects: A Narrative Review
Shaik, L., Kashyap, R., Thotamgari, S. R., Singh, R., & Khanna, S. (2020) · Cureus · doi:10.7759/cureus.11131 · Cited by 22 · see citing works
Holzer, P. D. (2017) · New approaches to the scientific study of religion · doi:10.1007/978-3-319-50924-2_31 · Cited by 21 · see citing works
The disrupted molecular circadian clock of monocytes and macrophages in allergic inflammation
Teppan, J., Schwanzer, J., Rittchen, S., Bärnthaler, T., Lindemann, J., Nayak, B. B., Reiter, B. F. E., Luschnig, P., Farzi, A., Heinemann, A., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1408772 · Cited by 20 · see citing works
de Gomes, M. G., Teixeira, F. E. G., de Carvalho, F. B., Pacheco, C. O., Neto, M. R. D. S., Giacomeli, R., Ramalho, J. B., dos Santos, R. B., Domingues, W. B., Campos, V. F., et al. (2020) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2020.577270 · Cited by 20 · see citing works
Huang, S., Wu, J., Gao, X., Zou, S., Chen, L., Yang, X., Sun, C., Du, Y., Zhu, B., Li, J., et al. (2018) · Molecular Immunology · doi:10.1016/j.molimm.2018.06.002 · Cited by 20 · see citing works
Galmiche, M. C., Achamrah, N., Déchelotte, P., Ribet, D., & Breton, J. (2021) · Nutrition Reviews · doi:10.1093/nutrit/nuab030 · Cited by 16 · see citing works
Knuplez, E., Kienzl, M., Trakaki, A., Schicho, R., Heinemann, Á., Sturm, E. M., & Marsche, G. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15368 · Cited by 15 · see citing works
Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells
Xiang, C., Chen, P., Zhang, Q., Li, Y., Pan, Y., Xie, W., Sun, J., & Liu, Z. (2021) · iScience · doi:10.1016/j.isci.2021.102849 · Cited by 15 · see citing works
Zenz, G., Farzi, A., Fröhlich, E. E., Reichmann, F., & Holzer, P. D. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00758-9 · Cited by 13 · see citing works
Altered Tryptophan-Kynurenine Pathway in Delirium: A Review of the Current Literature
Ang, H. P., Makpol, S., Nasaruddin, M. L., Zaidi, W. A. W., Ahmad, N. S., & Embong, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065580 · Cited by 13 · see citing works
Lam, R., Haider, S. H., Crowley, G., Caraher, E. J., Ostrofsky, D. F., Talusan, A., Kwon, S., Prezant, D. J., Wang, Y., Liu, M., et al. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17124318 · Cited by 14 · see citing works
Tucci, P., Bové, M., Sikora, V., Dimonte, S., Morgese, M. G., Schiavone, S., Mannelli, L. D. C., Ghelardini, C., & Trabace, L. (2022) · Pharmaceuticals · doi:10.3390/ph15091054 · Cited by 12 · see citing works
Dhaya, I., Griton, M., Raffard, G., Amri, M., Hiba, B., & Konsman, J. P. (2017) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2017.11.009 · Cited by 12 · see citing works
Neurological Infection, Kynurenine Pathway, and Parasitic Infection by Neospora caninum
Del’Arco, A. E., Argolo, D. S., Guillemin, G. J., Costa, M. D. F. D., Costa, S. L., & Pinheiro, A. M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.714248 · Cited by 11 · see citing works
Sini San ameliorates lipid metabolism in hyperprolactinemia rat with liver-depression
Xu, W., Tian, S., Mao, G., Li, Y., Qian, H., & Wenhua, T. (2024) · Current Research in Food Science · doi:10.1016/j.crfs.2024.100853 · Cited by 8 · see citing works
The molecular circadian clock of eosinophils: a potential therapeutic target for asthma
Teppan, J., Bärnthaler, T., Farzi, A., Durrington, H. J., Tavernier, G., Platt, H., Wolf, P., Heinemann, Á., & Böhm, E. (2025) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00149.2025 · Cited by 8 · see citing works
Sera of Neuromyelitis Optica Patients Increase BID-Mediated Apoptosis in Astrocytes
Zveik, O., Rechtman, A., Haham, N., Adini, I., Canello, T., Lavon, I., Brill, L., & Vaknin‐Dembinsky, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137117 · Cited by 7 · see citing works
Physiopathological Roles of White Adiposity and Gut Functions in Neuroinflammation
Spinedi, E., & Docena, G. H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252111741 · Cited by 7 · see citing works
Wang, Y., Wu, W., Zeng, F., Meng, X., Peng, M., Wang, D., Chen, Z., & Liu, W. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.115070 · Cited by 6 · see citing works
DeKorver, N. W., Chaudoin, T. R., & Bonasera, S. J. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00219 · Cited by 6 · see citing works
Zhu, W., Yuan, Y., Guan, X., Xie, Q., Sun, X., & Dong, Z. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123750 · Cited by 5 · see citing works
Characterization of fever and sickness behavior regulated by cytokines during infection
Li, W., Luo, S., & Wan, C. (2020) · Behaviour · doi:10.1163/1568539x-bja10028 · Cited by 5 · see citing works
Sidenkova, A. P., Myakotnykh, V. S., Сергеевна, В. Е., Мельник, А. А., Borovkova, T. A., & Proshchenko, D. A. (2022) · Psikhiatriya · doi:10.30629/2618-6667-2022-20-3-98-111 · Cited by 4 · see citing works
Nod-like receptors are critical for gut-brain axis signalingPreprint
Pusceddu, M. M., Barboza, M., Schneider, M., Stokes, P., Sladek, J. A., Torres‐Fuentes, C., Goldfild, L. R., Gillis, S. E., Brust‐Mascher, I., Rabasa, G., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/647032 · Cited by 3 · see citing works
Lee, I. N., Huang, T. L., Huang, Y. L., Hung, Y. Y., & Kang, H. Y. (2018) · Neuropsychiatry · doi:10.4172/neuropsychiatry.1000385 · Cited by 2 · see citing works
The interplay between genetics, the microbiome, DNA‐methylation & gene‐expression
Bonder, M. J. (2017) · Cited by 1 · see citing works
Gut Hormones and Neuropeptides as Mediators of Microbiome–Brain Communication
Holzer, P. D., & Farzi, A. (2020) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780190931544.013.1 · Cited by 1 · see citing works
Root-Bernstein, R. S. (2019) · Preprints.org · doi:10.20944/preprints201906.0028.v1
Chan, K. L. (2017) · TSpace (University of Toronto)
Григорьевич, М. Д., Deryabin, P. G., Grigoryan, S. S., Мишин, Д. В., Андронова, В. Л., Ei, I., Ga, G., & Ilyichev, A. V. (2020) · Doklady Biological Sciences · doi:10.1134/s0012496620020076
Environment-host-microbe interactions shape human metabolism
Chen, L., & Fu, J. (2021) · doi:10.33612/diss.171839167
Yang, J., Gao, Y., Han, L., Guo, Y., Zhang, Q., Miao, H., & 李天佐 (2026) · Neurochemistry International · doi:10.1016/j.neuint.2026.106277
Epigenetic factors in eating disorders: Clinical correlates and diagnostic specificity
Booij, L., Breton, É., Thaler, L., & Steiger, H. (2026) · Handbook of clinical neurology · doi:10.1016/b978-0-443-19043-8.00011-6
Haag, M., Herceg, K., Ip, C. K., Jačan, A., Reichmann, F., Herzog, H., Meinitzer, A., Holzer, P., Hassan, A. M., & Farzi, A. (2026) · Neurotherapeutics · doi:10.1016/j.neurot.2026.e01100
- Authors
- Farzi, A., Reichmann, F., Meinitzer, A., Mayerhofer, R., Jain, P., Hassan, A. M., Fröhlich, E. E., Wagner, K., Painsipp, E., Rinner, B., & Holzer, P.
- Affiliations
- Medical University of Graz (AT)
- Corresponding author
- Farzi, Aitak
- ORCID
- Venue
- Brain Behavior and Immunity
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 44
- Pages
- 106-120
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC4295938
- OpenAlex
- W1997503261
- Cited by
- 68
- References
- 79
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 1 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 6 · 2018: 5 · 2017: 10 · 2016: 6 · 2015: 5 · 2014: 1
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Austrian Science Fund (P23097-B18, P25912-B23, W1241-B18)
- Medical University of Graz
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- NOD1, NOD2, TLR4, lipopolysaccharide, sickness behavior, muramyl dipeptide, inflammatory cytokines, kynurenine, c-fos, neuroimmune interactions, immune activation, depression-like behavior
- MeSH terms
- Acetylmuramyl-Alanyl-Isoglutamine, Adjuvants, Immunologic, Animals, Brain, Corticosterone, Eating, Kynurenine, Lipopolysaccharides, Male, Mice, Inbred C57BL, Motor Activity, Oligopeptides, RNA, Messenger, Tryptophan, Cytokines, Proto-Oncogene Proteins c-fos, Toll-Like Receptor 4, Mice, Nod2 Signaling Adaptor Protein, Nod1 Signaling Adaptor Protein, Illness Behavior
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