Comparative Studies on Phospholipase A2 as a Marker for Gut Microbiota- liver-brain Axis in a rodent Model of Autism

Abeer       Al-Dbass; Abir    Ben    Bacha; Nadine    M.S.    Moubayed; Ramesa    Shafi    Bhat; Manar       Al-Mutairi; Osima    M.    Alnakhli; Majidh       Al-Mrshoud; Hanan       Alfawaz; Maha       Daghestani; Afaf       El-Ansary

doi:10.2174/1570164617999200519100634

Abstract

Background: Lipid homeostasis and gut flora can be related to many metabolic diseases, especially autism. Lipid metabolism in the brain can control neuronal structure and function and can also take part in signal transduction pathways to control metabolism in peripheral tissues, especially in the liver. Impaired phospholipid metabolism promotes oxidative stress and neuroinflammation and is, therefore, directly related to autism.

Objective: The effect of propionic acid (PPA) toxicity on lipid homeostasis in the gut-liver-brain axis was evaluated to understand their inter-connection. Cytosolic phospholipase A2 (cPLA2) concentration and activity was measured in autistic model and protective role of omega-3 (ω-3) and vitamin B12 was evaluated.

Methods: Animals were divided into five groups: Group I (control group); Group II (autistic model treated with neurotoxic dose of PPA); Group III (treated with vitamin B12 (16.7 mg/kg/day) for 30 days post PPA treatment); Group IV (treated with ω-3 (200 mg/kg body weight/day) for 30 days post PPA treatment; Group V (combined dose of ω-3 and Vitamin B12, for 30 days post PPA treatment). Phospholipase A2 activity and protein expression level in the liver homogenate of all the groups was analyzed by western blotting and was compared to brain cPLA2.

Results: PPA increased the levels of liver and brain cPLA2. However, independent or combined treatment with ω-3 and vitamin B12 was effective in neutralizing its effect. Moreover, PPA-induced dysbiosis, which was ameliorated with the above treatments.

Conclusion : This study showed the role of cPLA2 as a lipid metabolism marker, related to PPA-induced inflammation through a highly interactive gut-liver-brain axis.

Keywords: Autism, phospholipase A2, western blotting, gut microbiota, gut-liver-brain axis, metabolism.

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[1] 
Jandhyala, S.M.; Talukdar, R.; Subramanyam, C.; Vuyyuru, H.; Sasikala, M.; Nageshwar Reddy, D. Role of the normal gut microbiota. World J. Gastroenterol.,  2015, 21(29), 8787-8803.
[http://dx.doi.org/10.3748/wjg.v21.i29.8787] [PMID: 26269668] 
[2] 
Shamoon, M.; Martin, N.M.; O’Brien, C.L. Recent advances in gut Microbiota mediated therapeutic targets in inflammatory bowel diseases: emerging modalities for future pharmacological implications. Pharmacol. Res.,  2019, 148, 104344.
[http://dx.doi.org/10.1016/j.phrs.2019.104344] [PMID: 31400403] 
[3] 
Round, J.L.; Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol.,  2009, 9(5), 313-323.
[http://dx.doi.org/10.1038/nri2515] [PMID: 19343057] 
[4] 
Park, W. Gut microbiomes and their metabolites shape human and animal health. J. Microbiol.,  2018, 56(3), 151-153.
[http://dx.doi.org/10.1007/s12275-018-0577-8] [PMID: 29492871] 
[5] 
Feng, Q.; Chen, W.D.; Wang, Y.D. Gut microbiota: an integral moderator in health and disease. Front. Microbiol.,  2018, 9, 151.
[http://dx.doi.org/10.3389/fmicb.2018.00151] [PMID: 29515527] 
[6] 
Bhattarai, Y.; Muniz Pedrogo, D.A.; Kashyap, P.C. Irritable bowel syndrome: a gut microbiota-related disorder? Am. J. Physiol. Gastrointest. Liver Physiol.,  2017, 312(1), G52-G62.
[http://dx.doi.org/10.1152/ajpgi.00338.2016] [PMID: 27881403] 
[7] 
Wahlström, A. Outside the liver box: The gut microbiota as pivotal modulator of liver diseases. Biochim. Biophys. Acta Mol. Basis Dis.,  2019, 1865(5), 912-919.
[http://dx.doi.org/10.1016/j.bbadis.2018.07.004] [PMID: 31007175] 
[8] 
Tilg, H.; Cani, P.D.; Mayer, E.A. Gut microbiome and liver diseases. Gut,  2016, 65(12), 2035-2044.
[http://dx.doi.org/10.1136/gutjnl-2016-312729] [PMID: 27802157] 
[9] 
Diaz Heijtz, R. Fetal, neonatal, and infant microbiome: perturbations and subsequent effects on brain development and behavior. Semin. Fetal Neonatal Med.,  2016, 21(6), 410-417.
[http://dx.doi.org/10.1016/j.siny.2016.04.012] [PMID: 27255860] 
[10] 
Dinan, T.G.; Cryan, J.F. Microbes, immunity, and behavior: psychoneuroimmunology meets the microbiome. Neuropsychopharmacology,  2017, 42(1), 178-192.
[http://dx.doi.org/10.1038/npp.2016.103] [PMID: 27319972] 
[11] 
Sampson, T.R.; Mazmanian, S.K. Control of brain development, function, and behavior by the microbiome. 2015.
[http://dx.doi.org/10.1016/j.chom.2015.04.011] 
[12] 
Sherman, M.P.; Zaghouani, H.; Niklas, V. Gut microbiota, the immune system, and diet influence the neonatal gut-brain axis. Pediatr. Res.,  2015, 77(1-2), 127-135.
[http://dx.doi.org/10.1038/pr.2014.161] [PMID: 25303278] 
[13] 
Wall, R.; Cryan, J.F.; Ross, R.P.; Fitzgerald, G.F.; Dinan, T.G.; Stanton, C. Bacterial neuroactive compounds produced by psychobiotics. Adv. Exp. Med. Biol.,  2014, 817, 221-239.
[http://dx.doi.org/10.1007/978-1-4939-0897-4_10] [PMID: 24997036] 
[14] 
MacFabe, D.F.; Cain, D.P.; Rodriguez-Capote, K.; Franklin, A.E.; Hoffman, J.E.; Boon, F.; Taylor, A.R.; Kavaliers, M.; Ossenkopp, K.P. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav. Brain Res.,  2007, 176(1), 149-169.
[http://dx.doi.org/10.1016/j.bbr.2006.07.025] [PMID: 16950524] 
[15] 
El-Ansary, A.K.; Ben Bacha, A.; Kotb, M. Etiology of autistic features: thepersisting neurotoxic effects of propionic acid. J. Neuroinflammation,  2012, 24, 9-74.
[16] 
Kraimi, N.; Dawkins, M.; Gebhardt-Henrich, S.G.; Velge, P.; Rychlik, I.; Volf, J.; Creach, P.; Smith, A.; Colles, F.; Leterrier, C. Influence of the microbiota-gut-brain axis on behavior and welfare in farm animals: A review. Physiol. Behav.,  2019, 210, 112658.
[http://dx.doi.org/10.1016/j.physbeh.2019.112658] [PMID: 31430443] 
[17] 
Sharon, G.; Cruz, N.J.; Kang, D.W.; Gandal, M.J.; Wang, B.; Kim, Y.M.; Zink, E.M.; Casey, C.P.; Taylor, B.C.; Lane, C.J.; Bramer, L.M.; Isern, N.G.; Hoyt, D.W.; Noecker, C.; Sweredoski, M.J.; Moradian, A.; Borenstein, E.; Jansson, J.K.; Knight, R.; Metz, T.O.; Lois, C.; Geschwind, D.H.; Krajmalnik-Brown, R.; Mazmanian, S.K. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell,  2019, 177(6), 1600-1618.e17.
[http://dx.doi.org/10.1016/j.cell.2019.05.004] [PMID: 31150625] 
[18] 
Wang, S.; Harvey, L.; Martin, R.; van der Beek, E.M.; Knol, J.; Cryan, J.F.; Renes, I.B. Targeting the gut microbiota to influence brain development and function in early life. Neurosci. Biobehav. Rev.,  2018, 95, 191-201.
[http://dx.doi.org/10.1016/j.neubiorev.2018.09.002] [PMID: 30195933] 
[19] 
El-Ansary, A.; Chirumbolo, S.; Bhat, R.S.; Dadar, M.; Ibrahim, E.M.; Bjørklund, G. The role of lipidomics in autism spectrum disorder. Mol. Diagn. Ther.,  2019, 5.
[PMID: 31691195] 
[20] 
Aizawa, F.; Nishinaka, T.; Yamashita, T.; Nakamoto, K.; Koyama, Y.; Kasuya, F.; Tokuyama, S. Astrocytes release polyunsaturated fatty acids by lipopolysaccharide stimuli. Biol. Pharm. Bull.,  2016, 39(7), 1100-1106.
[http://dx.doi.org/10.1248/bpb.b15-01037] [PMID: 27374285] 
[21] 
Robichaud, P.P.; Surette, M.E. Polyunsaturated fatty acid-phospholipid remodeling and inflammation. Curr. Opin. Endocrinol. Diabetes Obes.,  2015, 22(2), 112-118.
[http://dx.doi.org/10.1097/MED.0000000000000138] [PMID: 25692925] 
[22] 
Law, M.H.; Cotton, R.G.; Berger, G.E. The role of phospholipases A2 in schizophrenia. Mol. Psychiatry,  2006, 11(6), 547-556.
[http://dx.doi.org/10.1038/sj.mp.4001819] [PMID: 16585943] 
[23] 
Qasem, H.; Al-Ayadhi, L.; Al Dera, H.; El-Ansary, A. Increase of cytosolic phospholipase A2 as hydrolytic enzyme of phospholipids and autism cognitive, social and sensory dysfunction severity. Lipids Health Dis.,  2017, 16(1), 117.
[http://dx.doi.org/10.1186/s12944-016-0391-4] [PMID: 28724385] 
[24] 
Stremmel, W.; Ehehalt, R.; Staffer, S.; Stoffels, S.; Mohr, A.; Karner, M.; Braun, A. Mucosal protection by phosphatidylcholine. Dig. Dis.,  2012, 30(Suppl. 3), 85-91.
[http://dx.doi.org/10.1159/000342729] [PMID: 23295697] 
[25] 
Kouzoukas, DE; Schreiber, JA; Tajuddin, NF; Kaja, S; Neafsey, EJ; Kim, HY; Collins, M.A. PARP inhibition in vivo blocks alcohol-induced brain neurodegeneration and neuroinflammatory cytosolic phospholipase A2 elevations. 2019.
[http://dx.doi.org/10.1016/j.neuint.2019.104497] 
[26] 
Kang, C.; Wang, B.; Kaliannan, K.; Wang, X.; Lang, H.; Hui, S.; Huang, L.; Zhang, Y.; Zhou, M.; Chen, M.; Mi, M. Gut Microbiota Mediates the Protective Effects of Dietary Capsaicin against Chronic Low-Grade Inflammation and Associated Obesity Induced by High-Fat Diet. MBio,  2017, 58(4), e00900-e00917.
[27] 
Tan, J.; McKenzie, C.; Potamitis, M.; Thorburn, A.N. Mackay, CR Chapter three - the role of short-chain fatty acids in health and disease. Adv. Immunol.,  2014, 121, 91-119.
[28] 
Zhang, F.M.; Wang, H.G.; Wang, M. Fecal microbiota transplantation for severe enterocolonic fistulizing Crohn’s disease. World J. Gastroenterol.,  2013, 19, 7213-7216.
[29] 
Li, S.S.; Zhu, A.; Benes, V.; Costea, P.I.; Hercog, R.; Hildebrand, F.; Huerta-Cepas, J.; Nieuwdorp, M.; Salojärvi, J.; Voigt, A.Y.; Zeller, G.; Sunagawa, S.; de Vos, W.M.; Bork, P. Durable coexistence of donor and recipient strains after fecal microbiota transplantation. Science,  2016, 352(6285), 586-589.
[http://dx.doi.org/10.1126/science.aad8852] [PMID: 27126044] 
[30] 
Alfawaz, H.; Bhat, R.S.; Al-Mutairi, M.; Alnakhli, O.M.; Al-Dbass, A.; AlOnazi, M.; Al-Mrshoud, M.; Hasan, I.H.; El-Ansary, A. Comparative study on the independent and combined effects of omega-3 and vitamin B12 on phospholipids and phospholipase A2 as phospholipid hydrolyzing enzymes in PPA-treated rats as a model for autistic traits. Lipids Health Dis.,  2018, 17(1), 205.
[http://dx.doi.org/10.1186/s12944-018-0850-1] [PMID: 30170600] 
[31] 
Alfawaz, H.; Al-Onazi, M.; Bukhari, S.I. The Independent and Combined Effects of Omega-3 and Vitamin B12 in Ameliorating Propionic Acid Induced Biochemical Features in Juvenile Rats as Rodent Model of Autism. J Mol Neurosci.,  2018, 66(3), 403-413.
[32] 
Aabed, K.; Shafi Bhat, R.; Moubayed, N.; Al-Mutiri, M.; Al-Marshoud, M.; Al-Qahtani, A.; Ansary, A. Ameliorative effect of probiotics (Lactobacillus paracaseii and Protexin®) and prebiotics (propolis and bee pollen) on clindamycin and propionic acid-induced oxidative stress and altered gut microbiota in a rodent model of autism. Cell. Mol. Biol.,  2019, 65(1), 1-7.
[http://dx.doi.org/10.14715/cmb/2019.65.1.1] [PMID: 30782287] 
[33] 
Rapoport, S.I.; Rao, J.S.; Igarashi, M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot. Essent. Fatty Acids,  2007, 77(5-6), 251-261.
[http://dx.doi.org/10.1016/j.plefa.2007.10.023] [PMID: 18060754] 
[34] 
Dennis, E.A. Diversity of group types, regulation, and function of phospholipase A2. J. Biol. Chem.,  1994, 6269(18), 13057-13060.
[35] 
Bosetti, F.; Weerasinghe, G.R. The expression of brain cyclooxygenase-2 is down-regulated in the cytosolic phospholipase A2 knockout mouse. J. Neurochem.,  2003, 87(6), 1471-1477.
[http://dx.doi.org/10.1046/j.1471-4159.2003.02118.x] [PMID: 14713302] 
[36] 
Rao, J.S.; Ertley, R.N.; DeMar, J.C., Jr; Rapoport, S.I.; Bazinet, R.P.; Lee, H.J. Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex. Mol. Psychiatry,  2007, 12(2), 151-157.
[http://dx.doi.org/10.1038/sj.mp.4001887] [PMID: 16983392] 
[37] 
Basselin, M.; Chang, L.; Seemann, R.; Bell, J.M.; Rapoport, S.I. Chronic lithium administration potentiates brain arachidonic acid signaling at rest and during cholinergic activation in awake rats. J. Neurochem.,  2003, 85(6), 1553-1562.
[http://dx.doi.org/10.1046/j.1471-4159.2003.01811.x] [PMID: 12787074] 
[38] 
Bell, J.G.; MacKinlay, E.E.; Dick, J.R.; MacDonald, D.J.; Boyle, R.M.; Glen, A.C. Essential fatty acids and phospholipase A2 in autistic spectrum disorders. Prostaglandins Leukot. Essent. Fatty Acids,  2004, 71(4), 201-204.
[http://dx.doi.org/10.1016/j.plefa.2004.03.008] [PMID: 15301788] 
[39] 
Finegold, S.M.; Dowd, S.E.; Gontcharova, V.; Liu, C.; Henley, K.E.; Wolcott, R.D.; Youn, E.; Summanen, P.H.; Granpeesheh, D.; Dixon, D.; Liu, M.; Molitoris, D.R.; Green, J.A., III Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe,  2010, 16(4), 444-453.
[http://dx.doi.org/10.1016/j.anaerobe.2010.06.008] [PMID: 20603222] 
[40] 
Parracho, H.M.; Bingham, M.O.; Gibson, G.R.; McCartney, A.L. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J. Med. Microbiol.,  2005, 54(Pt 10), 987-991.
[http://dx.doi.org/10.1099/jmm.0.46101-0] [PMID: 16157555] 
[41] 
Song, Y.L.; Liu, C.X.; McTeague, M.; Summanen, P.; Finegold, S.M. Clostridium bartlettii sp. nov., isolated from human faeces. Anaerobe,  2004, 10(3), 179-184.
[http://dx.doi.org/10.1016/j.anaerobe.2004.04.004] [PMID: 16701516] 
[42] 
Laine, V.J.O.; Grass, D.S.; Nevalainen, T.J. Protection by group II phospholipase A2 against Staphylococcus aureus. J. Immunol.,  1999, 162(12), 7402-7408.
[PMID: 10358193] 
[43] 
Nicolson, G.L.; Gan, R.; Nicolson, N.L.; Haier, J. Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders. J. Neurosci. Res.,  2007, 85(5), 1143-1148.
[http://dx.doi.org/10.1002/jnr.21203] [PMID: 17265454] 
[44] 
Jeong, S.; Kim, H.Y.; Kim, A.R.; Yun, C.H.; Han, S.H. 
                        Propionate Ameliorates 
                        Staphylococcus aureus
                         Skin Infection by Attenuating Bacterial Growth.
                     Front. Microbiol.,  2019, 10, 1363.
[http://dx.doi.org/10.3389/fmicb.2019.01363] [PMID: 31275281] 
[45] 
Acton, D.S.; Plat-Sinnige, M.J.; van Wamel, W.; de Groot, N.; van Belkum, A. Intestinal carriage of Staphylococcus aureus: how does its frequency compare with that of nasal carriage and what is its clinical impact? Eur. J. Clin. Microbiol. Infect. Dis.,  2009, 28(2), 115-127.
[http://dx.doi.org/10.1007/s10096-008-0602-7] [PMID: 18688664] 
[46] 
Sannasiddappa, T.H.; Costabile, A.; Gibson, G.R.; Clarke, S.R. The influence of Staphylococcus aureus on gut microbial ecology in an in vitro continuous culture human colonic model system. PLoS One,  2011, 6(8), e23227.
[http://dx.doi.org/10.1371/journal.pone.0023227] [PMID: 21858036] 
[47] 
Foreman-Wykert, A.K.; Weiss, J.; Elsbach, P. Phospholipid synthesis by Staphylococcus aureus during (Sub)Lethal attack by mammalian 14-kilodalton group IIA phospholipase A2. Infect. Immun.,  2000, 68(3), 1259-1264.
[http://dx.doi.org/10.1128/IAI.68.3.1259-1264.2000] [PMID: 10678935] 
[48] 
El-Ansary, A.K.; Bacha, A.G.; Al-Ayahdi, L.Y. Plasma fatty acids as diagnostic markersin autistic patients from Saudi Arabia. Lipids Health Dis.,  2000, 2011(10), 62.
[49] 
Sitkiewicz, I.; Stockbauer, K.E.; Musser, J.M. Secreted bacterial phospholipase A2 enzymes: better living through phospholipolysis. Trends Microbiol.,  2007, 15(2), 63-69.
[http://dx.doi.org/10.1016/j.tim.2006.12.003] [PMID: 17194592] 
[50] 
Li, Z.; Qu, M.; Sun, Y.; Wan, H.; Chai, F.; Liu, L.; Zhang, P. Blockage of cytosolic phospholipase A2 alpha sensitizes aggressive breast cancer to doxorubicin throughsuppressing ERK and mTOR kinases. Biochem. Biophys. Res. Commun.,  2018, 496(1), 153-158.
[51] 
Hiller, G.; Sundler, R. Activation of arachidonate release and cytosolic phospholipase A2 via extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in macrophages stimulated by bacteria or zymosan. Cell. Signal.,  1999, 11(12), 863-869.
[http://dx.doi.org/10.1016/S0898-6568(99)00058-3] [PMID: 10659994] 
[52] 
Witters, P.; Debbold, E.; Crivelly, K.; Vande Kerckhove, K.; Corthouts, K.; Debbold, B.; Andersson, H.; Vannieuwenborg, L.; Geuens, S.; Baumgartner, M.; Kozicz, T.; Settles, L.; Morava, E. Autism in patients with propionic acidemia. Mol. Genet. Metab.,  2016, 119(4), 317-321.
[http://dx.doi.org/10.1016/j.ymgme.2016.10.009] [PMID: 27825584] 
[53] 
Brusilow, S.W.; Koehler, R.C.; Traystman, R.J.; Cooper, A.J. Astrocyte glutamine synthetase: importance in hyperammonemic syndromes and potential target for therapy. Neurotherapeutics,  2010, 7(4), 452-470.
[http://dx.doi.org/10.1016/j.nurt.2010.05.015] [PMID: 20880508] 
[54] 
Ambrogini, P.; Torquato, P.; Bartolini, D.; Albertini, M.C.; Lattanzi, D.; Di Palma, M.; Marinelli, R.; Betti, M.; Minelli, A.; Cuppini, R.; Galli, F. Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: the role of vitamin E. Biochim. Biophys. Acta Mol. Basis Dis.,  2019, 1865(6), 1098-1112.
[http://dx.doi.org/10.1016/j.bbadis.2019.01.026] [PMID: 30703511] 
[55] 
Ueda, Y.; Yokoyama, H.; Nakajima, A.; Tokumaru, J.; Doi, T.; Mitsuyama, Y. Glutamate excess and free radical formation during and following kainic acid-induced status epilepticus. Exp. Brain Res.,  2002, 147(2), 219-226.
[http://dx.doi.org/10.1007/s00221-002-1224-4] [PMID: 12410337] 
[56] 
Choudhury, S.; Borah, A. Activation of NMDA receptor by elevated homocysteine in chronic liver disease contributes to encephalopathy. Med. Hypotheses,  2015, 85(1), 64-67.
[http://dx.doi.org/10.1016/j.mehy.2015.03.027] [PMID: 25881985] 

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DOI https://dx.doi.org/10.2174/1570164617999200519100634	Print ISSN 1570-1646
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Current Proteomics

Comparative Studies on Phospholipase A2 as a Marker for Gut Microbiota- liver-brain Axis in a rodent Model of Autism

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