Abstract
Background: Autism Spectrum Disorder (ASD) is a condition strongly associated with genetic predisposition and familial aggregation. Among ASD patients, different levels of symptoms severity are detectable, while the presence of intermediate autism phenotypes in close relatives of ASD probands is also known in literature. Recently, increasing attention has been paid to environmental factors that might play a role in modulating the relationship between genomic risk and development and severity of ASD. Within this framework, an increasing body of evidence has stressed a possible role of both gut microbiota and inflammation in the pathophysiology of neurodevelopment. The aim of this paper is to review findings about the link between microbiota dysbiosis, inflammation and ASD.
Methods: Articles ranging from 1990 to 2018 were identified on PUBMED and Google Scholar databases, with keyword combinations as: microbiota, immune system, inflammation, ASD, autism, broad autism phenotype, adult.
Results: Recent evidence suggests that microbiota alterations, immune system and neurodevelopment may be deeply intertwined, shaping each other during early life. However, results from both animal models and human samples are still heterogeneous, while few studies focused on adult patients and ASD intermediate phenotypes.
Conclusion: A better understanding of these pathways, within an integrative framework between central and peripheral systems, might not only shed more light on neural basis of ASD symptoms, clarifying brain pathophysiology, but it may also allow to develop new therapeutic strategies for these disorders, still poorly responsive to available treatments.
Keywords: Autism spectrum disorders, gut microbiota, immune system, inflammation, gut-brain axis, neurodevelopment.
[http://dx.doi.org/10.1176/appi.books.9780890425596]
[http://dx.doi.org/10.1017/S1092852915000450] [PMID: 26349624]
[http://dx.doi.org/10.1016/j.comppsych.2016.11.001] [PMID: 27918948]
[http://dx.doi.org/10.1007/s11065-011-9183-9] [PMID: 21989834]
[http://dx.doi.org/10.3389/fnins.2016.00346] [PMID: 27499732]
[http://dx.doi.org/10.1162/jocn.1997.9.4.548] [PMID: 23968217]
[http://dx.doi.org/10.1023/A:1026048320785] [PMID: 9813774]
[http://dx.doi.org/10.1002/ajmg.b.30612] [PMID: 17948871]
[http://dx.doi.org/10.1016/j.comppsych.2018.01.002] [PMID: 29500962]
[http://dx.doi.org/10.1016/j.comppsych.2017.11.007] [PMID: 29268154]
[http://dx.doi.org/ 10.1155/2018/1547975] [PMID: 29682383]
[http://dx.doi.org/10.1016/j.psyneuen.2018.01.008] [PMID: 29414026]
[http://dx.doi.org/10.1111/j.1469-7610.1977.tb00443.x] [PMID: 562353]
[http://dx.doi.org/10.1002/ajmg.b.31159] [PMID: 21438136]
[http://dx.doi.org/10.1111/jcpp.12499] [PMID: 26709141]
[http://dx.doi.org/10.1016/j.gde.2012.03.002] [PMID: 22463983]
[http://dx.doi.org/10.1016/j.neuroscience.2018.01.060] [PMID: 29427656]
[http://dx.doi.org/10.1146/annurev.publhealth.28.021406.144007] [PMID: 17367287]
[http://dx.doi.org/10.1097/01.chi.0000242244.00174.d9] [PMID: 17195733]
[http://dx.doi.org/10.3390/ijerph10094261] [PMID: 24030655]
[http://dx.doi.org/10.1016/S0022-3476(61)80261-8] [PMID: 13747230]
[http://dx.doi.org/10.1016/j.euroneuro.2014.02.004] [PMID: 24613076]
[http://dx.doi.org/10.3390/ph11020056] [PMID: 29867038]
[http://dx.doi.org/10.1038/mp.2014.59] [PMID: 24934179]
[http://dx.doi.org/10.1016/j.bbi.2011.08.007] [PMID: 21906670]
[http://dx.doi.org/10.1007/s12264-017-0103-8] [PMID: 28238116]
[http://dx.doi.org/10.1038/nrn3346] [PMID: 22968153]
[http://dx.doi.org/10.1016/j.molmed.2014.05.002] [PMID: 24956966]
[http://dx.doi.org/10.1007/978-1-4939-0897-4_17] [PMID: 24997043]
[http://dx.doi.org/10.1542/peds.2009-1878D] [PMID: 20048084]
[http://dx.doi.org/10.1371/journal.pone.0033224] [PMID: 22511918]
[http://dx.doi.org/ 10.3969/j.issn.1002-0829.2013.06.003] [PMID: 24991177]
[http://dx.doi.org/10.3389/fnut.2018.00040] [PMID: 29868601]
[http://dx.doi.org/10.3389/fphys.2018.00184] [PMID: 29563885]
[http://dx.doi.org/10.1016/j.clinthera.2015.04.002] [PMID: 26046241]
[http://dx.doi.org/10.3389/fnins.2017.00490] [PMID: 28966571]
[http://dx.doi.org/10.3389/fpsyt.2018.00205] [PMID: 29896124]
[http://dx.doi.org/10.1111/cmi.12301] [PMID: 24720613]
[http://dx.doi.org/10.1002/da.22084] [PMID: 23468190]
[http://dx.doi.org/10.1038/nn.4113] [PMID: 26404713]
[http://dx.doi.org/10.1016/j.ynstr.2016.03.001] [PMID: 27981187]
[http://dx.doi.org/10.1159/000375303] [PMID: 25792275]
[http://dx.doi.org/10.1038/nri2653] [PMID: 19855405]
[http://dx.doi.org/10.1152/ajpgi.00243.2009] [PMID: 20299599]
[http://dx.doi.org/10.1099/mic.0.040139-0] [PMID: 20656777]
[http://dx.doi.org/10.3748/wjg.v16.i33.4145] [PMID: 20806430]
[http://dx.doi.org/10.1186/1550-2783-9-45] [PMID: 22992437]
[http://dx.doi.org/10.1093/intimm/dxh186] [PMID: 15585605]
[http://dx.doi.org/10.1155/2015/527696] [PMID: 25802876]
[http://dx.doi.org/10.1016/S1521-6918(03)00055-6] [PMID: 14507584]
[http://dx.doi.org/10.1001/archpsyc.58.5.445] [PMID: 11343523]
[http://dx.doi.org/10.1111/j.1365-2567.2004.01976.x] [PMID: 15379975]
[http://dx.doi.org/10.1016/j.bbi.2004.10.003] [PMID: 15944074]
[http://dx.doi.org/10.1371/journal.pone.0028330] [PMID: 22164271]
[http://dx.doi.org/10.1016/j.jad.2012.02.023] [PMID: 22410503]
[http://dx.doi.org/10.1016/j.jad.2006.08.021] [PMID: 17007934]
[http://dx.doi.org/10.1186/s40168-016-0171-4] [PMID: 27338587]
[http://dx.doi.org/10.1007/s11481-011-9299-y] [PMID: 21822589]
[http://dx.doi.org/10.1038/ncomms15193] [PMID: 28443631]
[http://dx.doi.org/10.1073/pnas.1010529108] [PMID: 21282636]
[http://dx.doi.org/10.1016/j.bbi.2013.12.005] [PMID: 24333160]
[http://dx.doi.org/10.1007/s00401-009-0622-0] [PMID: 20012873]
[http://dx.doi.org/10.1017/S1740925X12000063] [PMID: 22613055]
[http://dx.doi.org/10.1038/nn.4030] [PMID: 26030851]
[http://dx.doi.org/10.1371/journal.pone.0015973] [PMID: 21283568]
[http://dx.doi.org/10.1016/j.jneuroim.2010.11.002] [PMID: 21115202]
[http://dx.doi.org/10.1176/appi.ajp.2015.14101358] [PMID: 26472628]
[http://dx.doi.org/10.1016/j.bbi.2015.10.003] [PMID: 26441134]
[http://dx.doi.org/10.1016/j.bbi.2010.02.001] [PMID: 20153418]
[http://dx.doi.org/10.1126/science.1228261] [PMID: 23449593]
[http://dx.doi.org/10.1186/s12974-015-0437-y] [PMID: 26602365]
[http://dx.doi.org/10.1007/s00213-016-4218-9] [PMID: 26847047]
[PMID: 9841910]
[http://dx.doi.org/10.4049/jimmunol.178.7.4641] [PMID: 17372023]
[http://dx.doi.org/10.1097/00005176-200404000-00009] [PMID: 15085020]
[http://dx.doi.org/10.1016/j.bbi.2010.10.023] [PMID: 21040780]
[http://dx.doi.org/10.1016/j.psyneuen.2012.03.007] [PMID: 22483040]
[http://dx.doi.org/10.1111/nmo.12198] [PMID: 23910373]
[http://dx.doi.org/10.1155/2016/8469018] [PMID: 28101105]
[http://dx.doi.org/10.1016/j.biopsych.2008.06.026] [PMID: 18723164]
[http://dx.doi.org/10.1097/01.JAA.0000532122.07789.f0] [PMID: 29698377]
[http://dx.doi.org/10.1016/j.cell.2013.11.024] [PMID: 24315484]
[http://dx.doi.org/10.1002/dneu.22581] [PMID: 29411548]
[http://dx.doi.org/10.1038/srep45356] [PMID: 28349974]
[http://dx.doi.org/10.1038/nature23910] [PMID: 28902840]
[http://dx.doi.org/10.1038/mp.2013.65] [PMID: 23689536]
[http://dx.doi.org/10.1186/1471-230X-11-22] [PMID: 21410934]
[http://dx.doi.org/10.1371/journal.pone.0068322] [PMID: 23844187]
[http://dx.doi.org/10.1371/journal.pone.0137725] [PMID: 26427004]
[http://dx.doi.org/10.1099/jmm.0.46101-0] [PMID: 16157555]
[http://dx.doi.org/10.1371/journal.pone.0024585] [PMID: 21949732]
[http://dx.doi.org/10.1128/AEM.05212-11] [PMID: 21784919]
[http://dx.doi.org/10.1016/j.anaerobe.2010.06.008] [PMID: 20603222]
[http://dx.doi.org/10.1371/journal.pone.0076993] [PMID: 24130822]
[http://dx.doi.org/10.1002/aur.1253] [PMID: 22997101]
[http://dx.doi.org/10.1016/S0022-3476(99)70052-1] [PMID: 10547242]
[http://dx.doi.org/10.1186/s40168-017-0242-1] [PMID: 28222761]
[http://dx.doi.org/10.1086/341914] [PMID: 12173102]
[http://dx.doi.org/10.1128/AEM.70.11.6459-6465.2004] [PMID: 15528506]
[http://dx.doi.org/10.1186/2040-2392-4-42] [PMID: 24188502]
[http://dx.doi.org/10.1016/j.physbeh.2014.10.033] [PMID: 25446201]
[PMID: 15798789]
[http://dx.doi.org/10.1016/j.bbr.2010.10.005] [PMID: 20937326]
[http://dx.doi.org/10.1186/1476-511X-13-140] [PMID: 25175350]
[http://dx.doi.org/10.1007/BF01531114] [PMID: 139400]
[http://dx.doi.org/10.1016/j.bbi.2006.08.005] [PMID: 17029701]
[http://dx.doi.org/10.1007/s00213-013-3290-7] [PMID: 24096533]
[PMID: 25523585]
[http://dx.doi.org/10.3389/fncel.2015.00519] [PMID: 26834565]
[http://dx.doi.org/10.1016/j.braindev.2014.03.016] [PMID: 24768169]
[http://dx.doi.org/10.1016/j.neuroscience.2016.03.013] [PMID: 26964681]
[http://dx.doi.org/10.1136/jim-2016-000070] [PMID: 27296457]
[http://dx.doi.org/10.21307/ane-2017-025] [PMID: 28094817]
[http://dx.doi.org/10.1016/j.jneuroim.2008.09.005] [PMID: 18929414]
[http://dx.doi.org/10.1007/BF02172828] [PMID: 8863094]
[http://dx.doi.org/10.1017/S0033291702006037] [PMID: 12455944]
[http://dx.doi.org/10.1002/aur.42] [PMID: 19343198]
[http://dx.doi.org/10.1196/annals.1381.010] [PMID: 17804536]
[http://dx.doi.org/10.1196/annals.1381.009] [PMID: 17804535]
[http://dx.doi.org/10.2217/bmm.14.1] [PMID: 24712424]
[http://dx.doi.org/10.1016/j.bbi.2013.12.020] [PMID: 24389156]
[http://dx.doi.org/10.1007/s11011-015-9784-8] [PMID: 26738726]
[http://dx.doi.org/10.1016/j.bbi.2007.12.006] [PMID: 18255258]
[http://dx.doi.org/10.1016/j.bbr.2009.01.013] [PMID: 19378383]
[http://dx.doi.org/10.1084/jem.20091419] [PMID: 20439540]
[http://dx.doi.org/10.1016/j.bbi.2010.08.003] [PMID: 20705131]
[http://dx.doi.org/10.1016/j.jneuroim.2010.10.025] [PMID: 21095018]
[http://dx.doi.org/10.1186/1479-7364-5-1-30] [PMID: 21106488]
[http://dx.doi.org/10.1371/journal.pone.0020470] [PMID: 21647375]
[http://dx.doi.org/10.3390/bs6040029] [PMID: 27983615]
[http://dx.doi.org/10.18632/oncotarget.19326] [PMID: 29137272]
[http://dx.doi.org/10.1590/1516-4446-2015-1843] [PMID: 28099628]
[PMID: 22473229]
[http://dx.doi.org/10.1016/j.jneuroim.2005.11.007] [PMID: 16360218]
[http://dx.doi.org/10.1186/s12974-015-0466-6] [PMID: 26728085]
[http://dx.doi.org/10.1002/aur.1940] [PMID: 29522267]
[http://dx.doi.org/10.1016/j.ntt.2012.07.006] [PMID: 22918031]
[http://dx.doi.org/10.1016/0165-5728(96)00014-8] [PMID: 8964908]
[http://dx.doi.org/10.1016/j.cyto.2018.03.034] [PMID: 29602155]
[http://dx.doi.org/10.1002/ana.20315] [PMID: 15546155]
[http://dx.doi.org/10.1016/j.biopsych.2010.05.024] [PMID: 20674603]
[http://dx.doi.org/10.1016/j.ijdevneu.2012.08.007] [PMID: 22940293]
[http://dx.doi.org/10.1016/j.neuroscience.2013.08.025] [PMID: 23994594]
[http://dx.doi.org/10.1186/1742-2094-9-265] [PMID: 23231720]
[http://dx.doi.org/10.1186/1742-2094-11-4] [PMID: 24400970]
[http://dx.doi.org/10.1186/1742-2094-10-38] [PMID: 23497090]
[http://dx.doi.org/10.1016/j.ijdevneu.2011.12.003] [PMID: 22197967]
[http://dx.doi.org/10.1016/j.biopsych.2015.08.007] [PMID: 26392128]
[http://dx.doi.org/10.1016/j.neulet.2010.01.033] [PMID: 20097267]
[http://dx.doi.org/10.1016/j.pnpbp.2006.08.020] [PMID: 17030376]
[http://dx.doi.org/10.1038/mp.2016.77] [PMID: 27217154]
[http://dx.doi.org/10.4049/jimmunol.1701755] [PMID: 29967099]
[http://dx.doi.org/10.1038/s41591-018-0021-y] [PMID: 29808008]
[http://dx.doi.org/10.3389/fnins.2016.00601] [PMID: 28105001]
[http://dx.doi.org/10.1038/ncomms4611] [PMID: 24781306]
[http://dx.doi.org/10.1126/scitranslmed.3009759] [PMID: 25411471]
[http://dx.doi.org/10.1038/mp.2017.15] [PMID: 28322282]
[http://dx.doi.org/10.1016/j.neuint.2016.10.011] [PMID: 27984170]
[http://dx.doi.org/10.4137/IJTR.S2129] [PMID: 20651948]
[http://dx.doi.org/10.1155/2016/8952520] [PMID: 26881063]
[http://dx.doi.org/10.1002/aur.1565] [PMID: 26497015]
[PMID: 14719046]
[http://dx.doi.org/10.1155/2011/161358] [PMID: 22114588]
[http://dx.doi.org/10.1542/peds.2007-3007] [PMID: 18829790]
[http://dx.doi.org/10.1007/s10803-009-0714-7] [PMID: 19280328]
[http://dx.doi.org/10.4172/2329-8901.1000102]
[http://dx.doi.org/10.1080/1028415X.2017.1347746] [PMID: 28686541]
[http://dx.doi.org/10.1016/j.jad.2017.11.063] [PMID: 29197739]
[http://dx.doi.org/ 10.1080/10408398.2017.1399860] [PMID: 29190117]
[http://dx.doi.org/10.3945/jn.114.198457] [PMID: 25527669]
[http://dx.doi.org/10.9758/cpn.2015.13.2.188] [PMID: 26243847]
[http://dx.doi.org/10.1186/s40168-016-0225-7] [PMID: 28122648]
[http://dx.doi.org/10.1136/gutjnl-2016-313017] [PMID: 28087657]
[http://dx.doi.org/10.1177/088307380001500701] [PMID: 10921511]
[http://dx.doi.org/10.1159/000492225] [PMID: 30184549]
[http://dx.doi.org/10.1038/sj.npp.1300130] [PMID: 12700706]
[http://dx.doi.org/10.1016/j.imbio.2016.07.001] [PMID: 27453459]
[http://dx.doi.org/10.1016/j.ejpn.2008.06.001] [PMID: 18625572]
[http://dx.doi.org/10.1007/s10803-008-0687-y] [PMID: 19148734]
[http://dx.doi.org/10.1186/1471-2377-14-70] [PMID: 24885033]
[http://dx.doi.org/10.1186/s13229-016-0068-x] [PMID: 26793298]