Acknowledgement
The authors would like to thank the Center for Cancer Cell Biology, Immunology, and Infection at RFUMS and Gastroenterology at James A. Lovell FHCC for help with this study. We would also like to thank Dr. Stefan Green at the University of Illinois Chicago RRC for performing the microbiome sequencing experiments. Bioinformatics analysis (microbiome) was performed by the University of Illinois Chicago Research Informatics Core, supported in part by NCATS through Grant UL1TR002003. This study was supported by the VA grant 5 I21 BX003760 to A.G.F and J.M.R.
References
- Office of Research and Development. Gulf War research strategic plan 2013-2017 (2015 update) [Internet]. Available at https://www.research.va.gov/pubs/docs/gwresearch-strategicplan.pdf [accessed on 28 October 2021].
- Eisen SA, Kang HK, Murphy FM, Blanchard MS, Reda DJ, Henderson WG, Toomey R, Jackson LW, Alpern R, Parks BJ, et al. Gulf War veterans' health: medical evaluation of a U.S. cohort. Ann Intern Med 2005;142:881-890. https://doi.org/10.7326/0003-4819-142-11-200506070-00005
- Kang HK, Mahan CM, Lee KY, Magee CA, Murphy FM. Illnesses among United States veterans of the Gulf War: a population-based survey of 30,000 veterans. J Occup Environ Med 2000;42:491-501. https://doi.org/10.1097/00043764-200005000-00006
- Presidential advisory committee on Gulf War veterans' illnesses. Final report. Washington D.C.: U.S. Government Printing Office; 1996.
- Gray GC, Reed RJ, Kaiser KS, Smith TC, Gastanaga VM. Self-reported symptoms and medical conditions among 11,868 Gulf War-era veterans: the Seabee Health Study. Am J Epidemiol 2002;155:1033-1044. https://doi.org/10.1093/aje/155.11.1033
- Kang HK, Li B, Mahan CM, Eisen SA, Engel CC. Health of US veterans of 1991 Gulf War: a follow-up survey in 10 years. J Occup Environ Med 2009;51:401-410. https://doi.org/10.1097/JOM.0b013e3181a2feeb
- Zhang B, Verne ML, Fields JZ, Verne GN, Zhou Q. Intestinal hyperpermeability in Gulf War veterans with chronic gastrointestinal symptoms. J Clin Gastroenterol 2019;53:e298-e302. https://doi.org/10.1097/MCG.0000000000001135
- Camilleri M, Gorman H. Intestinal permeability and irritable bowel syndrome. Neurogastroenterol Motil 2007;19:545-552. https://doi.org/10.1111/j.1365-2982.2007.00925.x
- Chassard C, Dapoigny M, Scott KP, Crouzet L, Del'homme C, Marquet P, Martin JC, Pickering G, Ardid D, Eschalier A, et al. Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome. Aliment Pharmacol Ther 2012;35:828-838. https://doi.org/10.1111/j.1365-2036.2012.05007.x
- Collins SM. A role for the gut microbiota in IBS. Nat Rev Gastroenterol Hepatol 2014;11:497-505. https://doi.org/10.1038/nrgastro.2014.40
- Ohman L, Tornblom H, Simren M. Crosstalk at the mucosal border: importance of the gut microenvironment in IBS. Nat Rev Gastroenterol Hepatol 2015;12:36-49. https://doi.org/10.1038/nrgastro.2014.200
- Saito YA. The role of genetics in IBS. Gastroenterol Clin North Am 2011;40:45-67. https://doi.org/10.1016/j.gtc.2010.12.011
- Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, Cox J, Kelly FM, Wilde J, Lennon MG, et al. Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα. Gut 2013;62:985-994. https://doi.org/10.1136/gutjnl-2011-301213
- Savas LS, White DL, Wieman M, Daci K, Fitzgerald S, Laday Smith S, Tan G, Graham DP, Cully JA, El-Serag HB. Irritable bowel syndrome and dyspepsia among women veterans: prevalence and association with psychological distress. Aliment Pharmacol Ther 2009;29:115-125. https://doi.org/10.1111/j.1365-2036.2008.03847.x
- Ostaff MJ, Stange EF, Wehkamp J. Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med 2013;5:1465-1483. https://doi.org/10.1002/emmm.201201773
- Langhorst J, Choi KE. The role of human defensins in gastrointestinal diseases. Expert Rev Clin Immunol 2011;7:779-787. https://doi.org/10.1586/eci.11.62
- Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC. Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr 2011;141:769-776. https://doi.org/10.3945/jn.110.135657
- Dong C. Regulation and pro-inflammatory function of interleukin-17 family cytokines. Immunol Rev 2008;226:80-86. https://doi.org/10.1111/j.1600-065X.2008.00709.x
- Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 2009;9:556-567. https://doi.org/10.1038/nri2586
- Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 2010;10:479-489. https://doi.org/10.1038/nri2800
- Reynolds JM, Angkasekwinai P, Dong C. IL-17 family member cytokines: regulation and function in innate immunity. Cytokine Growth Factor Rev 2010;21:413-423. https://doi.org/10.1016/j.cytogfr.2010.10.002
- Kumar P, Monin L, Castillo P, Elsegeiny W, Horne W, Eddens T, Vikram A, Good M, Schoenborn AA, Bibby K, et al. Intestinal interleukin-17 receptor signaling mediates reciprocal control of the gut microbiota and autoimmune inflammation. Immunity 2016;44:659-671. https://doi.org/10.1016/j.immuni.2016.02.007
- Lee JS, Tato CM, Joyce-Shaikh B, Gulen MF, Cayatte C, Chen Y, Blumenschein WM, Judo M, Ayanoglu G, McClanahan TK, et al. Interleukin-23-independent il-17 production regulates intestinal epithelial permeability. Immunity 2015;43:727-738. https://doi.org/10.1016/j.immuni.2015.09.003
- Li H, Chen J, Huang A, Stinson J, Heldens S, Foster J, Dowd P, Gurney AL, Wood WI. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci U S A 2000;97:773-778. https://doi.org/10.1073/pnas.97.2.773
- Yamaguchi Y, Fujio K, Shoda H, Okamoto A, Tsuno NH, Takahashi K, Yamamoto K. IL-17B and IL-17C are associated with TNF-alpha production and contribute to the exacerbation of inflammatory arthritis. J Immunol 2007;179:7128-7136. https://doi.org/10.4049/jimmunol.179.10.7128
- Hurst SD, Muchamuel T, Gorman DM, Gilbert JM, Clifford T, Kwan S, Menon S, Seymour B, Jackson C, Kung TT, et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol 2002;169:443-453. https://doi.org/10.4049/jimmunol.169.1.443
- Reynolds JM, Martinez GJ, Nallaparaju KC, Chang SH, Wang YH, Dong C. Cutting edge: regulation of intestinal inflammation and barrier function by IL-17C. J Immunol 2012;189:4226-4230. https://doi.org/10.4049/jimmunol.1103014
- Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, Lesch J, Hackney J, Kim J, Zhou M, Lai J, et al. IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat Immunol 2011;12:1159-1166. https://doi.org/10.1038/ni.2156
- Song X, Zhu S, Shi P, Liu Y, Shi Y, Levin SD, Qian Y. IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens. Nat Immunol 2011;12:1151-1158. https://doi.org/10.1038/ni.2155
- Song X, Gao H, Lin Y, Yao Y, Zhu S, Wang J, Liu Y, Yao X, Meng G, Shen N, et al. Alterations in the microbiota drive interleukin-17C production from intestinal epithelial cells to promote tumorigenesis. Immunity 2014;40:140-152. https://doi.org/10.1016/j.immuni.2013.11.018
- Chang SH, Reynolds JM, Pappu BP, Chen G, Martinez GJ, Dong C. Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E. Immunity 2011;35:611-621. https://doi.org/10.1016/j.immuni.2011.09.010
- Yang XO, Chang SH, Park H, Nurieva R, Shah B, Acero L, Wang YH, Schluns KS, Broaddus RR, Zhu Z, et al. Regulation of inflammatory responses by IL-17F. J Exp Med 2008;205:1063-1075. https://doi.org/10.1084/jem.20071978
- O'Callaghan JP, Kelly KA, Locker AR, Miller DB, Lasley SM. Corticosterone primes the neuroinflammatory response to DFP in mice: potential animal model of Gulf War Illness. J Neurochem 2015;133:708-721. https://doi.org/10.1111/jnc.13088
- Naqib A, Poggi S, Wang W, Hyde M, Kunstman K, Green SJ. Making and sequencing heavily multiplexed, high-throughput 16s ribosomal RNA gene amplicon libraries using a flexible, two-stage PCR protocol. Methods Mol Biol 2018;1783:149-169. https://doi.org/10.1007/978-1-4939-7834-2_7
- Moonsamy PV, Williams T, Bonella P, Holcomb CL, Hoglund BN, Hillman G, Goodridge D, Turenchalk GS, Blake LA, Daigle DA, et al. High throughput HLA genotyping using 454 sequencing and the Fluidigm Access ArrayTM System for simplified amplicon library preparation. Tissue Antigens 2013;81:141-149. https://doi.org/10.1111/tan.12071
- Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 2009;459:262-265. https://doi.org/10.1038/nature07935
- Xue X, Shah YM. In vitro organoid culture of primary mouse colon tumors. J Vis Exp 2013:e50210.
- Alhasson F, Das S, Seth R, Dattaroy D, Chandrashekaran V, Ryan CN, Chan LS, Testerman T, Burch J, Hofseth LJ, et al. Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation. PLoS One 2017;12:e0172914.
- Khaiboullina SF, DeMeirleir KL, Rawat S, Berk GS, Gaynor-Berk RS, Mijatovic T, Blatt N, Rizvanov AA, Young SG, Lombardi VC. Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis. Cytokine 2015;72:1-8. https://doi.org/10.1016/j.cyto.2014.11.019
- Smylie AL, Broderick G, Fernandes H, Razdan S, Barnes Z, Collado F, Sol C, Fletcher MA, Klimas N. A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome. BMC Immunol 2013;14:29.
- Plageman LR, Pauletti GM, Skau KA. Characterization of acetylcholinesterase in Caco-2 cells. Exp Biol Med (Maywood) 2002;227:480-486. https://doi.org/10.1177/153537020222700712
- Pickett MA, Dush MK, Nascone-Yoder NM. Acetylcholinesterase plays a non-neuronal, non-esterase role in organogenesis. Development 2017;144:2764-2770. https://doi.org/10.1242/dev.149831
- Du A, Xie J, Guo K, Yang L, Wan Y, OuYang Q, Zhang X, Niu X, Lu L, Wu J, et al. A novel role for synaptic acetylcholinesterase as an apoptotic deoxyribonuclease. Cell Discov 2015;1:15002.
- Kolls JK, McCray PB Jr, Chan YR. Cytokine-mediated regulation of antimicrobial proteins. Nat Rev Immunol 2008;8:829-835. https://doi.org/10.1038/nri2433
- Chaubey K, Alam SI, Waghmare CK, Singh L, Srivastava N, Bhattacharya BK. Differential proteome analysis of rat plasma after diisopropyl fluorophosphate (DFP) intoxication, a surrogate of nerve agent sarin. Chem Biol Interact 2019;298:66-71. https://doi.org/10.1016/j.cbi.2018.10.026
- Coughlin SS. A neuroimmune model of Gulf War Illness. J Environ Health Sci 2017;3:1-6. https://doi.org/10.15436/2378-6841.17.1665
- Macht VA, Woodruff JL, Grillo CA, Wood CS, Wilson MA, Reagan LP. Pathophysiology in a model of Gulf War Illness: contributions of pyridostigmine bromide and stress. Psychoneuroendocrinology 2018;96:195-202. https://doi.org/10.1016/j.psyneuen.2018.07.015
- Foster JA, Rinaman L, Cryan JF. Stress & the gut-brain axis: regulation by the microbiome. Neurobiol Stress 2017;7:124-136.
- Madison A, Kiecolt-Glaser JK. Stress, depression, diet, and the gut microbiota: human-bacteria interactions at the core of psychoneuroimmunology and nutrition. Curr Opin Behav Sci 2019;28:105-110. https://doi.org/10.1016/j.cobeha.2019.01.011
- Abou-Donia MB, Conboy LA, Kokkotou E, Jacobson E, Elmasry EM, Elkafrawy P, Neely M, Bass CR, Sullivan K. Screening for novel central nervous system biomarkers in veterans with Gulf War Illness. Neurotoxicol Teratol 2017;61:36-46. https://doi.org/10.1016/j.ntt.2017.03.002
- Craddock TJ, Fritsch P, Rice MA Jr, del Rosario RM, Miller DB, Fletcher MA, Klimas NG, Broderick G. A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome. PLoS One 2014;9:e84839.
- Johnson GJ, Slater BC, Leis LA, Rector TS, Bach RR. Blood biomarkers of chronic inflammation in Gulf War Illness. PLoS One 2016;11:e0157855.