發炎性腸胃道疾病（IBD）是一個反覆復發的腸胃道發炎疾病。由於發炎性腸胃道疾病還未有治癒的方法，因此目前對於發炎性腸胃道疾病的治療策略為減緩疾病病徵以及改善病人的生活品質。在發炎性腸胃道疾病的緩解以及復發期，焦慮症以及抑鬱症為患者常見的共病，並且嚴重影響病患生活品質。然而，發炎性腸胃道疾病與精神疾病共病的機轉尚未明確因此阻礙其治療。迷走神經為溝通腸胃道以及大腦重要的途徑。由於迷走神經能夠感測發炎訊息並且傳遞至大腦，我們假設其在調控腸胃道發炎共病的焦慮有重要的角色。在此研究中，我們建立了由硫酸葡聚糖（DSS）誘導的結腸炎小鼠模型，並量測了結腸炎小鼠中增強的類焦慮行為。透過切除不同迷走神經的分支以及利用皂草毒素特定阻斷上行迷走神經傳遞，我們研究了迷走神經的角色。根據實驗結果，腸胃道發炎誘發的小鼠類焦慮行為需透過雙側迷走神經上行傳遞。我們更進一步解析調控類焦慮行為的腦迴路，其中抑制了從藍斑核正腎上腺素神經元投射至基底外側杏仁核神經迴路的活性，DSS 處理小鼠所增強的類焦慮行為能被減緩。為了釐清在發炎腸道中可能活化迷走神經上行迴路誘導類焦慮行為的刺激，我們解析了調節腸道發炎先天性免疫的進展與迷走神經傳入中樞神經系統活化孤束核神經元的關聯性。依據結果，在DSS誘導的結腸炎中，巨噬細胞與M1 巨噬細胞堆積於大腸固有層的時間點和NTS神經元活化的時間點一至。再者，我們發現巨噬細胞會聚集在DSS處理小鼠中與腸胃道粘膜上行迷走神經附近。我們應用了巨噬細胞剔除以及轉殖促發炎巨噬細胞（M1 巨噬細胞）兩種方法更進一步研究巨噬細胞於結腸炎小鼠中調控類焦慮行為的角色。根據實驗結果，在結腸炎小鼠中剔除巨噬細胞降低其類焦慮行為，以及轉殖M1巨噬細胞透過迷走神經上行傳遞能誘發類焦慮行為。最後，為了識別在結腸炎小鼠中M1巨噬細胞活誘發類焦慮行為的潛在機制，我們鎖定腸道歸巢組合蛋白（a4b7）以及促發炎因子（TNFa 與IL-1 b）由於他們調節發炎性腸胃道疾病至病的功能。根據結果，阻斷巨噬細胞浸潤以及中和IL-1 b皆能有效緩解DSS處理小鼠中增強的類焦慮行為。此外，中和TNFa對於腸胃道發炎誘發焦慮共病的調控並無效果。綜上所述，我們解析迷走神經腸-腦訊息傳遞調控腸胃道發炎誘發焦慮共病的機轉。此外，我們透過現有針對巨噬細胞浸潤以及其IL-1 b分泌的治療方針，提供發炎性腸胃道疾病焦慮共病治療的新見解。

Inflammatory bowel disease (IBD) is a relapsing-remitting disorder characterized by chronic inflammation of the gastrointestinal (GI) tract. Since it is currently recognized as an uncurable disease, the treatment goal of IBD is set to minimize symptoms and improve living quality among patients. A major concern affecting patients living quality is anxiety disorder and depression which commonly observed within IBD patients in their remitting and relapsing stages. However, the mechanistic link between IBD and comorbid psychiatry disorders remains elusive thus hampers its treatment. Vagus nerve is a critical neural pathway communicating the gut and the brain. With the function of vagus nerve sensing and transmitting inflammatory signals to the brain, we hypothesized its role in the regulation of comorbid anxiety with gut inflammation. In our study, we established a mice model of colitis induced by dextran sodium sulfate (DSS) and examined the heightened anxiety-like behaviors of colitis mice. Role of the vagus nerve was studied by vagotomy approaches of multiple vagal branches and afferent neuron specific ablation by saporin toxin. According to our results, bilateral vagal afferent signaling is critical for the induction of anxiety-like behaviors in colitis mice. We further characterized the neural circuit within the brain that modulates the innate anxiety-like behaviors, which inhibition of circuit activity projecting from norepinephrine neurons in locus coeruleus to basal lateral amygdala reduced the heightened anxiety-like behaviors of DSS-treated mice. To understand the possible stimulant in the colitis gut to activate vagal afferent pathway for anxiety induction, we deciphered the correlation between colitis -mediating innate immune progression and the neuronal activity of central input of the vagus in the nucleus of the solitary tract (NTS). As the results indicated, the time-point of macrophage and M1-macrophage accumulation to the colonic lamina propria aligns to the activation of NTS neurons during the progression of DSS-induced colitis. In addition, we also showed proximity of accumulated macrophage to mucosal vagal afferents within DSS-treated mice. To further study the role of macrophage in heightened anxiety-like behavior of DSS-treated mice, we performed depletion of macrophage in DSS-treated mice and transplantation of M1-macorphage to wild type mice. According to results, depletion of macrophage reduced anxiety-like behavior of DSS-treated mice and M1-macrophage induces anxiety behavior via vagal afferent signaling. Last, to identify the potential mechanism for M1-macrophage to induce anxiety-like behavior within colitis mice, we targeted the gut homing integrin (a4b7) and pro-inflammatory cytokines of M1-macoprhage (TNFa and IL-1 b) owing to their function in mediating IBD pathogenesis. Accordingly, preventing the infiltration of macrophage and neutralizing IL-1 are both effective to reduce heightened anxiety-like behavior in DSS-treated mice. In addition, neutralizing TNF- was not effective in regulating colitis comorbid anxiety. Overall, we characterized the mechanistic link of gut-to-brain vagal signaling for colitis comorbid anxiety. Moreover, we provided new insight to the treatment of IBD comorbid anxiety by targeting the infiltration of macrophage and the secretion of IL-1 with established treatment strategy for IBD.

Abautret-Daly Á, Dempsey E, Parra-Blanco A, Medina C, Harkin A. Gut-brain actions underlying comorbid anxiety and depression associated with inflammatory bowel disease. Acta Neuropsychiatr. 2018;30(5):275-296.
Agostini A, Filippini N, Cevolani D, Agati R, Leoni C, Tambasco R, Calabrese C, Rizzello F, Gionchetti P, Ercolani M, Leonardi M, Campieri M. Brain functional changes in patients with ulcerative colitis: a functional magnetic resonance imaging study on emotional processing. Inflamm Bowel Dis. 2011;17(8):1769-1777.
Agostini A, Benuzzi F, Ballotta D, Rizzello F, Gionchetti P, Filippini N. Differential brain structural and functional patterns in crohn's disease patients are associated with different disease stages. Inflamm Bowel Dis. 2023;29(8):1297-1305.
Agirman G, Yu KB, Hsiao EY. Signaling inflammation across the gut-brain axis. Science. 2021;374(6571):1087-1092.
Bai L, Mesgarzadeh S, Ramesh KS, Huey EL, Liu Y, Gray LA, Aitken TJ, Chen Y, Beutler LR, Ahn JS, Madisen L, Zeng H, Krasnow MA, Knight ZA. Genetic identification of vagal sensory neurons that control feeding. Cell. 2019;179(5):1129-1143.
Bain CC, Scott CL, Uronen-Hansson H, Gudjonsson S, Jansson O, Grip O, Guilliams M, Malissen B, Agace WW, Mowat AM. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 2013;6(3):498-510.
Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, Deng Y, Blennerhassett PA, Fahnestock M, Moine D, Berger B, Huizinga JD, Kunze W, McLean PG, Bergonzelli GE, Collins SM, Verdu EF. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 2011;23(12):1132–1139.
Barrett JC, Lees CW. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016;387(10014):156-167.
Berthoud HR, Powley TL. Vagal afferent innervation of the rat fundic stomach: morphological characterization of the gastric tension receptor. J Comp Neurol. 1992;319(2):261-76.
Berthoud HR, Kressel M, Raybould HE, Neuhuber WL. Vagal sensors in the rat duodenal mucosa: distribution and structure as revealed by in vivo DiI-tracing. Anat Embryol (Berl). 1995;191(3):203-212.
Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. Auton Neurosci. 2000;85(1-3):1-17.
Bielefeldt K, Ozaki N, Gebhart GF. Experimental ulcers alter voltage-sensitive sodium currents in rat gastric sensory neurons. Gastroenterology. 2002;122(2):394-405.
Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458-462.
Bourin M, Hascoët M. The mouse light/dark box test. Eur J Pharmacol. 2003;463(1-3):55-65.
Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF. 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. 2011;108(38):16050–16055.
Browning KN, Verheijden S, Boeckxstaens GE. The vagus nerve in appetite regulation, mood, and intestinal inflammation. Gastroenterology. 2017;152(4):730-744.
Buchanan KL, Rupprecht LE, Kaelberer MM, Sahasrabudhe A, Klein ME, Villalobos JA, Liu WW, Yang A, Gelman J, Park S, Anikeeva P, Bohórquez DV. The preference for sugar over sweetener depends on a gut sensor cell. Nat Neurosci. 2022;25(2):191-200.
Cai Z, Wang S, Li J. Treatment of inflammatory bowel disease: A comprehensive review. Front Med (Lausanne). 2021;8:765474.
Calhoon GG, Tye KM. Resolving the neural circuits of anxiety. Nat Neurosci. 2015;18(10):1394-1404.
Cathomas F, Lin HY, Chan KL, Li L, Parise LF, Alvarez J, Durand-de Cuttoli R, Aubry AV, Muhareb S, Desland F, Shimo Y, Ramakrishnan A, Estill M, Ferrer-Pérez C, Parise EM, Wilk CM, Kaster MP, Wang J, Sowa A, Janssen WG, Costi S, Rahman A, Fernandez N, Campbell M, Swirski FK, Nestler EJ, Shen L, Merad M, Murrough JW, Russo SJ. Circulating myeloid-derived MMP8 in stress susceptibility and depression. Nature. 2024;626(8001):1108-1115.
Chang JT. Pathophysiology of inflammatory bowel diseases. N Engl J Med. 2020;383(27):2652-2664.
Chang RB, Strochlic DE, Williams EK, Umans BD, Liberles SD. Vagal sensory neuron subtypes that differentially control breathing. Cell. 2015;161(3):622-633.
Chassaing B, Aitken JD, Malleshappa M, Vijay-Kumar M. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol. 2014;104:15.25.1-15.25.14.
Chen J, Winston JH, Fu Y, Guptarak J, Jensen KL, Shi XZ, Green TA, Sarna SK. Genesis of anxiety, depression, and ongoing abdominal discomfort in ulcerative colitis-like colon inflammation. Am J Physiol Regul Integr Comp Physiol. 2015;308(1):R18–R27.
Chen LH, Sun YT, Chen YF, Lee MY, Chang LY, Chang JY, Shen MR. Integrating image-based high-content screening with mouse models identifies 5-hydroxydecanoate as a neuroprotective drug for paclitaxel-induced neuropathy. Mol Cancer Ther. 2015;14(10):2206–2214.
Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, Ahmad T, Andersen V, Andrews JM, Annese V, Brand S, Brant SR, Cho JH, Daly MJ, Dubinsky M, Duerr RH, Ferguson LR, Franke A, Gearry RB, Goyette P, Hakonarson H, Halfvarson J, Hov JR, Huang H, Kennedy NA, Kupcinskas L, Lawrance IC, Lee JC, Satsangi J, Schreiber S, Théâtre E, van der Meulen-de Jong AE, Weersma RK, Wilson DC; International Inflammatory Bowel Disease Genetics Consortium; Parkes M, Vermeire S, Rioux JD, Mansfield J, Silverberg MS, Radford-Smith G, McGovern DP, Barrett JC, Lees CW. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016;387(10014):156-167.
Cooper HS, Murthy SN, Shah RS, Sedergran DJ. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69(2):238–249.
Cryan JF, O'Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O'Connor R, Cruz-Pereira JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de Wouw M, Ventura-Silva AP, Wallace-Fitzsimons SE, Hyland N, Clarke G, Dinan TG. The microbiota-gut-brain axis. Physiol Rev. 2019;99(4):1877-2013.
Dempsey E, Abautret-Daly Á, Docherty NG, Medina C, Harkin A. Persistent central inflammation and region specific cellular activation accompany depression- and anxiety-like behaviours during the resolution phase of experimental colitis. Brain Behav Immun. 2019;80:616-632.
Dieleman LA, Ridwan BU, Tennyson GS, Beagley KW, Bucy RP, Elson CO. Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology. 1994;107(6):1643-1652.
Dieleman LA, Palmen MJ, Akol H, Bloemena E, Peña AS, Meuwissen SG, Van Rees EP. Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin Exp Immunol. 1998;114(3):385-391.
Diepenbroek C, Quinn D, Stephens R, Zollinger B, Anderson S, Pan A, de Lartigue G. Validation and characterization of a novel method for selective vagal deafferentation of the gut. Am J Physiol Gastrointest Liver Physiol. 2017;313(4):G342-G352.
Dragstedt, L. R., and Owens, F. M. Supra-diaphragmatic section of the vagus nerves in treatment of duodenal ulcer. Proc. Soc. Exp. Biol. Med. 1943;53:152–154.
Ek M, Kurosawa M, Lundeberg T, Ericsson A. Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci. 1998;18(22):9471-9479.
Emge JR, Huynh K, Miller EN, Kaur M, Reardon C, Barrett KE, Gareau MG. Modulation of the microbiota-gut-brain axis by probiotics in a murine model of inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 2016;310(11):G989–G998.
Foley, J.O., and DuBois, F.S. Quantitative studies of the vagus nerve in the cat. I. The ratio of sensory to motor fibers. J. Comp. Neurol. 1927;67:49–67.
Franklin K, Paxinos G, eds. The mouse brain in stereotaxic coordinates, compact: The coronal plates and diagrams. Elsevier Academic Press; 2008.
Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity. 2019;50(4):992-1006.
Gampierakis IA, Koutmani Y, Semitekolou M, Morianos I, Polissidis A, Katsouda A, Charalampopoulos I, Xanthou G, Gravanis A, Karalis KP. Hippocampal neural stem cells and microglia response to experimental inflammatory bowel disease (IBD). Mol Psychiatry. 2021;26(4):1248-1263.
Gao X, Duan S, Cao Y, Zhang Y. Change of monocytes/macrophages in ulcerative colitis patients with symptoms of anxiety and depression. BMC Gastroenterol. 2023;23(1):67.
Ghia JE, Blennerhassett P, Collins SM. Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression. J Clin Invest. 2008;118(6):2209-2218.
Gilliland A, Chan JJ, De Wolfe TJ, Yang H, Vallance BA. Pathobionts in inflammatory bowel disease: Origins, underlying mechanisms, and implications for clinical care. Gastroenterology. 2024;166(1):44-58.
Godinho-Silva C, Cardoso F, Veiga-Fernandes H. Neuro-immune cell units: A new paradigm in physiology. Annu Rev Immunol. 2019;37:19-46.
Goehler LE, Gaykema RP, Hansen MK, Anderson K, Maier SF, Watkins LR. Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton Neurosci. 2000;85(1-3):49-59.
Graff LA, Walker JR, Bernstein CN. Depression and anxiety in inflammatory bowel disease: a review of comorbidity and management. Inflamm Bowel Dis. 2009;15(7):1105-1118.
Guma M, Ronacher L, Liu-Bryan R, Takai S, Karin M, Corr M. Caspase 1-independent activation of interleukin-1beta in neutrophil-predominant inflammation. Arthritis Rheum. 2009;60(12):3642-3650.
Han DH, Kim WK, Lee C, Park S, Lee K, Jang SJ, Ko G. Co-administration of Lactobacillus gasseri KBL697 and tumor necrosis factor-alpha inhibitor infliximab improves colitis in mice. Sci Rep. 2022;12(1):9640.
Han W, Tellez LA, Perkins MH, Perez IO, Qu T, Ferreira J, Ferreira TL, Quinn D, Liu ZW, Gao XB, Kaelberer MM, Bohórquez DV, Shammah-Lagnado SJ, de Lartigue G, de Araujo IE. A neural circuit for gut-induced reward. Cell. 2018;175(3):665-678.
Han W, de Araujo IE. Dissection and surgical approaches to the mouse jugular-nodose ganglia. STAR Protoc. 2021;2(2):100474.
Han Y, Zhao T, Cheng X, Zhao M, Gong SH, Zhao YQ, Wu HT, Fan M, Zhu LL. Cortical inflammation is increased in a DSS-Induced colitis mouse model. Neurosci Bull. 2018;34(6):1058-1066.
Hansen MK, O'Connor KA, Goehler LE, Watkins LR, Maier SF. The contribution of the vagus nerve in interleukin-1beta-induced fever is dependent on dose. Am J Physiol Regul Integr Comp Physiol. 2001;280(4):R929-934.
Hübsch M, Neuhuber WL, Raab M. Muscarinic acetylcholine receptors in the mouse esophagus: focus on intraganglionic laminar endings (IGLEs). Neurogastroenterol Motil. 2013;25(8):e560-73. 
Iglesias M, Barreiro de Acosta M, Vázquez I, Figueiras A, Nieto L, Lorenzo A, Domínguez-Muñoz JE. Psychological impact of Crohn's disease on patients in remission: anxiety and depression risks. Rev Esp Enferm Dig. 2009;101(4):249-257.
Jain P, Materazzi S, De Logu F, Rossi Degl'Innocenti D, Fusi C, Li Puma S, Marone IM, Coppi E, Holzer P, Geppetti P, Nassini R. Transient receptor potential ankyrin 1 contributes to somatic pain hypersensitivity in experimental colitis. Sci Rep. 2020;10(1):8632.
Jia L, Lee S, Tierney JA, Elmquist JK, Burton MD, Gautron L. TLR4 signaling selectively and directly promotes CGRP release from vagal afferents in the mouse. eNeuro. 2021;8(1):0254-20.2020.
Jin H, Li M, Jeong E, Castro-Martinez F, Zuker CS. A body-brain circuit that regulates body inflammatory responses. Nature. 2024;630(8017):695-703.
Johnston RD, Logan RF. What is the peak age for onset of IBD? Inflamm Bowel Dis. 2008;14 Suppl 2:S4-5.
Kaelberer MM, Buchanan KL, Klein ME, Barth BB, Montoya MM, Shen X, Bohórquez DV. A gut-brain neural circuit for nutrient sensory transduction. Science. 2018;361(6408):eaat5236.
Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18(1):56-66.
Keeton RL, Mikocka-Walus A, Andrews JM. Concerns and worries in people living with inflammatory bowel disease (IBD): A mixed methods study. J Psychosom Res. 2015;78(6):573-578.
Klarer M, Arnold M, Günther L, Winter C, Langhans W, Meyer U. Gut vagal afferents differentially modulate innate anxiety and learned fear. J Neurosci. 2014;34(21):7067-7076.
Klarer M, Krieger JP, Richetto J, Weber-Stadlbauer U, Günther L, Winter C, Arnold M, Langhans W, Meyer U. Abdominal vagal afferents modulate the brain transcriptome and behaviors relevant to schizophrenia. J Neurosci. 2018;38(7):1634–1647.
Kobayashi T, Hibi T. Improving IBD outcomes in the era of many treatment options. Nat Rev Gastroenterol Hepatol. 2023;20(2):79-80.
Koga K, Descalzi G, Chen T, Ko HG, Lu J, Li S, Son J, Kim T, Kwak C, Huganir RL, Zhao MG, Kaang BK, Collingridge GL, Zhuo M. Coexistence of two forms of LTP in ACC provides a synaptic mechanism for the interactions between anxiety and chronic pain. Neuron. 2015;85(2):377–389.
Kornelsen J, McIver T, Uddin MN, Figley CR, Marrie RA, Patel R, Fisk JD, Carter S, Graff L, Mazerolle EL, Bernstein CN; Comorbidity and Cognition in Multiple Sclerosis (CCOMS) Study Group. Altered voxel-based and surface-based morphometry in inflammatory bowel disease. Brain Res Bull. 2023;203:110771.
Kim E, Tran M, Sun Y, Huh JR. Isolation and analyses of lamina propria lymphocytes from mouse intestines. STAR Protoc. 2022;3(2):101366.
Kunda PE, Cavicchia JC, Acosta CG. Lipopolysaccharides and trophic factors regulate the LPS receptor complex in nodose and trigeminal neurons. Neuroscience. 2014;280:60-72.
Kuniishi H, Yamada D, Wada K, Yamada M, Sekiguchi M. Stress induces insertion of calcium-permeable AMPA receptors in the OFC-BLA synapse and modulates emotional behaviours in mice. Transl Psychiatry. 2020;10(1):154.
Kwon KH, Murakami A, Hayashi R, Ohigashi H. Interleukin-1beta targets interleukin-6 in progressing dextran sulfate sodium-induced experimental colitis. Biochem Biophys Res Commun. 2005;337(2):647-54.
Lapointe TK, Basso L, Iftinca MC, Flynn R, Chapman K, Dietrich G, Vergnolle N, Altier C. TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis. Am J Physiol Gastrointest Liver Physiol. 2015;309(2):G87–G99.
Larson SJ, Dunn AJ. Behavioral effects of cytokines. Brain Behav Immun. 2001;15(4):371-87.
Lin RL, Gu Q, Khosravi M, Lee LY. Sustained sensitizing effects of tumor necrosis factor alpha on sensory nerves in lung and airways. Pulm Pharmacol Ther. 2017;47:29-37.
Lin YT, Chen CC, Huang CC, Nishimori K, Hsu KS. Oxytocin stimulates hippocampal neurogenesis via oxytocin receptor expressed in CA3 pyramidal neurons. Nat Commun. 2017;8(1):537.
Lin YT, Hsieh TY, Tsai TC, Chen CC, Huang CC, Hsu KS. Conditional deletion of hippocampal CA2/CA3a oxytocin receptors impairs the persistence of long-term social recognition memory in mice. J Neurosci. 2018;38(5):1218–1231.
Liu J, Perez SM, Zhang W, Lodge DJ, Lu XY. Selective deletion of the leptin receptor in dopamine neurons produces anxiogenic-like behavior and increases dopaminergic activity in amygdala. Mol Psychiatry. 2011;16(10):1024–1038.
Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, Ripke S, Lee JC, Jostins L, Shah T, Abedian S, Cheon JH, Cho J, Dayani NE, Franke L, Fuyuno Y, Hart A, Juyal RC, Juyal G, Kim WH, Morris AP, Poustchi H, Newman WG, Midha V, Orchard TR, Vahedi H, Sood A, Sung JY, Malekzadeh R, Westra HJ, Yamazaki K, Yang SK; International Multiple Sclerosis Genetics Consortium; International IBD Genetics Consortium; Barrett JC, Alizadeh BZ, Parkes M, Bk T, Daly MJ, Kubo M, Anderson CA, Weersma RK. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979-986.
Llorca-Torralba M, Suárez-Pereira I, Bravo L, Camarena-Delgado C, Garcia-Partida JA, Mico JA, Berrocoso E. Chemogenetic silencing of the locus coeruleus-basolateral amygdala pathway abolishes pain-induced anxiety and enhanced aversive learning in rats. Biol Psychiatry. 2019;85(12):1021–1035.
Loddo I, Romano C. Inflammatory bowel disease: Genetics, epigenetics, and pathogenesis. Front Immunol. 2015;6:551.
Lyte M, Li W, Opitz N, Gaykema RP, Goehler LE. Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium. Physiol Behav. 2006;89(3):350–357.
Makhmutova M, Weitz J, Tamayo A, Pereira E, Boulina M, Almaça J, Rodriguez-Diaz R, Caicedo A. Pancreatic β-Cells communicate with vagal sensory neurons. Gastroenterology. 2021;160(3):875-888.
Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011;474(7351):298-306.
Mantanona CP, Alsiö J, Elson JL, Fisher BM, Dalley JW, Bussey T, Pienaar IS. Altered motor, anxiety-related and attentional task performance at baseline associate with multiple gene copies of the vesicular acetylcholine transporter and related protein overexpression in ChAT::Cre+ rats. Brain Struct Funct. 2019;224(9):3095-3116.
Manzini R, Schwarzfischer M, Atrott K, Laimbacher A, Lang S, Wawrzyniak M, Rickenbacher A, Turina M, Hruz P, Lissner D, Siegmund B, Rogler G, Scharl M, Spalinger MR. Combination of vedolizumab with tacrolimus is more efficient than vedolizumab alone in the treatment of experimental colitis. Inflamm Bowel Dis. 2021;27(12):1986-1998.
Matteoli G, Boeckxstaens GE. The vagal innervation of the gut and immune homeostasis. Gut. 2013;62(8):1214-22.
McCall JG, Siuda ER, Bhatti DL, Lawson LA, McElligott ZA, Stuber GD, Bruchas MR. Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior. Elife. 2017 ;6:e18247.
Melgar S, Engström K, Jägervall A, Martinez V. Psychological stress reactivates dextran sulfate sodium-induced chronic colitis in mice. Stress. 2008;11(5):348-362.
Morais LH, Schreiber HL 4th, Mazmanian SK. The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol. 2021;19(4):241-255.
Nahon S, Lahmek P, Durance C, Olympie A, Lesgourgues B, Colombel JF, Gendre JP. Risk factors of anxiety and depression in inflammatory bowel disease. Inflamm Bowel Dis. 2012;18(11):2086-91.
Na YR, Stakenborg M, Seok SH, Matteoli G. Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nat Rev Gastroenterol Hepatol. 2019;16(9):531-543.
Neuhuber WL. Sensory vagal innervation of the rat esophagus and cardia: a light and electron microscopic anterograde tracing study. J Auton Nerv Syst. 1987;20(3):243-55.
Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5):329-42.
Nguyen T, Du J, Li YC. A protocol for macrophage depletion and reconstitution in a mouse model of sepsis. STAR Protoc. 2021;2(4):101004.
Niijima A. The afferent discharges from sensors for interleukin 1 beta in the hepatoportal system in the anesthetized rat. J Auton Nerv Syst. 1996;61(3):287-91.
Noble AJ, Nowak JK, Adams AT, Uhlig HH, Satsangi J. Defining interactions between the genome, epigenome, and the environment in inflammatory bowel disease: progress and prospects. Gastroenterology. 2023;165(1):44-60.
Nyuyki KD, Cluny NL, Swain MG, Sharkey KA, Pittman QJ. Altered brain excitability and increased anxiety in mice with experimental colitis: consideration of hyperalgesia and sex differences. Front Behav Neurosci. 2018;12:58.
Paintal As. A study of gastric stretch receptors; their role in the peripheral mechanism of satiation of hunger and thirst. J Physiol. 1954;126(2):255-70.
Papamichael K, Lin S, Moore M, Papaioannou G, Sattler L, Cheifetz AS. Infliximab in inflammatory bowel disease. Ther Adv Chronic Dis. 2019;10.
Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012;11:1959-1972.
Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods. 1985;3:149-167.
Phillips RJ, Powley TL. Tension and stretch receptors in gastrointestinal smooth muscle: re-evaluating vagal mechanoreceptor electrophysiology. Brain Res Brain Res Rev. 2000;34(1-2):1-26.
Piovani D, Danese S, Peyrin-Biroulet L, Nikolopoulos GK, Lytras T, Bonovas S. Environmental risk factors for inflammatory bowel diseases: An umbrella review of meta-analyses. Gastroenterology. 2019;157(3):647-659.
Prescott SL, Liberles SD. Internal senses of the vagus nerve. Neuron. 2022;110(4):579-599.
Raab M, Neuhuber WL. Glutamatergic functions of primary afferent neurons with special emphasis on vagal afferents. Int Rev Cytol. 2007;256:223-75.
Reichmann F, Hassan AM, Farzi A, Jain P, Schuligoi R, Holzer P. Dextran sulfate sodium-induced colitis alters stress-associated behaviour and neuropeptide gene expression in the amygdala-hippocampus network of mice. Sci Rep. 2015;5:9970.
Rezai-Zadeh K, Gate D, Town T. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol. 2009;4(4):462-75.
Rogers RC, Hermann GE. Tumor necrosis factor activation of vagal afferent terminal calcium is blocked by cannabinoids. J Neurosci. 2012;32(15):5237-41.
Sairenji T, Collins KL, Evans DV. An update on inflammatory bowel disease. Prim Care. 2017;44(4):673-692.
Salameh E, Meleine M, Gourcerol G, do Rego JC, do Rego JL, Legrand R, Breton J, Aziz M, Guérin C, Coëffier M, Savoye G, Marion-Letellier R. Chronic colitis-induced visceral pain is associated with increased anxiety during quiescent phase. Am J Physiol Gastrointest Liver Physiol. 2019;316(6):G692-G700.
Sanders TH, Weiss J, Hogewood L, Chen L, Paton C, McMahan RL, Sweatt JD. Cognition-enhancing vagus nerve stimulation alters the epigenetic landscape. J Neurosci. 2019;39(18):3454-3469.
Schleier L, Wiendl M, Heidbreder K, Binder MT, Atreya R, Rath T, Becker E, Schulz-Kuhnt A, Stahl A, Schulze LL, Ullrich K, Merz SF, Bornemann L, Gunzer M, Watson AJM, Neufert C, Atreya I, Neurath MF, Zundler S. Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing. Gut. 2020;69(2):252-263.
Schwartz ES, Christianson JA, Chen X, La JH, Davis BM, Albers KM, Gebhart GF. Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation. Gastroenterology. 2011;140(4):1283-1291.
Sellmeijer J, Mathis V, Hugel S, Li XH, Song Q, Chen QY, Barthas F, Lutz PE, Karatas M, Luthi A, Veinante P, Aertsen A, Barrot M, Zhuo M, Yalcin I. Hyperactivity of anterior cingulate cortex areas 24a/24b drives chronic pain-induced anxiodepressive-like consequences. J Neurosci. 2018;38(12):3102–3115.
Serafini MA, Paz AH, Nunes NS. Cholinergic immunomodulation in inflammatory bowel diseases. Brain Behav Immun Health. 2021;19:100401.
Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA, Costa-Mattioli M. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron. 2019;101(2):246-259.
Shafer LA, Walker JR, Restall G, Chhibba T, Ivekovic M, Singh H, Targownik LE, Bernstein CN. Association between IBD disability and reduced work productivity (Presenteeism): A population-based study in Manitoba, Canada. Inflamm Bowel Dis. 2019;25(2):352-359.
St-Amour I, Paré I, Alata W, Coulombe K, Ringuette-Goulet C, Drouin-Ouellet J, Vandal M, Soulet D, Bazin R, Calon F. Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier. J Cereb Blood Flow Metab. 2013;12:1983-1992.
Stakenborg N, Viola MF, Boeckxstaens GE. Intestinal neuro-immune interactions: focus on macrophages, mast cells and innate lymphoid cells. Curr Opin Neurobiol. 2020;62:68-75.
Steenbergen L, Maraver MJ, Actis-Grosso R, Ricciardelli P, Colzato LS. Recognizing emotions in bodies: Vagus nerve stimulation enhances recognition of anger while impairing sadness. Cogn Affect Behav Neurosci. 2021;21(6):1246-1261.
Steinberg BE, Silverman HA, Robbiati S, Gunasekaran MK, Tsaava T, Battinelli E, Stiegler A, Bouton CE, Chavan SS, Tracey KJ, Huerta PT. Cytokine-specific neurograms in the sensory vagus nerve. Bioelectron Med. 2016;3:7-17.
Sun Y, Zhang M, Chen CC, Gillilland M 3rd, Sun X, El-Zaatari M, Huffnagle GB, Young VB, Zhang J, Hong SC, Chang YM, Gumucio DL, Owyang C, Kao JY. Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice. Gastroenterology. 2013;144(7):1478-1487
Swiergiel AH, Dunn AJ. Effects of interleukin-1beta and lipopolysaccharide on behavior of mice in the elevated plus-maze and open field tests. Pharmacol Biochem Behav. 2007;86(4):651-659.
Szigethy E, Murphy SM, Ehrlich OG, Engel-Nitz NM, Heller CA, Henrichsen K, Lawton R, Meadows P, Allen JI. Mental health costs of inflammatory bowel diseases. Inflamm Bowel Dis. 2021;27(1):40-48.
Talbot S, Abdulnour RE, Burkett PR, Lee S, Cronin SJ, Pascal MA, Laedermann C, Foster SL, Tran JV, Lai N, Chiu IM, Ghasemlou N, DiBiase M, Roberson D, Von Hehn C, Agac B, Haworth O, Seki H, Penninger JM, Kuchroo VK, Bean BP, Levy BD, Woolf CJ. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron. 2015;87(2):341-354.
Teratani T, Mikami Y, Nakamoto N, Suzuki T, Harada Y, Okabayashi K, Hagihara Y, Taniki N, Kohno K, Shibata S, Miyamoto K, Ishigame H, Chu PS, Sujino T, Suda W, Hattori M, Matsui M, Okada T, Okano H, Inoue M, Yada T, Kitagawa Y, Yoshimura A, Tanida M, Tsuda M, Iwasaki Y, Kanai T. The liver-brain-gut neural arc maintains the Treg cell niche in the gut. Nature. 2020;585(7826):591-596.
The Lancet Gastroenterology Hepatology. The economic burden of inflammatory bowel disease. Lancet Gastroenterol Hepatol. 2023;8(5):391.
Tribbick D, Salzberg M, Connell W, Macrae F, Kamm M, Bates G, Cunningham G, Austin D, Knowles S. Differences across illness perceptions in inflammatory bowel disease and their relationships to psychological distress and quality of life. Gastroenterol Nurs. 2017;40(4):291–299.
Tseng YT, Schaefke B, Wei P, Wang L. Defensive responses: behaviour, the brain and the body. Nat Rev Neurosci. 2023;24(11):655-671.
Uematsu A, Tan BZ, Ycu EA, Cuevas JS, Koivumaa J, Junyent F, Kremer EJ, Witten IB, Deisseroth K, Johansen JP. Modular organization of the brainstem noradrenaline system coordinates opposing learning states. Nat Neurosci. 2017;20(11):1602-1611.
Valatas V, Vakas M, Kolios G. The value of experimental models of colitis in predicting efficacy of biological therapies for inflammatory bowel diseases. Am J Physiol Gastrointest Liver Physiol. 2013;305(11):G763-785.
Van Rooijen N, Hendrikx E. Liposomes for specific depletion of macrophages from organs and tissues. Methods Mol Biol. 2010;605:189-203.
Waise TMZ, Dranse HJ, Lam TKT. The metabolic role of vagal afferent innervation. Nat Rev Gastroenterol Hepatol. 2018;15(10):625-636.
Wall NR, Wickersham IR, Cetin A, De La Parra M, Callaway EM. Monosynaptic circuit tracing in vivo through Cre-dependent targeting and complementation of modified rabies virus. Proc Natl Acad Sci U S A. 2010;107(50):21848–21853.
Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421(6921):384-8.
Wang H, Foong JPP, Harris NL, Bornstein JC. Enteric neuroimmune interactions coordinate intestinal responses in health and disease. Mucosal Immunol. 2022;15(1):27-39.
Wang H, Labus JS, Griffin F, Gupta A, Bhatt RR, Sauk JS, Turkiewicz J, Bernstein CN, Kornelsen J, Mayer EA. Functional brain rewiring and altered cortical stability in ulcerative colitis. Mol Psychiatry. 2022;27(3):1792-1804.
Wang R, Li Z, Liu S, Zhang D. Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: a systematic analysis based on the Global Burden of Disease Study 2019. BMJ Open. 2023;13(3):e065186.
Wang YB, de Lartigue G, Page AJ. Dissecting the role of subtypes of gastrointestinal vagal afferents. Front Physiol. 2020;11:643.
Watkins LR, Goehler LE, Relton JK, Tartaglia N, Silbert L, Martin D, Maier SF. Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci Lett. 1995;183(1-2):27-31.
Williams RM, Berthoud HR, Stead RH. Vagal afferent nerve fibres contact mast cells in rat small intestinal mucosa. Neuroimmunomodulation. 1997;4(5-6):266-70.
Wirtz S, Popp V, Kindermann M, Gerlach K, Weigmann B, Fichtner-Feigl S, Neurath MF. Chemically induced mouse models of acute and chronic intestinal inflammation. Nat Protoc. 2017;12(7):1295-1309.
Yang D, Almanzar N, Chiu IM. The role of cellular and molecular neuroimmune crosstalk in gut immunity. Cell Mol Immunol. 2023;20(11):1259-1269.
Yang CY, Hung YC, Cheng KH, Ling P, Hsu KS. Loss of CC2D1A in glutamatergic neurons results in autistic-like features in mice. Neurotherapeutics. 2021;18(3):2021-2039.
Yau SY, Lau WM, Lee MC, Lee KF. Differential behavioral outcome of anxiety tests in runner rats treated with corticosterone. J Neurosci Behav Health. 2013;5(1):5–12.
Yoo BB, Mazmanian SK. The enteric network: Interactions between the immune and nervous systems of the gut. Immunity. 2017;46(6):910-926.
Youssef M, Hossein-Javaheri N, Hoxha T, Mallouk C, Tandon P. Work productivity impairment in persons with inflammatory bowel diseases: A systematic review and meta-analysis. J Crohns Colitis. 2024 :jjae057
Zanos TP, Silverman HA, Levy T, Tsaava T, Battinelli E, Lorraine PW, Ashe JM, Chavan SS, Tracey KJ, Bouton CE. Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity. Proc Natl Acad Sci U S A. 2018;115(21):E4843-E4852
Zanos TP. Recording and decoding of vagal neural signals related to changes in physiological parameters and biomarkers of disease. Cold Spring Harb Perspect Med. 2019;9(12):a034157.
Zeissig S, Rosati E, Dowds CM, Aden K, Bethge J, Schulte B, Pan WH, Mishra N, Zuhayra M, Marx M, Paulsen M, Strigli A, Conrad C, Schuldt D, Sinha A, Ebsen H, Kornell SC, Nikolaus S, Arlt A, Kabelitz D, Ellrichmann M, Lützen U, Rosenstiel PC, Franke A, Schreiber S. Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease. Gut. 2019;68(1):25-39.
Zmora N, Suez J, Elinav E. You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16(1):35-56.