Table 1.
Major studies on IBD-related neuroinflammation and associated systemic immune changes, neuronal alterations, and behavioral phenotypes.
| Reference | Genotype [Initial Age] |
Colitis Induction | Systemic Inflammation | Neuroinflammation | Neuronal Changes | Behavior |
|---|---|---|---|---|---|---|
| DSS-induced colitis | ||||||
| [59] | C57BL/6 mice [8w] |
2.5% DSS for 5d + 6d H2O (acute) | − | ↔ Il-1β, Il-6 | − | − |
| 2.5% DSS on d1-5, d12-16, d23-27 + 3d H2O (chronic) | ↑ Hmgb1 | ↑ Il-1β, Il-6, Hmgb1 (Hc), Il-10 (Hc, Cb) ↑ Gfap+ astrocytes, reactive morphology (Hc) ↑ Caspase-1, Gsdm (Cb, Hc), caspase-11 (Hc) |
↓ Brain activity ↓ Manganese uptake (Hc) |
↓ Long-term memory | ||
| [60] | Male C57BL/6 mice [10-11w] | 2.5% DSS for 4d/7d (acute) | ↑ Tnf-α, Il-1β, Il-6, Il-10 | ↑ Mϕs, monocytes (Hc) ↑ Gfap+ astrocytes (Hc) ↑ CD45lowCD11b+Iba1+ microglia (Hc) ↑ Tnf, Il-1β, Il-6, Il-10 (Hc) |
↑ Neurogenesis (Hc): ↑ Proliferation (Ki67) ↑ Maturation (Dcx) Altered NSC cell cycle |
− |
| 2% DSS on d1-7, d21-28, d42-49 (chronic) | ↑ Il-6, Il-10 | ↑ Mϕs, monocytes (Hc) ↑ Iba1+ myeloid cells (Hc) ↑ Tnf, Il-1β, Il-6, Il-10 (Hc) |
↓ Neurogenesis (Hc): ↓ Cell migration, integration |
↓ Exploratory behavior ↓ Spatial learning |
||
| [53] | C57BL/6 mice [10-12w] |
3% DSS for 1d and 3d + 2d H2O (acute) | ↑ Monocytes (d1, d3) ↑ Il-6 (d5) |
↑ Mϕs (d3, d5), monocytes (d5) ↑ Tmem119+ microglia (d3) ↑ Tmem119+ MHC-II+CD86+ microglia (d5) ↑ Iba1+ cell amoeboid morphology (Hc) |
− | − |
| 1.8% DSS for 7d + 14d H2O (acute + remission) | − | ↑ Iba1+ cell amoeboid morphology (acute, Hc) | − | ↓ Exploratory behavior ↓ Mobility (acute) |
||
| [56] | C57BL/6 mice [16w] |
2% DSS for 5d + 2d H2O (acute) |
↑ Il-6, Cxcl1, S100A8/A9 | ↑ Caspase-1 ↑ Tnf, Il-1β, Cxcl1, Lcn-2, S100A8/A9 ↑ Neutrophils, monocytes ↑ Iba1-IR |
↓ Bdnf | − |
| [61] | C57BL/6J mice [6-8w] | 3% DSS for 6d (acute) | ↑ Tnf, Ccl2, Il-6, Ifn-γ |
↑ Tnf, Il-1β, Il-6, Vcam-1 ↑ Monocytes, neutrophils, Mϕs ↔ CD45loCD11b+Cx3cr1hi microglia, CD68-IR ↓ MHC-II+ microglia |
− | ↑ Flurothyl-induced seizure susceptibility (reversed by anti-neutrophil and anti-Tnf treatment) |
| 3% DSS for 6d + 30d H2O (acute + remission) | − | ↑ Monocytes, neutrophils | − | ↑ Flurothyl-induced seizure susceptibility | ||
| 3% DSS on d1-6, d22-27, d44-49 + 7d H2O (chronic) | − | ↑ Monocytes, neutrophils, Mϕs | − | |||
| [54] | Male C57BL/6 mice [7-8w] | 3% DSS for 5d (acute) | ↑ Il-6 | ↑ Iba1-IR (Hc) ↑ Il-1β, Il-6 |
− | − |
| 3% DSS for 5d (acute) + hypoxia (6000 m) for 2d |
↑ Il-1β, Il-6 | ↑ Iba1-IR (Cx, Hc) ↑ Tnf, Il-1β, Il-6 |
− | − | ||
| [62] | C57BL/6 mice [3w] |
2% DSS for 5d + 5-7w H2O (acute + remission) |
− | ↑ Iba1, Il-1β, iNos2, Nod1, Nod2, Tlr2, Tlr4, Il-17ra (Hc) ↑ Iba1+ cells, amoeboid morphology (Hc) |
↓ Neurogenesis (Hc): ↔ Proliferation (Ki67) ↓ Maturation (Dcx) |
↓ Object recognition ↑ Anxiety |
| [63] | Male C57BL/6N mice [n.a.] | 2% DSS for 7d (acute) | − | ↓ Iba1-IR (Cx, Hc, MeA, Pvh), CD68-IR (Hc, MeA) ↓ Nos2, Iba-1, CD11b, CD206 (Cx) ↑ Ido-1, Tnf, CD86, Chil3 (Cx) ↑ CD45hiCD11b+ myeloid cells |
− | − |
| [64] | C57BL/6J mice [64w] | 1% DSS on d1-5, d8-12, d15-19, d22-26 + 11d H2O (chronic) |
− | ↑ Nlrp3 activation (brain, Men) ↑ Iba1+ myeloid cells (Cx, Hc) ↑ Gfap+/C3+ astrocytes (Cx, Hc) ↑ gut-derived T cell accumulation (Men) |
↓ Map2-IR (Cx, Hc) ↓ NeuN+ neurons (Cx, Hc) |
↑ Anxiety ↓ Spatial memory ↓ Object recognition |
| [24] | C57BL/6 mice [7-8w] |
5% DSS for 7d (acute) | ↑ Il-6 | ↑ Iba1-IR (Cx) ↑ Il-6, Tnf (Cx) |
− | − |
| [65] | Female C57BL/6 mice [8w] |
3% DSS on d1-5 + 2d H2O (acute) | ↑ Tnf, Il-6 | ↑ Iba1-IR, Il-6-IR (Hc) ↑ Tnf, Il-1β (Hc) |
− | − |
| 3% DSS on d1-5, d8-12, d15-19, d22-26 + 3d H2O (chronic) | ↑ Il-6 | ↑ Gfap-IR (Hc) ↑ Tnf, Il-1β, Gfap (Hc) |
↓ Neurogenesis (Hc): ↓ Proliferation (Ki67) ↓ Maturation (Dcx) |
− | ||
| [66] | Male C57BL/6 mice [24-40w] | 2% DSS on d1-3, d18-20 + 20d H2O (chronic) | − | ↓ Gfap-IR (Hc) ↑ Iba1-IR, ↔ CD68-IR (Hc) ↔ Il-6-IR, ↔ Cox-2-IR |
− | ↔ Locomotor activity ↔ Anxiety |
| [67] | Male ddY mice [6-7w] | 1.5% DSS for 7d (acute) | − | ↑ Iba1+ cells, amoeboid morphology (Hc) ↑ Gfap+ astrocytes, reactive morphology, IR (Hc) |
↓ NeuN-IR (Hc) ↓ Neurogenesis (Hc): ↓ Proliferation (BrdU) ↓ Maturation (Dcx) |
↑ Depressive-like behavior |
| [68] | Male Wistar rats [n.a.] | 5% DSS for 6-8d (acute) | − | ↑ Nos2 (Cx, Hc, Ht), Il-6 (Cx) ↑ iNOS-IR, 3-NT-IR (Me) ↑ Iba1+ cells, amoeboid morphology, IR (Me) |
↑ Ventricular volume ↑ FosB/∆FosB-IR (Nac, Drn) |
↓ Exploratory behavior ↑ Anhedonia |
| 5% DSS for 6-8d + 2-3d/7-10d H2O (acute + remission) | ↑ Ventricular volume ↑ FosB/∆FosB-IR (Drn) |
↑ Anhedonia ↑ Anxiety ↑ Depressive-like behavior |
||||
| Non-DSS-induced colitis | ||||||
| [69] | Male NMRI mice [n.a.] | 6 mg DNBS i.r. + 3d recovery | − | ↑ Tlr2, Tlr4, Myd-88, Hmgb1, Tnf, Il-6 (Hc) ↑ ROS production, ↓ GSH, ATP (Hc) |
↓ Bdnf (Hc) | ↑ Anxiety ↑ Depressive-like behavior |
| [70] | Male NMRI mice [n.a.] | 10 mg TNBS i.r. + 3d recovery | − | ↑ Nos2, Tnf (Hc) ↑ nitrite |
− | ↑ Depressive-like behavior (reversed by NO inhibition) |
| [71] | Male Sprague-Dawley rats [n.a.] | 25 mg TNBS i.l. + 4d or 10d recovery | − | ↑ Iba1+ cell amoeboid morphology (d4, Erc, Hc) ↔ Iba1+ cell amoeboid morphology (d10, Erc, Hc) ↑ Tnf (Hc) |
− | ↑ Pentylenetetrazole-induced seizure susceptibility |
| [61] | C57BL/6J mice [6-8w] |
T cell transfer-colitis: Splenic naïve CD4+ T cells (5*105) + Tregs (1*105) | ↑ Tnf, Ccl2, Il-6, Ifn-γ | ↑ Monocytes, T cells | − | ↑ Flurothyl-induced seizure susceptibility |
Studies only focusing on behavioral changes or on the expression of individual inflammatory genes in the brain were excluded. Most studies were performed using mice with DSS-induced colitis and differ in the applied experimental paradigm, partly explaining spatiotemporally diverging findings in the CNS. DSS-treatment paradigms were divided into acute (short-term DSS administration ≤ 8d) and chronic (long-term DSS administration in cycles) colitis. The brain region showing a particular immune response is indicated in brackets. If not indicated, changes were measured in the whole brain, and gender of experimental mice was not specified in the publications. ATP: adenosine triphosphate; Bdnf: brain-derived neurotrophic factor; C3: complement factor 3; Cx: Cortex; d: days; Dcx: doublecortin; DNBS: dinitrobenzene sulfonic acid; Drn: dorsal raphe neucleus; DSS: dextran sulfate sodium; Erc: entorhinal cortex; Gsdm: gasdermin; GSH: glutathione; Hc: hippocampus; Hmgb1: high-mobility group box 1; Ht: Hypothalamus; Il: interleukin; i.r.: intrarectal; IR: immunoreactivity; Mϕ: macrophage; Me: median eminence; MeA: medial amygdala; Men: meninges; n.a.: not available; NAc: Nucleus accumbens; NMRI: Naval Medical Research Institute; iNos: inducible nitric oxide synthase; NSCs: neural stem cells; Pvh: paraventricular nucleus of the hypothalamus; ROS: reactive oxygen species; TNBS: trinitrobenzene sulfonic acid, Tlr: toll-like receptor; Tnf: tumor necrosis factor; Tregs: regulatory T cells; w: weeks; ↑: increased; ↓: decreased; ↔: no change.