Fig. 6: Vagal–brain restoration of immune balance.

a, Activation of TRPA1 vagal neurons and DBH cNST neurons. AAV-DIO-hM3Dq was targeted bilaterally to the nodose ganglion of Trpa1-cre mice or the cNST of Dbh-cre mice. Control Cre-driver mice received AAV-DIO-mCherry. Mice were challenged with a lethal dose of LPS (see Methods), and the TRPA1 vagal or the DBH cNST neurons were activated by injection of CNO at 6-h intervals beginning 1 h before injection of LPS (four injections over 19 h). b, Activation of TRPA1 vagal (left) or DBH cNST (right) neurons rescues animals from LPS-induced sepsis. The graphs show survival curves. All groups received the same regime of CNO injections. mCherry (black lines; n = 9) and hM3Dq (green lines; n = 8 (vagal) and n = 9 (cNST)) are shown. Log-rank (Mantel–Cox) tests: P < 0.001 (vagal) and P < 0.001 (cNST). The red arrow denotes LPS injection. All mCherry control mice, in both groups, died within the first 4 days. c, DSS-induced ulcerative colitis. d, Activation of TRPA1 vagal neurons protects animals from DSS-induced colon damage. AAV-DIO-hM3Dq or mCherry was targeted bilaterally to the nodose ganglion of Trpa1-cre mice. All animals were provided with CNO in the drinking water (see Methods). Note the effect of DSS-induced inflammation on colon integrity (middle); the red arrows illustrate the loss of the distal colon in DSS-treated animals, but not in DSS-treated animals if this circuit was activated (right; n = 4; similar protection was observed in all animals). e, Bar graphs show levels of CXCL1 pro-inflammatory cytokine in control, DSS-treated and DSS-treated in combination with activation of TRPA1 vagal neurons. Values are mean ± s.e.m.; Mann–Whitney U-test: P = 0.03 (DSS, DSS + hM3Dq). f, Significant levels of occult stool blood is detected in the DSS-treated but not in the TRPA1 neuron-activated animals. Values are mean ± s.e.m.; Mann–Whitney U-test: P = 0.03. Schematics in panels a,c were created using BioRender (https://biorender.com).