Gut-derived ammonia modulates hypothalamic stress responses during viral infection

Colaco, H. G.; Gundacker, A.; Burrett, A.; Grozev, C.; Hofmann, A.; Seneca, J.; Endler, L.; Wong, J.; Sanchez, J.; Baumgartner, M.; Fell, C. W.; Lercher, A.; Siller, M.; Keszei, Z.; Viczenczova, C.; Richter, F. C.; Law, Y. K.; Antonio-Herrera, L.; Dearlove, B.; Balcar, L.; Kramer, G.; Reiberger, T.; Pjevac, P.; Campbell, C.; Pollak, D. D.; Bergthaler, A.

doi:10.64898/2026.07.06.736796

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bioRxiv · 10.64898/2026.07.06.736796

Gut-derived ammonia modulates hypothalamic stress responses during viral infection

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Abstract

The gut-brain axis integrates microbial and host metabolism to regulate systemic physiology, yet its role during viral infection remains poorly defined. Viral infection induces behavioral changes and neuroendocrine stress responses accompanied by profound alterations in gut microbial metabolism. Here, we show that chronic viral infection in mice increases systemic levels of microbiota-derived ammonia in a CD8 T cell-dependent manner. Increased ammonia accumulates in the brain and selectively activates neurons within the paraventricular hypothalamus (PVH), driving corticosterone release into the circulation. Pharmacological inhibition of ammonia detoxification exacerbates these effects, leading to increased corticosterone levels, aggravated sickness behavior, and dampened antiviral responses. Together, these findings identify gut-derived ammonia as a previously unrecognized immunometabolic signal linking antiviral T cell responses to hypothalamic control of systemic stress during viral infection. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/736796v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1291dbcorg.highwire.dtl.DTLVardef@5f223corg.highwire.dtl.DTLVardef@1c0aafaorg.highwire.dtl.DTLVardef@190502_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Colaco, H. G., Gundacker, A., Burrett, A., Grozev, C., Hofmann, A., Seneca, J., Endler, L., Wong, J., Sanchez, J., Baumgartner, M., Fell, C. W., Lercher, A., Siller, M., Keszei, Z., Viczenczova, C., Richter, F. C., Law, Y. K., Antonio-Herrera, L., Dearlove, B., Balcar, L., Kramer, G., Reiberger, T., Pjevac, P., Campbell, C., Pollak, D. D., Bergthaler, A.. 2026-07-09. Gut-derived ammonia modulates hypothalamic stress responses during viral infection. https://doi.org/10.64898/2026.07.06.736796

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