Cannabis-enriched oral Actinomyces induces anxiety-like behavior via impairing mitochondria and GABA signaling

Salman, T.; Luo, Z.; Johnson, D.; Noorani, A. A.; Wan, Z.; Bordieanu, B.; Ye, Z.-w.; Penrod-Martin, R.; Xian, H.; Fitting, S.; Kalivas, P.; Jiang, W.

doi:10.1101/2025.11.21.689724

bioRxiv · 10.1101/2025.11.21.689724

Cannabis-enriched oral Actinomyces induces anxiety-like behavior via impairing mitochondria and GABA signaling

Salman, T.·Luo, Z.·Johnson, D.·Noorani, A. A.·Wan, Z.·Bordieanu, B.·Ye, Z.-w.·Penrod-Martin, R.·Xian, H.·Fitting, S.·Kalivas, P.·Jiang, W.

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Abstract

The human oral microbiome is increasingly recognized as a contributor to brain health, yet its mechanisms remain unclear. Our previous work revealed that oral Actinomyces species was enriched in chronic cannabis smokers. Here, we show oral inoculation of cannabis use-associated Actinomyces species, especially A. meyeri, to wild-type C57BL/6 mice leads to anxiety-like behaviors, non-region-specific microglia activation, mitochondrial dysfunction, and reduced GABAergic neurotransmission, without evidence of bacterial translocation to the brain, neuroinflammation, and memory decline. Notably, Actinomyces species-producing metabolites, i.e., arginine and argininosuccinate, were increased in both oral swabs and brain following inoculation in vivo. These Actinomyces species-producing metabolites induced mitochondrial dysfunction and oxidative stress in neurons in vitro, indicating a neuropathogenic role and aligning with reduced GABAergic neurotransmission in vivo. Together, these results suggest that oral cannabis-associated dysbiosis impacts behavior through mitochondrial stress and impaired inhibitory signaling, indicating the oral-brain metabolic axis is potentially consequential in neuropsychiatric disorders. TeaserChronic heavy cannabis use-enriched oral bacteria can drive anxiety and neuropathogenesis in mice. Highlights{whitebullet} Cannabis-associated oral Actinomyces enrichment induces anxiety-like behavior in mice {whitebullet}Microglial activation occurs without neuroinflammation (IL-1{beta}, TNF-, and IL-6) {whitebullet}Mitochondrial hyperactivation and reduced inhibitory GABAergic signaling Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/689724v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@120b0b1org.highwire.dtl.DTLVardef@1304782org.highwire.dtl.DTLVardef@a6aa77org.highwire.dtl.DTLVardef@17d6d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Salman, T., Luo, Z., Johnson, D., Noorani, A. A., Wan, Z., Bordieanu, B., Ye, Z.-w., Penrod-Martin, R., Xian, H., Fitting, S., Kalivas, P., Jiang, W.. 2025-11-22. Cannabis-enriched oral Actinomyces induces anxiety-like behavior via impairing mitochondria and GABA signaling. https://doi.org/10.1101/2025.11.21.689724

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