A novel Bacillus aerolatus CX253 alleviates dextromethorphan-induced neurotoxicity via modulating the microbiota-gut-brain axis and hippocampal Apelin signaling pathway.
Shihuan Tian, E. Huang, Guoxia Zhang, Jiaxian Song, Wenhao Zhong, Jinjin Zhang, Xin Liu, Ming-Jin Yang, Hao Wang, Chao Liu, Hua Li, Lingli Chen
Brain, behavior, and immunity May 1, 2026 DOI: 10.1016/j.bbi.2026.106801 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice exposed to subchronic dose-escalation dextromethorphan |
| Interventions | Dextromethorphan Bacillus aerolatus CX253 |
| Key points | Subchronic dose-escalation dextromethorphan in mice altered gut microbiota, reduced fecal butyrate, impaired intestinal barrier function, raised peripheral and hippocampal inflammation, suppressed the Apelin-PI3K/Akt/mTOR pathway, and increased anxiety-like behavior and spatial memory impairment. Prophylactic Bacillus aerolatus CX253 preserved microbial diversity, restored butyrate, reduced inflammation, and improved neurobehavioral performance, with mediation analyses suggesting these effects were closely associated with elevated butyrate. |
Abstract
The increasing non-medical use of dextromethorphan (DM), particularly among adolescents, has raised concerns regarding its potential neurobiological consequences. However, the precise mechanisms underlying its neurotoxicity, particularly the involvement of the gut microbiota, remain unclear. A novel probiotic strain, Bacillus aerolatus CX253, has demonstrated the capacity to regulate gut microbial homeostasis and attenuate inflammatory responses, yet whether it can mitigate DM-induced neurotoxicity remains unknown. In the present study, a subchronic dose-escalation DM exposure model was established in mice. Through behavioral assessments, 16S rRNA sequencing, short-chain fatty acid (SCFA) analysis, and molecular-level investigations, we systematically evaluated the neurobehavioral effects of DM and the prophylactic efficacy of CX253. The results showed that DM exposure significantly altered gut microbial composition, characterized by increased abundance of Akkermansia and Desulfovibrionaceae and decreased abundance of Muribaculaceae. These alterations were accompanied by reduced fecal butyrate levels, impaired intestinal barrier function, and elevated circulating lipopolysaccharide (LPS) and inflammatory cytokines. At the central level, DM exposure led to upregulation of pro-inflammatory cytokines in the hippocampus, glial activation, and marked suppression of the pro-survival Apelin-PI3K/Akt/mTOR signaling pathway, ultimately manifesting as increased anxiety-like behaviors and impaired spatial memory. Prophylactic administration of CX253 preserved gut microbial diversity, enriched beneficial taxa including Bifidobacteriaceae, Bacteroides, and Lachnospiraceae_NK4A136_group, increased fecal butyrate levels, alleviated intestinal barrier dysfunction as well as peripheral and central inflammatory responses, and specifically restored the DM-suppressed Apelin-PI3K/Akt/mTOR pro-survival signaling pathway, thereby improving neurobehavioral performance. Correlation and mediation analyses further suggested that these protective effects were closely associated with elevated butyrate levels. Collectively, these findings not only expand the current understanding of the mechanisms underlying DM-induced neurotoxicity but also provide a novel mechanistic framework and a translationally promising candidate strain for microbiota-based preventive strategies targeting substance misuse-related neuropsychiatric disorders.