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Updated: Jan 8, 2026
Intracerebroventricular Delivery of Gut-Derived Microbial Metabolites in Freely Moving Mice
Published on: June 2, 2022
Consistent decline of acetylcholine in microbiota-gut-brain axis mediates antibiotic-induced anxiety via regulating
Ke Xu1,2, Yi Ren1,2, Shuang Zhao3,4
1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Abstract:
Antibiotics (AB) are widely abused in medicine and may be a risk factor for mental health. To better understand their effects, we observed mental disorder symptoms in AB-treated mice and patients, and investigated possible mechanisms. Using AB-treated mice, we found obvious anxiety-like behaviors, along with differential gut microbiota (mainly Firmicutes and Bacteroidota), reduced short-chain fatty acids (SCFAs), and disrupted gut-brain lipid metabolism. Acetylcholine decreased in feces, colon wall, serum, and hippocampus of AB-treated mice, and this reduction was significantly correlated with anxiety-like behaviors. Moreover, using AB-treated patients (n = 55), AB-naïve patients (n = 60), and healthy controls (n = 60), we also observed the obvious anxiety symptoms in AB-treated patients, along with differential gut microbiota (mainly Firmicutes), reduced SCFAs, and disrupted lipid metabolism in feces and serum. AB-treated patients showed consistently lower serum and fecal acetylcholine, which was highly correlated with anxiety symptoms. In both AB-treated mice and patients, co-occurrence analysis indicated that the "Bacteroides-acetylcholine" pair may play an important role in AB-induced anxiety. At the species levels, Bacteroides_caecimuris in AB-treated mice and Bacteroides_plebeius in AB-treated patients were both decreased and significantly correlated with acetylcholine. Furthermore, exogenous methacholine (an acetylcholine derivative) intervention effectively alleviated anxiety-like behaviors and suppressed hippocampal microglial activation in AB-treated mice. Together, our findings highlight the harmful effects of aggressive AB treatment on mood and show the potential of acetylcholine or its derivative to reverse this effect.
Insights
Antibiotic abuse is linked to anxiety. Researchers found reduced acetylcholine and altered gut bacteria in mice and patients, suggesting a potential treatment with acetylcholine derivatives to restore mood.
Area of Science:
- Neuroscience
- Microbiology
- Pharmacology
Background:
- Antibiotic (AB) overuse is a global concern.
- Potential links between antibiotic use and mental health disorders are emerging.
- The gut-brain axis plays a crucial role in regulating mood and behavior.
Purpose of the Study:
- To investigate the impact of antibiotics on mental health, specifically anxiety.
- To explore the underlying mechanisms involving gut microbiota, short-chain fatty acids (SCFAs), lipid metabolism, and acetylcholine.
- To evaluate the therapeutic potential of acetylcholine derivatives in mitigating antibiotic-induced anxiety.
Main Methods:
- Antibiotic-treated mice models were used to assess behavioral changes, gut microbiota composition, SCFA levels, lipid metabolism, and acetylcholine concentrations.
- Human studies included antibiotic-treated patients, antibiotic-naïve patients, and healthy controls, analyzing fecal and serum samples for microbial and metabolic profiles, and acetylcholine levels.
- Co-occurrence analysis identified key microbial-neurotransmitter interactions.
- Methacholine (an acetylcholine derivative) was administered to mice to assess its therapeutic effects.
Main Results:
- Antibiotic treatment induced anxiety-like behaviors in mice and patients.
- Significant alterations in gut microbiota composition (e.g., Firmicutes, Bacteroidota), reduced SCFAs, and disrupted lipid metabolism were observed in both groups.
- Decreased acetylcholine levels in feces, colon, serum, and hippocampus correlated strongly with anxiety symptoms.
- The "Bacteroides-acetylcholine" interaction, particularly involving decreased Bacteroides species, was implicated in antibiotic-induced anxiety.
- Methacholine administration alleviated anxiety-like behaviors and reduced hippocampal microglial activation in mice.
Conclusions:
- Aggressive antibiotic use negatively impacts mood, potentially leading to anxiety.
- Reduced acetylcholine levels and gut dysbiosis are key mechanisms underlying antibiotic-induced anxiety.
- Acetylcholine or its derivatives show promise as a therapeutic strategy to counteract antibiotic-associated mood disturbances.
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