Antibiotic-induced gut dysbiosis and cognitive, emotional, and behavioral changes in rodents: a systematic review and meta-analysis

Abstract

There are previous epidemiological studies reporting associations between antibiotic use and psychiatric symptoms. Antibiotic-induced gut dysbiosis and alteration of microbiota-gut-brain axis communication has been proposed to play a role in this association. In this systematic review and meta-analysis, we reviewed published articles that have presented results on changes in cognition, emotion, and behavior in rodents (rats and mice) after antibiotic-induced gut dysbiosis. We searched three databases-PubMed, Web of Science, and SCOPUS to identify such articles using dedicated search strings and extracted data from 48 articles. Increase in anxiety and depression-like behavior was reported in 32.7 and 40.7 percent of the study-populations, respectively. Decrease in sociability, social novelty preference, recognition memory and spatial cognition was found in 18.1, 35.3, 26.1, and 62.5 percent of the study-populations, respectively. Only one bacterial taxon (increase in gut Proteobacteria) showed statistically significant association with behavioral changes (increase in anxiety). There were no consistent findings with statistical significance for the potential biomarkers [Brain-derived neurotrophic factor (BDNF) expression in the hippocampus, serum corticosterone and circulating IL-6 and IL-1β levels]. Results of the meta-analysis revealed a significant association between symptoms of negative valence system (including anxiety and depression) and cognitive system (decreased spatial cognition) with antibiotic intake (p < 0.05). However, between-study heterogeneity and publication bias were statistically significant (p < 0.05). Risk of bias was evaluated to be high in the majority of the studies. We identified and discussed several reasons that could contribute to the heterogeneity between the results of the studies examined. The results of the meta-analysis provide promising evidence that there is indeed an association between antibiotic-induced gut dysbiosis and psychopathologies. However, inconsistencies in the implemented methodologies make generalizing these results difficult. Gut microbiota depletion using antibiotics may be a useful strategy to evaluate if and how gut microbes influence cognition, emotion, and behavior, but the heterogeneity in methodologies used precludes any definitive interpretations for a translational impact on clinical practice.

Keywords: anhedonia; antibiotics; anxiety; behavior; depression; gut microbiota; microbiota-gut-brain axis; social.

Figure 1

PRISMA flow diagram of article selection for this systematic review.

Figure 2

Forest plot of the random effects meta-analysis conducted using standardized mean differences of the latent time spend during Morris water maze test. “Study” is cross-referenced with the column “study population” in meta-analysis sheet in Supplementary material 2. Meta-data for each study can be assessed from this file. “SMD,” standardized mean difference; “RE,” random-effects model.

Figure 3

Forest plot of the random effects meta-analysis conducted using standardized mean differences of the time spend in center during open field test. “Study” is cross-referenced with the column “study population” in meta-analysis sheet in Supplementary material 2. Meta-data for each study can be assessed from this file. “SMD,” standardized mean difference; “RE,” random-effects model.

Figure 4

Forest plot of the random effects meta-analysis conducted using standardized mean differences of the immobile time during tail suspension test. “Study” is cross-referenced with the column “study population” in meta-analysis sheet in Supplementary material 2. Meta-data for each study can be assessed from this file. “SMD,” standardized mean difference; “RE,” random-effects model.

Figure 5

Forest plot of the random effects meta-analysis conducted on standardized mean differences of the immobile time during forced swim test. “Study” is cross-referenced with the column “study population” in meta-analysis sheet in Supplementary material 2. Meta-data for each study can be assessed from this file. “SMD,” standardized mean difference; “RE,” random-effects model.