Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice

Brain Behav Immun. 2018 Jan;67:230-245. doi: 10.1016/j.bbi.2017.09.001. Epub 2017 Sep 7.

Abstract

The microbiota-gut-brain axis (MGBA) regulates the reciprocal interaction between chronic inflammatory bowel and psychiatric disorders. This interaction involves multiple pathways that are highly debated. We examined the behavioural, biochemical and electrophysiological alterations, as well as gut microbiota composition in a model of antibiotic-induced experimental dysbiosis. Inflammation of the small intestine was also assessed. Mice were exposed to a mixture of antimicrobials for 2weeks. Afterwards, they received Lactobacillus casei DG (LCDG) or a vehicle for up to 7days via oral gavage. Perturbation of microbiota was accompanied by a general inflammatory state and alteration of some endocannabinoidome members in the gut. Behavioural changes, including increased immobility in the tail suspension test and reduced social recognition were observed, and were associated with altered BDNF/TrkB signalling, TRPV1 phosphorylation and neuronal firing in the hippocampus. Moreover, morphological rearrangements of non-neuronal cells in brain areas controlling emotional behaviour were detected. Subsequent probiotic administration, compared with vehicle, counteracted most of these gut inflammatory, behavioural, biochemical and functional alterations. Interestingly, levels of Lachnospiraceae were found to significantly correlate with the behavioural changes observed in dysbiotic mice. Our findings clarify some of the biomolecular and functional modifications leading to the development of affective disorders associated with gut microbiota alterations.

Keywords: Depression; Endocannabinoidome; Hippocampus; Microbiome; Social behavior.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage*
  • Behavior, Animal / drug effects
  • Brain-Derived Neurotrophic Factor / metabolism
  • Depression / metabolism
  • Depression / microbiology*
  • Dysbiosis / complications
  • Dysbiosis / metabolism
  • Dysbiosis / microbiology
  • Endocannabinoids / metabolism*
  • Gastrointestinal Microbiome / drug effects*
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Inflammation / complications
  • Inflammation / metabolism
  • Inflammation / microbiology*
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Intestines / microbiology
  • Male
  • Mice, Inbred C57BL
  • Neuroglia / drug effects
  • Neuroglia / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Probiotics / administration & dosage

Substances

  • Anti-Bacterial Agents
  • Brain-Derived Neurotrophic Factor
  • Endocannabinoids