BACKGROUND: Brain function is influenced by the gut through the microbiota-gut-brain axis, as shown in microbiota-depleted or experimentally infected animal models. However, the impact of commensal microbiota shifts remains poorly understood. Galectin-4 is an intestinal lectin that controls pathogenic bacterial infections via glycan binding. Using galectin-4-deficient mice, we aimed to explore whether moderate physiological-like variations of commensal microbiota contribute to neurological conditions.
METHODS: Gut microbiota were analyzed by 16S ribosomal RNA sequencing. Cognitive function and affective-like behaviors were evaluated using behavioral tests. In the hippocampus, long-term potentiation (LTP) was tested ex vivo and in vivo by electrophysiology and in vitro by immunofluorescence and Western blot. RNA sequencing was used for transcriptomic analyses. Golgi-Cox staining and electron microscopy were used for quantitative and morphological assessments of hippocampal dendritic spines and synapses.
RESULTS: Lgals4 knockout (KO) mice present an altered intestinal commensal microbiota in the absence of pathogens, deficient memory formation, and impaired hippocampal LTP in vivo and ex vivo. Furthermore, Lgals4-KO neurons show a reduced activation of AMPA receptors and CaMKII (calcium/calmodulin-dependent protein kinase II) upon chemically induced LTP in vitro. These mice also display significantly lower dendritic spine density and shorter spine length in hippocampal dendrites, as well as an increased area of the postsynaptic densities.
CONCLUSIONS: Our results define a new role for galectin-4 in the modulation of commensal bacteria. We also show that the absence of galectin-4 induces changes in gut microbial composition, along with synaptic alterations and memory impairment, supporting our hypothesis that variations in endogenous microbiota may cause or contribute to relevant neurological pathologies.
