Antibiotics are tremendously beneficial in reducing mortality rates by combating infections but their excessive use has led to severe antibiotic resistance worldwide. The ingestion of oral antibiotics dramatically alters the gut microbiome. Critically, there is limited understanding of the effects of a dysfunctional microbiome on brain function. Male C57BL/6J mice (2–4 months) were given drinking water containing antibiotics (ABX group; ampicillin, neomycin, gentamicin, metronidazole, and vancomycin) or untreated water (CON group). Separate cohorts received butyrate, a key microbiome-derived metabolite, either in the presence (ABXBA group) or absence (BA group) of antibiotics. The four groups were tested at 4 weeks of treatment. Mice were implanted with tetrode arrays targeted the medial entorhinal cortex (MEC) to record grid cells and local field potentials (LFPs). The permeability of the blood-brain barrier (BBB) was assessed with positron emission tomography using [11C]-aminoisobutyric acid (11C-AIB) and confirmed with immunohistochemistry for claudin-5 and occludin (tight junction proteins). MEC neural recordings reveal that grid cells from ABX mice have significantly lower grid scores (compared to CON mice) and increased power in theta, beta, and gamma bands of the LFP. Interestingly, we find no changes to theta-gamma coupling between groups. Our assessment of BBB integrity using 11C-AIB indicates increased permeabilization throughout the MEC of ABX mice, which is linked to decreased expression of occludin in the MEC of ABX mice. Remarkably, butyrate treatment in ABXBA mice preserves grid cell function and BBB integrity. These findings point to butyrate as a potential therapeutic supplement for microbiome depletion.