Alzheimer’s disease (AD), like other neurodegenerative disorders (NDs), is associated with chronic inflammation of the central nervous system via astrocyte and microglia activation. Previous work from our lab described Secreted Frizzled-related protein 1 (SFRP1) as a novel player in AD pathogenesis and neuro-inflammatory chronicity by modulating astrocyte-microglia crosstalk. The gut microbiome has increasingly attracted attention for its possible contribution to NDs through the gut-brain axis. In fact, microbiota-derived metabolites, such as short chain fatty acids (SCFA), have been related to microglia and astrocyte activity. Given that astrocytes are the main producers of SFRP1, we may expect the gut microbiota to modulate SFRP1 levels, potentially contributing to AD progression. To this end, we treated APP/PS1 female mice with antibiotics in the drinking water for four weeks. Fecal samples collected after treatment showed changes in microbial diversity and composition between treated and control groups. Antibiotic treatment reduced astrogliosis and induced a decreasing tendency of Aβ plaque burden in the cortex; while increasing SFRP1 levels exclusively in the hippocampus. Using liquid chromatography-mass spectrometry we observed a significant decrease of SCFAs in fecal, serum, and colonic samples of antibiotic-treated animals as compared to controls, whereas brain levels remained unaltered. Currently, we are performing the same antibiotic-treatment on APP/PS1 males and studying the effects of SCFAs in modulating an inflammatory-like response, induced by lipopolysaccharides, by exposing both compounds to astrocyte and microglia primary cultures. All in all, our preliminary observations suggest a potential astrocyte-location specific effect of the gut microbiota in an AD background.