Upregulation of endocannabinoids in fatty acid amide hydrolase (FAAH) knockout mice prevents staphylococcal enterotoxin B (SEB)-mediated acute lung injury through changes in the microbiome, immune and metabolic profiles

Abstract

Abstract Endogenous cannabinoids are considered key regulators of biological systems as they have been shown to exhibit anti-inflammatory properties, while the fatty acid amide hydrolase (FAAH) enzyme plays a role in degrading the endogenous cannabinoid, anandamide. Staphylococcus Enterotoxin B (SEB) is a superantigen that can cause acute lung injury (ALI) through inhalation. In this study, we found that FAAH knockout mice (FAAH−/−) were more resistant to developing SEB-induced ALI 48 hours after intranasal administration of 50 μg dose of SEB compared to wildtype (WT) mice. The SEB-treated FAAH −/− mice had similar clinical parameters and upregulation of endogenous anandamide as naïve FAAH−/− mice. The results from assessing the clinical profile by plethysmography showed unlike with WT groups, there were no significant changes in the functions of the lung in FAAH−/− exposed to SEB when compared to naive FAAH−/−. Immune profiling by flow cytometry revealed there were also no changes in T cells subsets or cytokine levels among naive or SEB-treated FAAH−/− mice. Furthermore, after MiSeq sequencing V3-V4 region of the 16S rRNA of colon/cecal flush and lung samples, both the bacterial phylogenetic and short chain fatty acid (SCFA) profiles showed no significant differences in naïve FAAH−/− mice compared to those treated with SEB, unlike WT groups that had significant differences in these profiles. Lastly, further investigation of the metabolic profile by glycolysis rate assay (GRA) of splenocytes from both experimental groups showed no significant differences in this metabolic pathway. Collectively, these data suggest that knockdown of the FAAH enzyme may lead to increase endogenous cannabinoid, anandamide, thereby preventing SEB-induced ALI.