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Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids (BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. hPXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.

Asthma is associated with significant morbidity. The gut microbiome has been shown to effect asthma development and exacerbation. In this study, we tested an oral supplement containing Boswellia serrata (Indian frankincense) tree resin on allergic pulmonary inflammation and gut microbiome. An OVA based allergic airway model was used and mice were orally gavaged 100 mg/kg of Boswellia serrata as a supplementation throughout asthma sensitization and challenge. Treated mice showed significant weight loss, lower total lung leukocytes, eosinophil and Th2 cytokines, improved histology scoring and reduced reactivity to methacholine challenge. Asthmatic mice without Boswellia serrata supplementation showed a decrease in overall bacterial diversity, while treated mice were protected against loss. Boswellia serrata treated mice had a significant increase in Bifidobacterium, which was identified as Bifidobacterium pseudolongum. Oral administration of B. pseudolongum also reduced airway inflammation, suggesting Boswellia serrata may work as an anti-asthma agent via increases in B. pseudolongum from prebiotic influences.