Understanding the physiological functions of the host xenobiotic-sensing nuclear receptors PXR and CAR on the gut microbiome using genetically modified mice

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.

Evaluation of plasma H2S levels and H2S synthesis in streptozotocin induced Type-2 diabetes-an experimental study based on Swietenia macrophylla seeds

<p><b>OBJECTIVE</b>To evaluate the plasma H2S levels and H2S synthesis activity in streptozotocin induced type 2 diabetes rats compared to the healthy controls and also to observe the effect of the aqueous extract of Swietenia macrophylla (S. macrophylla) seeds on the experimental groups.</p><p><b>METHODS</b>Seeds of S. macrophylla were separated, washed, shed-dried and finally extract was prepared. Thirty two wistar rats were selected for the experimental study. Streptozotocin was used for the induction of diabetes. H2S concentration in plasma was measured. H2S synthesizing activity in plasma was measured. Statistical analysis have done using Microsoft excel, Office 2003. Values were expressed by mean±SD. P<0.05 were considered statistically significant.</p><p><b>RESULTS</b>Fasting blood glucose level (7.74±0.02) mmol/L was significantly increased in diabetic rats. The glucose levels are significantly lowered in the rats treated with metformin (5.48±0.03) mmol/L as well as with aqueous extract of S. macrophylla seeds (3.72±0.04) mmol/L. The HbA1c percentages in different groups of study subjects also indicate similar trends. Our study shows both the plasma H2S levels (22.07±0.73) mmol/L and plasma H2S synthesis activity (0.411±0.005 mmol/100 g) are significantly reduced in the streptozotocin induced diabetic rats.</p><p><b>CONCLUSIONS</b>Although considering a small sample size, it can conclude that the fasting blood glucose levels are inversely related to plasma H2S levels as well as H2S synthesis activity in plasma and the extract of S. macrophylla is associated with increased plasma H2S levels with effective lowering of blood glucose in streptozotocin induced diabetic rats.</p>