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.

Tryptophan Metabolites in Irritable Bowel Syndrome: An Overnight Time-course Study

BACKGROUND/AIMS: Patients with irritable bowel syndrome (IBS) often report poor sleep quality. Whether poor sleep is associated with tryptophan (Trp) metabolites is unknown. We compared serum Trp metabolites in women with IBS and healthy controls (HCs) using targeted liquid chromatography mass spectrometry (LC-MS)-based profiling. In IBS only, we explored whether Trp metabolites are associated with IBS symptoms and subjective and objective sleep indices, serum cortisol, plasma adrenocorticotropic hormone (ACTH), and cortisol/ACTH levels. METHODS: Blood samples were obtained every 80 minutes in 21 HCs and 38 IBS subjects following an anticipation-of-public-speaking stressor during a sleep laboratory protocol. Subjects completed symptom diaries for 28 days. Adjacent values of metabolites were averaged to represent 4 time-periods: awake, early sleep, mid-sleep, and mid-to-late sleep. Thirteen of 20 targeted Trp metabolites were identified. RESULTS: Ten of 13 Trp metabolites decreased across the night, while nicotinamide increased in both groups. A MANOVA omnibus test performed after principal component analysis showed a significant difference in these 13 principal component (P = 0.014) between groups. Compared to HCs, nicotinamide levels were higher and indole-3-lactic acid levels lower in the IBS group. Melatonin and indole-3-acetic acid levels were associated with several subjective/objective sleep measures; decreased stool consistency/frequency and abdominal pain were positively associated with melatonin and serotonin in the IBS group. The kynurenine and kynurenic acid were associated with ACTH (positively) and cortisol/ACTH (negatively). CONCLUSIONS: Nighttime Trp metabolites may provide clues to poor sleep and stress with IBS. Further study of the mechanism of metabolite action is warranted.

Effects of arsenic trioxide combined with thalidomide for the treatment of relapsed/refractory multiple myeloma / 白血病·淋巴瘤

Objective To evaluate the efficacy and side effects of arsenic trioxide (ATO) combined with thalidomide in the treatment of relapsed/refractory multiple myeloma (MM). Methods 35 patients with relapsed/refractory MM were treated with ATO (10 mg/d) and Vit C (2 g/d) for 14 days,28 days per cycle.Meanwhile they were orally administered thalidomide 50 mg/d,and then one week later orally thalidomide was added to 100-150 mg/d. After 3 cycles of treatment, response and the side effects were evaluated. Patients responsed to the regimen were continued the treatment of thalidomide and were followed up to estimate the PFS. Responses were assessed according to the criteria of the EBMT.Adverse events were graded according to the criteria of the WHO.Results The overall response Was 71.43 ％ (25/35),CR 5.71％ (2/35),PR 34.29 ％ (12/35),MR 31.43 ％ (11/35).After a median follow-up of 11 months,the median PFS was 9 months.The major adverse reactions were digestive tract reaction,leukocytopenia,liver function damage,peripheral neuropathy.They were mild,and could be tolerated.Conclusions The combination of ATO and thalidomide is a feasible and active regimen in treatment of relapsed/refractory MM with better compliance in general.