Sexual dimorphism in glucose metabolism is shaped by androgen-driven gut microbiome.

Males are generally more susceptible to impaired glucose metabolism and type 2 diabetes (T2D) than females. However, the underlying mechanisms remain to be determined. Here, we revealed that gut microbiome depletion abolished sexual dimorphism in glucose metabolism. The transfer of male donor microbiota into antibiotics-treated female mice led the recipients to be more insulin resistant. Depleting androgen via castration changed the gut microbiome of male mice to be more similar to that of females and improved glucose metabolism, while reintroducing dihydrotestosterone (DHT) reversed these alterations. More importantly, the effects of androgen on glucose metabolism were largely abolished when the gut microbiome was depleted. Next, we demonstrated that androgen modulated circulating glutamine and glutamine/glutamate (Gln/Glu) ratio partially depending on the gut microbiome, and glutamine supplementation increases insulin sensitivity in vitro. Our study identifies the effects of androgen in deteriorating glucose homeostasis partially by modulating the gut microbiome and circulating glutamine and Gln/Glu ratio, thereby contributing to the difference in glucose metabolism between the two sexes.

Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota: a multi-center, double-blind, randomized, parallel-controlled study.

BACKGROUND: Berberine and Bifidobacterium have been reported to improve glucose tolerance in people with hyperglycemia or other metabolic disorders. This study aimed to assess the hypoglycemic effect and the regulation of the gut microbiota caused by berberine and Bifidobacterium and the possible additive benefits of their combination. METHODS: This was an 18-week, multi-center, randomized, double-blind, parallel-controlled study of patients newly diagnosed with hyperglycemia. After a 2-week run-in period, 300 participants were randomly assigned to the following four groups for 16 weeks of treatment: berberine (Be), Bifidobacterium (Bi), berberine and Bifidobacterium (BB), and placebo group. The primary efficacy endpoint was the absolute value of fasting plasma glucose (FPG) compared with baseline after 16 weeks of treatment. RESULTS: Between October 2015 and April 2018, a total of 297 participants were included in the primary analysis. Significant reductions of FPG were observed in the Be and BB groups compared with the placebo group, with a least square (LS) mean difference of - 0.50, 95% CI [- 0.85, - 0.15] mmol/L, and - 0.55, 95% CI [- 0.91, - 0.20] mmol/L, respectively. The Be and BB groups also showed significant reductions in 2-h postprandial plasma glucose. A pronounced decrease in HbA1c occurred in the BB group compared to the placebo group. Moreover, compared with the Bi and placebo groups, the Be and BB groups had more changes in the gut microbiota from the baseline. CONCLUSIONS: Berberine could regulate the structure and function of the human gut microbiota, and Bifidobacterium has the potential to enhance the hypoglycemic effect of berberine. These findings provide new insights into the hypoglycemic potential of berberine and Bifidobacterium. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03330184. Retrospectively registered on 18 October 2017.

Reversal of Functional Brain Activity Related to Gut Microbiome and Hormones After VSG Surgery in Patients With Obesity.

CONTEXT: Vertical sleeve gastrectomy (VSG) is becoming a prioritized surgical intervention for obese individuals; however, the brain circuits that mediate its effective control of food intake and predict surgical outcome remain largely unclear. OBJECTIVE: We investigated VSG-correlated alterations of the gut-brain axis. METHODS: In this observational cohort study, 80 patients with obesity were screened. A total of 36 patients together with 26 normal-weight subjects were enrolled and evaluated using the 21-item Three-Factor Eating Questionnaire (TFEQ), MRI scanning, plasma intestinal hormone analysis, and fecal sample sequencing. Thirty-two patients underwent VSG treatment and 19 subjects completed an average of 4-month follow-up evaluation. Data-driven regional homogeneity (ReHo) coupled with seed-based connectivity analysis were used to quantify VSG-related brain activity. Longitudinal alterations of body weight, eating behavior, brain activity, gastrointestinal hormones, and gut microbiota were detected and subjected to repeated measures correlation analysis. RESULTS: VSG induced significant functional changes in the right putamen (PUT.R) and left supplementary motor area, both of which correlated with weight loss and TFEQ scores. Moreover, postprandial levels of active glucagon-like peptide-1 (aGLP-1) and Ghrelin were associated with ReHo of PUT.R; meanwhile, relative abundance of Clostridia increased by VSG was associated with improvements in aGLP-1 secretion, PUT.R activity, and weight loss. Importantly, VSG normalized excessive functional connectivities with PUT.R, among which baseline connectivity between PUT.R and right orbitofrontal cortex was related to postoperative weight loss. CONCLUSION: VSG causes correlated alterations of gut-brain axis, including Clostridia, postprandial aGLP-1, PUT.R activity, and eating habits. Preoperative connectivity of PUT.R may represent a potential predictive marker of surgical outcome in patients with obesity.

Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment.

Antidiabetic medication may modulate the gut microbiota and thereby alter plasma and faecal bile acid (BA) composition, which may improve metabolic health. Here we show that treatment with Acarbose, but not Glipizide, increases the ratio between primary BAs and secondary BAs and plasma levels of unconjugated BAs in treatment-naive type 2 diabetes (T2D) patients, which may beneficially affect metabolism. Acarbose increases the relative abundances of Lactobacillus and Bifidobacterium in the gut microbiota and depletes Bacteroides, thereby changing the relative abundance of microbial genes involved in BA metabolism. Treatment outcomes of Acarbose are dependent on gut microbiota compositions prior to treatment. Compared to patients with a gut microbiota dominated by Prevotella, those with a high abundance of Bacteroides exhibit more changes in plasma BAs and greater improvement in metabolic parameters after Acarbose treatment. Our work highlights the potential for stratification of T2D patients based on their gut microbiota prior to treatment.

Antiproliferation and cell apoptosis inducing bioactivities of constituents from Dysosma versipellis in PC3 and Bcap-37 cell lines.

BACKGROUND: Recently, interest in phytochemicals from traditional Chinese medicinal herbs with the capability to inhibit cancer cells growth and proliferation has been growing rapidly due to their nontoxic nature. Dysosma versipellis as Bereridaceae plants is an endemic species in China, which has been proved to be an important Chinese herbal medicine because of its biological activity. However, systematic and comprehensive studies on the phytochemicals from Dysosma versipellis and their bioactivity are limited. RESULTS: Fifteen compounds were isolated and characterized from the roots of Dysosma versipellis, among which six compounds were isolated from this plant for the first time. The inhibitory activities of these compounds were investigated on tumor cells PC3, Bcap-37 and BGC-823 in vitro by MTT method, and the results showed that podophyllotoxone (PTO) and 4'-demethyldeoxypodophyllotoxin (DDPT) had potent inhibitory activities against the growth of human carcinoma cell lines. Subsequent fluorescence staining and flow cytometry analysis indicated that these two compounds could induce apoptosis in PC3 and Bcap-37 cells, and the apoptosis ratios reached the peak (12.0% and 14.1%) after 72 h of treatment at 20 µM, respectively. CONCLUSIONS: This study suggests that most of the compounds from the roots of D. versipellis could inhibit the growth of human carcinoma cells. In addition, PTO and DDPT could induce apoptosis of tumor cells.

High-dose isoflavones do not improve metabolic and inflammatory parameters in androgen-deprived men with prostate cancer.

The profound hypogonadism that occurs with androgen deprivation therapy (ADT) for prostate cancer (PCa) results in complications such as diabetes and metabolic syndrome that predispose to cardiovascular disease. Because phytoestrogens have been associated with an improvement in metabolic parameters, we evaluated their role in men undergoing ADT. Our objective was to evaluate the effects of high-dose isoflavones on metabolic and inflammatory parameters in men undergoing ADT. This was a randomized, double-blind, placebo-controlled, 12-week pilot study. Participants were randomly assigned to receive 20 g of soy protein containing 160 mg of total isoflavones vs taste-matched placebo (20 g whole milk protein). The study was conducted at a tertiary care center in the United States. Thirty-three men (isoflavones = 17, placebo = 16) undergoing ADT for PCa completed this pilot study. Mean age in the 2 groups was 69 years and the majority of men were Caucasians. Mean duration of ADT in both groups was approximately 2 years (P = .70). The 2 groups were well matched at baseline. After 12 weeks of intervention, there was no significant difference in either metabolic or inflammatory parameters between the 2 groups. We found that high-dose isoflavones over a course of 12 weeks do not improve metabolic or inflammatory parameters in androgen-deprived men.