Understanding the mechanism of the sexual dimorphism in susceptibility to obesity and metabolic syndrome (MS) is important for the development of effective interventions for MS. Here we show that gut microbiome mediates the preventive effect of estrogen (17β-estradiol) on metabolic endotoxemia (ME) and low-grade chronic inflammation (LGCI), the underlying causes of MS and chronic diseases. The characteristic profiles of gut microbiome observed in female and 17β-estradiol-treated male and ovariectomized mice, such as decreased Proteobacteria and lipopolysaccharide biosynthesis, were associated with a lower susceptibility to ME, LGCI, and MS in these animals. Interestingly, fecal microbiota-transplant from male mice transferred the MS phenotype to female mice, while antibiotic treatment eliminated the sexual dimorphism in MS, suggesting a causative role of the gut microbiome in this condition. Moreover, estrogenic compounds such as isoflavones exerted microbiome-modulating effects similar to those of 17β-estradiol and reversed symptoms of MS in the male mice. Finally, both expression and activity of intestinal alkaline phosphatase (IAP), a gut microbiota-modifying non-classical anti-microbial peptide, were upregulated by 17β-estradiol and isoflavones, whereas inhibition of IAP induced ME and LGCI in female mice, indicating a critical role of IAP in mediating the effects of estrogen on these parameters. In summary, we have identified a previously uncharacterized microbiome-based mechanism that sheds light upon sexual dimorphism in the incidence of MS and that suggests novel therapeutic targets and strategies for the management of obesity and MS in males and postmenopausal women.

Background: Microbiome-directed therapies are increasingly utilized to optimize thyroid function in both healthy individuals and those with thyroid disorders. However, recent doubts have been raised regarding the efficacy of probiotics, prebiotics, and synbiotics in improving thyroid function. This systematic review aimed to investigate the potential relationship between probiotics/prebiotics and thyroid function by analyzing the impact on thyroid hormone levels. Methods: We conducted a comprehensive systematic review and meta-analysis of randomized controlled trials that investigated the effects of probiotics, prebiotics, and synbiotics on free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), and thyroid stimulating hormone receptor antibody (TRAb) levels. We searched for articles from PubMed, Scopus, Web of Science, and Embase up until April 1st, 2023, without any language restriction. Quantitative data analysis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval as summary statistics. The methods and results were reported according to the PRISMA2020 statement. Results: A total of eight articles were included in this review. The meta-analysis showed no significant alterations in TSH (SMD: -0.01, 95% CI: −0.21, 0.20, P = 0.93; I²: 0.00%), fT4 (SMD: 0.04, 95% CI: −0.29, 0.21, P = 0.73; I²: 0.00%) or fT3 (SMD: 0.45, 95% CI: −0.14, 1.03, P = 0.43; I²: 78.00%), while a significant reduction in TRAb levels was observed (SMD: -0.85, 95% CI: -1.54, -0.15, P = 0.02; I²: 18.00%) following probiotics/prebiotics supplementation. No indication of publication bias was found. Conclusions: Probiotics/prebiotics supplementation does not influence thyroid hormone levels, but may modestly reduce TRAb levels in patients with Graves’ disease.

Gastrointestinal toxicity (GIT) is a debilitating side effect of Irinotecan (CPT-11) and limits its clinical utility. Gut dysbiosis has been shown to mediate this side effect of CPT-11 by increasing gut bacterial β-glucuronidase (GUSB) activity and impairing the intestinal mucosal barrier (IMB). We have recently shown the opposing effects of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) on the gut microbiome. We hypothesized that elevated levels of tissue n-3 PUFA with a decreased n-6/n-3 PUFA ratio would reduce CPT-11-induced GIT and associated changes in the gut microbiome. Using a unique transgenic mouse (FAT-1) model combined with dietary supplementation experiments, we demonstrate that an elevated tissue n-3 PUFA status with a decreased n-6/n-3 PUFA ratio significantly reduces CPT-11-induced weight loss, bloody diarrhea, gut pathological changes, and mortality. Gut microbiome analysis by 16S rRNA gene sequencing and QIIME2 revealed that improvements in GIT were associated with the reduction in the CPT-11-induced increase in both GUSB-producing bacteria (e.g., Enterobacteriaceae) and GUSB enzyme activity, decrease in IMB-maintaining bacteria (e.g., Bifidobacterium), IMB dysfunction and systemic endotoxemia. These results uncover a host–microbiome interaction approach to the management of drug-induced gut toxicity. The prevention of CPT-11-induced gut microbiome changes by decreasing the tissue n-6/n-3 PUFA ratio could be a novel strategy to prevent chemotherapy-induced GIT.

Background: Nitrate is a dietary intervention commonly used to enhance exercise capacity, including cardiopulmonary fitness, yet its effectiveness has been recently questioned at high altitudes. This meta-analysis systematically evaluates the effects of dietary nitrate supplements on cardiopulmonary fitness at high altitude, as reflected in the biomarker of cardiopulmonary fitness, paving the way for informed dietary strategies. Methods: We conducted a systematic assessment and meta-analysis of randomized controlled trials to examine the effects of dietary nitrate supplementation on biomarkers of cardiorespiratory health at high altitude. Studies were included if they involved healthy individuals (≥16 years of age) engaging in endurance activities such as hiking, long-distance running, mountain climbing, or bicycling at high altitude. Outcomes of interest included nitrite levels (NO₂-), maximal oxygen uptake (VO_2max), heart rate (HR), perceived exertion (RPE), and pulse oxygen saturation (SpO₂). Exclusion criteria included duplicate publications, non-human studies, studies with missing data that could not be retrieved, non-randomized clinical trials, and non-original research articles such as conference papers, expert consensus, or reviews. Our search for articles was conducted across PubMed, Scopus, Web of Science, and Embase, without any language restrictions. A random effects model was employed for quantitative data analysis, utilizing Standardized Mean Difference (SMD) and 95% confidence intervals as summary statistics. The methods and results were reported according to the PRISMA2020 statement. Results: A total of 9 studies with a sample size of 161 cases were included in the analysis. The meta-analysis indicated that dietary nitrate supplement significantly elevated NO₂^- concentration (95% CI: 1.38 to 3.12; SMD = 2.25, P < 0.00001; I² = 70%). However, there was no significant effect observed on VO_2max (95% CI: -0.58 to 0.23; SMD = -0.17, P = 0.76; I² = 0%), HR (95% CI: -0.31 to 0.23; SMD = -0.04, P = 0.77; I² = 0%), RPE scores (95% CI: -0.49 to 0.18; SMD = -0.16, P = 0.36; I² = 0%), and SpO₂ percentage (95% CI: -0.36 to 0.20; SMD = -0.08, P = 0.58; I² = 0%). Conclusions: The current meta-analysis indicates that dietary nitrate intake is less correlated with cardiopulmonary fitness at high altitudes, and further research is required to clarify its impact on exercise capacity.

Pancreatic β-cell failure is a pathological feature in type 1 diabetes. One promising approach involves inducing transdifferentiation of related pancreatic cell types, specifically α cells that produce glucagon. The chemokine stromal cell-derived factor-1 alpha (SDF-1α) is implicated in pancreatic α-to-β like cell transition. Here, the serum level of SDF-1α was lower in T1D with C-peptide loss, the miR-23a was negatively correlated with SDF-1α. We discovered that exosomal miR-23a, secreted from β cells, functionally downregulates the expression of SDF-1α, leading to increased Pax4 expression and decreased Arx expression in vivo. Adenovirus-vectored miR-23a sponge and mimic were constructed to further explored the miR-23a on pancreatic α-to-β like cell transition in vitro, which yielded results consistent with our cell-based assays. Suppression of miR-23a upregulated insulin level and downregulated glucagon level in STZ-induced diabetes mice models, effectively promoting α-to-β like cell transition. Our findings highlight miR-23a as a new therapeutic target for regenerating pancreatic β cells from α cells.

Rationale: Maturity onset diabetes of the young (MODY) is the most common type of monogenic diabetes, characterized by autosomal dominant inheritance, the age of onset is often <25 years old, and the clinical manifestations are atypical. MODY12 is caused by a rare missense mutation of adenosine triphosphate (ATP)-binding cassette transporter subfamily C member 8 (ABCC8) gene and more than 50 ABCC8 variants were associated with MODY12. Patient concerns: The patient was a 30-year-old Chinese Han man. He was overweight with a poor control of blood glucose. Diagnoses: The patient was diagnosed with MODY12. Interventions: The patient was given glimepiride (4 mg/d) with diet and exercise therapy to reduce blood glucose and weight. Outcomes: The level of fasting blood glucose and C-peptide was improved after 1 year treatment as well as body weight. Lessons: A Chinese Han adult with a heterozygous missense mutation c.3976G > A (p.Glu1326Lys) was diagnosed with MODY12, which was the new pathogenic mutation for the disease. This report expands the spectrum of variants causing MODY12 and reduces misdiagnosis.