Ximing Ran

The management of metabolic disorder associated with polycystic ovary syndrome (PCOS) has been suggested as an effective approach to improve PCOS which is highly involved with gut microbiota, while the underlying mechanism is unclear. Here, we investigated the role of inulin, a gut microbiota regulator, in the alleviation of PCOS. Our findings showed that inulin treatment significantly improved hyperandrogenism and glucolipid metabolism in both PCOS cohort and mice. Consistent with the cohort, inulin increased the abundance of microbial co-abundance group (CAG) 12 in PCOS mice, including Bifidobacterium species and other short-chain fatty acids (SCFAs)-producers. We further verified the enhancement of SCFAs biosynthesis capacity and fecal SCFAs content by inulin. Moreover, inulin decreased lipopolysaccharide-binding protein (LBP) and ameliorated ovarian inflammation in PCOS mice, whereas intraperitoneal lipopolysaccharide (LPS) administration reversed the protective effects of inulin. Furthermore, fecal microbiota transplantation (FMT) from inulin-treated patients with PCOS enhanced insulin sensitivity, improved lipid accumulation and thermogenesis, reduced hyperandrogenism and ovarian inflammatory response in antibiotic-treated mice. Collectively, these findings revealed that gut microbiota mediates the beneficial effects of inulin on metabolic disorder and ovarian dysfunction in PCOS. Therefore, modulating gut microbiota represents a promising therapeutic strategy for PCOS.

ABSTRACT Cholestasis is a common morbid state that may occur in different phases; however, a comprehensive evaluation of the long-term effect post-recovery is still lacking. In the hepatic cholestasis mouse model, which was induced by a temporary complete blockage of the bile duct, the stasis of bile acids and liver damage typically recovered within a short period. However, we found that the temporary hepatic cholestasis had a long-term effect on gut microbiota dysbiosis, including overgrowth of small intestinal bacteria, decreased diversity of the gut microbiota, and an overall imbalance in its composition accompanied by an elevated inflammation level. Additionally, we observed an increase in Escherichia-Shigella (represented by ASV136078), rich in virulence factors, in both small and large intestines following cholestasis. To confirm the causal role of dysregulated gut microbiota in promoting hepatic inflammation and injury, we conducted gut microbiota transplantation into germ-free mice. We found that recipient mice transplanted with feces from cholestasis mice exhibited liver inflammation, damage, and accumulation of hepatic bile acids. In conclusion, our study demonstrates that cholestasis disrupts the overall load and structural composition of the gut microbiota in mice, and these adverse effects persist after recovery from cholestatic liver injury. This finding suggests the importance of monitoring the structural composition of the gut microbiota in patients with cholestasis and during their recovery. IMPORTANCE Our pre-clinical study using a mouse model of cholestasis underscores that cholestasis not only disrupts the equilibrium and structural configuration of the gut microbiota but also emphasizes the persistence of these adverse effects even after bile stasis restoration. This suggests the need of monitoring and initiating interventions for gut microbiota structural restoration in patients with cholestasis during and after recovery. We believe that our study contributes to novel and better understanding of the intricate interplay among bile acid homeostasis, gut microbiota, and cholestasis-associated complications. Our pre-clinical findings may provide implications for the clinical management of patients with cholestasis.

<p>Supplementary Table S1 shows the correlations between African subpopulation genetic ancestry estimates calculated from germline DNA and tumor RNASeq.</p>

<p>Supplementary Table S2 shows the distribution of SNP type stratified by whether or not data from a participant's tumor sample met the proposed SNP threshold to improve genetic ancestry estimation and overall.</p>

<div>AbstractBackground:<p>Germline genetics may influence tumor molecular characteristics and ultimately cancer survival. Studies of tumor characteristics, including our epithelial ovarian cancer (EOC) studies of Black women in the United States, may have RNA sequencing (RNA-seq) data from archival tumor tissue but lack germline DNA for at least some individuals. Incomplete germline DNA measurements impede analyses of important measures such as global genetic ancestry, often used in downstream analyses, by reducing sample sizes.</p>Methods:<p>The study population consists of 184 women who participated in two population-based studies of EOC with both germline and formalin-fixed, paraffin-embedded (FFPE) tumor samples and an additional 58 women diagnosed with EOC from the same two studies with only FFPE tumor tissue. We used tumor RNA-seq data to calculate proportions of African, European, and Asian genetic ancestry using a pipeline built on the packages SeqKit, HISAT2, SAMtools, BCFtools, PLINK, and ADMIXTURE. Women from the 1000 Genomes Project were used as the reference populations, and germline genetic ancestry estimates from blood or saliva were used as the baseline comparison. We evaluated multiple quality control strategies to improve genetic ancestry estimation.</p>Results:<p>Correlations between tumor RNA-seq–derived estimates of genetic ancestry from our pipeline and germline-derived African and European genetic ancestry ranged between 0.76 and 0.94.</p>Conclusions:<p>RNA-seq data from archival FFPE tumor tissue can be confidently and efficiently used to approximate global genetic ancestry in an admixed population when germline DNA is unavailable.</p>Impact:<p>This approach supports analyses of genetic ancestry and cancer when germline samples are not available.</p></div>