Prevotella copri ameliorates cholestasis and liver fibrosis in primary sclerosing cholangitis by enhancing the FXR signalling pathway.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by bile duct inflammation, fibrosis, bile acid (BA) metabolism disorders and gut microbiota dysbiosis. At present, the aetiology and pathogenesis of PSC are not clear, and there is no specific or effective treatment available. Therefore, new research perspectives are needed to explore effective methods to treat PSC and improve symptoms. The intestinal microbiota of patients with PSC is known to be significantly different from that of healthy people. By comparing differentially abundant bacterial genera in PSC patients, it was found that the abundance of Prevotella copri (P. copri) was significantly decreased, suggesting that this species may have a protective effect against PSC disease. Therefore, comprehensively exploring the role and possible function of P. copri in the disease process is worthwhile. In this study, a PSC mouse model was established by feeding mice a customized diet supplemented with 0.1% (w/w) 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for one week, and the abundance of P. copri was confirmed to be decreased in this model. Previous studies in patients and animal models have demonstrated that gut microbiota intervention is an acceptable treatment for some diseases. We found that intervention with P. copri could significantly improve cholestasis and liver fibrosis by enhancing the FXR-related signalling pathway in PSC mice. Together, through the overall effect of P. copri on intestinal microbiota structure and its association with BAs, we speculate that P. copri intervention might be as potential biological treatment of PSC.

Effects of microplastics (MPs) and tributyltin (TBT) alone and in combination on bile acids and gut microbiota crosstalk in mice.

Microplastics (MPs) and tributyltin (TBT) are both potential environmental pollutants that enter organisms through the food chain and affect bodily functions. However, the effects and mechanisms of MPs and TBT exposure (especially the co-exposure of both pollutants) on mammals remain unclear. In this study, Ф5µm MPs (5MP) was administered alone or in combination with TBT to investigate the health risk of oral exposure in mice. All three treatments induced inflammation in the liver, altered gut microbiota composition and disturbed fecal bile acids profiles. In addition to decreasing triglyceride (TG) and increasing aspartate aminotransferase (AST) and macrophage-expressed gene 1 (Mpeg1), 5MP induced hepatic cholestasis by stimulating the expression of the cholesterol hydroxylase enzymes CYP8B1 and CYP27A1, and inhibiting multidrug resistance-associated protein 2 and 3 (MRP2, MRP3), and bile-salt export pump (BSEP) to prevent bile acids for entering the blood and bile. Correspondingly, 5MP treatment decreased 7-ketolithocholic acid (7-ketoLCA) and taurocholic acid (TCA), which were positively correlated with decreased Bacteroides and Marvinbryantia and negatively correlated with increased Bifidobacterium. In addition, TBT increased interferon γ (IFNγ) and Mpeg1 levels to induce inflammation, accompanied by decreased 7-ketoLCA, tauro-alpha-muricholic acid (T-alpha-MCA) and alpha-muricholic acid (alpha-MCA) levels, which were negatively related to Coriobacteriaceae_UCG-002 and Bifidobacterium. Co-exposure to 5MP and TBT also decreased TG and induced bile acids accumulation in the liver due to inhibited BSEP, which might be attributed to the co-regulation of decreased T-alpha-MCA and Harryflintia. In conclusion, the administration of 5MP and TBT alone and in combination could cause gut microbiome dysbiosis and subsequently alter bile acids profiles, while the combined exposure of 5MP and TBT weakened the toxic effects of 5MP and TBT alone.

A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8+ T cells in mice.

OBJECTIVE: Gut microbiota have been linked to inflammatory bowel disease (IBD) and colorectal cancer (CRC). Akkermansia muciniphila (A. muciniphila) is a gram-negative anaerobic bacterium that is selectively decreased in the faecal microbiota of patients with IBD, but its causative role and molecular mechanism in blunting colitis-associated colorectal cancer (CAC) remain inconclusive. This study investigates how A. muciniphila engages the immune response in CAC. DESIGN: Mice were given dextran sulfate sodium to induce colitis, followed by azoxymethane to establish CAC with or without pasteurised A. muciniphila or a specific outer membrane protein (Amuc_1100) treatment. Faeces from mice and patients with IBD or CRC were collected for 16S rRNA sequencing. The effects of A. muciniphila or Amuc_1100 on the immune response in acute colitis and CAC were investigated. RESULTS: A. muciniphila was significantly reduced in patients with IBD and mice with colitis or CAC. A. muciniphila or Amuc_1100 could improve colitis, with a reduction in infiltrating macrophages and CD8+ cytotoxic T lymphocytes (CTLs) in the colon. Their treatment also decreased CD16/32+ macrophages in the spleen and mesenteric lymph nodes (MLN) of colitis mice. Amuc_1100 elevated PD-1+ CTLs in the spleen. Moreover, A. muciniphila and Amuc_1100 blunted tumourigenesis by expanding CTLs in the colon and MLN. Remarkably, they activated CTLs in the MLN, as indicated by TNF-α induction and PD-1downregulation. Amuc_1100 could stimulate and activate CTLs from splenocytes in CT26 cell conditioned medium. CONCLUSIONS: These data indicate that pasteurised A. muciniphila or Amuc_1100 can blunt colitis and CAC through the modulation of CTLs.

Gut microbiota-mediated tributyltin-induced metabolic disorder in rats.

Tributyltin (TBT), an environmental pollutant widely used in antifouling coatings, can cause multiple-organ toxicity and gut microbiome dysbiosis in organisms, and can even cause changes in the host metabolomic profiles. However, little is known about the underlying effects and links of TBT-induced metabolic changes and gut microbiome dysbiosis. In this study, rats were exposed to TBT at a dose of 100 µg kg-1 body weight (BW) for 38 days, followed by multi-omics analysis, including microbiome, metabolomics, and metallomics. Results showed that TBT exposure reduced rat weight gain and decreased the serum triglyceride (TG) level. Metabolic analysis revealed that TBT fluctuated linoleic acid metabolism and glycerophospholipid metabolism in the liver; the tricarboxylic acid cycle (TCA cycle), nicotinate and nicotinamide metabolism, and arachidonic acid metabolism in serum; glycine, serine, and threonine metabolism, the one carbon pool by folate, nicotinate, and nicotinamide metabolism; and tryptophan metabolism in feces. Furthermore, TBT treatment dictated liver inflammation due to enhancing COX-2 expression by activating protein kinase R-like ER kinase (PERK) and C/EBP homologous protein (CHOP) to induce endoplasmic reticulum (ER) stress instead of stimulating arachidonic acid metabolism. Meanwhile, alteration of the intestinal flora [Acetivibrio]_ethanolgignens_group, Acetatifactor, Eisenbergiella, Lachnospiraceae_UCG-010, Enterococcus, Anaerovorax, and Bilophila under TBT exposure were found to be involved in further mediating liver inflammation, causing lipid metabolism abnormalities, such as TG, linoleic acid, and glycerophospholipids, and interfering with the energy supply process. Among these, [Acetivibrio]_ethanolgignens_group, Enterococcus, and Bilophila could be considered as potential biomarkers for TBT exposure based on receiver operator characteristic (ROC) curve analysis.

Doxorubicin obliterates mouse ovarian reserve through both primordial follicle atresia and overactivation.

Ovarian toxicity and infertility are major side effects of cancer therapy in young female cancer patients. We and others have previously demonstrated that doxorubicin (DOX), one of the most widely used chemotherapeutic chemicals, has a dose-dependent toxicity on growing follicles. However, it is not fully understood if the primordial follicles are the direct or indirect target of DOX. Using both prepubertal and young adult female mouse models, we comprehensively investigated the effect of DOX on all developmental stages of follicles, determined the impact of DOX on primordial follicle survival, activation, and development, as well as compared the impact of age on DOX-induced ovarian toxicity. Twenty-one-day-old CD-1 female mice were intraperitoneally injected with PBS or clinically relevant dose of DOX at 10 mg/kg once. Results indicated that DOX primarily damaged granulosa cells in growing follicles and oocytes in primordial follicles and DOX-induced growing follicle apoptosis was associated with the primordial follicle overactivation. Using the 5-day-old female mice with a more uniform primordial follicle population, our data revealed that DOX also directly promoted primordial follicle death and the DNA damage-TAp63α-C-CASP3 pathway was involved in DOX-induced primordial follicle oocyte apoptosis. Compared to 21-day- and 8-week-old female mice that were treated with the same dose of DOX, the 5-day-old mice had the most severe primordial follicle loss as well as the least degree of primordial follicle overactivation. Taken together, these results demonstrate that DOX obliterates mouse ovarian reserve through both primordial follicle atresia and overactivation and the DOX-induced ovarian toxicity is age dependent.

Female oncofertility attitude and knowledge: a survey of reproductive health professionals in Shanghai, China.

AIM: To evaluate the female oncofertility attitude and knowledge of reproductive health professionals in China. METHODS: An online survey was distributed to reproductive health professionals in Shanghai, China. RESULTS: Female professionals were more likely to consider that cancer patients would want to preserve their fertility. Participants with higher educational background tended to have a more positive attitude toward oncofertility. The majority of the participants (71.0%) obtained a fair or low level of oncofertility knowledge, and only 25.3% of them received scores at the 'good knowledge' level. CONCLUSION: There are significant gaps in the current oncofertility knowledge among reproductive health professionals in China, suggesting an urgent, unmet need for establishing an interdisciplinary fertility preservation training and service system.

A Survey Study of Attitude and Knowledge Regarding Female Fertility Preservation Among Reproductive Health Professionals in Fujian, China.

PURPOSE: Oncofertility is a newly developed medical field dedicated to preserving adolescent and young adult-aged cancer patients' fertility. For female cancer patients who desire to have children, fertility preservation has become an important concern before the cancer therapy. This study for the first time aimed to investigate attitude and knowledge regarding female fertility preservation among reproductive health professionals in China. METHODS: An online questionnaire assessing participants' demographics, experience, attitude, and basic knowledge regarding oncofertility was designed and distributed to reproductive health professionals in Fujian, one of the major regions for cancer and reproductive care in southeast China. RESULTS: The majority of participants (96.6%) who were familiar with fertility preservation were willing to collaborate with oncologists on preserving patients' fertility. However, ∼20% of participants were not familiar with the term fertility preservation, and 30.4% and 52.2% of them were never consulted by a cancer patient or an oncologist about the infertility risk from cancer therapy, respectively. Years of working experience, but not gender, educational background, and marital status, was significantly associated with participants' oncofertility experience and attitude. A majority of participants (79.3%) had a middle or low level of oncofertility knowledge, which was significantly linked to their educational background. CONCLUSION: Most of the surveyed reproductive health professionals held a positive attitude toward interdisciplinary collaboration with oncologists during oncofertility practice. However, the lack of their oncofertility knowledge highlighted the need of standard oncofertility education and training in China.

A preliminary investigation of metal element profiles in the serum of patients with bloodstream infections using inductively-coupled plasma mass spectrometry (ICP-MS).

BACKGROUND: We determined metal element profiles (MEPs) by inductively-coupled plasma mass spectrometry (ICP-MS) in the serum of patients with blood stream infection (BSI) and find out very important (VIP) metal elements in specific infections. METHODS: Sixty-eight metal elements were identified in both serum and the bacteria isolated from 14 BSI patients with Staphylococcus infection, 39 with Enterobacteriaceae infection, 5 with Enterococcus infection and 58 healthy subjects without infection by ICP-MS methods. Statistical analysis, Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA) were performed to process data among different groups, select differential metal elements and operate correlation analysis. RESULTS: The MEPs in the serum of BSI patients with 4 types of bacteria (Staphylococcus aureus, Escherichia coli, Enterococcus faecium, and Klebsiella pneumonia), and the corresponding MEPs of the bacteria were established. VIP metal elements were screened out in different BSI patients. Correlation analysis showed that there were some correlations between serum concentrations of metal elements and bacterial infection. CONCLUSION: We found differential metal elements in the serum of BSI patients compared with controls, thus providing a basis for the diagnosis, prevention and treatment of BSI from the perspective of metallomics.