Cultivated Enterococcus faecium B6 from children with obesity promotes nonalcoholic fatty liver disease by the bioactive metabolite tyramine.

Gut microbiota plays an essential role in nonalcoholic fatty liver disease (NAFLD). However, the contribution of individual bacterial strains and their metabolites to childhood NAFLD pathogenesis remains poorly understood. Herein, the critical bacteria in children with obesity accompanied by NAFLD were identified by microbiome analysis. Bacteria abundant in the NAFLD group were systematically assessed for their lipogenic effects. The underlying mechanisms and microbial-derived metabolites in NAFLD pathogenesis were investigated using multi-omics and LC-MS/MS analysis. The roles of the crucial metabolite in NAFLD were validated in vitro and in vivo as well as in an additional cohort. The results showed that Enterococcus spp. was enriched in children with obesity and NAFLD. The patient-derived Enterococcus faecium B6 (E. faecium B6) significantly contributed to NAFLD symptoms in mice. E. faecium B6 produced a crucial bioactive metabolite, tyramine, which probably activated PPAR-γ, leading to lipid accumulation, inflammation, and fibrosis in the liver. Moreover, these findings were successfully validated in an additional cohort. This pioneering study elucidated the important functions of cultivated E. faecium B6 and its bioactive metabolite (tyramine) in exacerbating NAFLD. These findings advance the comprehensive understanding of NAFLD pathogenesis and provide new insights for the development of microbe/metabolite-based therapeutic strategies.

Integrative metabolomics highlights gut microbiota metabolites as novel NAFLD-related candidate biomarkers in children.

Altered gut microbiota and metabolites are important for non-alcoholic fatty liver disease (NAFLD) in children. We aimed to comprehensively examine the effects of gut metabolites on NAFLD progression. We performed integrative metabolomics (untargeted discovery and targeted validation) analysis of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and obesity in children. Fecal samples were collected from 75 subjects in the discovery cohort (25 NAFL, 25 NASH, and 25 obese control children) and 145 subjects in an independent validation cohort (53 NAFL, 39 NASH, and 53 obese control children). Among 2,491 metabolites, untargeted metabolomics revealed a complete NAFLD metabolic map containing 318 increased and 123 decreased metabolites. Then, machine learning selected 65 important metabolites that can distinguish the severity of the NAFLD. Furthermore, precision-targeted metabolomics selected 5 novel gut metabolites from 20 typical metabolites. The functionality of candidate metabolites was validated in hepatocyte cell lines. In the end, this study annotated two novel elevated pathogenic metabolites (dodecanoic acid and creatinine) and a relationship between depleted protective gut microbiota (Butyricicoccus and Alistipes), increased inflammation (IL-1ß), lipid metabolism (TG), and liver function (ALT and AST). This study demonstrates the role of novel gut metabolites (dodecanoic acid and creatinine), as the fatty acid metabolism regulator contributing to NAFLD development through its influence on inflammation and liver function. IMPORTANCE: Altered gut microbiota and metabolites are a major cause of non-alcoholic fatty liver disease (NAFLD) in children. This study demonstrated a complete gut metabolic map of children with NAFLD, containing 318 increased and 123 decreased metabolites by untargeted metabolomic. Multiple validation approaches (machine learning and targeted metabolomic) selected five novel gut metabolites for targeted metabolomics, which can distinguish NAFLD status and severity. The gut microbiota (Butyricicoccus and Alistipes) and metabolites (creatinine and dodecanoic acid) were novel biomarkers associated with impaired liver function and inflammation and validated by experiments of hepatocyte cell lines. The data provide a better understanding of the importance of gut microbiota and metabolite alterations in NAFLD, which implies that the altered gut microbiota and metabolites may represent a potential target to prevent NAFLD development.

Dose-response associations of maternal age with pregnancy complications and multimorbidity among nulliparas and multiparas: A multicentric retrospective cohort study in southern China.

Background: Advanced maternal age is becoming an increasingly common issue worldwide, presenting substantial health risks to pregnant women. However, dose-response associations of maternal age with a comprehensive range of pregnancy complications and their multimorbidity remain unclear. Methods: We conducted a retrospective cohort study using data from China's National Maternal Near Miss Surveillance System for 2017-2018, including 18 hospitals in southern China. We included 135 274 pregnant women aged 15-54 years with a singleton birth. We used multivariable logistic regression and restricted cubic spline to examine dose-response associations between maternal age and various pregnancy complications, as well as multimorbidity. We employed the Apriori algorithm to mine the association rules among pregnancy complications and identify frequent multimorbidity patterns. Results: We found three distinct patterns of associations between maternal age and specific pregnancy complications. In relation to increasing maternal age, gestational diabetes mellitus, preeclampsia, and gestational hypertension showed nonlinear increasing trends for both nulliparas and multiparas, as did multimorbidity in nulliparas. Conversely, we observed linear increasing trends for placental previa in both nulliparas and multiparas, placental abruption in nulliparas, and multimorbidity in multiparas. Infection and severe anaemia had an approximate J-shaped curve among nulliparas, while postpartum haemorrhage exhibited a similar curve in both nulliparas and multiparas. Advanced maternal age was linked to an elevated risk of multimorbidity during pregnancy or postpartum period, exhibiting more complicated patterns. The most common multimorbidity patterns in this age group were "preeclampsia + gestational diabetes mellitus", "gestational hypertension + gestational diabetes mellitus", "infection + gestational diabetes mellitus", and "placental previa + gestational diabetes mellitus". Conclusions: Maternal age was associated with pregnancy complications and multimorbidity in three broad dose-response manners, including approximate J-shaped curves, as well as nonlinear and linear increasing trends, depending on the specific outcome and parity, which may suggest different underlying biological mechanisms. Women with advanced maternal age had a higher risk and more complicated patterns of multimorbidity during pregnancy or postpartum, suggesting that this group should be targeted for more intensive health care.

Association between inflammatory markers and non-alcoholic fatty liver disease in obese children.

Background: Given the high prevalence of non-alcoholic fatty liver disease (NAFLD) in obese children, non-invasive markers of disease to date are still limited and worth exploring. Objective: This study aimed to evaluate the association between inflammatory markers and NAFLD in obese children. Methods: We performed a case-control study in Hunan Children's Hospital from September 2020 to September 2021. Study participants were children with obesity diagnosed with NAFLD by abdominal ultrasound examination. Mean platelet volume (MPV), platelet distribution width (PDW), neutrophil, lymphocyte, monocyte, and platelet counts were extracted from medical records and inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Multivariable logistic regression analysis was performed to evaluate the association between inflammatory markers and NAFLD. We also used receiver operating characteristic curve analysis to assess the discriminative ability of inflammatory cytokines for NAFLD. Results: Two hundred and sixty-seven obese children were enrolled, including 176 NAFLD patients and 91 simple obesity controls. Multivariable logistic model indicated that increased interleukin (IL)-1ß [odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.04-1.27], IL-6 (OR = 1.28, 95% CI: 1.07-1.53), and IL-17 (OR = 1.04, 95% CI: 1.02-1.07) levels were significantly associated with NAFLD. In contrast, we observed non-significant associations for IL-8, IL-12, IL-21, IL-32, tumor necrosis factor-α (TNF-α), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), mean platelet volume (MPV), and platelet distribution width (PDW) with NAFLD. The area under the curves (AUCs) of IL-1ß, IL-6, and IL-17 to discriminate obese children with or without NAFLD were 0.94, 0.94, and 0.97, respectively. Conclusions: Our results indicated that IL-1ß, IL-6, and IL-17 levels were significantly associated with NAFLD. These inflammatory cytokines may serve as non-invasive markers to determine the development of NAFLD and potentially identify additional avenues for therapeutic intervention.

The Association Between Severity of Anemia During Pregnancy and Severe Maternal Outcomes: A Retrospective Cohort Study.

Purpose: Anemia is a worldwide common condition during pregnancy, conferring a number of health risks to mothers. However, very little is known about the association between severity of anemia and severe maternal outcomes. This study aimed to assess the association between severity of anemia during pregnancy and the risk of severe maternal outcomes. Patients and Methods: This retrospective cohort study was based on data from China's National Maternal Near Miss Surveillance System for the period 2017-2018, which included 18 hospitals in southern China. Pregnant women admitted for delivery were divided into 4 groups based on severity of anemia during pregnancy: no anemia, mild anemia, moderate anemia, and severe anemia groups. Severe maternal outcomes were a composite of life-threatening conditions (ie, organ dysfunction) as defined by the WHO criteria, occurring at any time after admission until discharge or death. Modified Poisson regression analyses and propensity score-weighted regression analyses were used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) of severe maternal outcomes among women with anemia of varying severity during pregnancy. Results: The incidence of severe maternal outcomes was 0.3% (417/138,556) in total, and the rates were 0.1% (85/99,755), 0.2% (30/18,502), 1.2% (234/19,697) and 11.3% (68/602) in no anemia, mild anemia, moderate anemia and severe anemia group, respectively. Compared with no anemia, the adjusted RR for severe maternal outcomes was 4.19 (95% CI, 3.20-5.50) in moderate anemia group and 22.12 (95% CI, 15.43-31.69) in severe anemia group; the weighted RR was 1.01 (95% CI, 1.01-1.01) in moderate anemia group and 1.11 (95% CI, 1.07-1.14) in severe anemia group. Conclusion: Moderate to severe anemia during pregnancy was independently associated with an increased risk of severe maternal outcomes. Maternal health care providers and pregnant women themselves should give more attention to the prevention and treatment of anemia during pregnancy, especially moderate to severe anemia.

Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease.

Background: Inflammatory cytokines have been considered to be significant factors contributing to the development and progression of non-alcoholic fatty liver disease (NAFLD). However, the role of inflammatory cytokines in NAFLD remains inconclusive. Objective: This study aimed to evaluate the association between inflammatory cytokines and NAFLD. Methods: PubMed, Web of Science, the Cochrane Library, and EMBASE databases were searched until 31 December 2021 to identify eligible studies that reported the association of inflammatory cytokine with NAFLD and its subtypes. We pooled odds ratios (ORs) and hazard risk (HRs) with 95% confidence intervals (CIs) and conducted heterogeneity tests. Sensitivity analysis and analysis for publication bias were also carried out. Results: The search in the databases identified 51 relevant studies that investigated the association between 19 different inflammatory cytokines and NAFLD based on 36,074 patients and 47,052 controls. The results of the meta-analysis showed significant associations for C-reactive protein (CRP), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) with NAFLD (ORs of 1.41, 1.08, 1.50, 1.15 and 2.17, respectively). In contrast, we observed non-significant associations for interferon-γ (IFN-γ), insulin-like growth factor (IGF-II), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), monocyte chemoattractant protein-1(MCP-1), and transforming growth factor-ß (TGF-ß) with NAFLD. Our results also showed that CRP, IL-1ß, and TNF-α were significantly associated with non-alcoholic steatohepatitis (NASH) and hepatic fibrosis. Conclusions: Our results indicated that increased CRP, IL-1ß, IL-6, TNF-α, and ICAM-1 concentrations were significantly associated with increased risks of NAFLD. These inflammatory mediators may serve as biomarkers for NAFLD subjects and expect to provide new insights into the aetiology of NAFLD as well as early diagnosis and intervention.

Chromosome identification by new molecular markers and genomic in situ hybridization in the Triticum-Secale-Thinopyrum trigeneric hybrids.

It is very important to use chromosome-specific markers for identifying alien chromosomes in advanced generations of distant hybridization. The chromosome-specific markers of rye and Thinopyrum elongatum, as well as genomic in situ hybridization, were used to identify the alien chromosomes in eight lines that were derived from the crossing between Triticum trititrigia (AABBEE) and triticale (AABBRR). The results showed that four lines contained all rye chromosomes but no Th. elongatum chromosomes. The line RE36-1 contained all of the rye chromosomes except for chromosome 2R. The lines RE33-2 and RE62-1 contained all rye chromosomes and 1E and 5E translocated chromosome, respectively. The line RE24-4 contained 12 rye chromosomes plus a 7E chromosome or 12 rye chromosomes plus one R-E translocated chromosome. Chromosome identification in the above lines was consistent using chromosome-specific markers and genomic in situ hybridization. These chromosome-specific markers provide useful tools for detecting alien chromosomes in trigeneric hybrids, and these lines could be utilized as valuable germplasm in wheat improvement.

Molecular Cytogenetic Characterization of two Triticum-Secale-Thinopyrum Trigeneric Hybrids Exhibiting Superior Resistance to Fusarium Head Blight, Leaf Rust, and Stem Rust Race Ug99.

Fusarium head blight (FHB), leaf rust, and stem rust are the most destructive fungal diseases in current world wheat production. The diploid wheatgrass, Thinopyrum elongatum (Host) Dewey (2n = 2x = 14, EE) is an excellent source of disease resistance genes. Two new Triticum-Secale-Thinopyrum trigeneric hybrids were derived from a cross between a hexaploid triticale (X Triticosecale Wittmack, 2n = 6x = 42, AABBRR) and a hexaploid Triticum trititrigia (2n = 6x = 42, AABBEE), were produced and analyzed using genomic in situ hybridization and molecular markers. The results indicated that line RE21 contained 14 A-chromosomes, 14 B-chromosomes, three pairs of R-chromosomes (4R, 6R, and 7R), and four pairs of E-chromosomes (1E, 2E, 3E, and 5E) for a total chromosome number of 2n = 42. Line RE62 contained 14 A-chromosomes, 14 B-chromosomes, six pairs of R-chromosomes, and one pair of translocation chromosomes between chromosome 5R and 5E, for a total chromosome number of 2n = 42. At the seedling and adult growth stages under greenhouse conditions, line RE21 showed high levels of resistance to FHB, leaf rust, and stem rust race Ug99, and line RE62 was highly resistant to leaf rust and stem rust race Ug99. These two lines (RE21 and RE62) display superior disease resistance characteristics and have the potential to be utilized as valuable germplasm sources for future wheat improvement.

Production and Molecular Cytogenetic Characterization of a Durum Wheat-Thinopyrum elongatum 7E Disomic Addition Line with Resistance to Fusarium Head Blight.

Wheatgrass, Thinopyrum elongatum (2n = 2x = 14, EE), is an important wild relative of wheat with many excellent traits, including resistance to Fusarium head blight (FHB), that can be used for durum wheat improvement. Through hybridization of the durum cultivar "Langdon" with the amphiploid 8801 (AABBEE), a disomic alien addition line (2n = 30) with a pair of Th. elongatum 7E chromosomes was obtained and confirmed using chromosome-specific molecular markers of Th. elongatum and genomic in situ hybridization (GISH). This line is meiotically and reproductively stable, generally forming 15 bivalents at meiosis including 14 pairs from Langdon and 1 from Th. elongatum with 2 chiasmata each as revealed by GISH analysis. At the adult growth stages under field conditions, this addition line shows high resistance to FHB, with less than 16% infection on visual observation in 2 years (2014 and 2015). This addition line is shorter in height and has narrower leaves and shorter spikes as compared to its parent Langdon. So the linkage group 7E might be a further source of wheat improvement by targeted introgression approaches.