A core microbiome signature as an indicator of health.

The gut microbiota is crucial for human health, functioning as a complex adaptive system akin to a vital organ. To identify core health-relevant gut microbes, we followed the systems biology tenet that stable relationships signify core components. By analyzing metagenomic datasets from a high-fiber dietary intervention in type 2 diabetes and 26 case-control studies across 15 diseases, we identified a set of stably correlated genome pairs within co-abundance networks perturbed by dietary interventions and diseases. These genomes formed a "two competing guilds" (TCGs) model, with one guild specialized in fiber fermentation and butyrate production and the other characterized by virulence and antibiotic resistance. Our random forest models successfully distinguished cases from controls across multiple diseases and predicted immunotherapy outcomes through the use of these genomes. Our guild-based approach, which is genome specific, database independent, and interaction focused, identifies a core microbiome signature that serves as a holistic health indicator and a potential common target for health enhancement.

Left ventricular strain changes at high altitude in rats: a cardiac magnetic resonance tissue tracking imaging study.

BACKGROUND: Long-term exposure to a high altitude environment with low pressure and low oxygen could cause abnormalities in the structure and function of the heart. Myocardial strain is a sensitive indicator for assessing myocardial dysfunction, monitoring myocardial strain is of great significance for the early diagnosis and treatment of high altitude heart-related diseases. This study applies cardiac magnetic resonance tissue tracking technology (CMR-TT) to evaluate the changes in left ventricular myocardial function and structure in rats in high altitude environment. METHODS: 6-week-old male rats were randomized into plateau hypoxia rats (plateau group, n = 21) as the experimental group and plain rats (plain group, n = 10) as the control group. plateau group rats were transported from Chengdu (altitude: 360 m), a city in a plateau located in southwestern China, to the Qinghai-Tibet Plateau (altitude: 3850 m), Yushu, China, and then fed for 12 weeks there, while plain group rats were fed in Chengdu(altitude: 360 m), China. Using 7.0 T cardiac magnetic resonance (CMR) to evaluate the left ventricular ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV) and stroke volume (SV), as well as myocardial strain parameters including the peak global longitudinal (GLS), radial (GRS), and circumferential strain (GCS). The rats were euthanized and a myocardial biopsy was obtained after the magnetic resonance imaging scan. RESULTS: The plateau rats showed more lower left ventricular GLS and GRS (P < 0.05) than the plain rats. However, there was no statistically significant difference in left ventricular EDV, ESV, SV, EF and GCS compared to the plain rats (P > 0.05). CONCLUSIONS: After 12 weeks of exposure to high altitude low-pressure hypoxia environment, the left ventricular global strain was partially decreased and myocardium is damaged, while the whole heart ejection fraction was still preserved, the myocardial strain was more sensitive than the ejection fraction in monitoring cardiac function.

Respiratory microbiota and radiomics features in the stable COPD patients.

BACKGROUNDS: The respiratory microbiota and radiomics correlate with the disease severity and prognosis of chronic obstructive pulmonary disease (COPD). We aim to characterize the respiratory microbiota and radiomics features of COPD patients and explore the relationship between them. METHODS: Sputa from stable COPD patients were collected for bacterial 16 S rRNA gene sequencing and fungal Internal Transcribed Spacer (ITS) sequencing. Chest computed tomography (CT) and 3D-CT analysis were conducted for radiomics information, including the percentages of low attenuation area below - 950 Hounsfield Units (LAA%), wall thickness (WT), and intraluminal area (Ai). WT and Ai were adjusted by body surface area (BSA) to WT/[Formula: see text] and Ai/BSA, respectively. Some key pulmonary function indicators were collected, which included forced expiratory volume in one second (FEV1), forced vital capacity (FVC), diffusion lung carbon monoxide (DLco). Differences and correlations of microbiomics with radiomics and clinical indicators between different patient subgroups were assessed. RESULTS: Two bacterial clusters dominated by Streptococcus and Rothia were identified. Chao and Shannon indices were higher in the Streptococcus cluster than that in the Rothia cluster. Principal Co-ordinates Analysis (PCoA) indicated significant differences between their community structures. Higher relative abundance of Actinobacteria was detected in the Rothia cluster. Some genera were more common in the Streptococcus cluster, mainly including Leptotrichia, Oribacterium, Peptostreptococcus. Peptostreptococcus was positively correlated with DLco per unit of alveolar volume as a percentage of predicted value (DLco/VA%pred). The patients with past-year exacerbations were more in the Streptococcus cluster. Fungal analysis revealed two clusters dominated by Aspergillus and Candida. Chao and Shannon indices of the Aspergillus cluster were higher than that in the Candida cluster. PCoA showed distinct community compositions between the two clusters. Greater abundance of Cladosporium and Penicillium was found in the Aspergillus cluster. The patients of the Candida cluster had upper FEV1 and FEV1/FVC levels. In radiomics, the patients of the Rothia cluster had higher LAA% and WT/[Formula: see text] than those of the Streptococcus cluster. Haemophilus, Neisseria and Cutaneotrichosporon positively correlated with Ai/BSA, but Cladosporium negatively correlated with Ai/BSA. CONCLUSIONS: Among respiratory microbiota in stable COPD patients, Streptococcus dominance was associated with an increased risk of exacerbation, and Rothia dominance was relevant to worse emphysema and airway lesions. Peptostreptococcus, Haemophilus, Neisseria and Cutaneotrichosporon probably affected COPD progression and potentially could be disease prediction biomarkers.

Circulating LPS from gut microbiota leverages stenosis-induced deep vein thrombosis in mice.

OBJECTIVE AND DESIGN: An accumulating body of evidence has shown that gut microbiota is involved in regulating inflammation; however, it remains undetermined if and how gut microbiota plays an important role in modulating deep venous thrombosis (DVT), which is an inflammation-involved thrombotic event. SUBJECTS: Mice under different treatments were used in this study. METHODS AND TREATMENT: We induced stenosis DVT in mice by partially ligating the inferior vena cava. Mice were treated with antibiotics, prebiotics, probiotics, or inflammatory reagents to modulate inflammatory states, and their effects on the levels of circulating LPS and DVT were examined. RESULTS: Antibiotic-treated mice or germ-free mice exhibited compromised DVT. Treatment of mice with either prebiotics or probiotics effectively suppressed DVT, which was accompanied with the downregulation of circulating LPS. Restoration of circulating LPS in these mice with a low dose of LPS was able to restore DVT. LPS-induced DVT was blocked by a TLR4 antagonist. By performing proteomic analysis, we identified TSP1 as one of the downstream effectors of circulating LPS in DVT. CONCLUSION: These results suggest that gut microbiota may play a nonnegligible role in modulating DVT by leveraging the levels of LPS in circulation, thus shedding light on the development of gut microbiota-based strategies for preventing and treating DVT.

Optimization of screening strategies for colorectal cancer based on fecal DNA and occult blood testing.

BACKGROUND: Fecal DNA and occult blood testing have been gradually developed for colorectal cancer (CRC) screening. Comparison of different testing strategies for these methods in CRC screening is in urgent need. This study aims to examine the efficacy of different testing strategies including multi-target fecal DNA testing, qualitative and quantitative fecal immunoassay tests (FITs). METHODS: Fecal samples were collected from patients diagnosed by colonoscopy. Tests using fecal DNA, quantitative FIT or qualitative FIT were performed on same fecal samples. Efficiency of different testing strategies within different populations was investigated. RESULTS: For high-risk populations (CRC and advanced adenoma), the positive rate of the three methods alone was 74.3-80%; the positive predictive values (PPVs) ranged from 37.3% to 77.8%, and the negative predictive values (NPVs) ranged from 86.3% to 92.2%. For combined testing strategies, the positive rate was 71.4-88.6%, PPVs ranged from 38.3% to 86.2%, and NPVs ranged from 89.6% to 92.9%. Parallel fecal multi-target DNA test and quantitative FIT appears to be superior when using a combined testing strategy. For the normal population, no significant difference was identified in efficacy between these methods when used alone and in combination. CONCLUSIONS: Single testing strategy among the three methods is more suitable for the general population screening, and the combined testing strategy is more suitable for high-risk populations screening. The use of different combination strategies may have superiority in CRC high-risk population screening, but cannot conclude significant differences which may be attributed to the small sample size, large samples controlled trials are needed.

Evaluation of Myocardial Microcirculation in Rats under a High-Altitude Hypoxic Environment by Computed Tomography Myocardial Perfusion Imaging.

This study aims to examine the changes in myocardial microcirculation in rats in a high-altitude hypoxic environment via computed tomography (CT) myocardial perfusion imaging technology. Rats in two groups were raised in different environments from 4 weeks of age for a period of 24 weeks. At 28 weeks of age, both groups underwent CT myocardial perfusion scanning, and the following myocardial perfusion parameters were measured: time to peak (TTP), mean transit time (MTT), blood flow (BF), and blood volume (BV). Following the scan, the rats were sacrificed, the cardiac index and right ventricular hypertrophy index were obtained, and hematoxylin-eosin (HE) staining was utilized to observe the pathological changes in the myocardium. In the group of rats that are subject to a high-altitude hypoxic environment for 24 weeks (the high-altitude group), the TTP and MTT values were increased (P < 0.05), the BF and BV values were lower (P < 0.05), the right heart mass was higher (P < 0.05) than that in the low-altitude group. As shown by the pathological results of HE staining, the gap between cardiomyocytes in the high-altitude group was widened, the arrangement of cardiomyocytes was irregular, and the cells were filled with a few fat vacuoles. The myocardial microcirculation is altered in a high-altitude hypoxic environment. In particular, the myocardium is in a state of inadequate perfusion, the BF in the myocardium slows down, and the right heart displays compensatory hypertrophy.

The effect of calorie intake, fasting, and dietary composition on metabolic health and gut microbiota in mice.

BACKGROUND: Calorie restriction (CR) and intermittent fasting (IF) can promote metabolic health through a process that is partially mediated by gut microbiota modulation. To compare the effects of CR and IF with different dietary structures on metabolic health and the gut microbiota, we performed an experiment in which mice were subjected to a CR or IF regimen and an additional IF control (IFCtrl) group whose total energy intake was not different from that of the CR group was included. Each regimen was included for normal chow and high-fat diet. RESULTS: We showed that in normal-chow mice, the IFCtrl regimen had similar positive effects on glucose and lipid metabolism as the CR regimen, but the IF regimen showed almost no influence compared to the outcomes observed in the ad libitum group. IF also resulted in improvements, but the effects were less marked than those associate with CR and IFCtrl when the mice were fed a high-fat diet. Moreover, CR created a stable and unique gut microbial community, while the gut microbiota shaped by IF exhibited dynamic changes in fasting-refeeding cycles. At the end of each cycle, the gut microbiota of the IFCtrl mice was similar to that of the CR mice, and the gut microbiota of the IF mice was similar to that of the ad libitum group. When the abundance of Lactobacillus murinus OTU2 was high, the corresponding metabolic phenotype was improved regardless of eating pattern and dietary structure, which might be one of the key bacterial groups in the gut microbiota that is positively correlated with metabolic amelioration. CONCLUSION: There are interactions among the amount of food intake, the diet structure, and the fasting time on metabolic health. The structure and composition of gut microbiota modified by dietary regimens might contribute to the beneficial effects on the host metabolism.

Charged Tubular Supramolecule Boosting Multivalent Interactions for the Drastic Suppression of Aß Fibrillation.

Anti-Aß therapy has dominated clinical trials for the prevention and treatment of Alzheimer's disease (AD). However, suppressing Aß aggregation and disintegrating mature fibrils simultaneously remains a great challenge. In this work, we developed a new strategy using a charged tubular supramolecule (CTS) with pillar[5]arene as the backbone and modifying amino and carboxyl groups at the tubular terminals (noted as CTS-A, CTS-A/C, and CTS-C, respectively) to suppress Aß fibrillation for the first time. According to the spectroscopic and microscopic characterizations, Aß40 fibrillation can be efficiently suppressed by CTS-A in a very low inhibitor:peptide (I:P) molar ratio (1:10). A greatly alleviated cytotoxic effect of Aß peptides after the inhibition or disaggregation process is further disclosed. The well-organized supramolecular structure drives multivalent interaction and gains enhanced efficiency on amyloid fibrillar modulation. These results open a new path for the design of supramolecules in the application of AD treatment.

Imaging Manifestations and Misdiagnosis Analysis of Six Cases of Bone Hydatid Disease.

We retrospectively evaluated the clinical and imaging features of 6 patients with bone hydatid disease confirmed by surgery and pathological examination. Among the 6 patients, 2 were infected with Echinococcosis granulosus metacestode and 4 were infected with E. multilocularis metacestode. The 2 cases with cystic echinococcosis were diagnosed by computed tomographic (CT) examination, and other 4 cases were diagnosed by magnetic resonance (MR) imaging. On the initial evaluation, 1 case each was misdiagnosed as a giant cell tumor or neurogenic tumor, and 2 were misdiagnosed as tuberculosis. The imaging manifestations of bone hydatid disease are complex, but most common findings include expansive osteolytic bone destruction, which may be associated with sclerosing edges or dead bone formation, localized soft tissue masses, and vertebral lesions with wedge-shaped changes and spinal stenosis. Combining imaging findings with the patient's epidemiological history and immunological examinations is of great help in improving the diagnosis and differential diagnosis of bone hydatid disease.

Primary bronchial myeloid sarcoma mimicking bronchogenic carcinoma: a case report.

BACKGROUND: Myeloid sarcoma (MS) rarely involves the bronchus, and primary bronchial MS has almost never been reported in mainland China. CASE PRESENTATION: A 65-year-old female patient was admitted with a 3-month history of cough. She was initially diagnosed with bronchogenic carcinoma according to chest computed tomography (CT). However, after a biopsy was taken from the endobronchial lesion by bronchoscopy and further immunohistochemical analysis was performed, the diagnosis of MS was made. Because her bone marrow was normal and she had no history of haematologic diseases, we further considered the diagnosis of primary bronchial MS. The patient received chemotherapy with HAG regimens, and the original mass completely resolved, as confirmed by chest CT scan after 3 cycles of treatment. Meanwhile, no abnormalities were found on re-examination via bronchoscopy. CONCLUSIONS: MS should be considered in the differential diagnosis in the presence of a suspicious pulmonary mass. Immunohistochemical analysis is necessary to confirm the diagnosis. Chemotherapy can lengthen the survival time for patients.

Rnf112 deletion protects brain against intracerebral hemorrhage (ICH) in mice by inhibiting TLR-4/NF-κB pathway.

Intracerebral hemorrhage (ICH) is reported as a common and often fatal type of stroke accompanied with high morbidity and mortality, and it frequently results in long-lasting neurological dysfunctions. However, the pathogenesis that contributes to ICH has not been fully understood. Rnf112, also known as Znf179, is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is modulated during brain progression and development. The study aimed to explore the role of Rnf112 in brain injury after ICH, as well as the underlying molecular mechanisms. The results indicated that ICH led to a significant decrease in Rnf112, which was confirmed in oxyhemoglobin (oxyHb)-incubated astrocytes and microglial cells. Moreover, the Rnf112 knockout (Rnf112-/-) mice and wild type (WT) mice induced by ICH were further employed. Compared to the WT/ICH group, Rnf112-/- mice exhibited accelerated brain injury, as evidenced by the increased brain water contents and neurological deficit scores (NDS). In comparison to WT/ICH group, a remarkable up-regulation in the release of pro-inflammatory cytokines, including tumor necrotic factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß, was observed in perihematoma tissues of Rnf112-/- mice on day 3 post-ICH. The process was along with promoted glial fibrillary acidic protein (GFAP) and Iba1 expression and reduced NeuN levels. Furthermore, ICH-induced increases in toll-like receptor (TLR)-4 and myeloid differentiation primary response protein (MyD88) expression were exacerbated by the loss of Rnf112. The phosphorylated expression of IKKα, inhibitor of NF-κB (IκBα) and nuclear factor-kappa B (NF-κB) induced by ICH in perihematoma tissues of mice was markedly enhanced in Rnf112-/- mice. Rnf112 repression-induced inflammatory response was verified in lipopolysaccharide (LPS)-incubated glial cells. In contrast, over-expressing Rnf112 markedly attenuated ICH-induced brain injury by restraining inflammation via inactivating TLR-4/NF-κB pathway. In summary, our findings suggested that Rnf112 expression was highly involved in the progression of ICH, and targeting Rnf112 signaling might be a promising therapeutic strategy against ICH development.

The gut microbiota changed by ketogenic diets contribute to glucose intolerance rather than lipid accumulation.

The ketogenic diet (KD) is a popular option for managing body weight, though its influence on glucose and lipid metabolism was still inconclusive. Gut microbiota is modulated by dietary pattens and has been associated with the changes of metabolic homeostasis induced by KD. Here, we found that two types of KDs, KD1 (8.8% carbohydrate, 73.4% fat, 17.9% protein, 5.7 kcal/g) and KD2 (0.4% carbohydrate, 93.2% fat, 6.4% protein, 6.7 kcal/g), induced changes of gut microbiota and its metabolites, contributing to glucose intolerance but not lipid accumulation in mice. Following a 2-week intervention with KDs, mice fed on KD1 displayed symptoms related to obesity, whereas KD2-fed mice exhibited a decrease in body weight but had severe hepatic lipid accumulation and abnormal fatty acid metabolism, while both KDs led to significant glucose intolerance. Compared to the mice fed on a standard chow diet, the conventional mice fed on both KD1 and KD2 had significant shifted gut microbiota, lower levels of short chain fatty acids (SCFAs) and composition alteration of cecal bile acids. By using an antibiotic cocktail (ABX) to deplete most of the gut microbiota in mice, we found the disturbances induced by KDs in lipid metabolism were similar in the ABX-treated mice to their conventional companions, but the disturbances in glucose metabolism were absent in the ABX-treated mice. In conclusion, these findings suggest that ketogenic diets disrupted glucose and lipid metabolism, at least in mice, and highlight the gut microbial culprits associated with KD induced glucose intolerance rather than lipid accumulation.

Reconstruction characteristics of gut microbiota from patients with type 1 diabetes affect the phenotypic reproducibility of glucose metabolism in mice.

The human microbiota-associated (HMA) mice model, especially the germ-free (GF)-humanized mice, has been widely used to probe the causal relationships between gut microbiota and human diseases such as type 1 diabetes (T1D). However, most studies have not clarified the extent to which the reconstruction of the human donor microbiota in recipient mice correlates with corresponding phenotypic reproducibility. In this study, we transplanted fecal microbiota from five patients with T1D and four healthy people into GF mice, and microbiota from each donor were transplanted into 10 mice. Mice with similar microbiota structure to the donor exhibited better phenotypic reproducibility. The characteristics of the microbial community assembly of donors also influenced the phenotypic reproducibility in mice, and individuals with a higher proportion of stochastic processes showed more severe disorders. Microbes enriched in patients with T1D had a stronger colonization potential in mice with impaired glucose metabolism, and microbiota functional features related to T1D were better reproduced in these mice. This indicates that assembly traits and colonization efficacy of microbiota influence phenotypic reproducibility in GF-humanized mice. Our findings provide important insights for using HMA mice models to explore links between gut microbiota and human diseases.

Evaluation of cardiac index and right ventricular hypertrophy index in rats under a chronic hypoxic environment at high altitude.

High-altitude areas are characterized by low pressure and hypoxia, which have a significant impact on various body systems. This study aimed to investigate the alterations in cardiac index and right ventricular hypertrophy index(RVHI) in rats at different altitudes.Twenty-one male Sprague-Dawley (SD) rats aged 4 weeks were randomly divided into three groups based on altitude. The rats were raised for 28 weeks and then transferred to Qinghai University Plateau Medicine Laboratory. Body weight was measured, heart organs were isolated and weighed, and cardiac index and right ventricular hypertrophy index were determined. Statistical analysis was performed on the data from the three groups. Compared with the plain group, the body weight of the middle-altitude group was significantly decreased (P < 0.05), and cardiac index, RVHI-1, RVHI-2 increased significantly ((P < 0.05). The body weight, whole heart mass, right ventricular mass were significantly decreased in high-altitude group (P < 0.05), RVHI-1 and RVHI-2 were significantly increased (P < 0.05). Compared with the middle-altitude group, the body weight, whole heart mass and right ventricular mass of the high-altitude group were significantly decreased (P < 0.05), and RVHI-1 and RVHI-2 were significantly increased (P < 0.05). Increasing altitude led to a decrease in body weight, whole heart mass, and right ventricular mass in rats, indicating structural changes in the right heart. Additionally, the proportion of right heart to body weight and whole heart increased with altitude.

"Triple-Punch" Strategy Exosome-Mimetic Nanovesicles for Triple Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is the most malignant breast cancer, with high rates of relapse and metastasis. Because of the nonspecific targeting of chemotherapy and insurmountable aggressiveness, TNBC therapy lacks an effective strategy. Exosomes have been reported as an efficient drug delivery system (DDS). CD82 is a tumor metastasis inhibitory molecule that is enriched in exosomes. Aptamer AS1411 specifically targets TNBC cells due to its high expression of nucleolin. We generated a "triple-punch" cell membrane-derived exosome-mimetic nanovesicle system that integrated with CD82 overexpression, AS1411 conjugation, and doxorubicin (DOX) delivery. CD82 enrichment effectively inhibits the migration of TNBC cells. AS1411 conjugation specifically targets TNBC cells. DOX loading effectively inhibits proliferation and induces apoptosis of TNBC cells. Our results demonstrate a system of exosome-mimetic nanovesicles with "triple-punch" that may facilitate TNBC therapeutics.

Evaluation of blood cellular and biochemical parameters in rats under a chronic hypoxic environment at high altitude.

BACKGROUND: The purpose of this study was to explore the changes in blood cellular and biochemical parameters of rats in a natural environment of low pressure and low oxygen on the plateau. METHODS: Male Sprague-Dawley rats in two groups were raised in different environments from 4 weeks of age for a period of 24 weeks. They were raised to 28 weeks of age and then transported to the plateau medical laboratory of Qinghai University. Blood cellular and biochemical parameters were measured and the data of the two groups were statistically analyzed. RESULTS: 1. RBC in the HA group was higher than that in the Control group, but there was no significant difference between the two groups (p > 0.05), Compared with the Control group, HGB, MCV, MCH, MCHC and RDW in the HA group were significantly higher (p < 0.05). 2. Compared with the Control group, WBC, LYMP, EO, LYMP% and EO% in the HA group decreased significantly (p < 0.05), and ANC% increased significantly (p < 0.05). 3. In the platelet index, compared with the Control group, PLT in the HA group was significantly reduced (p < 0.05), PDW, MRV, P-LCR were significantly increased (p < 0.05). 4. In blood biochemical indicators, compared with the Control group, AST, TBIL, IBIL, LDH in the HA group decreased significantly (p < 0.05), CK in the HA group increased significantly (p < 0.05). CONCLUSIONS: 1. The indexes related to red blood cells, white blood cells, platelets and some biochemical indexes in the blood of rats at high altitude have changed. 2. Under the high altitude environment, the oxygen carrying capacity of SD rats is improved, the resistance to disease may be reduced, the coagulation and hemostasis functions may be affected, and there is a risk of bleeding. The liver function, renal function, heart function and skeletal muscle energy metabolism may be affected. 3. This study can provide an experimental basis for the research on the pathogenesis of high-altitude diseases from the perspective of blood.KEY MESSAGESIn this study, red blood cells, white blood cells, platelets and blood biochemical indicators were included in the real plateau environment to comprehensively analyze the changes of blood cellular and biochemical parameters in rats under the chronic plateau hypobaric hypoxia environment.From the perspective of blood, this study can provide an experimental basis for research on the pathogenesis of high-altitude diseases.Explore the data support of oxygen-carrying capacity, disease resistance and energy metabolism of the body in the natural environment at high altitude.

Depletion of gut microbiota influents glucose metabolism and hyperandrogenism traits of mice with PCOS induced by letrozole.

Background: Polycystic ovary syndrome (PCOS) is a multifaceted disorder that impacts metabolism, reproduction, as well as endocrine function, characterized by excessive levels of androgen and insulin resistance. The gut microbiota has been implicated in the pathogenesis of PCOS. However, the precise mechanisms through which the gut microbiota influences PCOS still require further elucidation. Methods: The PCOS mouse model was established through the administration of letrozole to both conventional and antibiotics-treated mice. The evaluation of glucose metabolism, sex hormone levels, and ovarian morphology was conducted. Furthermore, the fecal samples from each group of mice were subjected to 16S rRNA gene sequencing, and functional prediction of gut microbiota was proceeded using PICRUSt2 to explore potential mechanisms. Results: By using letrozole-induced PCOS mice model, we manifested that antibiotic intervention significantly reduced the serum total testosterone level and ameliorated glucose intolerance. Antibiotic treatment reduced the number of amplicon sequence variants (ASVs), as well as the Shannon and Simpson index. Meanwhile, letrozole induced a significant increase in the Shannon and Simpson index instead of ASVs. Through random forest model analysis, the results revealed significant alterations in three distinct groups of microbiota, namely Clostridia_vadinBB60_group, Enterorhabdus, and Muribaculaceae after letrozole treatment. Further correlation analysis revealed a positive association between alterations in these microbiota and both serum total testosterone levels and the area under the curve (AUC) of blood glucose in IPGTT. The administration of antibiotics led to a decrease in the absolute abundance of 5 ASVs belonging to unclassified Clostridia_vadinBB60_group, unclassified Enterorhabdus, and unclassified Muribaculaceae, which exhibited a positive correlation with the levels of total testosterone in mice serum, as well as the area under the curve of blood glucose in IPGTT. Moreover, 25 functional pathways of gut microbiome were significantly discrepant between the letrozole-treated mice with and without antibiotics. Conclusion: These results suggest that disturbance of the gut microbiota may take participate in the progression of PCOS and manipulating the composition of the gut microbiota may be a therapeutic approach for managing PCOS.

Microbiome Features Differentiating Unsupervised-Stratification-Based Clusters of Patients with Abnormal Glycometabolism.

The alteration of gut microbiota structure plays a pivotal role in the pathogenesis of abnormal glycometabolism. However, the microbiome features identified in patient groups stratified solely based on glucose levels remain controversial among different studies. In this study, we stratified 258 participants (discovery cohort) into three clusters according to an unsupervised method based on 16 clinical parameters involving the levels of blood glucose, insulin, and lipid. We found 67 cluster-specific microbiome features (i.e., amplicon sequence variants [ASVs]) based on 16S rRNA gene V3-V4 region sequencing. Specifically, ASVs belonging to Barnesville and Alistipes were enriched in cluster 1, in which participants had the lowest blood glucose levels, high insulin sensitivity, and a high-fecal short-chain fatty acid concentration. ASVs belonging to Prevotella copri and Ruminococcus gnavus were enriched in cluster 2, which was characterized by a moderate level of blood glucose, serious insulin resistance, and high levels of cholesterol and triglyceride. Cluster 3 was characterized by a high level of blood glucose and insulin deficiency, enriched with ASVs in P. copri and Bacteroides vulgatus. In addition, machine learning classifiers using the 67 cluster-specific ASVs were used to distinguish individuals in one cluster from those in the other two clusters both in discovery and testing cohorts (n = 83). Therefore, microbiome features identified based on the unsupervised stratification of patients with more inclusive clinical parameters may better reflect microbiota alterations associated with the progression of abnormal glycometabolism. IMPORTANCE The gut microbiota is altered in patients with type 2 diabetes (T2D) and prediabetes. The association of particular bacteria with T2D, however, varied among studies, which has made it challenging to develop precision medicine approaches for the prevention and alleviation of T2D. Blood glucose level is the only parameter in clustering patients when identifying the T2D-related bacteria in previous studies. This stratification ignores the fact that patients within the same blood glucose range differ in their insulin resistance and dyslipidemia, which also may be related to disordered gut microbiota. In addition to parameters of blood glucose levels, we also used additional parameters involving insulin and lipid levels to stratify participants into three clusters and further identified cluster-specific microbiome features. We further validated the association between these microbiome features and glycometabolism with an independent cohort. This study highlights the importance of stratification of patients with blood glucose, insulin, and lipid levels when identifying the microbiome features associated with the progression of abnormal glycometabolism.

Pathobionts from chemically disrupted gut microbiota induce insulin-dependent diabetes in mice.

BACKGROUND: Dysbiotic gut microbiome, genetically predisposed or chemically disrupted, has been linked with insulin-dependent diabetes (IDD) including autoimmune type 1 diabetes (T1D) in both humans and animal models. However, specific IDD-inducing gut bacteria remain to be identified and their casual role in disease development demonstrated via experiments that can fulfill Koch's postulates. RESULTS: Here, we show that novel gut pathobionts in the Muribaculaceae family, enriched by a low-dose dextran sulfate sodium (DSS) treatment, translocated to the pancreas and caused local inflammation, beta cell destruction and IDD in C57BL/6 mice. Antibiotic removal and transplantation of gut microbiota showed that this low DSS disrupted gut microbiota was both necessary and sufficient to induce IDD. Reduced butyrate content in the gut and decreased gene expression levels of an antimicrobial peptide in the pancreas allowed for the enrichment of selective members in the Muribaculaceae family in the gut and their translocation to the pancreas. Pure isolate of one such members induced IDD in wildtype germ-free mice on normal diet either alone or in combination with normal gut microbiome after gavaged into stomach and translocated to pancreas. Potential human relevance of this finding was shown by the induction of pancreatic inflammation, beta cell destruction and IDD development in antibiotic-treated wildtype mice via transplantation of gut microbiome from patients with IDD including autoimmune T1D. CONCLUSION: The pathobionts that are chemically enriched in dysbiotic gut microbiota are sufficient to induce insulin-dependent diabetes after translocation to the pancreas. This indicates that IDD can be mainly a microbiome-dependent disease, inspiring the need to search for novel pathobionts for IDD development in humans. Video Abstract.

7.0T cardiac magnetic resonance imaging of right ventricular function in rats with high-altitude deacclimatization.

Background: High-altitude deacclimatization syndrome (HADAS) is a severe public health issue. The study of the changes in right ventricular function caused by high-altitude deacclimatization (HADA) is of great significance for the prevention and treatment of HADAS. Methods: Six-week-old, male Sprague Dawley (SD) rats were randomly divided into the plain, plateau and the HADA group. Rats in the plateau and plain group were exposed to altitudes of 3,850 and 360 m, respectively, for 12 weeks. Rats in HADA group were exposed to the plateau altitude of 3,850 m for 12 weeks and subsequently transported to the plain altitude of 360 m for 4 weeks. Right ventricular ejection fraction (RVEF), end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and myocardial strain parameters, including the global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS), were evaluated by 7.0T cardiac magnetic resonance (CMR). The levels of red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT) in the blood were measured, and hematoxylin-eosin (HE) staining was used to observe the pathological changes in the myocardium. Results: In rats in the plateau group, the right ventricular fibrous space was slightly widened, and partial focal steatosis were observed. However, in the HADA group, only a few focal steatoses were found. Rats in the plateau group had elevated levels of RBC, HGB and HCT, increased right ventricular end-diastolic volume (RVEDV), right ventricular end-systolic volume (RVESV) and right ventricular stroke volume (RVSV), and decreased right ventricular global longitudinal strain (RVGLS), right ventricular global circumferential strain (RVGCS), and right ventricular global radial strain (RVGRS) compared to rats in the plain group (P<0.001). The RVEDV, RVGCS, and RVGRS in the HADA group basically returned to the plain state. Interestingly, the RVESV in the HADA group was higher, while the RVSV, RVEF, and RVGLS were lower than those in the other two groups. Conclusions: After 12 weeks of exposure to high-altitude environment, there were some pathological changes and the whole contractile strain of the right ventricle was observed. Some pathological changes in the myocardial tissue and stroma recovered after returning to the plain for 4 weeks. However, the right ventricular systolic function and strain did not recover completely.