An excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the factors causing excessive BA excretion remain ...incompletely studied. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D. By performing BA-related metabolic and metagenomic analyses in 290 IBS-D patients and 89 healthy volunteers, we found that 24.5% of IBS-D patients exhibited excessive excretion of total BAs and alteration of BA-transforming bacteria in feces. Notably, the increase in Clostridia bacteria (e.g., C. scindens) was positively associated with the levels of fecal BAs and serum 7α-hydroxy-4-cholesten-3-one (C4), but negatively correlated with serum fibroblast growth factor 19 (FGF19) concentration. Furthermore, colonization with Clostridia-rich IBS-D fecal microbiota or C. scindens individually enhanced serum C4 and hepatic conjugated BAs but reduced ileal FGF19 expression in mice. Inhibition of Clostridium species with vancomycin yielded opposite results. Clostridia-derived BAs suppressed the intestinal FGF19 expression in vitro and in vivo. In conclusion, this study demonstrates that the Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients, which provides a mechanistic hypothesis with testable clinical implications.
Irritable bowel syndrome (IBS) is one of the functional gastrointestinal disorders characterized by chronic and/or recurrent symptoms of abdominal pain and irregular defecation. Changed gut ...microbiota has been proposed to mediate IBS; however, contradictory results exist, and IBS-specific microbiota, metabolites, and their interactions remain poorly understood. To address this issue, we performed metabolomic and metagenomic profiling of stool and serum samples based on discovery (n = 330) and validation (n = 101) cohorts. Fecal metagenomic data showed moderate dysbiosis compared with other diseases, in contrast, serum metabolites showed significant differences with greater power to distinguish IBS patients from healthy controls. Specifically, 726 differentially abundant serum metabolites were identified, including a cluster of fatty acyl-CoAs enriched in IBS. We further identified 522 robust associations between differentially abundant gut bacteria and fecal metabolites, of which three species including Odoribacter splanchnicus, Escherichia coli, and Ruminococcus gnavus were strongly associated with the low abundance of dihydropteroic acid. Moreover, dysregulated tryptophan/serotonin metabolism was found to be correlated with the severity of IBS depression in both fecal and serum metabolomes, characterized by a shift in tryptophan metabolism towards kynurenine production. Collectively, our study revealed serum/fecal metabolome alterations and their relationship with gut microbiome, highlighted the massive alterations of serum metabolites, which empower to recognize IBS patients, suggested potential roles of metabolic dysregulation in IBS pathogenesis, and offered new clues to understand IBS depression comorbidity. Our study provided a valuable resource for future studies, and would facilitate potential clinical applications of IBS featured microbiota and/or metabolites.
Here we show, using new RNA-sequencing (RNA-seq) data, that NMR cells are considerably more resistant to transcriptomic changes induced by oncogenic HRAS than mouse, blind mole-rat and human cells, ...indicating that suppressed RAS signalling is an anti-cancer mechanism in NMR cells that can be interrupted by high expression of HRAS(G12V), rendering NMR cells susceptible to oncogenic transformation. Consistently, multiple Gene Ontology (GO) terms that were significantly changed by SV40LT and HRAS(G12V) in mouse cells, such as cell cycle, cell division and mitotic nuclear division, were not altered or altered to a much lower extent in NMR cells (Extended Data Fig. 2a). In mice, partial inactivation of PI3K or AKT enhances metabolic function and extends lifespan14,15. ...the natural suppression of the PI3K-AKT pathway in NMR probably contributes not only to cancer resistance, but also to a long lifespan. Acknowledgements This study is supported by US National Institutes of Health grant AG047200 to V.G. and A.S., and Natural Science Foundation of China grant 81672818, Science Technology and Innovation Committee of Shenzhen Municipality grant JCYJ20160331190123578 and Guangzhou Science and Technology Program key project 201604020005 to X.F. Author contributions The list of authors is different from the original study, because new data were included in this Reply.
Metabolic status and gut microecology are implicated in psoriasis. Methotrexate (MTX) is usually the first-line treatment for this disease. However, the relationship between MTX and host metabolic ...status and the gut microbiota is unclear. This study aimed to characterize the features of blood metabolome and gut microbiome in patients with psoriasis after treatment with MTX. Serum and stool samples were collected from 15 patients with psoriasis. Untargeted liquid chromatography–mass spectrometry and metagenomics sequencing were applied to profile the blood metabolome and gut microbiome, respectively. We found that the response to MTX varied according to metabolomic and metagenomic features at baseline; for example, patients who had high levels of serum nutrient molecular and more enriched gut microbiota had a poor response. After 16 weeks of MTX, we observed a reduction in microbial activity pathways, and patients with a good response showed more microbial activity and less biosynthesis of serum fatty acid. We also found an association between the serum metabolome and the gut microbiome before intervention with MTX. Carbohydrate metabolism, transporter systems, and protein synthesis within microbes were associated with host metabolic clusters of lipids, benzenoids, and organic acids. These findings suggest that the metabolic status of the blood and the gut microbiome is involved in the effectiveness of MTX in psoriasis, and that inhibition of symbiotic intestinal microbiota may be one of the mechanisms of action of MTX. Prospective studies in larger sample sizes are needed to confirm these findings.
Blood stasis constitution in traditional Chinese medicine (TCM) is believed to render individuals more susceptible to metabolic diseases. However, the biological underpinnings of this constitutional ...imbalance remain unclear.
This study explored the association between blood stasis constitution, serum metabolic markers including uric acid (UA), high-density lipoprotein cholesterol (HDLC), their ratio (UHR), serum metabolites, and gut microbiota. Clinical data, fecal and serum samples were acquired from 24 individuals with a blood stasis constitution and 80 individuals with a balanced constitution among healthy individuals from Guangdong. Gut microbiota composition analysis and serum metabolomics analysis were performed.
Females with a blood stasis constitution had higher UA levels, lower HDLC levels, and higher UHR in serum, suggesting a higher risk of metabolic abnormalities. Analysis of the gut microbiome revealed two distinct enterotypes dominated by Bacteroides or Prevotella. Intriguingly, blood stasis subjects were disproportionately clustered within the Bacteroides-rich enterotype. Metabolomic analysis identified subtle differences between the groups, including lower phenylalanine and higher trimethylaminoacetone levels in the blood stasis. Several differential metabolites displayed correlations with HDLC, UA, or UHR, unveiling potential new markers of metabolic dysregulation.
These findings elucidate the intricate interplay between host constitution, gut microbiota, and serum metabolites. The concept of blood stasis offers a unique perspective to identify subtle alterations in microbiome composition and metabolic pathways, potentially signaling underlying metabolic vulnerability, even in the presence of ostensibly healthy profiles. Continued investigation of this TCM principle may reveal critical insights into the early biological processes that foreshadow metabolic deterioration.
Objective
In this study, we aimed to explore the alterations in gut microbiota composition and cytokine responses related to disease progression, severity, and outcomes in patients with hypertensive ...intracerebral hemorrhage (ICH).
Methods
Fecal microbiota communities of 64 patients with ICH, 46 coronary heart disease controls, and 23 healthy controls were measured by sequencing the V3-V4 region of the 16S ribosomal RNA (16S rRNA) gene. Serum concentrations of a broad spectrum of cytokines were examined by liquid chips and ELISA. Relationships between clinical phenotypes, microbiotas, and cytokine responses were analyzed in the group with ICH and stroke-associated pneumonia (SAP), the major complication of ICH.
Results
In comparison with the control groups, the gut microbiota of the patients with ICH had increased microbial richness and diversity, an expanded spectrum of facultative anaerobes and opportunistic pathogens, and depletion of anaerobes.
Enterococcus
enrichment and
Prevotella
depletion were more significant in the ICH group and were associated with the severity and functional outcome of ICH. Furthermore,
Enterococcus
enrichment and
Prevotella
depletion were also noted in the SAP group in contrast to the non-SAP group.
Enterococci
were also promising factors in the prognosis of ICH. The onset of ICH induced massive, rapid activation of the peripheral immune system. There were 12 cytokines (Eotaxin, GM-CSF, IL-8, IL-9, IL-10, IL-12p70, IL-15, IL-23, IL-1RA, IP-10, RANTES, and TNF-α) changed significantly with prolongation of ICH, and the Th2 responses correlated with the 90-day outcomes. Cytokines TNF-α, IP-10, IL-1RA, IL-8, IL-18, and MIP-1β in SAP group significantly differed from non-SAP group. Among these cytokines, only IP-10 levels decreased in the SAP group.
Enterococcus
was positively associated with IL-1RA and negatively associated with IP-10, while
Prevotella was
inversely associated in both the ICH and SAP groups.
Conclusion
This study revealed that gut dysbiosis with enriched
Enterococcus
and depleted
Prevotella
increased the risk of ICH and subsequently SAP. The altered gut microbiota composition and serum cytokine profiles are potential biomarkers that reflect the inciting physiologic insult/stress involved with ICH.
Objectives
The intestinal microbiota is essential in absorbing nutrients and defending against pathogens and is associated with various diseases, including obesity, type 2 diabetes, and hypertension. ...As an alternative medicine, Traditional Chinese Medicine (TCM) has long been used in disease treatment and healthcare, partly because it may mediate gut microbiota. However, the specific effects of TCM on the abundance and interactions of microbiota remain unknown. Moreover, using TCM ingredients and data detailing changes in the abundance of gut microorganisms, we developed bioinformatic methods that decipher the impact of TCM on microorganism interactions.
Methods
The dynamics of gut microorganisms affected by TCM treatments is explored using a mouse model, which provided the abundance of 70 microorganisms over time. The Granger causality analysis was used to measure microorganism interactions. Novel “serial connection” and “diverging connection” models were used to identify molecular mechanisms underlying the impact of TCM on gut microorganism interactions, based on microorganism proteins, TCM chemical ingredients, and KEGG reaction equations.
Results
Codonopsis pilosula
(Dangshen),
Cassia twig
(Gui Zhi),
Radices saussureae
(Mu Xiang), and Sijunzi Decoction did not cause an increase in the abundance of harmful microorganisms. Most TCMs decreased the abundance of
Bifidobacterium pseudolongum
, suggesting a
Bifidobacterium pseudolongum
supplement should be used during TCM treatment. The Granger causality analysis indicated that TCM treatment changes more than half the interactions between the 70 microorganisms, and “serial connection” and “diverging connection” models suggested that changes in interactions may be related to the reaction number connecting species proteins and TCM ingredients. From a species diversity perspective, a TCM decoction is better than a single herb for healthcare. The Sijunzi Decoction only significantly increased the abundance of
Bifidobacterium pseudolongum
and did not cause a decrease in the abundance of other species but was found to improve the alpha diversity with the lowest replacement rate.
Conclusions
Because most of the nine TCMs are medicinal and edible plants, we expect the methods and results presented can be used to optimize and integrate microbiota and TCMs into healthcare processes. Moreover, as a control study, these results can be combined with future disease mouse models to link variations in species abundance with particular diseases.
The human gut microbiome is a reservoir for antibiotic resistance gene (ARG). Therefore, characterizing resistome distribution and potential disease markers can help manage antibiotics at the ...clinical level. While much population-level research has highlighted the strong effect of donor geographic origin on ARG prevalence in the human gut, little is known regarding the effects of other properties, such as age, sex, and disease. Here we employed 2,037 fecal metagenomes from 12 countries. By quantifying the known resistance genes for 24 types of antibiotics in each community, we showed that tetracycline, aminoglycoside, beta-lactam, macrolide-lincosamide-streptogramin (MLS), and vancomycin resistance genes were the dominant ARG types in the human gut. We then compared the ARG profiles of 1427 healthy individuals from the 2,037 samples and observed significant differences across countries. This was consistent with expectations that regional antibiotic usage and exposure in medical and food production contexts affect distribution. Although no specific uniform pattern of ARG was observed, a significant increase in resistance potential among multiple disease groups implied that the disease condition may be another source of ARG variance. In particular, the co-occurrence pattern of some enriched bacterial species and ARGs that were obtained in type 2 diabetes (T2D) and liver cirrhosis patients implied that some disease-associated species may be potential hosts of enriched ARGs, which could be potential biomarkers for the prediction and intervention of such diseases. Overall, our study identifies factors associated with the human gut resistome, including substantial effects of region and heterogeneous effects of disease status, and highlights the value of ARG analysis in disease research and clinical applications.
Genomic imprinting is regulated by lncRNAs and is important for embryogenesis, physiology and behaviour in mammals. Aberrant imprinting causes diseases and disorders. Experimental studies have ...examined genomic imprinting primarily in humans and mice, thus leaving some fundamental issues poorly addressed. The cost of experimentally examining imprinted genes in many tissues in diverse species makes computational analysis of lncRNAs' DNA binding sites valuable.
We performed lncRNA/DNA binding analysis in imprinting clusters from multiple mammalian clades and discovered the following: (i) lncRNAs and imprinting sites show significant losses and gains and distinct lineage-specificity; (ii) binding of lncRNAs to promoters of imprinted genes may occur widely throughout the genome; (iii) a considerable number of imprinting sites occur in only evolutionarily more derived species; and (iv) multiple lncRNAs may bind to the same imprinting sites, and some lncRNAs have multiple DNA binding motifs. These results suggest that the occurrence of abundant lncRNAs in mammalian genomes makes genomic imprinting a mechanism of adaptive evolution at the epigenome level.
The data and program are available at the database LongMan at lncRNA.smu.edu.cn.
zhuhao@smu.edu.cn.
Supplementary data are available at Bioinformatics online.
Because of the varying concentration of atmospheric PM2.5 have strong nonlinear characteristics, the traditional forecast methods are difficult to make accurate prediction. In this paper the ...parameters included PM10, SO2, NO2, temperature, pressure, humidity, wind direction, wind speed are selected as the influence factors, and the prediction models based on RBF neural network are constructed. Then the model is used to predict the concentration of PM2.5 and compared with the classic BP network model. The result shows that the RBF neural network model has more advantages in the prediction of PM2.5.
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