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BioRxiv : the Preprint Server For... Jan 2024The human gut microbiome is a complex ecosystem with profound implications for health and disease. This recognition has led to a surge in multi-omic microbiome studies,...
The human gut microbiome is a complex ecosystem with profound implications for health and disease. This recognition has led to a surge in multi-omic microbiome studies, employing various molecular assays to elucidate the microbiome's role in diseases across multiple functional layers. However, despite the clear value of these multi-omic datasets, rigorous integrative analysis of such data poses significant challenges, hindering a comprehensive understanding of microbiome-disease interactions. Perhaps most notably, multiple approaches, including univariate and multivariate analyses, as well as machine learning, have been applied to such data to identify disease-associated markers, namely, specific features (e.g., species, pathways, metabolites) that are significantly altered in disease state. These methods, however, often yield extensive lists of features associated with the disease without effectively capturing the multi-layered structure of multi-omic data or offering clear, interpretable hypotheses about underlying microbiome-disease mechanisms. Here, we address this challenge by introducing an intermediate integration-based method for analyzing multi-omic microbiome data. MintTea combines a canonical correlation analysis (CCA) extension, consensus analysis, and an evaluation protocol to robustly identify disease-associated multi-omic modules. Each such module consists of a set of features from the various omics that both shift in concord, and collectively associate with the disease. Applying MintTea to diverse case-control cohorts with multi-omic data, we show that this framework is able to capture modules with high predictive power for disease, significant cross-omic correlations, and alignment with known microbiome-disease associations. For example, analyzing samples from a metabolic syndrome (MS) study, we found a MS-associated module comprising of a highly correlated cluster of serum glutamate- and TCA cycle-related metabolites, as well as bacterial species previously implicated in insulin resistance. In another cohort, we identified a module associated with late-stage colorectal cancer, featuring and species and several fecal amino acids, in agreement with these species' reported role in the metabolism of these amino acids and their coordinated increase in abundance during disease development. Finally, comparing modules identified in different datasets, we detected multiple significant overlaps, suggesting common interactions between microbiome features. Combined, this work serves as a proof of concept for the potential benefits of advanced integration methods in generating integrated multi-omic hypotheses underlying microbiome-disease interactions and a promising avenue for researchers seeking systems-level insights into coherent mechanisms governing microbiome-related diseases.
PubMed: 37461534
DOI: 10.1101/2023.07.03.547607 -
Microbiology Spectrum Aug 2023The pivotal roles of gut microbiota in severe acute pancreatitis-associated acute lung injury (SAP-ALI) are increasingly revealed, and recent discoveries in the gut-lung...
Mechanisms of Qingyi Decoction in Severe Acute Pancreatitis-Associated Acute Lung Injury via Gut Microbiota: Targeting the Short-Chain Fatty Acids-Mediated AMPK/NF-κB/NLRP3 Pathway.
The pivotal roles of gut microbiota in severe acute pancreatitis-associated acute lung injury (SAP-ALI) are increasingly revealed, and recent discoveries in the gut-lung axis have provided potential approaches for treating SAP-ALI. Qingyi decoction (QYD), a traditional Chinese medicine (TCM), is commonly used in clinical to treat SAP-ALI. However, the underlying mechanisms remain to be fully elucidated. Herein, by using a caerulein plus lipopolysaccharide (LPS)-induced SAP-ALI mice model and antibiotics (Abx) cocktail-induced pseudogermfree mice model, we tried to uncover the roles of the gut microbiota by administration of QYD and explored its possible mechanisms. Immunohistochemical results showed that the severity of SAP-ALI and intestinal barrier functions could be affected by the relative depletion of intestinal bacteria. The composition of gut microbiota was partially recovered after QYD treatment with decreased / ratio and increased relative abundance in short-chain fatty acids (SCFAs)-producing bacteria. Correspondingly increased levels of SCFAs (especially propionate and butyrate) in feces, gut, serum, and lungs were observed, generally consistent with changes in microbes. Western-blot analysis and RT-qPCR results indicated that the AMPK/NF-κB/NLRP3 signaling pathway was activated after oral administration of QYD, which was found to be possibly related to the regulatory effects on SCFAs in the intestine and lungs. In conclusion, our study provides new insights into treating SAP-ALI through modulating the gut microbiota and has prospective practical value for clinical use in the future. Gut microbiota affects the severity of SAP-ALI and intestinal barrier function. During SAP, a significant increase in the relative abundance of gut pathogens (Escherichia, , Enterobacter, , ) was observed. At the same time, QYD treatment decreased pathogenic bacteria and increased the relative abundance of SCFAs-producing bacteria (, , , , ). In addition, The AMPK/NF-κB/NLRP3 pathway mediated by SCFAs along the gut-lung axis may play an essential role in preventing the pathogenesis of SAP-ALI, which allows for reduced systemic inflammation and restoration of the intestinal barrier.
Topics: Mice; Animals; Pancreatitis; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; AMP-Activated Protein Kinases; Gastrointestinal Microbiome; Acute Disease; Prospective Studies; Acute Lung Injury; Fatty Acids, Volatile
PubMed: 37338348
DOI: 10.1128/spectrum.03664-22 -
Animal Bioscience Aug 2023The objective of this study was to develop a novel endolysin (PanLys.1) for the specific killing of the ruminal hyper-ammonia-producing bacterium Peptostreptococcus...
OBJECTIVE
The objective of this study was to develop a novel endolysin (PanLys.1) for the specific killing of the ruminal hyper-ammonia-producing bacterium Peptostreptococcus anaerobius (P. anaerobius).
METHODS
Whole genome sequences of P. anaerobius strains and related bacteriophages were collected from the National Center for Biotechnology Information database, and the candidate gene for PanLys.1 was isolated based on amino acid sequences and conserved domain database (CDD) analysis. The gene was overexpressed using a pET system in Escherichia coli BL21 (DE3). The lytic activity of PanLys.1 was evaluated under various conditions (dosage, pH, temperature, NaCl, and metal ions) to determine the optimal lytic activity conditions. Finally, the killing activity of PanLys.1 against P. anaerobius was confirmed using an in vitro rumen fermentation system.
RESULTS
CDD analysis showed that PanLys.1 has a modular design with a catalytic domain, amidase-2, at the N-terminal, and a cell wall binding domain, from the CW-7 superfamily, at the C-terminal. The lytic activity of PanLys.1 against P. anaerobius was the highest at pH 8.0 (p<0.05) and was maintained at 37°C to 45°C, and 0 to 250 mM NaCl. The activity of PanLys.1 significantly decreased (p<0.05) after Mn2+ or Zn2+ treatment. The relative abundance of P. anaerobius did not decrease after administration PanLys.1 under in vitro rumen conditions.
CONCLUSION
The application of PanLys.1 to modulate P. anaerobius in the rumen might not be feasible because its lytic activity was not observed in in vitro rumen system.
PubMed: 37170521
DOI: 10.5713/ab.22.0454 -
DEN Open Apr 2024Although prednisolone treatment is effective in Cronkhite-Canada syndrome (CCS), its mechanisms of action are poorly understood. We performed analyses of cytokine...
Although prednisolone treatment is effective in Cronkhite-Canada syndrome (CCS), its mechanisms of action are poorly understood. We performed analyses of cytokine expression and fecal microbiota in a patient with the concurrent occurrence of CCS and rectal cancer, in whom regression of polyposis was achieved by prednisolone. Regression of CCS polyps was accompanied by downregulation of proinflammatory cytokine expression and alterations in microbiota composition; a decrease in and with the promotion of inflammation. We could not completely exclude the possibility that alterations in fecal microbiota composition might be influenced by the presence of advanced cancer. However, this case suggests that the administration of PSL might lead to the regression of CCS polyps through alterations in gut microbiota composition and suppression of proinflammatory cytokine responses.
PubMed: 37168272
DOI: 10.1002/deo2.222 -
Chinese Medical Journal Dec 2023Type 2 diabetes mellitus (T2DM) is an independent risk factor for colorectal cancer (CRC), and the patients with CRC and T2DM have worse survival. The human gut...
BACKGROUND
Type 2 diabetes mellitus (T2DM) is an independent risk factor for colorectal cancer (CRC), and the patients with CRC and T2DM have worse survival. The human gut microbiota (GM) is linked to the development of CRC and T2DM, respectively. However, the GM characteristics in patients with CRC and T2DM remain unclear.
METHODS
We performed fecal metagenomic and targeted metabolomics studies on 36 samples from CRC patients with T2DM (DCRC group, n = 12), CRC patients without diabetes (CRC group, n = 12), and healthy controls (Health group, n = 12). We analyzed the fecal microbiomes, characterized the composition and function based on the metagenomics of DCRC patients, and detected the short-chain fatty acids (SCFAs) and bile acids (BAs) levels in all fecal samples. Finally, we performed a correlation analysis of the differential bacteria and metabolites between different groups.
RESULTS
Compared with the CRC group, LefSe analysis showed that there is a specific GM community in DCRC group, including an increased abundance of Eggerthella , Hungatella , Peptostreptococcus , and Parvimonas , and decreased Butyricicoccus , Lactobacillus , and Paraprevotella . The metabolomics analysis results revealed that the butyric acid level was lower but the deoxycholic acid and 12-keto-lithocholic acid levels were higher in the DCRC group than other groups ( P < 0.05). The correlation analysis showed that the dominant bacterial abundance in the DCRC group ( Parvimonas , Desulfurispora , Sebaldella , and Veillonellales , among others) was negatively correlated with butyric acid, hyodeoxycholic acid, ursodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, cholic acid and glycocholate. However, the abundance of mostly inferior bacteria was positively correlated with these metabolic acid levels, including Faecalibacterium , Thermococci , and Cellulophaga .
CONCLUSIONS
Unique fecal microbiome signatures exist in CRC patients with T2DM compared to those with non-diabetic CRC. Alterations in GM composition and SCFAs and secondary BAs levels may promote CRC development.
Topics: Humans; Gastrointestinal Microbiome; Diabetes Mellitus, Type 2; Microbiota; Bacteria; Fatty Acids, Volatile; Colorectal Neoplasms; Butyrates; Feces
PubMed: 36959686
DOI: 10.1097/CM9.0000000000002421