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Immunity Feb 2023The physiological and immune changes that occur during pregnancy are associated with worsened disease outcomes during infection and sepsis. How these perturbations...
The physiological and immune changes that occur during pregnancy are associated with worsened disease outcomes during infection and sepsis. How these perturbations exacerbate inflammation has not been explored. Here, using antibiotic treatment and fecal microbial transfers, we showed that sepsis susceptibility is driven by pregnancy-induced changes to gut microbiome in mice and humans. Integrative multiomics and genetically engineered bacteria revealed that reduced Parabacteroides merdae (P. merdae) abundance during pregnancy led to decreased formononetin (FMN) and increased macrophage death. Mechanistically, FMN inhibited macrophage pyroptosis by suppressing nuclear accumulation of hnRNPUL2 and subsequent binding to the Nlrp3 promoter. Treatment with FMN or deletion of murine hnRNPUL2 protected against septic inflammation. Intestinal abundances of P. merdae and FMN inversely correlated with the progression of septic patients. Our data reveal a microbe-immune axis that is disrupted in pregnant septic hosts, highlighting the potential of the FMN-hnRNPUL2-NLRP3 axis in providing promising therapeutic strategies for sepsis.
Topics: Pregnancy; Female; Humans; Animals; Mice; Gastrointestinal Microbiome; Pyroptosis; NLR Family, Pyrin Domain-Containing 3 Protein; Macrophages; Sepsis; Inflammation
PubMed: 36792573
DOI: 10.1016/j.immuni.2023.01.015 -
Theranostics 2021Prior chronic treatment with statins has been shown to be associated with more favorable outcomes in patients with acute coronary syndrome (ACS). Specific changes in...
Multi-omics study reveals that statin therapy is associated with restoration of gut microbiota homeostasis and improvement in outcomes in patients with acute coronary syndrome.
Prior chronic treatment with statins has been shown to be associated with more favorable outcomes in patients with acute coronary syndrome (ACS). Specific changes in the gut microbiota and microbial metabolites have been shown to influence the progression of coronary artery disease. However, the critical microbial and metabolomic changes associated with the cardiovascular protective effects of statins in ACS remain elusive. In the present study, we performed 16S rRNA sequencing and serum metabolomic analysis in 36 ACS patients who had received chronic statin treatment, 67 ACS patients who had not, and 30 healthy volunteers. A follow-up study was conducted. Metagenomic functional prediction of important bacterial taxa was achieved using PICRUSt2. : Statins modulated the gut microbiome of ACS patients towards a healthier status, i.e., reducing potentially pathogenic bacteria such as but increasing beneficial bacteria such as , and . Moreover, prior chronic statin therapy was associated with improved outcome in ACS patients. Multi-omics analysis revealed that specific changes in bacterial taxa were associated with disease severity or outcomes either directly or by mediating metabolites such as fatty acids and prenol lipids. Finally, we discovered that important taxa associated with statins were correlated with fatty acid- and isoprenoid-related pathways that were predicted by PICRUSt2. Our study suggests that statin treatment might benefit ACS patients by modulating the composition and function of the gut microbiome, which might result in improved circulating metabolites and reduced metabolic risk. Our findings provide new insights for understanding the heterogenic roles of statins in ACS patients through host gut microbiota metabolic interactions.
Topics: Acute Coronary Syndrome; Bacteria; Female; Follow-Up Studies; Gastrointestinal Microbiome; Healthy Volunteers; Homeostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Metabolomics; Middle Aged; RNA, Ribosomal, 16S
PubMed: 33897881
DOI: 10.7150/thno.55946 -
Gut Microbes 2023The gut microbiota is involved in the production of numerous metabolites that maintain host wellbeing. The assembly of the gut microbiome is highly dynamic, and...
The gut microbiota is involved in the production of numerous metabolites that maintain host wellbeing. The assembly of the gut microbiome is highly dynamic, and influenced by many postnatal factors, moreover, little is known about the development of the gut metabolome. We showed that geography has an important influence on the microbiome dynamics in the first year of life based on two independent cohorts from China and Sweden. Major compositional differences since birth were the high relative abundance of in the Swedish cohort and in the Chinese cohort. We analyzed the development of the fecal metabolome in the first year of life in the Chinese cohort. Lipid metabolism, especially acylcarnitines and bile acids, was the most abundant metabolic pathway in the newborn gut. Delivery mode and feeding induced particular differences in the gut metabolome since birth. In contrast to C-section newborns, medium- and long-chain acylcarnitines were abundant at newborn age only in vaginally delivered infants, associated by the presence of bacteria such as and . Our data provide a basis for understanding the maturation of the fecal metabolome and the metabolic role of gut microbiota in infancy.
Topics: Gastrointestinal Microbiome; Humans; Infant, Newborn; Infant; China; Bile Acids and Salts; Amino Acids; Sweden; Bacteroides; Streptococcus; Feces; Lipid Metabolism; Feeding Behavior; Metabolic Networks and Pathways; Delivery, Obstetric; Female; Pregnancy; Cesarean Section; Longitudinal Studies; Male
PubMed: 37424334
DOI: 10.1080/19490976.2023.2231596 -
The Journal of Biological Chemistry Apr 2016Clan CD cysteine peptidases, a structurally related group of peptidases that include mammalian caspases, exhibit a wide range of important functions, along with a...
Clan CD cysteine peptidases, a structurally related group of peptidases that include mammalian caspases, exhibit a wide range of important functions, along with a variety of specificities and activation mechanisms. However, for the clostripain family (denoted C11), little is currently known. Here, we describe the first crystal structure of a C11 protein from the human gut bacterium, Parabacteroides merdae (PmC11), determined to 1.7-Å resolution. PmC11 is a monomeric cysteine peptidase that comprises an extended caspase-like α/β/α sandwich and an unusual C-terminal domain. It shares core structural elements with clan CD cysteine peptidases but otherwise structurally differs from the other families in the clan. These studies also revealed a well ordered break in the polypeptide chain at Lys(147), resulting in a large conformational rearrangement close to the active site. Biochemical and kinetic analysis revealed Lys(147) to be an intramolecular processing site at which cleavage is required for full activation of the enzyme, suggesting an autoinhibitory mechanism for self-preservation. PmC11 has an acidic binding pocket and a preference for basic substrates, and accepts substrates with Arg and Lys in P1 and does not require Ca(2+) for activity. Collectively, these data provide insights into the mechanism and activity of PmC11 and a detailed framework for studies on C11 peptidases from other phylogenetic kingdoms.
Topics: Bacterial Proteins; Bacteroidaceae; Crystallography, X-Ray; Cysteine Proteases; Gastrointestinal Microbiome; Humans; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 26940874
DOI: 10.1074/jbc.M115.706143 -
Protein Science : a Publication of the... Dec 2018β-Glucuronidase (GUS) enzymes in the gastrointestinal tract are involved in maintaining mammalian-microbial symbiosis and can play key roles in drug efficacy and...
β-Glucuronidase (GUS) enzymes in the gastrointestinal tract are involved in maintaining mammalian-microbial symbiosis and can play key roles in drug efficacy and toxicity. Parabacteroides merdae GUS was identified as an abundant mini-Loop 2 (mL2) type GUS enzyme in the Human Microbiome Project gut metagenomic database. Here, we report the crystal structure of P. merdae GUS and highlight the differences between this enzyme and extant structures of gut microbial GUS proteins. We find that P. merdae GUS exhibits a distinct tetrameric quaternary structure and that the mL2 motif traces a unique path within the active site, which also includes two arginines distinctive to this GUS. We observe two states of the P. merdae GUS active site; a loop repositions itself by more than 50 Å to place a functionally-relevant residue into the enzyme's catalytic site. Finally, we find that P. merdae GUS is able to bind to homo and heteropolymers of the polysaccharide alginic acid. Together, these data broaden our understanding of the structural and functional diversity in the GUS family of enzymes present in the human gut microbiome and point to specialization as an important feature of microbial GUS orthologs.
Topics: Bacteroidaceae; Catalytic Domain; Crystallography, X-Ray; Gastrointestinal Microbiome; Glucuronidase; Humans; Models, Molecular; Protein Conformation
PubMed: 30230652
DOI: 10.1002/pro.3507 -
Frontiers in Cellular and Infection... 2017Human gut microbiota is believed to be directly or indirectly involved in cardiovascular diseases and hypertension. However, the identification and functional status of...
Human gut microbiota is believed to be directly or indirectly involved in cardiovascular diseases and hypertension. However, the identification and functional status of the hypertension-related gut microbe(s) have not yet been surveyed in a comprehensive manner. Here we characterized the gut microbiome in hypertension status by comparing fecal samples of 60 patients with primary hypertension and 60 gender-, age-, and body weight-matched healthy controls based on whole-metagenome shotgun sequencing. Hypertension implicated a remarkable gut dysbiosis with significant reduction in within-sample diversity and shift in microbial composition. Metagenome-wide association study (MGWAS) revealed 53,953 microbial genes that differ in distribution between the patients and healthy controls (false discovery rate, 0.05) and can be grouped into 68 clusters representing bacterial species. Opportunistic pathogenic taxa, such as, spp., spp., and were frequently distributed in hypertensive gut microbiome, whereas the short-chain fatty acid producer, such as, spp. and , were higher in controls. The number of hypertension-associated species also showed stronger correlation to the severity of disease. Functionally, the hypertensive gut microbiome exhibited higher membrane transport, lipopolysaccharide biosynthesis and steroid degradation, while in controls the metabolism of amino acid, cofactors and vitamins was found to be higher. We further provided the microbial markers for disease discrimination and achieved an area under the receiver operator characteristic curve (AUC) of 0.78, demonstrating the potential of gut microbiota in prediction of hypertension. These findings represent specific alterations in microbial diversity, genes, species and functions of the hypertensive gut microbiome. Further studies on the causality relationship between hypertension and gut microbiota will offer new prospects for treating and preventing the hypertension and its associated diseases.
Topics: Bacteria; Dysbiosis; Feces; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Hypertension; Male; Metagenome; Middle Aged; Whole Genome Sequencing
PubMed: 28884091
DOI: 10.3389/fcimb.2017.00381 -
Frontiers in Cellular and Infection... 2022Aging is now the most profound risk factor for almost all non-communicable diseases. Studies have shown that probiotics play a specific role in fighting aging. We used...
Aging is now the most profound risk factor for almost all non-communicable diseases. Studies have shown that probiotics play a specific role in fighting aging. We used metagenomic sequencing to study the changes in gut microbes in different age groups and found that aging had the most significant effect on subjects' gut microbe structure. Our study divided the subjects (n=614) into two groups by using 50 years as the age cut-off point for the grouping. Compared with the younger group, several species with altered abundance and specific functional pathways were found in the older group. At the species level, the abundance of , , , , , and were increased in older individuals. They were positively correlated to the pathways responsible for lipopolysaccharide (LPS) biosynthesis and the degradation of short-chain fatty acids (SCFAs). On the contrary, the levels of , , and were decreased in the older group, which negatively correlated with the above pathways (p-value<0.05). Functional prediction revealed 92 metabolic pathways enriched in the older group significantly higher than those in the younger group (p-value<0.05), especially pathways related to LPS biosynthesis and the degradation of SCFAs. Additionally, we established a simple non-invasive model of aging, nine species (, , , , , , , , and ) were selected to construct the model. The area under the receiver operating curve (AUC) of the model implied that supplemented probiotics might influence aging. We discuss the features of the aging microbiota that make it more amenable to pre-and probiotic interventions. We speculate these metabolic pathways of gut microbiota can be associated with the immune status and inflammation of older adults. Health interventions that promote a diverse microbiome could influence the health of older adults.
Topics: Aged; Bacteroides; Bacteroides fragilis; Bacteroidetes; Bifidobacterium longum; Clostridiales; Escherichia coli; Feces; Firmicutes; Gastrointestinal Microbiome; Humans; Lipopolysaccharides
PubMed: 35959379
DOI: 10.3389/fcimb.2022.877914 -
New Microbes and New Infections Mar 2022Strain Quantibio-BCGUT is a new species from the genus Parabacteroides that was isolated from a stool sample of a 49-year-old healthy Chinese male adult. Cells are...
Strain Quantibio-BCGUT is a new species from the genus Parabacteroides that was isolated from a stool sample of a 49-year-old healthy Chinese male adult. Cells are Gram-negative and obligate anerobic bacilli. Strain Quantibio-BCGUT exhibits 95.86% 16S rRNA gene sequence similarity to Parabacteroides merdae strain JCM 9497 (NR_041343.1), the phylogenetically closely related species with standing in nomenclature. Major fatty acids are C16:0, C18:0 and C19:0-IS. Quantibio-BCGUT exhibits a high level of resistance to aztreonam. Growth occurred at pH 5.5-9.0. Optimal growth was observed at 35 °C in YCFA medium in anerobic condition, no growth occurs at 25 °C or 50 °C. Strain grows in YCFA medium in the presence of 0.1%-2.0% (w/v) NaCl (optimum 1.0%). Based on the phenotypic and phylogenetic evidence, OrthoANI values and results of the biochemical tests, the new species is named Parabacteroides pekinense sp. nov., for which strain Quantibio-BCGU T (= CGMCC = QHBCGU) is proposed as the type strain.
PubMed: 35496671
DOI: 10.1016/j.nmni.2022.100973 -
Frontiers in Microbiology 2022β-glucuronidases (GUS) of intestinal bacteria remove glucuronic acid from glucoronides, reversing phase II metabolism of the liver and affecting the level of active...
β-glucuronidases (GUS) of intestinal bacteria remove glucuronic acid from glucoronides, reversing phase II metabolism of the liver and affecting the level of active deconjugated metabolites deriving from drugs or xenobiotics. Two hundred seventy-nine non-redundant GUS sequences are known in the gut microbiota, classified in seven structural categories (NL, L1, L2, mL1, mL2, mL1,2, and NC) with different biocatalytic properties. In the present study, the intestinal metagenome of 60 healthy subjects from five geographically different cohorts was assembled, binned, and mined to determine qualitative and quantitative differences in GUS profile, potentially affecting response to drugs and xenobiotics. Each metagenome harbored 4-70 different GUS, altogether accounting for 218. The amount of intestinal bacteria with at least one GUS gene was highly variable, from 0.7 to 82.2%, 25.7% on average. No significant difference among cohorts could be identified, except for the Ethiopia (ETH) cohort where GUS-encoding bacteria were significantly less abundant. The structural categories were differently distributed among the metagenomes, but without any statistical significance related to the cohorts. GUS profiles were generally dominated by the category NL, followed by mL1, L2, and L1. The GUS categories most involved in the hydrolysis of small molecules, including drugs, are L1 and mL1. Bacteria contributing to these categories belonged to , , , , , , , and . Bacteria harboring L1 GUS were generally scarcely abundant (<1.3%), except in three metagenomes, where they reached up to 24.3% for the contribution of and Bacteria harboring mL1 GUS were significantly more abundant (mean = 4.6%), with representing a major contributor. Albeit mL1 enzymes are less active than L1 ones, likely plays a pivotal role in the deglucuronidation, due to its remarkable abundance in the microbiomes. The observed broad interindividual heterogeneity of GUS profiles, particularly of the L1 and mL1 categories, likely represent a major driver of pharmacomicrobiomics variability, affecting drug response and toxicity. Different geographical origins, genetic, nutritional, and lifestyle features of the hosts seemed not to be relevant in the definition of glucuronidase activity, albeit they influenced the richness of the GUS profile.
PubMed: 35308380
DOI: 10.3389/fmicb.2022.826994 -
Gut Microbes 2024Ulcerative colitis (UC) is a challenging form of inflammatory bowel disease, and its etiology is intricately linked to disturbances in the gut microbiome. To identify...
Ulcerative colitis (UC) is a challenging form of inflammatory bowel disease, and its etiology is intricately linked to disturbances in the gut microbiome. To identify the potential alleviators of UC, we employed an integrative analysis combining microbial community modeling with advanced machine learning techniques. Using metagenomics data sourced from the Integrated Human Microbiome Project, we constructed individualized microbiome community models for each participant. Our analysis highlighted a significant decline in both α and β-diversity of strain-level microbial populations in UC subjects compared to controls. Distinct differences were also observed in the predicted fecal metabolite profiles and strain-to-metabolite contributions between the two groups. Using tree-based machine learning models, we successfully identified specific microbial strains and their associated metabolites as potential alleviators of UC. Notably, our experimental validation using a dextran sulfate sodium-induced UC mouse model demonstrated that the administration of ATCC 43,184 and N-acetyl-D-mannosamine provided notable relief from colitis symptoms. In summary, our study underscores the potential of an integrative approach to identify novel therapeutic avenues for UC, paving the way for future targeted interventions.
Topics: Animals; Mice; Humans; Colitis, Ulcerative; Gastrointestinal Microbiome; Inflammatory Bowel Diseases; Colitis; Machine Learning
PubMed: 38563656
DOI: 10.1080/19490976.2024.2336877