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Brain, Behavior, and Immunity Oct 2023The correlation between human gut microbiota and psychiatric diseases has long been recognized. Based on the heritability of the microbiome, genome-wide association... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The correlation between human gut microbiota and psychiatric diseases has long been recognized. Based on the heritability of the microbiome, genome-wide association studies on human genome and gut microbiome (mbGWAS) have revealed important host-microbiome interactions. However, establishing causal relationships between specific gut microbiome features and psychological conditions remains challenging due to insufficient sample sizes of previous studies of mbGWAS.
METHODS
Cross-cohort meta-analysis (via METAL) and multi-trait analysis (via MTAG) were used to enhance the statistical power of mbGWAS for identifying genetic variants and genes. Using two large mbGWAS studies (7,738 and 5,959 participants respectively) and12 disease-specific studies from the Psychiatric Genomics Consortium (PGC), we performed bidirectional two-sample mendelian randomization (MR) analyses between microbial features and psychiatric diseases (up to 500,199 individuals). Additionally, we conducted downstream gene- and gene-set-based analyses to investigate the shared biology linking gut microbiota and psychiatric diseases.
RESULTS
METAL and MTAG conducted in mbGWAS could boost power for gene prioritization and MR analysis. Increases in the number of lead SNPs and mapped genes were witnessed in 13/15 species and 5/10 genera after using METAL, and MTAG analysis gained an increase in sample size equivalent to expanding the original samples from 7% to 63%. Following METAL use, we identified a positive association between Bacteroides faecis and ADHD (OR, 1.09; 95 %CI, 1.02-1.16; P = 0.008). Bacteroides eggerthii and Bacteroides thetaiotaomicron were observed to be positively associated with PTSD (OR, 1.11; 95 %CI, 1.03-1.20; P = 0.007; OR, 1.11; 95 %CI, 1.01-1.23; P = 0.03). These findings remained stable across statistical models and sensitivity analyses. No genetic liabilities to psychiatric diseases may alter the abundance of gut microorganisms.Using biological annotation, we identified that those genes contributing to microbiomes (e.g., GRIN2A and RBFOX1) are expressed and enriched in human brain tissues.
CONCLUSIONS
Our statistical genetics strategy helps to enhance the power of mbGWAS, and our genetic findings offer new insights into biological pleiotropy and causal relationship between microbiota and psychiatric diseases.
Topics: Humans; Gastrointestinal Microbiome; Genome-Wide Association Study; Mendelian Randomization Analysis; Microbiota; Mental Disorders
PubMed: 37557965
DOI: 10.1016/j.bbi.2023.08.003 -
Proceedings of the National Academy of... Jul 2023Extracellular vesicles are produced in all three domains of life, and their biogenesis has common ancient origins in eukaryotes and archaea. Although bacterial vesicles...
Extracellular vesicles are produced in all three domains of life, and their biogenesis has common ancient origins in eukaryotes and archaea. Although bacterial vesicles were discovered several decades ago and multiple roles have been attributed to them, no mechanism has been established for vesicles biogenesis in bacteria. For this reason, there is a significant level of skepticism about the biological relevance of bacterial vesicles. (), a prominent member of the human intestinal microbiota, produces significant amounts of outer membrane vesicles (OMVs) which have been proposed to play key physiological roles. Here, we employed a dual marker system, consisting of outer membrane- and OMV-specific markers fused to fluorescent proteins to visualize OMV biogenesis by time-lapse microscopy. Furthermore, we performed comparative proteomic analyses to show that, in , the OMV cargo is adapted for the optimal utilization of different polysaccharides. We also show that a negatively charged N-terminal motif acts as a signal for protein sorting into OMVs irrespective of the nutrient availability. Our results demonstrate that OMV production is the result of a highly regulated process in .
Topics: Humans; Proteomics; Extracellular Vesicles; Bacteroides thetaiotaomicron; Diet; Polysaccharides; Bacterial Outer Membrane Proteins
PubMed: 37364113
DOI: 10.1073/pnas.2306314120 -
Cell Reports Aug 2023To understand how a bacterium ultimately succeeds or fails in adapting to a new host, it is essential to assess the temporal dynamics of its fitness over the course of...
To understand how a bacterium ultimately succeeds or fails in adapting to a new host, it is essential to assess the temporal dynamics of its fitness over the course of colonization. Here, we introduce a human-derived commensal organism, Bacteroides thetaiotaomicron (Bt), into the guts of germ-free mice to determine whether and how the genetic requirements for colonization shift over time. Combining a high-throughput functional genetics assay and transcriptomics, we find that gene usage changes drastically during the first days of colonization, shifting from high expression of amino acid biosynthesis genes to broad upregulation of diverse polysaccharide utilization loci. Within the first week, metabolism becomes centered around utilization of a predominant dietary oligosaccharide, and these changes are largely sustained through 6 weeks of colonization. Spontaneous mutations in wild-type Bt also evolve around this locus. These findings highlight the importance of considering temporal colonization dynamics in developing more effective microbiome-based therapies.
Topics: Humans; Animals; Mice; Bacteroides thetaiotaomicron; Acclimatization; Biological Assay; Gene Expression Profiling; Microbiota
PubMed: 37598339
DOI: 10.1016/j.celrep.2023.113009 -
American Journal of Physiology.... May 2024Fecal microbiota transplantation (FMT) is a promising therapy for inflammatory bowel disease (IBD) via rectifying gut microbiota. The aim of this study was to identify a...
Fecal microbiota transplantation (FMT) is a promising therapy for inflammatory bowel disease (IBD) via rectifying gut microbiota. The aim of this study was to identify a mechanism of how specific bacteria-associated immune response contributes to alleviated colitis. Forty donors were divided into high () and low () groups according to the diversity and the abundance of and by 16S rRNA sequencing. FMT was performed on dextran sulfate sodium (DSS)-induced colitis in mice. Mice with colitis showed significant improvement in intestinal injury and immune imbalance after FMT with ( < 0.05). and were identified as targeted strains in donor feces by real-time PCR and droplet digital PCR. Mice with colitis were treated with mono- or dual-bacterial gavage therapy. Dual-bacterial therapy significantly ameliorated intestinal injury compared with mono-bacterial therapy ( < 0.05). Dual-bacterial therapy increased the M2/M1 macrophage polarization and improved the Th17/Treg imbalance and elevated IL-10 production by Tregs compared with the DSS group ( < 0.05). Metabolomics showed increased abundance of lecithin in the glycerophospholipid metabolism pathway. In conclusion, , as the key bacteria in donor feces, alleviate colitis in mice. The mechanism may involve increasing lecithin and regulating IL-10 production of intestinal Tregs. We demonstrate that donors with high abundance of and ameliorate dextran sulfate sodium (DSS)-induced colitis in mice by fecal microbiota transplantation (FMT). The combination therapy of and is superior to mono-bacterial therapy in ameliorating colitis in mice, of which mechanism may involve promoting lecithin and inducing IL-10 production of intestinal Tregs.
Topics: Animals; Fecal Microbiota Transplantation; Colitis; Faecalibacterium prausnitzii; Mice; Gastrointestinal Microbiome; Male; Humans; Bacteroides thetaiotaomicron; Dextran Sulfate; Mice, Inbred C57BL; Interleukin-10; Adult; Female; Feces; Disease Models, Animal; Middle Aged
PubMed: 38502145
DOI: 10.1152/ajpgi.00303.2023 -
The ISME Journal Nov 2023Bacterial growth often alters the environment, which in turn can impact interspecies interactions among bacteria. Here, we used an in vitro batch system containing mucin...
Bacterial growth often alters the environment, which in turn can impact interspecies interactions among bacteria. Here, we used an in vitro batch system containing mucin beads to emulate the dynamic host environment and to study its impact on the interactions between two abundant and prevalent human gut bacteria, the primary fermenter Bacteroides thetaiotaomicron and the butyrate producer Roseburia intestinalis. By combining machine learning and flow cytometry, we found that the number of viable B. thetaiotaomicron cells decreases with glucose consumption due to acid production, while R. intestinalis survives post-glucose depletion by entering a slow growth mode. Both species attach to mucin beads, but only viable cell counts of B. thetaiotaomicron increase significantly. The number of viable co-culture cells varies significantly over time compared to those of monocultures. A combination of targeted metabolomics and RNA-seq showed that the slow growth mode of R. intestinalis represents a diauxic shift towards acetate and lactate consumption, whereas B. thetaiotaomicron survives glucose depletion and low pH by foraging on mucin sugars. In addition, most of the mucin monosaccharides we tested inhibited the growth of R. intestinalis but not B. thetaiotaomicron. We encoded these causal relationships in a kinetic model, which reproduced the observed dynamics. In summary, we explored how R. intestinalis and B. thetaiotaomicron respond to nutrient scarcity and how this affects their dynamics. We highlight the importance of understanding bacterial metabolic strategies to effectively modulate microbial dynamics in changing conditions.
Topics: Humans; Bacteroides thetaiotaomicron; Bacteroides; Mucins; Glucose
PubMed: 37670028
DOI: 10.1038/s41396-023-01501-1 -
Gut Microbes 2024Gut microbiota plays an essential role in the progression of nonalcoholic fatty liver disease (NAFLD), making the gut-liver axis a potential therapeutic strategy....
Gut microbiota plays an essential role in the progression of nonalcoholic fatty liver disease (NAFLD), making the gut-liver axis a potential therapeutic strategy. Bacteroides genus, the enriched gut symbionts, has shown promise in treating fatty liver. However, further investigation is needed to identify specific beneficial Bacteroides strains for metabolic disorders in NAFLD and elucidate their underlying mechanisms. In this study, we observed a positive correlation between the abundance of () and the alleviation of metabolic syndrome in the early and end stages of NAFLD. Administration of to HFD-fed mice for 12 weeks reduced body weight and fat accumulation, decreased hyperlipidemia and insulin resistance, and prevented hepatic steatohepatitis and liver injury. Notably, did not affect these indicators in low-fat diet (LFD)-fed mice and exhibited good safety. Mechanistically, regulated gut microbial composition, characterized by a decreased Firmicutes/Bacteroidetes ratio in HFD-Fed mice. It also increased gut-liver folate levels and hepatic metabolites, alleviating metabolic dysfunction. Additionally, treatment with increased the proportion of polyunsaturated fatty acid in the mouse liver, offering a widely reported benefit for NAFLD improvement. In conclusion, this study provides evidence that ameliorates NAFLD by regulating gut microbial composition, enhancing gut-liver folate and unsaturated fatty acid metabolism, highlighting the therapeutic role of as a potential probiotic for NAFLD.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Bacteroides thetaiotaomicron; Gastrointestinal Microbiome; Diet, High-Fat; Liver; Mice, Inbred C57BL
PubMed: 38277137
DOI: 10.1080/19490976.2024.2304159 -
Open Forum Infectious Diseases Jul 2023The increasing prevalence of anaerobic bacteremia is a major concern worldwide and requires longitudinal monitoring.
Distribution, Trends, and Antimicrobial Susceptibility of , , , and Species Causing Bacteremia in Japan During 2011-2020: A Retrospective Observational Study Based on National Surveillance Data.
BACKGROUND
The increasing prevalence of anaerobic bacteremia is a major concern worldwide and requires longitudinal monitoring.
METHODS
We present one of the largest and longest longitudinal studies on the prevalence and antimicrobial resistance of , , , and spp. isolated from blood culture samples using national comprehensive surveillance data in Japan during 2011-2020 as part of the Japan Nosocomial Infections Surveillance.
RESULTS
Data for 41 949 spp., 40 603 spp., 7013 spp., and 5428 spp. isolates were obtained. The incidences of bacteremia caused by , , and significantly increased during the period ( < .0001). Among the 20 species analyzed, 18 showed no significant changes in susceptibility over time, including , , and . However, resistance to clindamycin increased in ( = .0312), and resistance to ampicillin increased in ( = .0008).
CONCLUSIONS
Our comprehensive national surveillance data analysis demonstrated a continuous increase in the incidence of anaerobic bacteremia, particularly in , , and . This may be linked to the increasing number of colorectal cancer cases or advancing methods for species identification and susceptibility testing, requiring cautious interpretation. The discovery of an upsurge in anaerobic bacteremia and potential alterations in susceptibility highlights the necessity for more extensive studies in this field.
PubMed: 37469615
DOI: 10.1093/ofid/ofad334 -
Microbiology Spectrum Jun 2023Alterations caused by Trypanosoma cruzi in the composition of gut microbiome may play a vital role in the host-parasite interactions that shapes physiology and immune...
Alterations caused by Trypanosoma cruzi in the composition of gut microbiome may play a vital role in the host-parasite interactions that shapes physiology and immune responses against infection. Thus, a better understanding of this parasite-host-microbiome interaction may yield relevant information in the comprehension of the pathophysiology of the disease and the development of new prophylactic and therapeutic alternatives. Therefore, we implemented a murine model with two mice strains (BALB/c and C57BL/6) to evaluate the impact of Trypanosoma cruzi (Tulahuen strain) infection on the gut microbiome utilizing cytokine profiling and shotgun metagenomics. Higher parasite burdens were observed in cardiac and intestinal tissues, including changes in anti-inflammatory (interleukin-4 [IL-4] and IL-10) and proinflammatory (gamma interferon, tumor necrosis factor alpha, and IL-6) cytokines. Bacterial species such as Bacteroides thetaiotaomicron, Faecalibaculum rodentium, and Lactobacillus johnsonii showed a decrease in relative abundance, while Akkermansia muciniphila and Staphylococcus xylosus increased. Likewise, as infection progressed, there was a decrease in gene abundances related to metabolic processes such as lipid synthesis (including short-chain fatty acids) and amino acid synthesis (including branched-chain amino acids). High-quality metagenomic assembled genomes of L. johnsonii and A. muciniphila among other species were reconstructed, confirming, functional changes associated with metabolic pathways that are directly affected by the loss of abundance of specific bacterial taxa. Chagas disease (CD) is caused by the protozoan Trypanosoma cruzi, presenting acute and chronic phases where cardiomyopathy, megaesophagus, and/or megacolon stand out. During the course of its life cycle, the parasite has an important gastrointestinal tract transit that leads to severe forms of CD. The intestinal microbiome plays an essential role in the immunological, physiological, and metabolic homeostasis of the host. Therefore, parasite-host-intestinal microbiome interactions may provide information on certain biological and pathophysiological aspects related to CD. The present study proposes a comprehensive evaluation of the potential effects of this interaction based on metagenomic and immunological data from two mice models with different genetic, immunological, and microbiome backgrounds. Our findings suggest that there are alterations in the immune and microbiome profiles that affect several metabolic pathways that can potentially promote the infection's establishment, progression, and persistence. In addition, this information may prove essential in the research of new prophylactic and therapeutic alternatives for CD.
Topics: Mice; Animals; Disease Models, Animal; Mice, Inbred C57BL; Chagas Disease; Trypanosoma cruzi; Microbiota
PubMed: 37140369
DOI: 10.1128/spectrum.00199-23 -
MBio Nov 2023-Cresol sulfate (CS) and indoxyl sulfate (IS), gut microbiome-derived metabolites, are traditionally associated with cardiovascular disease (CVD) risks in the setting of...
-Cresol sulfate (CS) and indoxyl sulfate (IS), gut microbiome-derived metabolites, are traditionally associated with cardiovascular disease (CVD) risks in the setting of impaired kidney function. While pharmacologic provision of CS or IS can promote pro-thrombotic phenotypes, neither the microbial enzymes involved nor direct gut microbial production have been linked to CVD. Untargeted metabolomics was performed on a discovery cohort ( = 1,149) with relatively preserved kidney function, followed by stable isotope-dilution mass spectrometry quantification of CS and IS in an independent validation cohort ( = 3,954). Genetic engineering of human commensals to produce -cresol and indole gain-of-function and loss-of-function mutants, followed by colonization of germ-free mice, and studies on host thrombosis were performed. Systemic CS and IS levels were independently associated with all-cause mortality. Both and within colonized germ-free mice -cresol productions were recapitulated by collaboration of two organisms: a strain that converts tyrosine to 4-hydroxyphenylacetate, and a strain that decarboxylates 4-hydroxyphenylacetate to cresol. We then engineered a single organism, , to produce cresol, indole, or both metabolites. Colonizing germ-free mice with engineered strains we show the gut microbial genes for cresol () and indole () are sufficient to confer a pro-thrombotic phenotype . Moreover, human fecal metagenomics analyses show that abundances of and are associated with CVD. These studies show that CS and IS, two abundant microbiome-derived metabolites, play a broader potential role in CVD than was previously known. They also suggest that therapeutic targeting of gut microbial cresol- and indole-producing pathways represent rational targets for CVD.IMPORTANCEAlterations in gut microbial composition and function have been linked to numerous diseases. Identifying microbial pathways responsible for producing molecules that adversely impact the host is an important first step in the development of therapeutic interventions. Here, we first use large-scale clinical observations to link blood levels of defined microbial products to cardiovascular disease risks. Notably, the previously identified uremic toxins -cresol sulfate and indoxyl sulfate were shown to predict 5-year mortality risks. After identifying the microbes and microbial enzymes involved in the generation of these uremic toxins, we used bioengineering technologies coupled with colonization of germ-free mice to show that the gut microbial genes that generate -cresol and indole are sufficient to confer -cresol sulfate and indoxyl sulfate formation, and a pro-thrombotic phenotype . The findings and tools developed serve as a critical step in both the study and targeting of these gut microbial pathways .
PubMed: 37947418
DOI: 10.1128/mbio.01331-23 -
Acta Crystallographica. Section F,... Jul 2023The resistance of the emerging human pathogen Stenotrophomonas maltophilia to tetracycline antibiotics mainly depends on multidrug efflux pumps and ribosomal protection...
The resistance of the emerging human pathogen Stenotrophomonas maltophilia to tetracycline antibiotics mainly depends on multidrug efflux pumps and ribosomal protection enzymes. However, the genomes of several strains of this Gram-negative bacterium code for a FAD-dependent monooxygenase (SmTetX) homologous to tetracycline destructases. This protein was recombinantly produced and its structure and function were investigated. Activity assays using SmTetX showed its ability to modify oxytetracycline with a catalytic rate comparable to those of other destructases. SmTetX shares its fold with the tetracycline destructase TetX from Bacteroides thetaiotaomicron; however, its active site possesses an aromatic region that is unique in this enzyme family. A docking study confirmed tetracycline and its analogues to be the preferred binders amongst various classes of antibiotics.
Topics: Humans; Stenotrophomonas maltophilia; Crystallography, X-Ray; Anti-Bacterial Agents; Tetracycline; Oxytetracycline; Microbial Sensitivity Tests
PubMed: 37405486
DOI: 10.1107/S2053230X23005381