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Frontiers in Microbiology 2021Evidence supports the observational associations of gut microbiota with a variety of psychiatric disorders, but the causal nature of such associations remains obscure....
Evidence supports the observational associations of gut microbiota with a variety of psychiatric disorders, but the causal nature of such associations remains obscure. Aiming to comprehensively investigate their causal relationship and to identify specific causal microbe taxa for psychiatric diseases, we conducted a two-sample Mendelian randomization (MR) analysis of gut microbiome with 15 psychiatric diseases. Specifically, the microbiome genome-wide association study (GWAS) in 18,473 individuals from the MiBioGen study was used as exposure sample, and the GWAS for 15 psychiatric diseases was used as outcome samples. One-hundred ninety bacterial taxa from six levels were available for analysis. At a multiple-testing corrected significance level (phylum < 5.56 × 10, class < 3.33 × 10, order < 2.63 × 10, family < 1.67 × 10, genus < 4.90 × 10, and species < 3.33 × 10), the following eight causal associations from seven bacterial features (one phylum + three classes + one order + one family + one species) were identified: family with autism spectrum disorder ( = 5.31 × 10), class with bipolar disorder ( = 1.53 × 10), class with schizophrenia ( = 1.33 × 10), class and order with Tourette syndrome ( = 2.51 × 10 and 2.51 × 10), phylum and class with extroversion ( = 8.22 × 10 and 1.09 × 10), and species with neuroticism ( = 8.92 × 10). Sensitivity analysis showed no evidence of reverse causality, pleiotropy, and heterogeneity. Our findings offered novel insights into the gut microbiota-mediated development mechanism of psychiatric disorders.
PubMed: 35185808
DOI: 10.3389/fmicb.2021.737197 -
Cell Oct 2020A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the...
A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.
Topics: Adipose Tissue; Animals; Bacterial Translocation; Biodiversity; Biomarkers; Cell Polarity; Cells, Cultured; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Microbiome; Gene Expression Regulation; Germ-Free Life; Humans; Ileum; Lipopolysaccharides; Macrophages; Mesentery; Metagenome; Metagenomics; Mice; Mice, Inbred C57BL; Phenotype; RNA, Ribosomal, 16S; Stem Cells
PubMed: 32991841
DOI: 10.1016/j.cell.2020.09.009 -
Virulence Dec 2023is an emerging spore-forming anaerobe that is often observed in -associated inflammatory bowel disease (IBD) exacerbations. Unlike , neither produces toxins nor...
is an emerging spore-forming anaerobe that is often observed in -associated inflammatory bowel disease (IBD) exacerbations. Unlike , neither produces toxins nor possesses toxin-encoding genetic loci, but is commonly found in both intestinal and extra-intestinal infections. Membrane lipid rafts are composed of dynamic assemblies of cholesterol and sphingolipids, allowing bacteria to gain access to cells. However, the direct interaction between and lipid rafts that confers bacteria the ability to disrupt the intestinal barrier and induce pathogenesis remains unclear. In this study, we investigated the associations among nucleotide-binding oligomerization domain containing 2 (NOD2), lipid rafts, and cytotoxicity in -infected gut epithelial cells. Our results revealed that lipid rafts were involved in -induced NOD2 expression and nuclear factor (NF)-κB activation, triggering an inflammatory response. Reducing cholesterol by simvastatin significantly dampened -induced cell death, indicating that the -induced pathogenicity of cells was lipid raft-dependent. These results demonstrate that NOD2 mobilization into membrane rafts in response to -induced cytotoxicity results in aggravated pathogenicity.
Topics: Clostridioides difficile; Clostridium; NF-kappa B; Membrane Microdomains; Cholesterol
PubMed: 37798913
DOI: 10.1080/21505594.2023.2265048 -
Clostridium innocuum: Microbiological and clinical characteristics of a potential emerging pathogen.Anaerobe Oct 2021Clostridium innocuum is an anaerobic, gram-positive, spore-forming bacterium identified by Smith and King in 1962 after being isolated from a patient with an appendiceal... (Review)
Review
Clostridium innocuum is an anaerobic, gram-positive, spore-forming bacterium identified by Smith and King in 1962 after being isolated from a patient with an appendiceal abscess. Its name, C. innocuum, reflected its clinically "innocuous" nature based on observed lack of virulence in animal models of infection. Since that time, C. innocuum has been identified as both part of the normal intestinal flora and the cause of a rare, intrinsically vancomycin-resistant opportunistic infection in immunocompromised patients. More recently, reports from Taiwan suggest that C. innocuum, in addition to being a known extraintestinal pathogen, may also be a diarrheal pathogen that causes a C. difficile infection-like antibiotic-associated diarrheal illness. However, unanswered questions about the clinical relevance of C. innocuum remain. Here we review the microbiological and clinical characteristics of this emerging pathogen.
Topics: Animals; Clostridium Infections; Communicable Diseases, Emerging; Diarrhea; Firmicutes; Humans
PubMed: 34332070
DOI: 10.1016/j.anaerobe.2021.102418 -
MSphere Feb 2023are a polyphyletic group of Gram-positive, spore-forming anaerobes in the phylum that significantly impact metabolism and functioning of the human gastrointestinal...
are a polyphyletic group of Gram-positive, spore-forming anaerobes in the phylum that significantly impact metabolism and functioning of the human gastrointestinal tract. Recently, were divided into two separate classes, and , based on phenotypic and 16S rRNA gene-based differences. While include many well-known pathogenic bacteria, remain relatively uncharacterized, particularly regarding their role as a pathogen versus commensal. Despite wide recognition as a commensal, the erysipelotrichial species Clostridium innocuum has recently been associated with various disease states. To further understand the ecological and potential virulent role of C. innocuum, we conducted a genomic comparison across 38 C. innocuum isolates and 194 publicly available genomes. Based on colony morphology, we isolated multiple C. innocuum cultivars from the feces of healthy human volunteers ( = 5). Comparison of the 16S rRNA gene of our isolates against publicly available microbiota data sets in healthy individuals suggests a high prevalence of C. innocuum across the human population (>80%). Analysis of single nucleotide polymorphisms (SNPs) across core genes and average nucleotide identify (ANI) revealed the presence of four clades among all available genomes ( = 232 total). Investigation of carbohydrate and protein utilization pathways, including comparison against the carbohydrate-activating enzyme (CAZyme) database, demonstrated inter- and intraclade differences that were further substantiated . Collectively, these data indicate genetic variance within the C. innocuum species that may help clarify its role in human disease and health. are a group of medically important anaerobes as both commensals and pathogens. Recently, a new class of containing a number of reassigned clostridial species has emerged, including Clostridium innocuum. Recent studies have implicated C. innocuum as a potential causative agent of diarrhea in patients from whom Clostridioides difficile could not be isolated. Using genomic and comparison, this study sought to characterize C. innocuum in the healthy human gut. Our analyses suggest that C. innocuum is a highly prevalent and diverse species, demonstrating clade-specific differences in metabolism and potential virulence. Collectively, this study is the first investigation into a broader description of C. innocuum as a human gut inhabitant.
Topics: Humans; Clostridium; Gastrointestinal Microbiome; Prevalence; RNA, Ribosomal, 16S
PubMed: 36541771
DOI: 10.1128/msphere.00569-22 -
Frontiers in Immunology 2023An association between Graves' disease (GD) and the gut microbiome has been identified, but the causal effect between them remains unclear.
BACKGROUND
An association between Graves' disease (GD) and the gut microbiome has been identified, but the causal effect between them remains unclear.
METHODS
Bidirectional two-sample Mendelian randomization (MR) analysis was used to detect the causal effect between GD and the gut microbiome. Gut microbiome data were derived from samples from a range of different ethnicities (18,340 samples) and data on GD were obtained from samples of Asian ethnicity (212,453 samples). Single nucleotide polymorphisms (SNPs) were selected as instrumental variables according to different criteria. They were used to evaluate the causal effect between exposures and outcomes through inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger, and simple mode methods. -statistics and sensitivity analyses were performed to evaluate bias and reliability.
RESULTS
In total, 1,560 instrumental variables were extracted from the gut microbiome data (< 1 × 10). The classes [odds ratio (OR) = 3.603] and , as well as the genera group, , and UCG 011 were identified as risk factors for GD. The family and the genus (OR = 0.489) were protective factors for GD. In addition, 13 instrumental variables were extracted from GD (< 1 × 10), causing one family and eight genera to be regulated. The genus group ( = 0.024, OR = 0.918) and ( = 0.049, OR = 1.584) had the greatest probability of being regulated. Significant bias, heterogeneity, and horizontal pleiotropy were not detected.
CONCLUSION
A causal effect relationship exists between GD and the gut microbiome, demonstrating regulatory activity and interactions, and thus providing evidence supporting the involvement of a thyroid-gut axis.
Topics: Humans; Gastrointestinal Microbiome; Mendelian Randomization Analysis; Reproducibility of Results; Graves Disease; Clostridiales; Lactobacillales
PubMed: 36865531
DOI: 10.3389/fimmu.2023.977587 -
BMC Medical Genomics Oct 2023Epidemiological studies have indicated a potential link between the gut microbiome and autoimmune liver disease (AILD) such as autoimmune hepatitis (AIH), primary...
BACKGROUND
Epidemiological studies have indicated a potential link between the gut microbiome and autoimmune liver disease (AILD) such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The relationship between the gut microbiome and autoimmune liver disease is still uncertain due to confounding variables. In our study, we aim to shed light on this relationship by employing a two-sample Mendelian randomization approach.
METHODS
We conducted a two-sample Mendelian randomization (MR) study using the R package "TwoSampleMR". The exposure data consisted of genetic variants associated with 194 bacterial traits obtained from the MiBioGen consortium. Summary statistics for AILD were obtained from the GWAS Catalog website. Furthermore, a series of sensitivity analyses were performed to validate the initial MR results.
RESULTS
There were two, four and three bacteria traits associated with an increased risk of AIH. PBC, and PSC respectively. In contrast, there were five, two and five bacteria traits associated with a decreased risk for AIH, PBC and PSC. Notably, the genus_Clostridium_innocuum_group showed a negative association with AIH (OR = 0.67, 95% CI: 0.49-0.93), and the genus_Actinomyces was found to be genetically associated with a decreased risk of PSC (OR = 0.62, 95% CI: 0.42-0.90).
CONCLUSIONS
Our study identified the causal impact of specific bacterial features on the risk of AILD subtypes. Particularly, the genus_Clostridium_innocuum_group and the genus_Actinomyces demonstrated significant protective effects against AIH and PSC respectively. These findings provide further support for the potential use of targeted probiotics in the management of AILD.
Topics: Humans; Liver Cirrhosis, Biliary; Gastrointestinal Microbiome; Mendelian Randomization Analysis; Cholangitis, Sclerosing; Liver Diseases; Hepatitis, Autoimmune
PubMed: 37789337
DOI: 10.1186/s12920-023-01670-0 -
Nature Communications Feb 2024Commensal bacteria generate immensely diverse active metabolites to maintain gut homeostasis, however their fundamental role in establishing an immunotolerogenic...
Commensal bacteria generate immensely diverse active metabolites to maintain gut homeostasis, however their fundamental role in establishing an immunotolerogenic microenvironment in the intestinal tract remains obscure. Here, we demonstrate that an understudied murine commensal bacterium, Dubosiella newyorkensis, and its human homologue Clostridium innocuum, have a probiotic immunomodulatory effect on dextran sulfate sodium-induced colitis using conventional, antibiotic-treated and germ-free mouse models. We identify an important role for the D. newyorkensis in rebalancing Treg/Th17 responses and ameliorating mucosal barrier injury by producing short-chain fatty acids, especially propionate and L-Lysine (Lys). We further show that Lys induces the immune tolerance ability of dendritic cells (DCs) by enhancing Trp catabolism towards the kynurenine (Kyn) pathway through activation of the metabolic enzyme indoleamine-2,3-dioxygenase 1 (IDO1) in an aryl hydrocarbon receptor (AhR)-dependent manner. This study identifies a previously unrecognized metabolic communication by which Lys-producing commensal bacteria exert their immunoregulatory capacity to establish a Treg-mediated immunosuppressive microenvironment by activating AhR-IDO1-Kyn metabolic circuitry in DCs. This metabolic circuit represents a potential therapeutic target for the treatment of inflammatory bowel diseases.
Topics: Humans; Animals; Mice; Kynurenine; Lysine; Receptors, Aryl Hydrocarbon; Colitis; Bacteria; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Firmicutes
PubMed: 38351003
DOI: 10.1038/s41467-024-45636-x -
Emerging Infectious Diseases Mar 2022Vancomycin-resistant Clostridium innocuum was recently identified as an etiologic agent for antibiotic-associated diarrhea in humans. We conducted a case-control study...
Vancomycin-resistant Clostridium innocuum was recently identified as an etiologic agent for antibiotic-associated diarrhea in humans. We conducted a case-control study involving 152 C. innocuum-infected patients during 2014-2019 in Taiwan, using 304 cases of Clostridioides difficile infection (CDI) matched by diagnosis year, age (+2 years), and sex as controls. The baseline characteristics were similar between the 2 groups. C. innocuum-infected patients experienced more extraintestinal clostridial infection and gastrointestinal tract-related complications than did patients with CDI. The 30-day mortality rate among C. innocuum-infected patients was 14.5%, and the overall rate was 23.0%. Chronic kidney disease, solid tumor, intensive care unit admission, and shock status were 4 independent risk factors for death. C. innocuum identified from clinical specimens should be recognized as a pathogen requiring treatment, and because of its intrinsic vancomycin resistance, precise identification is necessary to guide appropriate and timely antimicrobial therapy.
Topics: Anti-Bacterial Agents; Case-Control Studies; Child, Preschool; Clostridium Infections; Firmicutes; Humans; Taiwan
PubMed: 35195517
DOI: 10.3201/eid2803.204421 -
Gastroenterology Jan 2024The gut microbiota plays a significant role in the pathogenesis of both forms of inflammatory bowel disease (IBD), namely, Crohn's disease (CD) and ulcerative colitis... (Review)
Review
The gut microbiota plays a significant role in the pathogenesis of both forms of inflammatory bowel disease (IBD), namely, Crohn's disease (CD) and ulcerative colitis (UC). Although evidence suggests dysbiosis and loss of beneficial microbial species can exacerbate IBD, many new studies have identified microbes with pathogenic qualities, termed "pathobionts," within the intestines of patients with IBD. The concept of pathobionts initiating or driving the chronicity of IBD has largely focused on the putative aggravating role that adherent invasive Escherichia coli may play in CD. However, recent studies have identified additional bacterial and fungal pathobionts in patients with CD and UC. This review will highlight the characteristics of these pathobionts and their implications for IBD treatment. Beyond exploring the origins of pathobionts, we discuss those associated with specific clinical features and the potential mechanisms involved, such as creeping fat (Clostridium innocuum) and impaired wound healing (Debaryomyces hansenii) in patients with CD as well as the increased fecal proteolytic activity (Bacteroides vulgatus) seen as a biomarker for UC severity. Finally, we examine the potential impact of pathobionts on current IBD therapies, and several new approaches to target pathobionts currently in the early stages of development. Despite recognizing that pathobionts likely contribute to the pathogenesis of IBD, more work is needed to define their modes of action. Determining whether causal relationships exist between pathobionts and specific disease characteristics could pave the way for improved care for patients, particularly for those not responding to current IBD therapies.
Topics: Humans; Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease; Intestines; Feces
PubMed: 37734419
DOI: 10.1053/j.gastro.2023.09.019