-
Microbiome Sep 2023Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease that carries mutations in NOTCH3....
BACKGROUND
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease that carries mutations in NOTCH3. The clinical manifestations are influenced by genetic and environmental factors that may include gut microbiome.
RESULTS
We investigated the fecal metagenome, fecal metabolome, serum metabolome, neurotransmitters, and cytokines in a cohort of 24 CADASIL patients with 28 healthy household controls. The integrated-omics study showed CADASIL patients harbored an altered microbiota composition and functions. The abundance of bacterial coenzyme A, thiamin, and flavin-synthesizing pathways was depleted in patients. Neurotransmitter balance, represented by the glutamate/GABA (4-aminobutanoate) ratio, was disrupted in patients, which was consistent with the increased abundance of two major GABA-consuming bacteria, Megasphaera elsdenii and Eubacterium siraeum. Essential inflammatory cytokines were significantly elevated in patients, accompanied by an increased abundance of bacterial virulence gene homologs. The abundance of patient-enriched Fusobacterium varium positively correlated with the levels of IL-1β and IL-6. Random forest classification based on gut microbial species, serum cytokines, and neurotransmitters showed high predictivity for CADASIL with AUC = 0.89. Targeted culturomics and mechanisms study further showed that patient-derived F. varium infection caused systemic inflammation and behavior disorder in Notch3 mice potentially via induction of caspase-8-dependent noncanonical inflammasome activation in macrophages.
CONCLUSION
These findings suggested the potential linkage among the brain-gut-microbe axis in CADASIL. Video Abstract.
Topics: Animals; Mice; CADASIL; Gastrointestinal Microbiome; Mental Disorders; Cytokines; gamma-Aminobutyric Acid
PubMed: 37684694
DOI: 10.1186/s40168-023-01638-3 -
Frontiers in Microbiology 2023Gut microbiota plays an important role in colorectal cancer (CRC) pathogenesis through microbes and their metabolites, while oral pathogens are the major components of...
OBJECTIVE
Gut microbiota plays an important role in colorectal cancer (CRC) pathogenesis through microbes and their metabolites, while oral pathogens are the major components of CRC-associated microbes. Multiple studies have identified gut and fecal microbiome-derived biomarkers for precursors lesions of CRC detection. However, few studies have used salivary samples to predict colorectal polyps. Therefore, in order to find new noninvasive colorectal polyp biomarkers, we searched into the differences in fecal and salivary microbiota between patients with colorectal polyps and healthy controls.
METHODS
In this case-control study, we collected salivary and fecal samples from 33 patients with colorectal polyps (CP) and 22 healthy controls (HC) between May 2021 and November 2022. All samples were sequenced using full-length 16S rRNA sequencing and compared with the Nucleotide Sequence Database. The salivary and fecal microbiota signature of colorectal polyps was established by alpha and beta diversity, Linear discriminant analysis Effect Size (LEfSe) and random forest model analysis. In addition, the possibility of microbiota in identifying colorectal polyps was assessed by Receiver Operating Characteristic Curve (ROC).
RESULTS
In comparison to the HC group, the CP group's microbial diversity increased in saliva and decreased in feces ( < 0.05), but there was no significantly difference in microbiota richness ( > 0.05). The principal coordinate analysis revealed significant differences in β-diversity of salivary and fecal microbiota between the CP and HC groups. Moreover, LEfSe analysis at the species level identified and as the major contributors to the salivary microbiota, and and to the fecal microbiota of patients with polyps. Salivary and fecal bacterial biomarkers showed Area Under ROC Curve of 0.8167 and 0.8051, respectively, which determined the potential of diagnostic markers in distinguishing patients with colorectal polyps from controls, and it increased to 0.8217 when salivary and fecal biomarkers were combined.
CONCLUSION
The composition and diversity of the salivary and fecal microbiota were significantly different in colorectal polyp patients compared to healthy controls, with an increased abundance of harmful bacteria and a decreased abundance of beneficial bacteria. A promising non-invasive tool for the detection of colorectal polyps can be provided by potential biomarkers based on the microbiota of the saliva and feces.
PubMed: 37655344
DOI: 10.3389/fmicb.2023.1182346 -
Microbiome Nov 2023The mechanism of microbiota assembly is one of the main problems in microbiome research, which is also the primary theoretical basis for precise manipulation of...
BACKGROUND
The mechanism of microbiota assembly is one of the main problems in microbiome research, which is also the primary theoretical basis for precise manipulation of microbial communities. Bacterial quorum sensing (QS), as the most common means for bacteria to exchange information and interactions, is characterized by universality, specificity, and regulatory power, which therefore may influence the assembly processes of human microbiota. However, the regulating role of QS in microbiota assembly is rarely reported. In this study, we developed an optimized in vitro oral biofilm microbiota assembling (OBMA) model to simulate the time-series assembly of oral biofilm microbiota (OBM), by which to excavate the QS network and its regulating power in the process.
RESULTS
By using the optimized OBMA model, we were able to restore the assembly process of OBM and generate time-series OBM metagenomes of each day. We discovered a total of 2291 QS protein homologues related to 21 QS pathways. Most of these pathways were newly reported and sequentially enriched during OBM assembling. These QS pathways formed a comprehensive longitudinal QS network that included successively enriched QS hubs, such as Streptococcus, Veillonella-Megasphaera group, and Prevotella-Fusobacteria group, for information delivery. Bidirectional cross-talk among the QS hubs was found to play critical role in the directional turnover of microbiota structure, which in turn, influenced the assembly process. Subsequent QS-interfering experiments accurately predicted and experimentally verified the directional shaping power of the longitudinal QS network in the assembly process. As a result, the QS-interfered OBM exhibited delayed and fragile maturity with prolonged membership of Streptococcus and impeded membership of Prevotella and Fusobacterium.
CONCLUSION
Our results revealed an unprecedented longitudinal QS network during OBM assembly and experimentally verified its power in predicting and manipulating the assembling process. Our work provides a new perspective to uncover underlying mechanism in natural complex microbiota assembling and a theoretical basis for ultimately precisely manipulating human microbiota through intervention in the QS network. Video Abstract.
Topics: Humans; Quorum Sensing; Bacterial Proteins; Bacteria; Biofilms; Streptococcus; Microbiota
PubMed: 37926838
DOI: 10.1186/s40168-023-01699-4 -
Frontiers in Cellular and Infection... 2023Immunoglobulin G4 (IgG4) is a member of the human immunoglobulin G (IgG) subclass, a protein involved in immunity to pathogens and the body's resistance system....
INTRODUCTION
Immunoglobulin G4 (IgG4) is a member of the human immunoglobulin G (IgG) subclass, a protein involved in immunity to pathogens and the body's resistance system. IgG4-related diseases (IgG4-RD) are intractable diseases in which IgG4 levels in the blood are elevated, causing inflammation in organs such as the liver, pancreas, and salivary glands. IgG4-RD are known to be more prevalent in males than in females, but the etiology remains to be elucidated. This study was conducted to investigate the relationship between gut microbiota (GM) and serum IgG4 levels in the general population.
METHODS
In this study, the relationship between IgG4 levels and GM evaluated in male and female groups of the general population using causal inference. The study included 191 men and 207 women aged 40 years or older from Shika-machi, Ishikawa. GM DNA was analyzed for the 16S rRNA gene sequence using next-generation sequencing. Participants were bifurcated into high and low IgG4 groups, depending on median serum IgG4 levels.
RESULTS
ANCOVA, Tukey's HSD, linear discriminant analysis effect size, least absolute shrinkage and selection operator logistic regression model, and correlation analysis revealed that , , , and group were associated with IgG4 levels in women, while , group, , 1, and were associated with IgG4 levels in men. Linear non-Gaussian acyclic model indicated three genera, , group, and , and showed a presumed causal association with IgG4 levels in women.
DISCUSSION
This differential impact of the GM on IgG4 levels based on sex is a novel and intriguing finding.
Topics: Humans; Male; Female; Gastrointestinal Microbiome; Immunoglobulin G4-Related Disease; RNA, Ribosomal, 16S; Salivary Glands; Immunoglobulin G
PubMed: 37908763
DOI: 10.3389/fcimb.2023.1272398 -
Journal of Translational Medicine Aug 2023For many years, the role of the microbiome in tumor progression, particularly the tumor microbiome, was largely overlooked. The connection between the tumor microbiome...
Weighted gene coexpression network analysis and machine learning reveal oncogenome associated microbiome plays an important role in tumor immunity and prognosis in pan-cancer.
BACKGROUND
For many years, the role of the microbiome in tumor progression, particularly the tumor microbiome, was largely overlooked. The connection between the tumor microbiome and the tumor genome still requires further investigation.
METHODS
The TCGA microbiome and genome data were obtained from Haziza et al.'s article and UCSC Xena database, respectively. Separate WGCNA networks were constructed for the tumor microbiome and genomic data after filtering the datasets. Correlation analysis between the microbial and mRNA modules was conducted to identify oncogenome associated microbiome module (OAM) modules, with three microbial modules selected for each tumor type. Reactome analysis was used to enrich biological processes. Machine learning techniques were implemented to explore the tumor type-specific enrichment and prognostic value of OAM, as well as the ability of the tumor microbiome to differentiate TP53 mutations.
RESULTS
We constructed a total of 182 tumor microbiome and 570 mRNA WGCNA modules. Our results show that there is a correlation between tumor microbiome and tumor genome. Gene enrichment analysis results suggest that the genes in the mRNA module with the highest correlation with the tumor microbiome group are mainly enriched in infection, transcriptional regulation by TP53 and antigen presentation. The correlation analysis of OAM with CD8+ T cells or TAM1 cells suggests the existence of many microbiota that may be involved in tumor immune suppression or promotion, such as Williamsia in breast cancer, Biostraticola in stomach cancer, Megasphaera in cervical cancer and Lottiidibacillus in ovarian cancer. In addition, the results show that the microbiome-genome prognostic model has good predictive value for short-term prognosis. The analysis of tumor TP53 mutations shows that tumor microbiota has a certain ability to distinguish TP53 mutations, with an AUROC value of 0.755. The tumor microbiota with high importance scores are Corallococcus, Bacillus and Saezia. Finally, we identified a potential anti-cancer microbiota, Tissierella, which has been shown to be associated with improved prognosis in tumors including breast cancer, lung adenocarcinoma and gastric cancer.
CONCLUSION
There is an association between the tumor microbiome and the tumor genome, and the existence of this association is not accidental and could change the landscape of tumor research.
Topics: Female; Humans; Prognosis; Gene Regulatory Networks; Breast Neoplasms; Ovarian Neoplasms; RNA, Messenger
PubMed: 37573394
DOI: 10.1186/s12967-023-04411-0 -
Frontiers in Cellular and Infection... 2023Cerebral small vessel disease (CSVD) is a cluster of microvascular disorders with unclear pathological mechanisms. The microbiota-gut-brain axis is an essential...
BACKGROUND
Cerebral small vessel disease (CSVD) is a cluster of microvascular disorders with unclear pathological mechanisms. The microbiota-gut-brain axis is an essential regulatory mechanism between gut microbes and their host. Therefore, the compositional and functional gut microbiota alterations lead to cerebrovascular disease pathogenesis. The current study aims to determine the alteration and clinical value of the gut microbiota in CSVD patients.
METHODS
Sixty-four CSVD patients and 18 matched healthy controls (HCs) were included in our study. All the participants underwent neuropsychological tests, and the multi-modal magnetic resonance imaging depicted the changes in brain structure and function. Plasma samples were collected, and the fecal samples were analyzed with 16S rRNA gene sequencing.
RESULTS
Based on the alpha diversity analysis, the CSVD group had significantly decreased Shannon and enhanced Simpson compared to the HC group. At the genus level, there was a significant increase in the relative abundances of Parasutterella, Anaeroglobus, Megasphaera, Akkermansia, Collinsella, and Veillonella in the CSVD group. Moreover, these genera with significant differences in CSVD patients revealed significant correlations with cognitive assessments, plasma levels of the blood-brain barrier-/inflammation-related indexes, and structural/functional magnetic resonance imaging changes. Functional prediction demonstrated that lipoic acid metabolism was significantly higher in CSVD patients than HCs. Additionally, a composite biomarker depending on six gut microbiota at the genus level displayed an area under the curve of 0.834 to distinguish CSVD patients from HCs using the least absolute shrinkage and selection operator (LASSO) algorithm.
CONCLUSION
The evident changes in gut microbiota composition in CSVD patients were correlated with clinical features and pathological changes of CSVD. Combining these gut microbiota using the LASSO algorithm helped identify CSVD accurately.
Topics: Humans; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Brain; Magnetic Resonance Imaging; Cerebral Small Vessel Diseases
PubMed: 37496806
DOI: 10.3389/fcimb.2023.1231541 -
Scientific Reports Nov 2023Crohn's disease (CD) is a chronic inflammatory bowel disease. An imbalanced microbiome (dysbiosis) can predispose to many diseases including CD. The role of oral...
Crohn's disease (CD) is a chronic inflammatory bowel disease. An imbalanced microbiome (dysbiosis) can predispose to many diseases including CD. The role of oral dysbiosis in CD is poorly understood. We aimed to explore microbiome signature and dysbiosis of the salivary microbiome in CD patients, and correlate microbiota changes to the level of inflammation. Saliva samples were collected from healthy controls (HC) and CD patients (n = 40 per group). Salivary microbiome was analyzed by sequencing the entire 16S rRNA gene. Inflammatory biomarkers (C-reactive protein and calprotectin) were measured and correlated with microbiome diversity. Five dominant species were significantly enriched in CD, namely Veillonella dispar, Megasphaera stantonii, Prevotella jejuni, Dolosigranulum pigrum and Lactobacillus backii. Oral health had a significant impact on the microbiome since various significant features were cariogenic as Streptococcus mutans or periopathogenic such as Fusobacterium periodonticum. Furthermore, disease activity, duration and frequency of relapses impacted the oral microbiota. Treatment with monoclonal antibodies led to the emergence of a unique species called Simonsiella muelleri. Combining immunomodulatory agents with monoclonal antibodies significantly increased multiple pathogenic species such as Salmonella enterica, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Loss of diversity in CD was shown by multiple diversity indices. There was a significant negative correlation between gut inflammatory biomarkers (particularly calprotectin) and α-diversity, suggesting more inflammation associated with diversity loss in CD. Salivary dysbiosis was evident in CD patients, with unique microbiota signatures and perturbed species that can serve as disease biomarkers or potential targets for microbiota modulation. The interplay of various factors collectively contributed to dysbiosis, although each factor probably had a unique effect on the microbiome. The emergence of pathogenic bacteria in the oral cavity of CD patients is alarming since they can disturb gut homeostasis and induce inflammation by swallowing, or hematogenous spread of microbiota, their metabolites, or generated inflammatory mediators.
Topics: Humans; Crohn Disease; Dysbiosis; RNA, Ribosomal, 16S; Gastrointestinal Microbiome; Microbiota; Inflammation; Biomarkers; Antibodies, Monoclonal; Leukocyte L1 Antigen Complex
PubMed: 37932491
DOI: 10.1038/s41598-023-46714-8 -
Applied and Environmental Microbiology Jan 2024Butyrate, a physiologically active molecule, can be synthesized through metabolic interactions among colonic microorganisms. Previously, in a fermenting trial of human...
Butyrate, a physiologically active molecule, can be synthesized through metabolic interactions among colonic microorganisms. Previously, in a fermenting trial of human fecal microbiota, we observed that the butyrogenic effect positively correlated with the increasing population and an unidentified species. Therefore, we hypothesized that a cross-feeding phenomenon exists between and , where is the butyrate producer, and its growth relies on the metabolites generated by . To validate this hypothesis, three bacterial species (, , and ) were isolated from fecal cultures fermenting hydrolyzed xylan; pairwise cocultures were conducted between the and isolates; the microbial interactions were determined based on bacterial genome information, cell growth, substrate consumption, metabolite quantification, and metatranscriptomics. The results indicated that two isolates contained distinct gene clusters for xylan utilization and expressed varying substrate preferences. In contrast, alone scarcely grew on the xylose-based substrates. The growth of was significantly elevated by coculturing it with bifidobacteria, while the two species responded differently in the kinetics of cell growth and substrate consumption. Coculturing led to the depletion of lactate and increased the formation of butyrate. An RNA-seq analysis further revealed the upregulation of genes involved in the lactate utilization and butyrate formation pathways. We concluded that lactate generated by through catabolizing xylose fueled the growth of and triggered the synthesis of butyrate. Our findings demonstrated a novel cross-feeding mechanism to generate butyrate in the human colon.IMPORTANCEButyrate is an important short-chain fatty acid that is produced in the human colon through microbial fermentation. Although many butyrate-producing bacteria exhibit a limited capacity to degrade nondigestible food materials, butyrate can be formed through cross-feeding microbial metabolites, such as acetate or lactate. Previously, the literature has explicated the butyrate-forming links between and and between and . In this study, we provided an alternative butyrate synthetic pathway through the interaction between and is a species named in 2014 and is indigenous to the human intestinal tract. Scientific studies explaining the function of in the human colon are still limited. Our results show that proliferated based on the lactate generated by bifidobacteria and produced butyrate as its end metabolic product. The pathways identified here may contribute to understanding butyrate formation in the gut microbiota.
Topics: Humans; Lactic Acid; Bifidobacterium; Xylans; Xylose; Butyrates; Megasphaera; Fermentation
PubMed: 38126785
DOI: 10.1128/aem.01019-23 -
Translational Animal Science 2023Our objective was to evaluate the effects of combinations of and as direct-fed microbials (DFM) on ruminal microbiome during an acute acidosis challenge in a...
Our objective was to evaluate the effects of combinations of and as direct-fed microbials (DFM) on ruminal microbiome during an acute acidosis challenge in a continuous culture system. Treatments provided a DFM dose of 1 × 10 colony-forming unit (CFU)/mL, as follows: control (no DFM), YM1 ( and strain 1), YM2 ( and strain 2), and YMM ( and half of the doses of strains 1 and 2). We conducted four experimental periods of 11 d, which consisted of non-acidotic days (1 to 8) and acidotic challenge days (9 to 11) to establish acute ruminal acidosis conditions with a common basal diet containing 12% neutral detergent fiber and 58% starch. Treatments were applied from days 8 to 11, and samples of liquid and solid-associated bacteria were collected on days 9 to 11. Overall, 128 samples were analyzed by amplification of the V4 region of bacterial 16S rRNA, and data were analyzed with R and SAS for alpha and beta diversity, taxa relative abundance, and correlation of taxa abundance with propionate molar proportion. We observed a lower bacterial diversity (Shannon index, = 0.02) when YM1 was added to the diet in comparison to the three other treatments. Moreover, compared to control, addition of YM1 to the diet increased relative abundance of phylum ( = 0.05) and family ( = 0.05) in the solid fraction and tended to increase abundance of family ( = 0.10) and genus ( = 0.09) in the liquid fraction. Correlation analysis indicated a positive association between propionate molar proportion and relative abundance of ( = 0.36, = 0.04) and ( = 0.36, = 0.05) in the solid fraction. The inclusion of YM1 in high-grain diets with a high starch content resulted in greater abundance of bacteria involved in succinate synthesis which may have provided the substrate for the greater propionate synthesis observed.
PubMed: 38023425
DOI: 10.1093/tas/txad123 -
Schizophrenia Bulletin Sep 2023Intestinal microbiota is intrinsically linked to human health. Evidence suggests that the composition and function of the microbiome differs in those with schizophrenia... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND HYPOTHESIS
Intestinal microbiota is intrinsically linked to human health. Evidence suggests that the composition and function of the microbiome differs in those with schizophrenia compared with controls. It is not clear how these alterations functionally impact people with schizophrenia. We performed a systematic review and meta-analysis to combine and evaluate data on compositional and functional alterations in microbiota in patients with psychosis or schizophrenia.
STUDY DESIGN
Original studies involving humans and animals were included. The electronic databases PsycINFO, EMBASE, Web of Science, PubMed/MEDLINE, and Cochrane were systematically searched and quantitative analysis performed.
STUDY RESULTS
Sixteen original studies met inclusion criteria (1376 participants: 748 cases and 628 controls). Ten were included in the meta-analysis. Although observed species and Chao 1 show a decrease in diversity in people with schizophrenia compared with controls (SMD = -0.14 and -0.66 respectively), that did not reach statistical significance. We did not find evidence for variations in richness or evenness of microbiota between patients and controls overall. Differences in beta diversity and consistent patterns in microbial taxa were noted across studies. We found increases in Bifidobacterium, Lactobacillus, and Megasphaera in schizophrenia groups. Variations in brain structure, metabolic pathways, and symptom severity may be associated with compositional alterations in the microbiome. The heterogeneous design of studies complicates a similar evaluation of functional readouts.
CONCLUSIONS
The microbiome may play a role in the etiology and symptomatology of schizophrenia. Understanding how the implications of alterations in microbial genes for symptomatic expression and clinical outcomes may contribute to the development of microbiome targeted interventions for psychosis.
Topics: Humans; Schizophrenia; Gastrointestinal Microbiome; Psychotic Disorders
PubMed: 37210594
DOI: 10.1093/schbul/sbad049