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Gut Apr 2024Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear.
DESIGN
Using an mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation.
RESULTS
FMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of and family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes.
CONCLUSION
The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.
Topics: Humans; Mice; Animals; Pulmonary Disease, Chronic Obstructive; Lung; Pneumonia; Inflammation; Carbohydrates
PubMed: 38331563
DOI: 10.1136/gutjnl-2023-330521 -
Journal of Advanced Research Oct 2023The perturbations of gut microbiota could interact with excessively activated immune responses and play key roles in the etiopathogenesis of ulcerative colitis (UC)....
INTRODUCTION
The perturbations of gut microbiota could interact with excessively activated immune responses and play key roles in the etiopathogenesis of ulcerative colitis (UC). Desulfovibrio, the most predominant sulfate reducing bacteria (SRB) resided in the human gut, was observed to overgrow in patients with UC. The interactions between specific gut microbiota and drugs and their impacts on UC treatment have not been demonstrated well.
OBJECTIVES
This study aimed to elucidate whether Desulfovibrio vulgaris (D. vulgaris, DSV) and its flagellin could activate nucleotide-binding oligomerization domain-like receptors (NLR) family of apoptosis inhibitory proteins (NAIP) / NLR family caspase activation and recruitment domain-containing protein 4 (NLRC4) inflammasome and promote colitis, and further evaluate the efficacy of eugeniin targeting the interaction interface of D. vulgaris flagellin (DVF) and NAIP to attenuate UC.
METHODS
The abundance of DSV and the occurrence of macrophage pyroptosis in human UC tissues were investigated. Colitis in mice was established by dextran sulfate sodium (DSS) and gavaged with DSV or its purified flagellin. NAIP/NLRC4 inflammasome activation and macrophage pyroptosis were evaluated in vivo and in vitro. The effects of eugeniin on blocking the interaction of DVF and NAIP/NLRC4 and relieving colitis were also assessed.
RESULTS
The abundance of DSV increased in the feces of patients with UC and was found to be associated with disease activity. DSV and its flagellin facilitated DSS-induced colitis in mice. Mechanistically, RNA sequencing showed that gene expression associated with inflammasome complex and pyroptosis was upregulated after DVF treatment in macrophages. DVF was further demonstrated to induce significant macrophage pyroptosis in vitro, depending on NAIP/NLRC4 inflammasome activation. Furthermore, eugeniin was screened as an inhibitor of the interface between DVF and NAIP and successfully alleviated the proinflammatory effect of DVF in colitis.
CONCLUSION
Targeting DVF-induced NAIP/NLRC4 inflammasome activation and macrophage pyroptosis ameliorates UC. This finding is of great significance for exploring the gut microbiota-host interactions in UC development and providing new insights for precise treatment.
Topics: Humans; Mice; Animals; Inflammasomes; Flagellin; Desulfovibrio vulgaris; Colitis, Ulcerative; Macrophages; Calcium-Binding Proteins; CARD Signaling Adaptor Proteins; Neuronal Apoptosis-Inhibitory Protein
PubMed: 37586642
DOI: 10.1016/j.jare.2023.08.008 -
Cells Jun 2023Multiple sclerosis (MS) is a chronic, progressive neuroinflammatory disease with a complex pathophysiological background. A variety of diverse factors have been... (Review)
Review
Multiple sclerosis (MS) is a chronic, progressive neuroinflammatory disease with a complex pathophysiological background. A variety of diverse factors have been attributed to the propagation of inflammation and neurodegeneration in MS, mainly genetic, immunological, and environmental factors such as vitamin D deficiency, infections, or hormonal disbalance. Recently, the importance of the gut-brain axis for the development of many neurological conditions, including stroke, movement disorders, and neuroinflammatory disorders, has been postulated. The purpose of our paper was to summarize current evidence confirming the role of the gut microbiome in the pathophysiology of MS and related disorders, such as neuromyelitis optica spectrum disorder (NMO-SD). For this aim, we conducted a systematic review of the literature listed in the following databases: Medline, Pubmed, and Scopus, and were able to identify several studies demonstrating the involvement of the gut microbiome in the pathophysiology of MS and NMO-SD. It seems that the most relevant bacteria for the pathophysiology of MS are those belonging to , , , , , , , and , while and have been demonstrated to play a role in the pathophysiology of NMO-SD. Following this line of evidence, there is also some preliminary data supporting the use of probiotics or other agents affecting the microbiome that could potentially have a beneficial effect on MS/NMO-SD symptoms and prognosis. The topic of the gut microbiome in the pathophysiology of MS is therefore relevant since it could be used as a biomarker of disease development and progression as well as a potential disease-modifying therapy.
Topics: Humans; Multiple Sclerosis; Gastrointestinal Microbiome; Neuromyelitis Optica; Vitamin D Deficiency; Inflammation
PubMed: 37443793
DOI: 10.3390/cells12131760 -
Frontiers in Cellular and Infection... 2023Previous research has posited a potential correlation between the gut microbiota and the onset of appendicitis; however, the precise causal connection between...
BACKGROUND
Previous research has posited a potential correlation between the gut microbiota and the onset of appendicitis; however, the precise causal connection between appendicitis and the gut microbiota remains an unresolved and contentious issue.
METHODS
In this investigation, we performed a Mendelian randomization (MR) analysis employing publicly accessible summary data extracted from genome-wide association studies (GWAS) to elucidate the potential causal nexus between the gut microbiota and the development of appendicitis. We initially identified instrumental variables (IVs) through a comprehensive array of screening methodologies, subsequently executing MR analyses using the Inverse Variance Weighted (IVW) technique as our primary approach, supplemented by several alternative methods such as MR Egger, weighted median, simple mode, and weighted mode. Additionally, we implemented a series of sensitivity analysis procedures, encompassing Cochran's Q test, MR-Egger intercept test, Mendelian Randomized Polymorphism Residual and Outlier (MR-PRESSO) test, and a leave-one-out test, to affirm the robustness and validity of our findings.
RESULTS
Our investigation indicates that an elevated prevalence of Deltaproteobacteria, Christensenellaceae, Desulfovibrionaceae, Eubacterium ruminantium group, Lachnospiraceae NK4A136 group, Methanobrevibacter, Desulfovibrionales, and Euryarchaeota is inversely associated with the risk of appendicitis. Conversely, we observed a positive correlation between an increased abundance of Family XIII, Howardella, and Veillonella and the susceptibility to appendicitis. Sensitivity analyses have corroborated the robustness of these findings, and Mendelian randomization analyses provided no indications of reverse causality.
CONCLUSION
Our Mendelian randomization (MR) analysis has unveiled potential advantageous or detrimental causal associations between the gut microbiota and the occurrence of appendicitis. This study offers novel theoretical and empirical insights into the understanding of appendicitis pathogenesis, along with its implications for preventive and therapeutic strategies.
Topics: Humans; Gastrointestinal Microbiome; Appendicitis; Genome-Wide Association Study; Mendelian Randomization Analysis; Causality; Clostridiales
PubMed: 38162578
DOI: 10.3389/fcimb.2023.1320992 -
Age and Ageing Jul 2023observational studies have indicated that gut microbiome dysbiosis was associated with Alzheimer's disease (ad). However, the results are largely inconsistent and it... (Observational Study)
Observational Study
BACKGROUND
observational studies have indicated that gut microbiome dysbiosis was associated with Alzheimer's disease (ad). However, the results are largely inconsistent and it remains unknown whether the association is causal in nature.
METHODS
leveraging observational studies and genome-wide association studies (GWAS) on the gut microbiome in ad patients, we pooled the microbiome data (N = 1,109) to screen the microbiota significantly altered in ad patients and then conducted Mendelian randomisation (MR) study to determine the causal associations between altered microbiota (N = 18,340) and ad using two different ad GWAS datasets (N = 63,926 and N = 472,868) using the inverse variance-weighted (IVW) method.
RESULTS
the combined effect sizes from observational studies showed that 8 phyla, 18 classes, 22 orders, 37 families, 78 genera and 109 species significantly changed in ad patients. Using the MR analysis, we found that two classes, one order, one family and one genus were suggestively associated with ad consistently in two different GWAS datasets. Both observational studies and MR analysis simultaneously showed that Desulfovibrionales (order) and Desulfovibrionaceae (family), which were mainly implicated in dissimilatory sulfate reduction, were significantly associated with an elevated risk of ad.
CONCLUSIONS
our findings demonstrated that the abundance of sulfate-reducing bacteria was increased in ad patients, which was causally linked to an increased risk of ad. Further efforts are warranted to clarify the underlying mechanisms, which will provide new insight into the prevention and treatment of ad.
Topics: Humans; Alzheimer Disease; Bacteria; Genome-Wide Association Study; Microbiota; Polymorphism, Single Nucleotide; Sulfates; Mendelian Randomization Analysis
PubMed: 37466641
DOI: 10.1093/ageing/afad112 -
Nature Communications Apr 2024The etiopathogenesis of diverticulitis, among the most common gastrointestinal diagnoses, remains largely unknown. By leveraging stool collected within a large...
The etiopathogenesis of diverticulitis, among the most common gastrointestinal diagnoses, remains largely unknown. By leveraging stool collected within a large prospective cohort, we performed shotgun metagenomic sequencing and untargeted metabolomics profiling among 121 women diagnosed with diverticulitis requiring antibiotics or hospitalizations (cases), matched to 121 women without diverticulitis (controls) according to age and race. Overall microbial community structure and metabolomic profiles differed in diverticulitis cases compared to controls, including enrichment of pro-inflammatory Ruminococcus gnavus, 1,7-dimethyluric acid, and histidine-related metabolites, and depletion of butyrate-producing bacteria and anti-inflammatory ceramides. Through integrated multi-omic analysis, we detected covarying microbial and metabolic features, such as Bilophila wadsworthia and bile acids, specific to diverticulitis. Additionally, we observed that microbial composition modulated the protective association between a prudent fiber-rich diet and diverticulitis. Our findings offer insights into the perturbations in inflammation-related microbial and metabolic signatures associated with diverticulitis, supporting the potential of microbial-based diagnostics and therapeutic targets.
Topics: Humans; Female; Gastrointestinal Microbiome; Middle Aged; Diverticulitis; Feces; Aged; Prospective Studies; Bilophila; Metabolomics; Case-Control Studies; Clostridiales; Bile Acids and Salts; Adult; Dietary Fiber; Metabolome; Metagenomics
PubMed: 38684664
DOI: 10.1038/s41467-024-47859-4 -
International Journal of Biological... Jul 2023Amuc_1100 (hereafter called Amuc) is a highly abundant pili-like protein on the outer membrane of Akkermansia muciniphila and has been found to be effective for in...
Amuc_1100 (hereafter called Amuc) is a highly abundant pili-like protein on the outer membrane of Akkermansia muciniphila and has been found to be effective for in anti-obesity, which is probably through the activation of TLR2. However, the precise mechanisms underlying the contributions of TLR2 to obesity resistance remain unknown. Here, TLR2 knockout mice were used to decipher the anti-obesity mechanism of Amuc. Mice exposed to a high-fat diet (HFD) were treated with Amuc (60 μg) every other day for 8 weeks. The results showed that Amuc supplementation decreased mouse body weight and lipid deposition by regulating fatty acid metabolism and reducing bile acid synthesis by activating TGR5 and FXR and strengthening the intestinal barrier function. The ablation of TLR2 partially reversed the positive effect of Amuc on obesity. Furthermore, we revealed that Amuc altered the gut microbiota composition by increasing the relative abundance of Peptostreptococcaceae, Faecalibaculum, Butyricicoccus, and Mucispirillum_schaedleri_ASF457, and decreasing Desulfovibrionaceae, which may serve as a contributor for Amuc to reinforce the intestinal barrier in HFD-induced mice. Therefore, the anti-obesity effect of Amuc was accompanied by the mitigation of gut microbes. These findings provide support for the use of Amuc as a therapy targeting obesity-associated metabolic syndrome.
Topics: Mice; Animals; Diet, High-Fat; Gastrointestinal Microbiome; Toll-Like Receptor 2; Metabolic Syndrome; Verrucomicrobia; Obesity; Fatty Acids; Bile Acids and Salts; Mice, Inbred C57BL
PubMed: 37119914
DOI: 10.1016/j.ijbiomac.2023.124650 -
The Journal of Nutritional Biochemistry Dec 2023Multiple sclerosis (MS) is a disease of the central nervous system that involves the immune system attacking the protective covering of nerve fibers. This disease can be...
Multiple sclerosis (MS) is a disease of the central nervous system that involves the immune system attacking the protective covering of nerve fibers. This disease can be influenced by both environmental and genetic factors. Evidence has highlighted the critical role of the intestinal microbiota in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). The composition of gut microflora is mainly determined by dietary components, which, in turn, modulate host homeostasis. A diet rich in naringenin at 0.5% can effectively mitigate the severity of EAE in mice. However, there is little direct data on the impact of naringenin at optimal doses on EAE development, as well as its intestinal microbiota and metabolites. Our study revealed that 2.0% naringenin resulted in the lowest clinical score and pathological changes in EAE mice, and altered the gene expression profiles associated with inflammation and immunity in spinal cord tissue. We then used untargeted metabolomics and 16S rRNA gene sequences to identify metabolites and intestinal microbiota, respectively. Naringenin supplementation enriched gut microbiota in EAE mice, including increasing the abundance of Paraprevotellaceae and Comamonadaceae, while decreasing the abundance of Deltaproteobacteria, RF39, and Desulfovibrionaceae. Furthermore, the changes in gut microbiota affected the production of metabolites in the feces and brain, suggesting a role in regulating the gut-brain axis. Finally, we conducted a fecal transplantation experiment to validate that gut microbiota partly mediates the effect of naringenin on EAE alleviation. In conclusion, naringenin has potential immunomodulatory effects that are influenced to some extent by the gut microbiome.
Topics: Mice; Animals; Encephalomyelitis, Autoimmune, Experimental; Brain-Gut Axis; RNA, Ribosomal, 16S; Multiomics; Multiple Sclerosis
PubMed: 37741298
DOI: 10.1016/j.jnutbio.2023.109448 -
Clinical and Experimental Rheumatology Jan 2024To assess whether there is a bidirectional causal relationship between the composition of gut microbiota and rheumatoid arthritis (RA), and to identify specific...
OBJECTIVES
To assess whether there is a bidirectional causal relationship between the composition of gut microbiota and rheumatoid arthritis (RA), and to identify specific pathogenic bacterial taxa via the Mendelian randomisation (MR) analysis.
METHODS
We acquired single nucleotide polymorphisms (SNPs) associated with the composition of gut microbiota (n=18,340) and with RA (n=331,313) from publicly available genome-wide association studies (GWAS). The genome-wide threshold was 1 × 10-5 in the forward MR analysis and was 5 × 10-8 in the reverse MR analysis. Inverse variance weighted (IVW) was the main method to analyse causality, and MR results were verified by several sensitivity analyses including weighted median, MR Egger, and MR Pleiotropy Residual Sum and Outlier (PRESSO).
RESULTS
The IVW method suggested that eight taxa were positively correlated with RA, including: MollicutesRF9 (pIVW <0.01), Alphaproteobacteria (pIVW <0.01), Betaproteobacteria (p IVW =0.04), Bacteroidaceae (pIVW <0.01), Adlercreutzia (pIVW <0.01), Bacteroides (pIVW <0.01), Butyricimonas (p IVW =0.03) and Holdemanella (pIVW =0.03). Six bacterial taxa were negatively correlated with RA, including Desulfovibrionales (pIVW = 0.01), Methanobacteriales (pIVW <0.01), Methanobacteria (PIVW <0.01), Desulfovibrionaceae (pIVW <0.01), Methanobacteriaceae (pIVW <0.01) and Butyrivibrio (pIVW =0.02). Heterogeneity (p>0.05) and pleiotropy (p>0.05) analysis confirmed the robustness of the MR results.
CONCLUSIONS
We identified some specific bacterial taxa that were causally associated with the risk of RA, providing new insights into prevention and diagnosis of RA.
Topics: Humans; Gastrointestinal Microbiome; Genome-Wide Association Study; Arthritis, Rheumatoid; Polymorphism, Single Nucleotide
PubMed: 37812479
DOI: 10.55563/clinexprheumatol/p9ig7c -
Beneficial Microbes Sep 2023Food allergy is an important health problem that affects human quality of life and socioeconomic development, and its treatment requires improvement. Intestinal flora...
Food allergy is an important health problem that affects human quality of life and socioeconomic development, and its treatment requires improvement. Intestinal flora dysbiosis is closely associated with food allergies. A sensitised mouse model was established by the intraperitoneal injection of ovalbumin (OVA). The mice were randomly divided into four groups: control, model, high-dose (H), and low-dose (L) inulin. The mice were administered water containing different concentrations of inulin four weeks before the OVA injection. Body weight changes were monitored. After the last OVA injection, the mice were scored for allergic reactions. The levels of total immunoglobulin E (IgE) and diamine oxidase (DAO) in the serum and secretory IgA (sIgA) in the small intestinal mucus were measured, and 16S rRNA sequencing of the faecal flora was performed to evaluate microbial parameters. The intestinal flora biomarkers, correlations between them, and biochemical indicators were analysed. Inulin treatment had no effect on the body weight of OVA-sensitised mice but attenuated allergic reactions and intestinal injury in mice. Compared with the control group, the model group had significantly higher levels of serum DAO and IgE and significantly lower levels of intestinal mucus IgA. IgA levels in the intestinal mucus of mice treated with inulin prior to OVA sensitisation were higher than those in non-inulin-treated OVA-sensitised mice. Furthermore, analysis of operational taxonomic units showed that inulin treatment decreased the abundance of Alloprevotella, Rikenellaceae RC9, Eubacterium siraeum, and Eubacterium xylanophilum, and increased the abundance of Blautia and Lachnospiraceae. Serum DAO levels were positively associated with Eubacterium siraeum, Alloprevotella, Eubacterium xylanophilum, and Odoribacter and negatively associated with Blautia, Tyzzerella, Alistipes, Desulfovibrionaceae, and Ruminococcaceae UCG005. In addition, IgE levels were positively associated with Eubacterium siraeum, Alloprevotella, Eubacterium xylanophilum, Odoribacter, and Citrobacter and negatively associated with Blautia, unclassified Ruminococcaceae, and Alistipes. IgA exhibited significant positive correlation with Blautia, norank_f_Eubacterium coprostanoligenes, Alistipes, norank Desulfovibrionaceae, Muribaculum, and Ruminococcaceae U C G 005 and significant negative correlation with Eubacterim siraeum, Eubacterium xylanophilum, Odoribacter, and Citrobacter. Inulin exerts a protective effect against food allergies in mice, which is partially mediated by alterations in the gut microbiota.
Topics: Animals; Inulin; Gastrointestinal Microbiome; Mice, Inbred BALB C; Mice; Ovalbumin; Disease Models, Animal; Immunoglobulin E; Food Hypersensitivity; Female; RNA, Ribosomal, 16S; Feces; Bacteria; Immunoglobulin A, Secretory; Immunoglobulin A
PubMed: 38661353
DOI: 10.1163/18762891-20220094